Death: Perspectives from the Philosophy of Biology [1 ed.] 3031144163, 9783031144165

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Death Perspectives from the Philosophy of Biology

Philippe Huneman

Death “It is exceedingly rare to meet a learned book expertly addressing and synthesizing three disparate fields. It is even more remarkable when such a book also tackles a central yet secretive or suppressed topic about who we are as humans and as living beings. The impressive scholar Philippe Huneman has delivered such a book: an encyclopedic volume energetically excavating and fusing the philosophy, history of science, and evolutionary theory behind a deep and mysterious question: ‘why death?’. This brilliant book illuminates how our best Western philosophy and science have contemplated and researched death, and it also suggests paths forward for future investigations. Let go of your fears and pick up this extraordinary book!” —Rasmus Grønfeldt Winther, Professor of Humanities, University of California Santa Cruz, USA “Death is such a certainty that most people never really stop to consider why this must be so. And because there is nothing it is like to be dead, or at least no way of knowing what it is like, many philosophers as well have presumed that death is a topic about which they can have nothing to say. In this very original and creative work, Philippe Huneman shows us why both of these presumptions are premature: he offers us nothing less than a rigorous philosophy of death and dying. Beginning with the debates that emerge out of the late-18th-century opposition between mechanism and vitalism, Huneman gives the reader a sweeping tour of modern life science that moves through the evolutionary synthesis of the 20th century and recent research in genetics, and concludes with a profound reflection on the ontology of death as seen from a naturalistic point of view. Historically and scientifically informed, philosophically rich and counterintuitive, this book is certain to carve out a new path for future researchers in the philosophy of biology and related fields.” —Justin E. H. Smith, University Professor of the History and Philosophy of Science, Paris City University “Biology offers few certainties but one of the deepest ones is that all sexually reproducing organisms die. While evolutionary biologists have occasionally worried about the meaning of death, mainly by studying the evolution of ageing processes, philosophers and historians have until now avoided talk of death. In this marvelous new book Philippe Huneman changes all that, delving into the history of biological studies of death and bringing the philosophical discussion up to date with the current postgenomic age. This book will be essential reading for philosophers of biology as well as of great interest to historians of science and biologists.” —Sahotra Sarkar, Professor of Philosophy, University of Texas at Austin, USA

Philippe Huneman

Death Perspectives from the Philosophy of Biology

Philippe Huneman CNRS/ Université Paris I Panthéon Sorbonne Institut d’Histoire et de Philosophie des Sciences et des Techniques Paris, France

ISBN 978-3-031-14416-5    ISBN 978-3-031-14417-2 (eBook) https://doi.org/10.1007/978-3-031-14417-2 © The Editor(s) (if applicable) and The Author(s) 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Cover illustration: © Marina Lohrbach_shutterstock.com This Palgrave Macmillan imprint is published by the registered company Springer Nature Switzerland AG. The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Acknowledgements

They say that no man is an island; I don’t know geography enough to assess this claim, but I know for sure that no book is an island. This one has been nurtured, nourished and fueled by many books and papers, but above all, by many discussions with amazing scholars whose knowledge hopefully percolated within these pages. I am therefore grateful to: Friends who read the manuscript and helped me with their precious comments and suggestions, without which the result would not be of any interest: Christophe Bouton, Eric Bapteste, Christopher Donohue, Sébastien Dutreuil, Philippe Jarne, Alice Lebreton Mansuy, Tim Lewens, Charles Wolfe. Biologists who were generous enough to let me share some of their innovative work on death and senescence: Eric Bapteste, Michael Rera, Pierre Durand. And the many philosophers and biologists with whom, by discussing over the years, I have been able to understand slightly better than I used to do the enigmas of life and death—among them, and even though they are too numerous to be all mentioned here, let me name André Ariew, Denis Walsh, Mark Bedau, Frédéric Bouchard, Thomas Reydon, Hugh Desmond, Robert Richards, Phillip Sloan, Robert Brandon, Virginie Maris, Sonia Kéfi, Annick Lesne, Alex Rosenberg, Anya Plutynski, Francesca Merlin, Claude Romano, François Munoz, Andy Gardner, Minus van Baalen, Régis Ferrière, Silvia De Monte, Charles Wolfe, Laura Nuno de la Rosa Garcia, Johannes Martens, Antonine Nicoglou, Arnaud Pocheville, Guillaume Lecointre, Thomas Heams, Marshall Abrams, v

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ACKNOWLEDGEMENTS

Grant Ramsey, Manuel Blouin, Isabelle Drouet, Michel Veuille, Pierre-­ Henri Gouyon, Marion Vorms, Thomas Pradeu, Ariel Lindner, Etienne Danchin, Camille Noûs, and all the others, including the master and grad students who provided me with invaluable and fruitful discussions along the years. And I am not grateful to the current neoliberal research policy that pervades the whole academic world; all of us, we can think and work only against it, and in spite of its existence. The first section of the book has been partly translated from a French text by Anita Conrade. I am very grateful to her invaluable work. It was partly based on a book I published in 1998, entitled Bichat: la vie et la mort (Paris: Puf). Anita Conrade also language checked half of the rest of the book, as did Hugh Desmond; I was also helped regarding language issues by Charles Wolfe and Denis Walsh; I’m most grateful to all of them. The grant ANR-DFG Gendar “Generalized Darwinism” covered expenses related to some work done in this book. This book is dedicated to the memory of my two masters, Gérard Lebrun and Jean Gayon. I hope that I managed in my work to grasp some reflections of their philosophical flame, and slightly pursue their philosophical pathways.

 ACKNOWLEDGEMENTS 

The disciple of a Sufi of Baghdad was sitting in the corner of an inn one day when he heard two figures talking. From what they said he realized that one of them was the Angel of Death. “I have several calls to make in this city during the next three weeks,” the Angel was saying to his companion. Terrified, the disciple concealed himself until the two had left. Then applying his intelligence to the problem of how to cheat a possible call from death, he decided that if he kept away from Baghdad he should not be touched. From this reasoning it was but a short step to hiring the fastest horse available and spurring it night and day towards the distant town of Samarkand. Meanwhile Death met the Sufi teacher and they talked about various people. “And where is your disciple so-and-so?” asked Death. “He should be somewhere in this city, spending this time in contemplation, perhaps in a caravanserai,” said the teacher. “Surprising,” said the Angel; “because he is on my list. Yes, here it is: I have to collect him in four weeks’ time at Samarkand, of all places.” Tales of the Dervishes, Idries Shah I reason, we could die— The best Vitality cannot excel Decay, But, what of that? Emily Dickinson. I have seen the future my friend: it’s murder. Leonard Cohen.

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Contents

1 Introduction:  The Philosophical Riddle of Death, from a Biological Point of View  1 1.1 Philosophy and the Oblivion of Biology  3 1.2 Philosophical and Biological Issues  6 1.3 What Is Death and What Are Its Criteria?  7 1.4 Gradients of Death, Vital Processes, and Aging 11 1.5 The Question “Why Death?” 19 1.6 Overview of the Biological Facts of Death 25 1.7 This Book’s Endeavor 31 1.8 Who Could Read This Book? 34 1.9 The Book’s Structure 35 References 36 Part I How Do We Die? Proximate Causes of Death and the Rise of Experimental Physiology  39 2 How Late-Eighteenth-Century Physiologists Understood the Living World and Their Task 41 2.1 Physiology and Mechanism 43 2.1.1 The Mechanistic Conception 43 2.1.2 Georg-Ernest Stahl’s Vitalism: Opposition to a Mechanist Worldview 45 2.1.3 Physiology and Classical Natural Philosophy 48 ix

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2.2 Vitalism 52 2.2.1 Haller and Bordeu 52 2.2.2 The “Animal Economy” 53 2.3 Bichat’s Dilemma 58 References 61 3 Bichat’s  Theories and Their Genealogy 65 3.1 The Vitalist Definition of Life 66 3.2 Devising Divisions 68 3.3 Properties and Tissues 71 3.4 Bichat’s Anatomical Method 79 3.5 Bichat’s Difficulties 83 References 84 4 Physiology in Bichat’s Physiological Researches on Life and Death 85 4.1 The First Part: “Researches on Life” 85 4.1.1 The Particularities of the Animal and Organic Lives 85 4.1.2 Habits, Society, Passions 87 4.1.3 Animal Life and Its Development: Physiology as a Part of Natural History of Man 90 4.2 Bichat as Anthropologist 96 References 98 5 Bichat’s  Experimental Physiology in the Recherches (Part 2): Death as an Epistemic Facilitator 99 5.1 Conceptions of Death and Sensibility to Death: End of a Dualism 99 5.2 Life and Experiments on Death105 5.3 Sequence-Schemata112 5.4 Organs and Functions114 5.5 Interpreting the “Recherches sur la mort”: A New Understanding of the Living117 5.5.1 Physiology, Anatomy, Pathological Anatomy117 5.5.2 Concepts and Institutions119 5.6 The Specificity of the Living According to the Nascent Experimental Physiology126 References127

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6 Life  and Death in Experimental Physiology After Bichat131 6.1 François Magendie and Bichat132 6.2 Claude Bernard’s Critiques137 6.2.1 Critique of Anatomical-Clinical Medicine138 6.2.2 The milieu intérieur and the Critique of Vitalism140 6.3 The Novelty of General Physiology According to Claude Bernard145 6.4 Life and Death in Claude Bernard’s Work149 6.4.1 The Experimental Approach149 6.4.2 The Characterization of Life and Its Relationship to Death152 6.5 The Two Pathways155 6.5.1 Creation, Evolution’s Directive155 6.5.2 Bernard’s Hesitations and the Conflict Between Morphology and Physiology158 6.6 Conclusion161 References164 Part II The Ultimate Causes: Why Do We—and All Others Creatures—Die? And What Should the Answer Do to Philosophy? 167 7 A  Providentialist Metaphysics and the Traditional Economics of Death: Mortality and Individuality169 7.1 The Providentialist Metaphysics170 7.2 Providentialist Metaphysics, Individuality, and Death in Biology: Darwin and Weismann175 7.2.1 Biology, Geosciences, and Chemistry: Using Providentialist Schemes of Death175 7.2.2 Darwinizing the Scheme: Weismann, Soma, Germen, and Death177 7.2.3 Death, Individuals, and the Good of the Group181 7.2.4 Facing Difficulties of All Sorts183 References185

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8 The  Evolutionary Synthesis’ View of Death: Peter Medawar, George C. Williams, and the Riddles of Senescence187 8.1 A Biologist on Selection and What Apparently Resists Its “Paramount Power”187 8.2 Why Would We Have Sex and Die?189 8.3 Mutation Accumulation and Antagonistic Pleiotropy: Framing the Evolutionary Conception193 8.4 Enters Indirect Natural Selection: “Antagonistic Pleiotropy”196 8.5 Ecology, Evolution, and Physiology: The Novel Territory of the Question About Biological Death203 8.6 Conclusion: Charting the Shadow of Selection209 References212 9 Epistemology  of Death (1): Goals and Evidence215 9.1 What Are the Objects of Enquiry? The Equivocations of “Aging” and “Death”216 9.1.1 Senescence216 9.1.2 Aging, Death, and the Contrast Classes218 9.1.3 Lifespans and Life History223 9.2 How to Gather Evidence About Death and Senescence?227 9.2.1 Humans and Curves228 9.2.2 Producing Evidence About Death: Comparisons243 References249 10 Epistemology  of Death (2): Experiments, Tests and Mechanisms253 10.1 Producing Evidence About Death: Two Levels of Laboratory Experiments (Dietary Restrictions and Genomics)254 10.1.1 Diet254 10.1.2 Experiments and Genomics256 10.1.3 Experiments on Stem Cells and the Role of Intestinal Epithelium266 10.2 Selection Experiments on Model Organisms and in the Wild268

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10.3 Mechanisms, Evolutionary Processes, Causes: The Evidential Structure of Evolutionary Theories of Death and Senescence and Their Epistemic Issues275 10.3.1 Death and Irrationality: A Parallel276 10.3.2 Diversity of Aging Mechanisms and the Rival Evolutionary Hypotheses278 10.3.3 Testing Competing Hypotheses: The Conundrum279 10.3.4 Undecidability?285 10.3.5 Epistemic Opacity of Death and Senescence288 10.4 A Somewhat Alternative Theory: Disposable Soma Theory301 10.4.1 Introducing DST302 10.4.2 DST: Trading Reproduction vs Repair vs Growth306 10.4.3 DST and Other Evolutionary Accounts: An Attempt at Characterization307 10.5 Conclusion. The Pluralistic Picture312 10.5.1 Theory Families, Explanatory Pluralism, and Singular Developments312 10.5.2 Being Pluralist About Explanatory Pluralism315 References323 11 Ontology  (1): The Modern Economics of Death and Its Trade-Offs331 11.1 Trade-Offs and Life History333 11.2 The Diversity of the Trade-Offs Underpinning Senescence340 11.2.1 Trade-Offs, According to Williams341 11.2.2 Trade-Offs in the Disposable Soma Theory342 11.3 Multiplying and Combining the Types of Trade-Offs347 11.4 What Is Traded? Currencies, Stochasticity, and Limits of Trade-Offs352 11.4.1 Multiple Currencies, Multiple Weights: Introducing Stochasticity and Constraints352 11.4.2 The Commensurability Issue: Fitness Trade-Offs and an Incursion into Community Ecology358 11.5 Fitness as a General Equivalent? The Roots of Trade-Offs and Some Epistemic Undecidabilities362 11.5.1 Trade-Offs, Fitness, and Time362 11.5.2 Senescence and Fitness: Contemplating the Plurality of Discounting Rates367

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11.5.3 The Logics of Trade-Offs: The Limits of an Economics of Death373 References376 12 Ontology  (2) Death Programs and Their Discontents381 12.1 The Disputed Question: Is There a Death Program?381 12.2 What Is at Stake?386 12.3 The No-Program Consensus391 12.4 Aging Programs, Reloaded (1): Unraveling Apoptosis396 12.5 Aging Programs, Reloaded (2). Yeast, Bacteria, and Their Suicides403 12.5.1 Aging Bacteria404 12.5.2 Suicide Bacteria407 12.6 Epistemological Considerations412 References415 13 Ontology  (3): The Case for Programs: Altruistic Suicide, Quasi-Programs and Smurfs419 13.1 Investigating Programmed Cell Death (PCD) in Unicellulars: Talk of Cell Senescence and Suicide420 13.2 Altruistic Programs Versus Quasi Programs426 13.3 Becoming Smurf: The Discontinuous View of Aging and Its Consequences441 13.4 Inquiring About the Possibility of Aging Programs: Altruistic Suicide, Kin Selection, Population Structures445 References456 14 Death  Is a Social Issue461 14.1 Social Structures462 14.2 Social Interactions467 14.3 Discounting Rates: Temporal and Social473 14.4 Coda: The Parts and the Whole: Darwinian Style477 14.4.1 Parts and Wholes: Kant and Darwin and Cell Death477 14.4.2 Back to Black483 References485

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15 Conclusion489 References497 References499 Author Index535 Subject Index539

List of Figures

Fig. 1.1 Fig. 9.1 Fig. 9.2

Life cycle of Physarum polycephalum (Wikipedia Commons) 29 Gompertz law 232 Match between Gompertz law and decline in selection intensity (After Carnes et al., 1996). Notice that they consider a post-reproductive period where Williams thinks there is none; however, he counts parental care for grandchildren, especially in humans, as reproductive, which is not the case with the present authors, hence the discrepancy 233 Fig. 9.3 Mortality curves in several species compared. (After Olshansky, 2010)234 Fig. 9.4 Mortality and fertility curves in relation to age, in numerous species. (After Jones et al., 2013) 240 Fig. 9.5 The three types of senescence patterns (from Baudisch and Vaupel (2012)) 243 Fig. 10.1 The intertwining of TOR and insulin pathway in the production of longevity (after Flatt & Partridge, 2018). See text: TOR is a major metabolic hub, and it connects to the insulin signaling pathway; both include genes whose mutant alleles may increase longevity in nematodes 257 Fig. 10.2 Schema of the Dauer phase (after Kenyon, 2011) 259 Fig. 10.3 Lifespan (bar) and reproductive (rectangles) periods for guppies in low vs high predation regimes. (After Reznick et al., 2006)274

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List of Figures

Fig. 11.1 Curve showing growth/survival trade-offs related to fertility. The reproductive effort at age i is given by the intersection of the curve with the line Ai–Bi, where Ai is that value of pi that would provide the same unit reproductive value vi entirely through survival/growth, i.e. with zero fecundity. Bi is that value of bi that would provide the same unit reproductive value entirely through fecundity, i.e. with zero survival/ growth. (After Taylor, 1991) 335 Fig. 11.2 Example of the trade-offs between reproduction and survival that determine fitness of an organism. Several traits trade off these two functions, and those trade-offs involve distinct currencies. (After Cohen et al., 2017) 353 Fig. 11.3 Hyperdimensional space representing currencies that support trade-­offs between traits and the problem of a conversion rate R? between rates of convertibility expressed in distinct currencies369 Fig. 12.1 The schema of apoptosis (Lee & Lee, 2019) 409 Fig. 13.1 Simplified scheme of the origin and evolution of the eukaryotic PCD system (after Koonin & Aravind, 2002). Thick arrows: vertical evolution; red arrows: horizontal gene transfer; red connectors: recruitment of eukaryotic-specific protein domains 425 Fig. 13.2 Simulation results: Cell population growth dynamics (a). Wild type: Programmed aging (suicide); (b) Mutant: Stochastic aging (no program, caspases neutralized). Red cells are new cells (from Fabrizio et al., 2004) 428 Fig. 13.3 Once development is complete, the program continues, inducing hyperfunctions that potentially produce diseases, in addition to accumulated alterations that will ultimately kill the organism. (After Blagosklonny, 2009) 434 Fig. 13.4 Pharmacological inhibition of the TOR pathway. Effect of calorie restriction and rapamycin input are represented. (After Blagosklonny, 2006) 436 Fig. 13.5 Various possible continued developmental programs, affecting distinct parts of the developmental system. (After de Magalhães & Church, 2005) 440 Fig. 13.6 Cell suicide in E. coli as a function of spatial structure (mixing vs. structure). (After Fukuyo et al., 2012) 454

  List of Figures 

Effect of local dispersal on the evolution of lifespan (After Travis, 2004). (a) Global dispersal. Programed age of death increases with time (b) Local dispersal. Programmed age at death decreases; selection “favors individuals with an intermediate age of death d.” Trajectories are shown for five starting values of d: 10, 20, 50, 75, and 100 Fig. 14.2 Various effects of extrinsic mortality on longevity, depending on social parameters. (After Lucas & Keller, 2020) Fig. 14.3 Predictions from the Hamiltonian model, where mortality is related to fertility, which defines the force of selection (F(a)); and from Lee’s “transfer theory,” where transfers from parent to offspring are taken into account as underpinning the dynamics (T(a)). (After Lee, 2003)

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Fig. 14.1

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CHAPTER 1

Introduction: The Philosophical Riddle of Death, from a Biological Point of View Or, Why a Book About Biological Death in Philosophy? What to Find in It?

When I first studied philosophy, in high school, I was struck by a double page in our textbook, showing the views of two philosophers about death. On my right, there was Plato: “the one aim of those who practice philosophy in the proper manner is to practice for dying and death” (Phaedo, 64a3–4); to my left stood Spinoza: “The free man thinks about nothing less than about death, and his wisdom is a meditation of life rather than of death” (Ethics, Proposition 67). This textbook was based on the idea that philosophy is made of opposite pairs of stances about any standard problem—consciousness, freedom, fairness, history, etc. Later on, I would drastically change my mind about this principle, but at the time, it was quite attractive. I found it fascinating that on the same passably metaphysical topic, namely death, great figures in philosophy would disagree. At the time, following the herd, I cherished Spinoza the way a soccer fan adores his favorite team. I therefore embraced his rather pragmatic view about death. This was only mildly consequential. I knew that most philosophers were deeply fascinated with death, and would write down deep thoughts about it, but I had no desire to be part of this game. If I had to be a philosopher, I would not encumber myself with souls, afterlives, and the meaning of “passing.” Yet, in various ways, the topic kept knocking on my door after my formative years. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_1

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As a philosopher, I understood that even though philosophy is not, in essence, a debate, the way a court trial might be, the opposition between the philosopher deeply concerned by what’s beyond, generaliter, and her colleague absolutely immune to fascinations of the supernatural, was a leitmotive of philosophy. The second attitude was eventually labeled “deflationism,” and many of the deepest philosophical objects were the object of a quarrel between an ordinary thinker and a deflationist. Truth, for instance, is currently disputed between those who see in it a noble and major concept likely to define a value (“truthfulness”), and the deflationist philosophers, following Horwich (1998), who stand firm on the claim that “‘A’ is true if ‘A’” says about truth all that needs to be known. But such schisms existed long before the label “deflationist.” The famous clash between Heidegger and Carnap, for instance, is about the word “to be.” Some philosophers think that “to be” is the deepest concept in the English language (or any language) and that questioning it intensively would lead to solving the highest riddles in the universe—while others just see “to be” as a verb infinitive among many others. Thus, once I became more familiar with philosophy, I was not surprised that two sides could be found to the question of death, depending upon whether “death is nothing for us,” as the Epicureans used to say, or whether death is the highest thing in the universe, since “philosophizing is learning about how to die,” as another of Plato’s disciples, Michel de Montaigne, would famously write. Many years after this brief exposure to the death-deflationists and the death-maximalists among philosophers, I again encountered the topic of death. This time, however, it was in a context almost free of metaphysics. It happened when I read Xavier Bichat’s Recherches philosophiques sur la vie et la mort, at the beginning of a long-lasting investigation into the emergence of what we call biology. Here, death was a biological matter rather than a philosophical one— and for me, the philosophical issue was precisely how such biological knowledge could capture death, and how relevant it was to it. Bichat was one of the architects of modern experimental physiology, and he is also known as a father of pathological anatomy, the field that intends to find out which anatomical failures correspond to which diseases. He wrote a book called Recherches physiologiques sur la vie et la mort, which included two parts, one being named “Recherches physiologiques sur la mort.” The fact that half a book about the process of death belonged to the foundational moments of the science of life in action—that is, “physiology”— was striking and puzzling for me.

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Bichat also coined a definition of life that is often quoted, and that was praised by philosophers such as Hegel and Schopenhauer. Actually, he had the honor of being commented upon and celebrated by two diametrically opposed thinkers (Schopenhauer having built his system on his hatred of Hegel). This definition reads: “Life is the set of functions that resist death.” It sounds deep, and it is. But, later on, Claude Bernard, who continued the tradition of experimental physiology in France, mocked it as a mere triviality: granted, life is not death and death is not life, but the statement is empirically empty, to a Bernardian analytic philosopher. Once again, we find the division between a major, almost philosophical, emphasis on death, and a deflationist view pointing out that the apparently profound statements are simply tautologies. It seems that this cleavage is hard to avoid when reflecting on death, in biology as in philosophy, be it metaphysics, or ethics.

1.1   Philosophy and the Oblivion of Biology But philosophers are not so keen on considering the biology and the signs of death, even though they may be interested in issues like the frequency of violent death, when examining the rise of civilizations (Elias, 1994). It’s not that they deny that death is a biological phenomenon. It is merely that, very often, what biologists say about death is rarely considered in philosophical reflections about death. For instance, Heidegger in Sein und Zeit famously sees human beings—what he calls, for reasons irrelevant here, Dasein—as Sein-zum-Tode, being-towards-death. It means that death is a core component of the very meaning of human existence because, for example, the fact of death alone structures the possibility of choice, since it forces us to sacrifice some possibilities for others, because our time is finite (e.g. May, 2021; Nagel, 1993; Williams, 1973) What is striking here is that one of the most influential philosophical discourses on death in the twentieth century—Heidegger’s phenomenology—does not even recognize that death has something to do with biology. Of course, Heidegger’s thought may be understood as a general bracketing, denial, or dismissing (depending upon one’s favorite reading) of biology in general—“Dasein” is never understood as a living being, by the way. But making death into a foundational signification within human life while depriving death of any biological character is an impressive instantiation of the divide between biological discourses and philosophical discourses about death.

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In principle, this denial is not illegitimate. A major philosophical question about death concerns the value of death, and whether it is good, or bad, or neutral, for us (e.g. Scarre, 2007; Fischer, 1993; Luper, 2009). This practical question matters for the conduct of life. It has been also massively influenced by a millennium of Christian concern for death. As historian Philippe Ariès explained, in the Middle Ages and even after, the event of death was a major spiritual event and people used to prepare themselves for it; it was expected to be very painful (and was, compared to most deaths today, which happen in a hospital setting). Moreover, one would have to behave appropriately, because it was also a test for the afterlife. Philosophers did not generally contribute to such religious discourses, but their thinking about death could not have been untouched by these general anthropological attitudes. Yet this value question about death obviously percolates into metaphysics. It’s hard to make sense of what death should be for me, if I never think about the question “why death?” My beliefs in relation to death may strongly depend upon the reason death exists. For philosophers, the reason may often be a justification, in the sense of a statement such as “we have to die because this or that should happen.” Justifications are often provided by the philosophical tradition when it comes to bad things: in the theological context, philosophers designed “theodicies.” Among them Leibniz proposed arguably the most elaborate one, but in principle it’s always the same notion: bad or negative things exist because they are the price to pay for a higher good. In his Civitas Dei, Augustine, who witnessed the event, relates that virgins were raped at the time of the fall of Rome. However, through this horrible torment, they experienced the important knowledge that bodies are corruptible but not the soul. As I’ll show in detail in this book, theodicy-style thinking is at work regarding death, even among secular philosophers, and biologists. Theodicies intend to show that the bad, the evil, and the tragic are not so negative in comparison to either what could be the case, or to the whole universe. Their negativity is attenuated because it is redeemed. Yet it can even be wholly deleted; such justification by deletion occurs in reasoning such as “negativity doesn’t exist, so this bad thing you worry about is in fact not even a thing.” In a nutshell, that is Spinoza’s famous reasoning about all that is negative. Thus, death, as something apparently negative, would be the object of the same sort of argument as all negative properties: they don’t exist, they can’t really affect us, and if they do, it’s

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because our ideas about them are confused or wrong. All we need to do is change these ideas, and we will acquire the proper behavior and attitude regarding death. Philosophy has been strongly shaped by these discourses, theological and/or metaphysical. It is not surprising that they offer biology very little space. Take Vladimir Jankelevitch, an important French philosopher of the mid-twentieth century. He is not read as much now as he used to be, but his writings are still commented on and appreciated. Jankelevitch was capable of writing on minute, intangible subjects. One of his books is entitled Le je ne sais quoi et le presque rien (“The I-don’t-know-what and the almost-nothing” would be a free translation…) and it’s a three-volume work. In a 400-page opus about death entitled La Mort, Jankelevitch never cites a major biologist or biological theory. He uses Greek words such as catabole and anabole, and he mostly glosses about the fact that, regarding death, there is nothing really to say (but it takes many pages to say it). Death is about life, hence biology, obviously, but it’s not even perceptible in this philosophical work devoted solely to death. As is often the case in philosophy, philosophers discuss philosophers: Jankelevitch discusses Leibniz, Nietzsche, and Spinoza, who discuss Plato and Epicure. Nothing bad, once again, about this, which has to do with what philosophy essentially is. Granted, biology as an autonomous science is assumed to have emerged in the late eighteenth century. Before that, medicine dealt with death, and philosophy has a strong relationship with medicine—consider the topic “philosophy as a medicine for the soul”—so philosophers may discuss medical aspects of death. But the fact that there have been tremendous advances in the biology of death since Plato, and more precisely, since the 1960s, cannot a priori said to be irrelevant to the problem of death, and one could wonder about the fact that it does not affect this philosophical interrogation. Granted, one could say that, just as a philosophical question about the “meaning of life,” the “good life,” or the “value of life” can be answered without any reference to biological knowledge, philosophizing about death does not require much biology. And that is why Plato and Epicurus are still meaningful regarding the philosophy of death, although they knew nothing about the causes, evolution, and stages of death. But this analogy is flawed: whereas, notwithstanding the question of the “good life,” highly concerted philosophical research about biology is flourishing, the interplay between philosophy of death and biology of death has not even yet been explored. Although death is a quasi-universal phenomenon

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among organisms of all species (and such universal phenomena are indeed rare), it is invariably overlooked by philosophers, or covered by the question “how should I relate to my death and possibly to the death of others?” This neglect is a reason for contributing elements to a philosophy of biological death to come. In this book, I will address biological death, and intend to philosophically make sense of two kinds of literature: the physiology of death, which since the nineteenth century focuses on the processes through which people die, and the evolutionary biology of death, which intends to explain why living beings have in general to die—a fate that most often takes the form of what we call aging or senescence. In the rest of this introduction, and because few philosophy treatises have raised this dual questioning, I’ll explain how those questions emerge on the basis of a philosophical and a biological literature.

1.2   Philosophical and Biological Issues Philosophers rarely ask why death. Like Jankelevitch or Heidegger, they may consider that there is no real “why.” In an anthology of essays about death by philosophers and by Woody Allen, editor JM Fischer initially warns that this book concerns “more basic and abstract problems concerning the nature of death: Can death be a bad thing for the individual who dies? What is the nature of the evil of death, if it is an evil? If death can harm a person, who is the subject of the harm, and when does the harm occur? If death can be a bad thing for a person, would immortality be good?” (Fischer, 1993, 3). In the same volume, Thomas Nagel devoted a thoughtful paper on what death means to us, and whether it is bad because it deprives us of something—countering Epicure’s argument that we cannot be deprived, once dead, because we are not there—and why the asymmetry identified and denounced by Lucretius, between the time when we were not born (to which we are indifferent) and the time we are dead (which we fear) is justified (Nagel, 1993). None of these questions concern biology. It’s not even easy to see how potential answers to these questions would be changed, in case biology were very different from what it actually is. To some extent, metaphysical questions about death could be fully decoupled from biology, because one considers that death is less the cessation of life than the end of existence of a person. This would mean that, once granted that some evolved computers can think, and possibly be persons because they think, deliberate, and act on the basis of their volition, then they would “die” when they were

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destroyed, for instance. And inversely, death would not be a property of plants, or animals like oysters, since they lack personhood. Ian McEwan’s 2019 novel, Machines Like Me, portrays a counterfactual world of the 1980s in which the Internet, social media, and self-driving cars already exist, and Alan Turing is alive and well. Turing’s pioneering research in AI has given rise to androids endowed with consciousness. The novel’s narrator, Charlie Friend, has purchased one of these “devices” and sees it as a living being. Finally, when he has to destroy it—because the android implements higher moral standards than those a human being can bear—he feels some guilt, but not as much guilt as the murder of a human being would have caused. Interestingly, the plausibility of the feelings and emotions Charlie experiences after Adam’s “murder” indicates that the radical personalist view of death as the end of some person, decoupled from biology, may not be easily detached from the idea that death is about end of a natural life. Granted, one can still argue that the “basic and abstract problems” about death, handled by philosophers, are about the end of consciousness or personhood. Butterflies die, but they don’t philosophize about it. The death we examine is that of creatures likely to think about death. The death-maximalist thesis inaugurated by Plato seems to make sense only in this view of personhood, because it concerns a being likely to ask the question of the value of her life, her acts, her choices. Thus, there is indeed an argument for neglecting biology when philosophers think about death. Whatever life can be, death has to do with the end of life, about life ended, whereas biology is about life, although it acknowledges that some entities have this property of life and then are likely to die and be dead. Yet, while death is about personhood, it requires personhood in addition to life, unless one thinks, as mentioned above, that death is by essence about the end of personhood notwithstanding the thing on which personhood supervenes: ordinarily, it’s a living being but, as I said, things may change quickly because of AI. Those questions lead us to consider in greater detail what “death” means.

1.3   What Is Death and What Are Its Criteria? Death is the cessation of life and the absence of life (in something previously alive). The word, in many languages, has three meanings: a process—the transition from life to nonlife, and a state—the inexistence of a life, within a body, or even with no tangible body, as when we say “the

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dead” and refer, for instance, to the writers or philosophers of the past. It may also mean the event of death, which is not the state of being dead, but also results from the dying process. This event of passing—away, or into something else, instantaneously—was, as I said, following Ariès (1977), a key event in the life of all Christians during the Middle Ages. Long after that, it was a test for one’s entire life. The dying process can be itself summarized into an almost-event, as with accidental death. In 42nd Parallel, the first novel in his USA trilogy, Dos Passos considers a character named Joe Williams. At one point, in the streets of New York, the author depicts him walking and thinking. Then he is hit by a truck and “that was the end of Joe Williams.” This sentence illustrates how the process of death can be reduced to an event. Inversely, “dying” may also be a long process when appear terminal diseases, such as some cancers. And what can be said about death from Huntington’s chorea (HC), a hereditary disease like a ticking neurodegenerative bomb? It strikes people at around forty and leads to dementia and death within a few years later, because of a deleterious allele. When did the dying process actually begin, in such a case? It is reasonable to consider some conventions here. We don’t say that a person suffering from HC is dying at birth, even though the inexorable process begins at that time. The HC process differs from the mere process of aging, which also usually starts long before death, and whose timing and steps are unpredictable. Yet we could say that dying begins after the HC phenotypes start to be manifest, although we would not talk of a dying process occurring once the signs of aging, namely, physiological deteriorations, appear. The facts don’t seem to fit the semantics rigidly here. Although the definition of dying process may not be devoid of conventions, one could suppose that the state of death is purely objective. However, this is not exactly the case. Even though the concept of death as the deprivation of life in an organism might be uncontroversial, there is no unanimity about criteria of death, whereby one evaluates whether a body is in this state of death, and hence is permanently deprived of life. These criteria are required to decide when someone is dead, which is essential even if we will never know what death is. As Fischer (1993) and Luper (2009) recall, the traditional criteria of death were crude: absence of respiration, movement, and heartbeat were the hallmark of death. This was not perfect criteria, and I’ll talk later about the fear of “false positive” diagnoses of death in the eighteenth century.

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However, in the twentieth century, emergency medical techniques—defibrillators, resuscitation, and life-support devices (ventilators, blood circulation pumps) implied a redefinition of the criteria of death, since people whose hearts or lungs had failed were still considered to be alive. The Harvard Medical School created an Ad Hoc Committee to Examine the Definition of Death in 1968. It added the criterion of “irreversible coma,” or permanent nonfunctioning brain, to the traditional ones, irreversible cessation of respiration and circulatory activity. That was when the brain came to the fore. Nowadays, cessation of brain activity is considered a criterion of death in many countries, because it is supposed to make any return to life impossible. However, an active brain, even in a comatose state, leaves intact the possibility that the person may come back to life, which happens in 10 or 15% of the cases of coma. Brain death is therefore a reason for hospital personnel to stop maintaining cardiac and respiratory activity. It also triggers all the medical and social practices that are related to death in our societies: organ extraction and transplant, mourning, inheritance, etc. However, in the US, some states refused to adopt the Harvard definition. Hence, someone could be dead in Kansas but alive in a neighboring state, if that state hadn’t recognized the Harvard criterion. Kansas was indeed the first state to include a reference to brain death in its “Act Relating to and Defining Death” (Nipper, 2017). In 1978, US president Jimmy Carter formed the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research in order to forge a Uniform Determination of Death Act, likely to hold in every state. This document is now a reference worldwide when it comes to determining whether someone is dead—in other words, the criteria of death. It aims at “general physiological standards rather than medical criteria and tests, which will change with advances of biomedical knowledge and refinements in techniques.” One could read this sentence as an intention to leave criteria open, and concentrate on definitions, but the definition– criterion distinction is not so obvious. A criterion x of X allows one to decide whether something a is or is not X; however, there are several tests to determine whether x is satisfied. Tests can be seen as criteria of second order. The whole point of the “general physiological standards” sought by the Committee is that one looks for criteria making it possible to state with certainty that a body is lifeless and will remain lifeless (provided that one’s definition of life includes the possibility of ceasing to be alive and then recovering life, exactly like seeds or organisms that go through a

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phase of suspended life, see below). These standards can then be assessed by various tests, which indeed will always depend upon the capacities and knowledge of physicians. The presidential commission issued the following statement: “death is a unitary phenomenon which can be accurately demonstrated either on the traditional grounds of irreversible cessation of heart and lung functions or on the basis of irreversible loss of all functions of the entire brain.” Notice that what death is is not said—its definition, strictly speaking. Whatever death is, it can be “demonstrated” by two methods: the traditional one (heart and lung) and the modern one. That is the document’s most salient point. Two remarks, here. First, the three organs mentioned there were precisely the topic of the first synthetic, extensive, and experimental study on dying and death, entitled “Physiological researches on death,” written by nineteenth-century French physician Xavier Bichat as the second part of his 1801 Recherches physiologiques sur la vie et la mort. These investigations actually consisted in looking at the effects of these three organs on the cessation of life, thus the persistence of this triplet of organs when one undertakes a scientific examination of death is noticeable. I’ll analyze these Recherches in detail in the first part of this book, since the epistemological history of concepts will be my first take on the problem of death here (as justified below). Nevertheless, it is important to see that Bichat’s Recherches stand in a long-term history of the conceptions of death and its criteria. Both this work and the Commission report are benchmarks in the continuing effort to understand the interrelations of brain, heart, and lung functions. “Three organs—the heart, lungs and brain—assume special significance because their interrelation is very close and the irreversible cessation of any one of them very quickly stops the other two and consequently halts the integrated functioning of the organism as a whole.” This triumvirate that supports death was first stated in Bichat’s Recherches sur la mort and, as we see it, continuously infused the thinking on biological death. Second, the Commission’s report refers to both the traditional and the contemporary brain-based criteria of death. But it also distinguishes aspects of brain death. The brain stem controls the autonomic nervous system, ensuring the organism’s integrity. The higher brain, by contrast, is in command of psychological functions like thought. Some patients may be in a vegetative state, their higher brain being destroyed, but the brain stem subsists and continues to allow the organism to function as a whole. “When artificial means of support mask this loss of integration as

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measured by the old methods, brain-oriented criteria and tests provide a new window on the same phenomenon.” In addition to this “whole-brain approach to death,” the Commission also considers a “higher brain formulation,” that would state someone is dead because the higher brain functions have ceased irreversibly. However, the Commission bypassed the option, because it involves making sense of the “person” presumably supported by these views, and introduces too much arbitrary judgment. As Nair-Collins (2021) put it, “higher brain theorists are literally talking about something else,” not biological death. Hence, it is preferable to interpret the definition in terms of irreversible cessation of the “whole brain.” But the USA and the UK differ regarding their criteria of brain death. As we saw above, in the USA, the cessation of brain activity is what means death. However, “the UK position is that one dies if and only if one’s brain stem irretrievably ceases to function” (Luper, 2009, 52). Because of this minimal conventionalism, criteria of death as Luper (2009) indicates—as criteria for brain death—are ambiguous, or “elusive,” as he says. Yet although brain stem function is taken as a criterion of death only in the UK, this concurs with the US conception, since brain stem cessation quickly hampers the organism’s integration. Now, as Luper (2009) insists, integration is still questionable. Integration can be artificial; namely, run by hospital machines. In this case, integration does not prove life, since the whole point of updating the criteria of death was to improve our capacity to determine when to disconnect someone from the machines. But when we consider natural integration, we see that some people who lack natural integration are nevertheless alive—for instance, people who have an artificial heart or even a pacemaker. Taking the key role of the brain as the agent of the organism’s functional integration remains problematic in the sense that, first, it does not avoid any conventionalism and, second, it is still unable to eliminate all vagueness in the determination of death.

1.4  Gradients of Death, Vital Processes, and Aging Actually, and implicit in all these ongoing debates about criteria of death, what death is, and its relation to life, depends upon what “I” means, or more generally, what is referred to when I talk about a person. In this

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context, Luper (2009) tackles in detail this question outlined by Fischer (1993). Clearly “I” does not refer to my body; once dead, this body would not be a person, hence equating my person to my body is not correct. Some philosophers consider that the subject is the person, a subject of self-­ awareness; others, that it’s the human animal (they call themselves “animalists”) (Olson, 1997); others, that it’s the mind. These accounts go together with accounts of identity or conditions of persistence of an agent. Each entails a different notion of death: “we can say something about what death will be on each of the three main accounts of what we are. Given animalism, we are human beings, and death will be the irreversible cessation of the vital processes by which our existence as human beings is sustained. On the mind essentialist view, it is our existence as minds that death will end. For the person essentialist, death ends our existence as beings capable of self-awareness.” (Luper, 2009, 48). This diversity of concepts of death is not easily overcome. As a general consequence, it entails that some philosophical conceptions about death will focus on human death, since human beings are at least those who have self-awareness and cognitive abilities or mind; other conceptions will focus on death of humans, but also of cats and frogs. To quote Fischer (1993) again: “Whereas some philosophers have divided their discussions of death so that they have given different accounts of the death of humans and that of (say) cows or insects, others have preferred a unitary account of death that would apply to all living creatures (and not just humans or persons).” Applying the concept of death may differ in extreme cases between these distinct concepts. For instance, persons who are brain-dead and in a vegetative state maintained by breathing and circulating machines are dead with respect to the “mindist” view of humans; they are not dead according to the animalist view of humans. Of course, there could be philosophical reasons to dismiss these cases because they are very marginal; what counts would be the general overlap between these concepts of death. Some philosophers may disagree. Marginal or even imaginary cases are important to understand and clarify the concepts at stake. Luper (2009) considers what would happen if there were machines that could reassemble the parts of someone who is dead: would it be the same individual? Would she have been dead in between her two existences, pre- and post-­ reassembly? What about cases where the body is dead, but all the mental states have been downloaded and saved somewhere, and might in a distant future put to work again in another body?

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But these philosophical puzzles parallel the famous riddles put forth by analytic philosophers in the 1960s: brains in a vat, zombies, swamp-men, and so on. In the present context, they also echo some claims made by people studying gerontology, or self-made prophets about the possibility of indefinitely repairing human beings, or preserving the integrity mental states in the form of the unique map of neuronal connections called the connectome, to download them a few centuries in the future. For instance, Aubrey de Grey, the pope of these transhumanists, claims that among us are people who’ll live up to 200 years, thanks to all these technological possibilities. I won’t be directly addressing these claims in this book, but they constitute the context of many current philosophical reflections about death. They confer some substance to philosophical analyses about whether persons who are disassembled and reassembled, or cryogenized and revived, are still alive, or died and then came back to life, or died and then another person emerged. However, I can’t think that biologically impossible medical procedures will cast a light on the nature of death, if death has something essential to do with life. And I think that no analysis of death can wholly decouple death from life. Granted, some authors can focus their reflections about death on the death of humans, and argue that it’s the most philosophically important part of the phenomenon, but they can’t argue that the death that concerns us humans has nothing to do with life. Luper’s analyses of the nature of death implicitly concur. He says: “your death, like the death of anything else that is alive, can be understood as a process or as the outcome of that process (the state of death). The process of death ends when your capacity to maintain yourself using vital processes is completely lost (denouement death), after passing through a point at which its completion is inevitable (threshold death).” He calls death that happens to things that may or may not be alive, such as humanoids, “personal death,” and it’s another concept than natural death. This definition in terms of “capacity to maintain oneself using vital processes” is an improvement upon the most spontaneous definition that sees death as a deprivation of life. Some cessations of life are reversible: seeds, or bacteria that have entered suspended life for centuries, are alive, but vital processes are suspended in them; yet they have the capacity of these vital processes. We talk of “dormant life,” a condition very frequent in nature. Dead bodies are not dormant. In heart surgery, the vital processes are suspended, since they are executed by a machine. But they are restarted after the operation. Hence, patients are alive but momentarily deprived of

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vital processes (but not of their capacity). It’s the same thing with frozen embryos. Likewise, if a technique exists to revive people who have been cryogenized, similar to the technique that already exists for small organisms, we should talk about living people whose vital processes are suspended. Interestingly, if we consider another transhumanist dream, the possibility of downloading the content of my brain (whatever that may be) in a machine, storing it there, and uploading it a few centuries later into a body produced through genetic technologies, the case is quite different. Here, I have been dead after downloading, and I’m born again when the mental states are uploaded in the new “me.” Of course, this is mostly a playground for analytic philosophers, where they can endlessly debate whether this second individual with my brain states is me, someone else, another me, etc. Gilmore (2021) considers the case of cryptobiosis, namely, the state of an organism whose metabolism is not detectable anymore, but can be reverted and start again. Seeds and spore do that, but also tardigrades, microscopic animals that freeze their lives and dehydrate. When conditions change, they may come back to life. As ice or dust, they seem to be dead. Because the state is reversible, though, they could be viewed as alive. However, it seems that only one of these views is true. Gilmore (2021) rejects this commonsensical alternative, and claims that the tardigrade is dead and alive at the same time. For cases where “alive” and “dead” are not easy to decide, such as people whose brain is dead, but who can breathe, whose blood circulates, etc., when supported by a machine—the cases that precipitated the existence of the Harvard Commission that revised our view death—the subjects can be dead or alive, depending whether one considers that integration is still complete, or that some functions are not irreversibly lost. Scarre (2007) suggests that these strange cases, mostly provided by technology, real or imagined, augment the cases of potential death far beyond what our vernacular concept was intended to capture. “Our notions of death and dying have evolved in contexts in which the possibility of cryogenic preservation techniques was never envisaged. Consequently, their employment in the new context is problematic and can only be sorted out by means of stipulative decisions” (Scarre, 2007, 8). Hence, no wonder that we are not always able to decide whether x is dead or alive in one of these newly defined cases. Lizza (2021, 14) concurs: “while we do have a biological nature, technology has intervened in that nature to create new phenomena that challenge our ordinary concepts of life and

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death.” Considering the case of an imaginary Wilbur, frozen before a hypothetical awakening in the future, Scarre indicates that even if it’s counterintuitive to say that Wilbur died, and was then frozen and then awakened (if this happens), it hinges on the fact that the notion of death includes irreversibility. However, one has to decide whether this connotation is a logical ingredient of the concept, or an addition granted only by our traditional use of the concepts, associated with ordinary life in the past. “The main objection to saying that someone in Wilbur’s position has died before his body is deep frozen is that any future restoration to health would then amount to a resurrection of Wilbur from the dead. But would that description really be so very objectionable? It would, if it were essential to our concept of death that death was irreversible. But this seems rather doubtful.” Another option would be to think of death and life as two poles of a gradient: dormant life, life supported by hospital machinery, life of frozen wealthy people, life of elderly people with pacemakers, and life of some young adult, are degrees in life. Various biological species may be restricted to one range of positions within this gradient. Death comes by degrees: degrees of alteration of vital processes, first taken as actual processes, and then taken as capacities. This view may be attractive, but it is open to an objection: once degrees of life are defined by degrees of vital processes, young and old people, or disabled and abled people, would instantiate different degrees of life. But how would we compare, say, a centenarian, who can’t live autonomously and hear or talk, and someone undergoing heart surgery? No two states of life are a priori comparable, which can be taken as problematic. Were this option applied as a means to “measure” life, it could prove in practice even more difficult than adapting, like Gilmore (2021), the compound term dead/alive for all the difficult, vague, or intermediary cases I just described. Yet there is something compelling in this view, even if it is counterintuitive. It allows states that are less than alive but not quite dead. But it may have unpleasant consequences, when one assumes that the value of life is proportional to something along this life–death gradient—consequences reminding us of some of the harshest controversies raised by Peter Singer. (However, this implies introducing the topic of “value,” and there are plausibly many other ways to think of the relation between value and amount of life.) But, you object, there are many contexts in which life and death should plainly be opposed. Dead people should be buried. Live people should

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not. The solution here is that this binary distinction is no longer biological, unlike the gradient I just indicated. It comes from considering many social values, as well as legal requirements. And the transition from the continuous space of amount of life (or degrees of vital processes), to the “yes or no” concept of life and death, is not naturally prescribed, since it involves values and political choices. Hence, boundaries between life and death other than the ones used in a specific country, under one legal system, and including the brain death criteria in the President’s Commission from 1978 (see above) would be possible. Authors like John Lizza would concur here. Lizza objects to the Commission’s legal definition of death on the grounds that it gives too much weight to biology. In any community, he argues, cultural, philosophical, and even religious considerations play and should play a role in predicating the alive/dead distinction. “Restricting the account of what it means for one of us to die to only biological considerations has strongly counterintuitive results in actual and hypothetical cases” (Lizza, 2021, 15). From the strict biological viewpoint, a decapitated body is similar to a brain-dead body; namely, some integration still exists but the brain doesn’t do anything. The case of a brain-dead person artificially kept alive by machines, and therefore having functional integration, shows that by seeing this case as a case of continued but brainless life, the President’s Commission is at odds with what we would naturally say. Thus, “although life and death are biological in nature, this biological nature is insufficient to determine the boundaries of our being in legal and social contexts”(ib., 17). The main message, here, concurring with my gradient-style conception of biological death, is that the boundary between dead or alive for us humans is not a pure fact of biology. It involves social and legal norms and conventions, which implies a degree of social relativity, or abritrariness. But, considering the facts of biology—namely, here, the facts that would apparently also hold for animals—in any case, Luper’s analysis in terms of “capacities for vital processes” is rich, because it distinguishes state and process of death, and, within the process, distinguishes “threshold” and “denouement.” This emphasizes the complexity of the very notion of death. Yet it is also open to one major objection: we know that death is empirically inevitable; thus, the mere process of aging, hence the whole process of life itself, or at least life after the acme of reproductive period, could be seen as a threshold death. Granted, Luper (2009) thinks of this threshold as exemplified by identifiable events such as the start of a cancerous development or a heart attack that cannot be reversed. However,

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one can still say that a first event proper to aging (which will be examined later) is just threshold death, since there is no way for life to go back to another state, and the result is necessarily death. Having such a general and early threshold death might also seem counterintuitive. Notwithstanding the final decision on Luper’s proposal and the radical view of a death gradient, such reasoning shows that death and aging have to be understood together, or that it’s hard to think philosophically about death and neglect the phenomenon of aging or senescence. After all, the transhumanist claims about overcoming death are more generally claims that aging phenomena could be stopped or reversed. This will delay death, and ultimately—albeit in the very distant future—suppress it, a claim or a hope that is radically new in human history. Many papers regarding gerontology and aging consider the use of the findings applied to anti-aging research, be it against aging-related diseases (cardiovascular diseases, osteoporosis, Alzheimer’s, Parkinson’s, and neurological disorders, etc.) or aging itself. In a more recent paper, Schumacher et al. (2021) claim that “DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing.” This is potentially ground-breaking, because many processes, as I’ll later show in detail, concur in aging: somatic mutations, mitochondrial disorders, accumulation of free radicals, etc. Due to this fact, it was still an issue to decide whether aging is like erosion; namely, an aggregation of many independent causes (such as wind, rain, and waves in the case of land erosion), or whether it stems from a single cause which ultimately causes death, as seems to be the case with DNA damage, according to this paper. As an example of this link between research on aging and anti-aging projects the abstract concludes: “Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.” Thus, in the present book, much will be said about aging. So let me dispel at the very beginning the possible objection that this book about death is in reality about senescence. Well, yes and no. Yes, because much of the biological literature I’ll study, especially in the second part, is about senescence. But no, because senescence is defined in relation to death. In our species at least, death occurs generally as the end of a process called aging or senescence. And senescence can be seen as the increase of the probability of dying through time. Once one asks “why death?” the question “why would we age?” seems a perfectly reasonable proxy for the former. Questioning senescence provides answers to the question why we

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die, since senescence is, at first stake, a decrease in the capacities for vital functions that stops at death; but the questioning about death is more general: it includes an investigation about aging, which leads to death, but also questions about the lifespan of each species, or the process of dying itself (for instance, after a disease or a stroke) that is not part of the examination of senescence. Hence this book is indeed about the biology of death, even though a major part of the literature I address is about aging. But “why death?” is, above all, a question about necessary death. Tolstoy tells of a character called Ivan Illich, a wealthy Saint Petersburg gentleman living a comfortable life with his family. In early old age, Ivan Illich is afflicted by a strange, uncomfortable illness after surviving an ordinary fall from his horse. Although he downplays his sensations, he sees a doctor, but pays little attention to the latter’s opinion. At some point he understands that he is dying, and desperately tries to find a meaning in these events. It’s all the more difficult that all his family and relatives act as if nothing were happening. This text, possibly the strongest ever written on death, shows perfectly the fact that Ivan Illich starts thinking of death when he ceases denying he is dying. Up to that point, of course, it can be taken as an illustration of what Heidegger says about inauthenticity, the mode of existence mostly adopted by us humans; namely, the denial of the fact that, by essence we are being-for-death. As in Pascal’s notion of divertissement—that is, the things we do to avoid thinking that we are mortals—the inauthentic subject, who is the subject most of us are most of the time, proves the existential importance of the necessary fact of death by the mere fact that she is continually involved in a strategy of avoiding thinking about it. But once he realizes that he will die, Ivan Illich wants to understand why he dies, and why now. Then what do you want now? To live? Live how? Live as you lived in the law courts when the usher proclaimed ‘The judge is coming! The judge is coming, the judge!’ he repeated to himself. ‘Here he is, the judge. But I am not guilty!’ he exclaimed angrily. ‘What is it for?’ And he ceased crying, but turning his face to the wall continued to ponder on the same question: Why, and for what purpose, is there all this horror? But however much he pondered, he found no answer. And whenever the thought occurred to him, as it often did, that it all resulted from his not having lived as he ought to have done, he at once recalled the correctness of his whole life and dismissed so strange an idea. (p. 60)

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Tolstoy suggests here that the way one’s life is, and whether it’s a good life or not, may not be apparent until the prospect of death becomes tangible—and by “tangible,” I mean at the point where what Luper (2009) calls “threshold death” is reached: an irreversible process that culminates in actual death. This is when a quest for the reasons for death emerges in the form of a question about a necessity: “why should I have to die?” This questions the inexorability of death within life, and, precisely, death as it occurs in terminal illness, a tormenting process leading to death. “Why should we die?” is a question about a necessity, hence about something universal regarding a given class—and here, the class of dying creatures is living organisms. “Why death?” by extension questions why should all living creatures die. All (multicellular) organisms seem to die, so answering ‘“why would I die?” is the same as answering “why do they die?” Death intervenes after the process of aging, at least in the lineage of mammals, to which we belong, and in many others—hence the question on death becomes a question about this process. It is unconditionally a living process, so the question “Why?”, as I wanted to show, can’t bracket life and biology—unlike, for instance, the death of thinking robots, whose existence does not include aging. More than that—and here is the case I wanted to make—thinking about the necessity of death imposes thinking about aging and its necessity, namely, about biology, which is the science of all living organisms. Even though death can be understood as a personist death, thus maximizing the distance between this concept and biology, I’d argue that because of aging, questioning the ineluctability of death involves some biology; or at least, could legitimately involve biology. Persons as persons (and not “as living things”) don’t necessarily age.

1.5  The Question “Why Death?” When they do ask this question, philosophers often come up with a justification—a story that makes sense of death as a necessary outcome of some processes. I’ll get into the details later on (Part II, Chap. 7), but provisionally I’ll give as an example Hegel’s logic of life in his Philosophy of Nature (the second part of his Encyclopedia of Philosophical Science, a text that integrates much content from biological sciences and extensively cites Bichat). One has to wait for Part II for a more robust demonstration of the generality of this stance, but I take Hegel, here, as the best (and easiest

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to grasp) illustration of the conceptual scheme that governs many traditional philosophers’ arguments on biological death. Death, here, is understood as the rise of the “species,” the universal, on the basis of the living individual, which is at the same time Universal— because Life is a form of the “Concept,” namely, the adequacy of the subjective and the objective—and a Particular, since it’s a form instantiated by a particular individual. The living individual has to die in order to let the universal rise. This is embedded in the famously very complex structures of Hegel’s logics, but this is the general justification of death, and it instantiates what I called the theodicy character of classical philosophy of death. And it’s obviously not an explanation of death. It’s a way of making sense of death, an account, a justification in the sense that one justifies oneself when one gives a reason for one’s actions. To some extent—and rather provocatively—it extends the logics of myth. Myths, as it has been famously shown by anthropologists such as Levi–Strauss, intended to make sense of crucial phenomena at a moment and in a situation where there was no knowledge available for that task. As a result, sexual division and death are recurring objects of mythologies in societies all over the world. These mythologies are not random; they have ancestors and sisters, and they ultimately could be sorted into a possible phylogeny of myths. Philosophies of death cannot give rise to phylogenetic trees, the way native American or African myths do, but they share many elements with this way of conferring meaning to things. Many myths about death assume that people were, in an archaic past, eternal, and then something happened, and they became mortal. In some myths, a man unknowingly and unwillingly contracted a debt from Death, and has to pay Death back later on. Paulme (1967) tells a West African myth from Ivory Coast in which a hunter meets Death, receives a gift from her, and from this day on is indebted to death; legitimately and naturally, Death, then, comes for having the debt paid, and the guy dies. Debt is a justification for why death; traditional philosophers won’t be immune to this debt-based reasoning, as I’ll show in Chap. 7. We philosophers are used to relying, if not on myths, at least on justifications for death. One such justification is the idea that without death, life would have no meaning: meaningful choice would be impossible, since no action irreversibly precludes another one. This is an important issue relative to death, well exemplified by Borges’s short story, “The Immortal.” The narrator tells us about many experiences he had, in various places and

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times. At some point, we think he is very old, but finally we realize that he is Homer; he is the narrator from whom narration originated, who is always there to tell the stories. However, because he is immortal, he is experiencing a deep despair about his impossibility to end all of this. He is searching for the river Lethe, which can turn him into a mortal. Only then can he become someone; as an immortal, he is no-one, just endorsing all possible identities. Philosophers, especially after Bernard Williams, extensively discussed the issue of whether mortality endows human existence with meaning, of which it would be deprived by eternity. As Williams put it in his influential paper “The Makropulos Case: Reflections on the Tedium of Immortality,” “Immortality, or a state without death, would be meaningless (…); so, in a sense, death gives the meaning to life” (Williams, 1973, 82). E. Makropulos is a character in a story by Karel Capek, turned into an opera by Leos Janacek—a woman who lives forever, by inhabiting a series of identities, but who gets so bored that finally she kills herself. The parallel with Borges’ Immortal is obvious. Williams argues that “there is no desirable or significant property that life would have more of, or have more unqualifiedly, if we lasted forever.” He examines many aspects of the question, especially what an immortal life would be like, and whether life experiences would actually be repetitive. But then why would Makropulos allow repetition, given that she could have highly varied experiences instead? At some point, the constancy of her character is challenged (82). The issue of who lives the immortal life keeps popping up in these discussions, as it does in Borges’ short story. That underpins the question of meaning and is a reason why Williams claims that “an endless life would be a meaningless one, and that we could have no reason for living eternally a human life.” Meaning in a life occurs only if there are relations of fulfillment or disappointment between expectations, actions, and outcomes. If the distinct aspects of the self become so varied that they lose their connections, there can be no such relations. For this reason, death appears in the end as metaphysically undecidable: as Todd May summarizes it by taking into account the more commonsensical fact that death destroys some arising meanings, “death at once provides a framework of meaningfulness for our lives, and leaches that meaningfulness from us” (May, 2021, 157). The metaphor of an agent as a narrator of her own life is helpful here: “You expect to die, just like an author expects to finish her novel and a reader expects to turn the final page. Frustrating them would seem to have grave consequences” (Mitchell-Yellin, 2021, 132). Human lives are always

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and constantly re-experienced in a narrative, addressed to others but sometimes left untold, and this narrativity grants the validity of such analogy. Heidegger’s Sein-zum-Tode could be understood in this way, as an expression of the intrinsic relation between human action as meaningful action and the possibility, always there, and at the same time inexorable, of death. Moreover, as to the phenomenologist, since death is the only unsubstitutable event, the one that only me can experience, it becomes “the possibility of the impossible” (Sein und Zeit)—since no one is there to experience this experience that can only be mine, but in the mode of “my impossible.” Saying that Dasein is being-for-death is a way to express that its existence first and foremost matters for itself, and that this stems from the fact of its mortality. Later on Hans Jonas conceived of life and death along those lines, when in his last lecture he said in a striking formulation that “the possibility of death is the necessity against which life struggles, yet the necessity of death’s necessity is life’s blessing, for without it we go as strangers in the world” (Jonas, 1992, 34). This essential subjectivity of death, as we would say, grounds the possibility of living an authentic and meaningful life, which may not exclusively be tied to Heidegger’s often obscure and reactionary metaphysics. For instance Martha Nussbaum writes: “In raising a child, in cherishing a lover, in performing a demanding task of work, or thought or artistic creation, we are aware, at some level, that the thought that each of these efforts is structured and contained by finite time.” (The Therapy of Desire, cited in May, 2021, 159). What appears then, through philosophical arguments elaborated in very different conceptual backgrounds, is a connection between mortality, subjectivity, and the pattern of personal agency, which means a coherent structure of projects, expectations, means, and ends. For projects to be my projects, they must not be indefinitely switchable for an infinity of other projects; if they are, they cannot be recognized as my projects, and embraced and articulated within a narrative to become the meaning, expressed or implicit, of my own existence. Death ensures the finiteness of time, which makes for the possibility of this pattern of personal agency, which in turn can be translated into narratives of the self. But, of course, this justification is mostly about personal death; it won’t explain anything about death in general in nature. It emphasizes the connection between death and meaning, a connection which opposes the other, often-discussed relationship: namely, that death is a bad thing because it deprives someone of the possibility of leading more meaningful

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life. This latter argument, for example, makes sense of our intuition that death is worse for young people than for the elderly—namely, that the deprivation is worse for the former. The boredom argument does not explain the “why” of death, but it could be understood this way: “we live or can live a meaningful life; we act in a meaningful way in life; if we were immortal, meaningful life would be impossible; hence mortality is a necessary fact given our capacity for meaningful action.” However, this reasoning makes death the reason for meaningful practical life: as medieval philosophers would say, it’s the ratio essendi of meaningful life; and the fact that we live a morally meaningful life, based on the fact that we make choices and have preferences, is the ratio cognoscendi of death. That which makes it the case that death affects human beings is not what explains death. Many versions of this reasoning exist in the literature. My point is that it’s a justification, not an explanation. Moreover, all steps of the reasoning are objectionable. One could say that, even in eternity, even if one has time to do the infinity of things one wants, one would have to choose to do A before B or B before A. Also, “infinity” is vague: mathematicians know there are various kinds of infinity (numerable, innumerable, etc.). Next, meaning and choice are not necessarily connected. The list of objections goes on. Later, I’ll examine in detail the traditional justifications for death given by many philosophers, justifications that intend to provide a ratio essendi rather than a ratio cognoscendi, for death. They can therefore also appear to be explanations, because they provide the reason why organisms die rather than remain immortal. Aristotle, for example, would justify death by the fact that life entails death. But biologists don’t “do” myths. They no longer enter into the hermeneutics of the meaning of natural things, a dominant form of the philosophy of nature in the early nineteenth century (Huneman, 2006). Finally, they have come up with an explanation of death. After the characterization of death throughout the early history of physiological researches on death, this is the second major concern in this book—the post-1950s biological explanation for death, within the framework of Darwinian evolutionary biology. It is a major breakthrough. After all, death was mostly the subject of philosophical interpretations, justifications that can be seen as explanations. Death was so unexplainable that many myths were forged in order to make sense of it. And then, the concepts of Darwinian biology finally gave us an explanation of death. It’s an evolutionary explanation, and more than half of this book will be devoted to it, so I won’t enter into the details here. But it would be surprising if these evolutionary explanations

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of death and the phenomena related to it did not contribute elements to the philosophical problem of death. Interestingly, the last major philosophical book about death, The Philosophy of Death (Luper, 2009) does not even mention these major advances—namely, evolutionary theories suggested by Peter Medawar and George Williams in the late 1950s. Nor are they mentioned in Luper’s excellent entry for “Death” in the Stanford online Encyclopedia of Philosophy. Even though Jay Rosenberg’s Thinking Clearly about Death considers some of the recent developments of evolutionary biology regarding biological individuality, and goes into cell biology and cell death more than many other books, it offers us a strong and detailed reflection on death in the style of analytic philosophy, concentrating on the death of persons and never mentioning Darwin, or the two biologists who forged the current framework for understanding death, namely, Peter Medawar and George Williams. It is the same with Death, by Geoffrey Scarre, or Confrontations with the Reaper—A Philosophical Study of the Nature and Value of Death, by Fred Feldman (Feldman, 1992; Scarre, 2007). Although they consider “what is death?” and may envisage that death is also something biological, they overlook the fact that we have evolutionary explanations of the reasons for death. Samuel Scheffler’s Death and the Afterlife (2013) sets out a strong argument focusing on doomsday to show that the structure of valuing and what matters is at least oriented towards after our death. But Scheffler equates doomsday with a (philosophically fascinating) scenario where nobody dies but everybody becomes sterile, resulting in the same humanless state of the world. Whatever the biology of death may be, it’s not relevant to his argument. The philosophy of biology, in turn, as a specialized branch of philosophical literature, never directly addressed death as a topic. Granted, the major theoretical issues that underpin the theories of death and aging— namely, adaptation and levels of selection—are paradigmatically discussed. But the philosophers of biology have never directly tackled aging and death, either from the standpoint of biological philosophy, namely, the effort to make sense of biological ontology based on our best science, or from the side of current epistemological inquiry into some of the major biological paradigms. This distance between philosophy and science is striking, and a major rationale for my book is the will to see whether any substantial philosophical issues and perspectives can be elaborated on the basis of various biologists’ research into the phenomena of death. Among them, I’ll strongly

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focus on Bichat, who authored the first modern study of death from the viewpoint of experimental physiology (more reasons for this choice will become clearer further along in the book). The main question of my book is the following: “what can the biological study of death in nature contribute to the philosophical interrogation of death?” An additional question— given that the issue of death also concerns the meaning and nature of life—is then: “what could this biology of death tell us regarding life and biology in general?” In the next part, I shall look at the questions an “explanation of death” should answer. In the last, I’ll explain the argument and strategy of this book.

1.6  Overview of the Biological Facts of Death Death is not only a social, ethical, or political fact, it is first and foremost a general biological fact, and biology intends to explain why death. However, it is well known that biology is the science of diversity. Although all elementary particles of the same type—all electrons, all protons, all muons— are identical, and stars, for instance, can be classified into a limited number of categories, life is enormously diverse. This diversity is due to the fact that life evolved, and by evolving, created and filled a huge number of niches. Hence, “death,” albeit all-pervasive, is not absolutely universal. It takes on diverse forms (the transition through a dormant state, as I mentioned, is one peculiarity of the phenomenon). Explaining death also means explaining this diversity. Differences in longevity are one obvious example of diversity. Timescales vary by several orders of magnitude. Many insects live for a few hours or 1 day. On the other hand, certain trees can be very, very old. The Jurupa oak, a colony of Quercus palmerii trees in Riverside County, California, survives by cloning itself, and is about 13,000 years old. But Pando, a quaking aspen in the Fishlake National Forest in Utah, is 80,000 years old. It is an individual male, a clonal colony that has a single root, spans over 120 acres, and weighs 6000 tons. A stem—a trunk—lives for about 130 years. Incidentally, the fact that these are nonsexual organisms surviving clonally hints at one of the major themes of the second part of this book (on evolutionary explanations), the relationship between reproduction and survival. Nonclonal trees can live for a long time, but not as long as clonal ones. Nevertheless, there is a Great Basin bristlecone pine (Pinus longaeva)

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called Methusaleh in California that is 4852 years old. It may live several hundred more years if it’s left alone. But once dormant life is taken into account, we can jump far back in the past. Cold allows for dormancy, as we know. In Siberia, researchers revived tissues of an Ice Age Silene stenophylla flower frozen in the permafrost. It’s about 32,000 years old. As for animals, in 2018, along the Arctic Circle in Siberia, in the Duvanny Yar outcrop on the Kolyma River, a team found 42,000-year-old nematodes—a famous species of worm—in a Pleistocene squirrel burrow. The worms were dormant, but could be revived. Microscopic organisms, however, set the greatest records for longevity. In 1995, biologist Raul Cano extracted colonies of bacteria from bees encased in amber in the Dominican Republican and revived them. They are about 35 million years old, and are similar to bacteria colonizing present-­day hives. Cano also revived a unicellular eukaryote, a yeast called Saccharomyces cerevisiae, found in amber in Myanmar. It’s 25–45 million years old. The finding prompted him to start Fossil Fuels Brewing, to produce beer from this yeast. Lastly, scientists in New Mexico found unidentified bacteria dating from the Permian period, about 250 million years ago, and the strains have been revived. We have already met the riddle of dormancy. It’s hard to say that these organisms are dead while dormant; at least, Gilmore (2021) would claim they are dead and alive. Luper (2009) distinguished reviving from restoring on the basis of disassembled atoms, and something that is not dead is said to be revived. Thus, even though these creatures had an unusual way of living, they lived for hundreds of millions of years. In the case of bacteria, the fact may not seem so striking. After all, for a long time, bacteria and unicellular organisms in general were presumed to be immortal. As I’ll explain in depth afterwards, one way of framing the question of biological death was by contrasting theoretically immortal single-celled organisms with multicellular ones, doomed to die. Nevertheless, the lifespans of these trees and plants are undeniably impressive. They may not be immortal, but they are extremely ancient, and they survive by either going dormant, or relying on clonality. The Jurupa Oak is even stranger, because the event that triggers clone production is fire. Thus, the life cycle of these clonal trees regularly involves phases of fire. A biologist would say that its survival system is an adaptation to frequent fires, as weird as this may sound. Let’s sketch a few of the ontological puzzles implicit in the diversity just described.

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(a) First, there is an identity issue, quite apart from all of the puzzles I mentioned (disassembled persons, frozen ones, artificially sustained life, etc.). Regarding bacteria, it is true that the strain dating from 250 million years ago is old, but what about individual bacteria? Given that they are clonally reproduced cells, they are all the same; but are they always the same individual? Well, not exactly, because mutations always occur from parent to daughter cell. There will be a difference of a small n for every 10,000 nucleotides in the DNA of the mother cell and the daughter cell, preventing the two from being totally identical. But after all, in the body of a mammal, there are differences between time periods, since somatic cells undergo mutations, and yet we say it’s the same organism. So why couldn’t we consider the bacteria to be all the same single individual—that is, the colony, since bacteria are often colonial organisms? If we do, we get close to the case of the Pando aspen or Jurupa oak. All stems are like ramets of a same plant: they’re clonal, hence identical from the genetic viewpoint. But why do we say that Pando is one 80,000-year-old individual, while a pine tree that disperses seeds that travel great distances and finally produce a forest is not the member of one gigantic tree? The difference is that Pando’s connection through the root makes it into one individual that is very old, whereas the lack of connection between pine trees would lead us to say something different: a forest of pine trees that grew from seeds and died is very old as a forest, but the individuals are not extremely old. The colonial bacteria would be quite identical to the case of Pando because they are colonies; they are aggregated within the colony, the way Pando’s trunks are through the root. It seems to me that it is correct to say “Pando, the individual, is 80,000 years old,” and so is “these bacteria are 250 million years old.” In this case, when a trunk dies in Pando, it’s like a cell dying in my body; and the long life of Pando’s supervenes on the shorter lives of the trunks, in the same way as my life emerges on the basis of the somatic cells that always die after a few years in my body. Suppose now—like analytic philosophers writing on death—that we have a sophisticated machine that clones people. Take Mendel. Mendel 0 is Mendel; Mendel 1 is cloned after Mendel at 40, Mendel 2 cloned after Mendel 1 at 40, and so on. In this case, if

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Mendel lives eternally through (Mendel n), we would still say that each of these Mendels is born and dies, but that the Mendel lineage is eternal. This is analogous to what happens in a species: individuals die, but the species is somehow eternal (although, of course, on a longer timescale, it becomes extinct). This is exactly what in his treatise De generatione et corruptione Aristotle says to explain that the immortality of the species occurs through the death of its members, and, as eternal, imitates in a poorer way the eternity of stars (which are eternal but retain their individuality). My point is the following: to talk about an individual dying, or being eternal, we have to distinguish the individual (Mendel i) and the lineage (the {Mendels i }, i varying from 0 to infinity). In some cases, it’s the lineage that is eternal, even though its members are almost identical. In the case of (Mendel i), a specific argument is the psychological continuity, which is a criterion of identity for human beings, and which obviously is not met in the case of the lineage. With individuals of other species, this criterion is inaccurate. What counts, fundamentally, is physical cohesion. So in the case of (Mendel i), the lineage is eternal and the individuals die; in the case of Pando, it seems that the individual itself is eternal; in the case of bacteria, I’m not sure a knockout argument can be given. There is a huge body of literature on what biological individuality is (e.g. Bouchard, 2010; Clarke, 2013; Bouchard & Huneman, 2013, Godfrey-Smith, 2013), and this is not the place to address it. I just suggested a few remarks about the degree to which the question of the immortality and death of biological individuals may face an ontological problem and, in some cases, assume some conventions. (b) In a word, what occurs here is the distinction between levels. Mendel i, and the (Mendel) lineage, are related in the same way as cells are related to the organism containing them. Cells die, the organism subsists much longer; Mendel i dies, (Mendel) as a lineage subsists. Hence, addressing the question of death and, even before that, identifying death, requires that this distinction be made. Moreover, the relationship between the temporary and the persistent must be characterized. The question of biological death is the question of why individuals die. Asking the question assumes that this distinction, between what counts as a low-level individual and what counts as a high-level individual—the lineage—can be explicated. But there is something else, when we come to the case

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of these individuals whose life cycle seems weird, like dormant bacteria or fire-addicted oaks. Among the myxomycetes (part of the phylum Amoebozoa, which includes all amoebas), we find the species Physarum polycephalum, which possesses singular properties. It’s a unicellular slime mold consisting of a plasmodium made up of a web of protoplasmic veins ensuring nutrition (slime molds are a major concern for biologists (Bonner (1959) synthesizes some of the science) and philosophers interested in individuality and in the origins of cognition). As a first biological singularity, it includes several identical nuclei within the cell. It can go into a very long dormancy phase, where it’s protected from the outside. It grows by extension, and when resources are scarce, the nuclei form spores by meiosis, which may be released and then fuse; they then recreate a plasmodium (assuming they are of different sexes, which is easy because there are 720 possible mating types for Physarum polycephalum) (Fig. 1.1). In the laboratory, this slime mold is immortal, since it is fed regularly. Its weird life cycle is not the only oddity. As a consequence of its multiplicity of nuclei, removing a part of the slime mold and transplanting it somewhere else results in the development of a new slime mold, almost genetically identical (since it possesses all the nuclei to grow a new cell). Thus, it can become a

Fig. 1.1  Life cycle of Physarum polycephalum (Wikipedia Commons)

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colony of nonaggregated plasmodium, which survives indefinitely. Hence, such a slime mold seems never to die; and even if it’s clonal like Pando, in principle, it could also produce multiple copies of itself that exist in various environments, and therefore could colonize a whole ecosystem or more. But the distinction between the whole thing and the trunk, the two levels of the individuals and the parts that may live shorter lives, is not respected here: other clones of a given slime mold live independently, and may live as long as their “ancestor,” or longer. What constitutes the low-level—the equivalent of the trunks in Pando, or my cells, or (Mendel i) in the (Mendel) lineage, are the nuclei of the cell; these nuclei are identical and numerous, as are the trunks in Pando, or the cells in a metazoan organism. This blurs our intuition about who dies and who is immortal—it seems that mortality is bypassed at all levels. (c) Death is irreversible, according to most definitions. Because cryptobiosis—the name for the dormant state of cells and organisms— is reversible, it is not death. Also, natural death occurs after an aging process which is itself irreversible—at least most of the time. However, in some species, even though they are not immortal like the slime mold, and are metazoan, this irreversibility is challenged. Such challenges may come with an idiosyncratic way of being an individual: namely, when growth and reproduction contrast with ordinary metazoan growth and reproduction, which is the most familiar to us. Hydra are freshwater organisms of the phylum Cnidaria and class Hydrozoa. Seemingly, they do not age, thanks to their regenerative properties: cut into two pieces, the hydra regenerates two identical hydras. Martínez (1998) argued that, because they continuously self-regenerate, hydras are immortal; no sign of deterioration can be found in a hydra after a long while. Researchers are interested in the transcription factor “forkhead box O” (FoxO) that drives regeneration; certain transhumanist cite these findings to fuel their experiments in fighting senescence. The so-called “immortal jellyfish” Turritopsis dohrnii starts off as a larva, and then settles down on the sea floor to give rise to a colony of polyps. These polyps then generate jellyfish which bud off and live as free-­swimming individuals. But at any time, Turritopsis individuals may revert to the polyp stage, and form a new polyp colony that is always genetically identical. Turritopsis cells are singular in that, with

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a same genome, after development they can assume different cellular fates (the way our muscle cells or blood cells do), but they can also revert to a state of undifferentiation, and then differentiate again—a cycle that could, in principle, go on forever. Thus, there are several processes through which certain animals bypass death: dormancy—the strategy used by slime molds, yeast, and bacteria; clonal development, like Pando; regeneration into new animals, like the hydra; and rejuvenation or reversion to undifferentiated cells, like the immortal jellyfish. So death is almost universal among living organisms, but some species have evolved avoidance strategies. Thus, the biological question about death should explain the quasi-universality of death, and why it is the norm—and also these strange situations where the arrow of time seems defeated.

1.7  This Book’s Endeavor To put it bluntly, in this book, I want to confront philosophical questions about death (and indirectly, about life) with the biology of death. This implies that the philosophy of biology will be taken as an important resource when it comes to thinking about death, although its relevance to the major treatments of the death question by philosophers is often scanty. Metaphorically speaking, this book is primarily about bridging the gap between philosophy and biology, as I have extensively argued in this introduction. This implies that the book will not address every aspect of the issue of death, even though I have mentioned them here in order to contextualize the question of death in philosophy. Such issues as the value of death and its relation to personhood will be omitted—since here, from now on, I’ll consider biology. And since I think of death as almost universal among organisms, the special status of human beings in relation to death is irrelevant. Of course, I won’t address moral questions connected to death, namely, suicide, euthanasia, or murder, all of which are admirably engaged by the philosophers I have cited so far. But there are three other kinds of bridges that are sketched in this book, and before explaining its structure I’ll present them. First, obviously I will address philosophy sensu stricto, and metaphysical issues regarding death, on the basis of arguments from philosophy of science. Second, and this touches directly upon the structure of the book, I want to articulate the history of science with the philosophy of science The

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first part of the book introduces a long analysis of the Recherches sur la mort by Xavier Bichat, and explains the pivotal role it had in physiology. It is a case study in what is often called “historical epistemology”: namely, tackling an epistemological issue—regarding, here, the possibility of physiological knowledge—through the analysis of a historical process, that is, here, the constitution of experimental physiology, its methods, its objects. The second part of the book will address the explanation of death that I indicated above, which comes from evolutionary biology. Here, I argue from the viewpoint of the philosophy of science in analytical way, or, at least, by favoring analytical arguments over historical analyses—even though I will trace the major arguments back to their sources. Thus, I am convinced that the problem of death in biology has to be understood through a strategy that embraces these two major stances in philosophical study of science. This is not the place to question these commonly used labels, even though I’m not sure they adequately capture the ongoing philosophical research. But the fact is that my analyses will cover two corpora, the historicity of the constitution of experimental physiology in relation to the question of death, and the structure of the evolutionary biology of death nowadays, including theories and hypotheses that are too new to have been corroborated or proved robust. Third, the duality of the book’s structure stems from a classical, textbook-­style divide within biology. It’s often attributed to Ernst Mayr in his 1961 paper “Cause and effect in biology,” even though one can see aspects of it elsewhere—namely, the distinction between functional and evolutionary biology. Mayr says that a biological phenomenon requires two kinds of explanation, which touch upon two kinds of causes. To cite Mayr’s example, “why does a migratory bird migrate?” can be answered by unraveling the functioning of its nervous system and its wings and muscles, the role played by cues (temperature, length of the day), and the genes that make its nervous system and physiology likely to respond in this way to these cues. But the same question requires also an explanation that looks at the role this flight to warmer climates plays in the bird’s life cycle, and at the flight route. This flight route can be explained by winds and currents that shorten the journey. The journey is caused by the fact that natural selection acted on older populations of this species and ancestral species to establish the migrating behavior, which provided a major advantage in terms of survival and reproduction over individuals that stayed and endured the cold. Next, the trajectory wired into the brains of these birds optimizes energy expenditure as a function of prevailing winds. In a word,

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evolution by natural selection explains both the behavior and the genetic makeup that supports this behavior. The first set of causes are “proximate causes” located in the lifetime and the body of the bird; the latter set are “ultimate causes”: they occur in the very long term, and they concern populations of ancestral species (in which “migrating” made a difference to those who did it). The term “ultimate” connotes both ancestrality and goal, or end. In the first case, we are thinking of what happened in the distant past, to the ancestral species. In the second, we are thinking of the way natural selection seems to explain a kind of teleology, because it often shapes organisms adequately to their environment. The first part of this book is about the physiology of death, so it’s about proximate causes. Here, the question is tackled mostly in historical epistemology style. The second part addresses the evolutionary biology of death. It has an immediate appeal to philosophers because here I consider an answer to the question “why do we die, why do all living things die?” And this question touches upon major philosophical enigmas, as I recalled above. The physiology of death addresses the “death” event. “How does it occur?” asks Bichat. It also concerns an elucidation of the process of dying—and the connection between state and process will be examined in the first part of the book. The evolutionary question about why we die addresses the process of dying, the state and the event, without distinction. It concerns also, eminently, the diversity of dying, since evolution is about diversity—hence diversity of processes and mostly of lifespans. Since Bichat’s Recherches, the physiology of death seems to have answered the question of how we die, while the evolutionary approach addresses the question of “why.” The how vs why is often a way to contrast functional and evolutionary biology. However, since the physiology of death intends to find the causes of the event “death,” it also raises a “why” question, given that, very often, causes answer “why” questions. And evolutionary biology does ask “why.” But it’s another “why”: on a different time scale, and addressing different phenomena. In physiology, killing an organism in a control experiment and asking why does it die is a way to answer “how do organisms die,” and therefore “how” and “why” intertranslate. But giving an evolutionary reason for the fact that in general organisms die and species x dies earlier than species y answers a set of “why questions” whose explanandum is not exactly the same as the former. Thus, the last “bridge” offered tentatively by the present book is about this dialogue between the functional biology of death and evolutionary biology—two kinds of “why.” In the conclusion, I will summarize how,

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together, the two of them can deliver a lesson to philosophers, notwithstanding the sharp contrasts between their approaches and explananda. The process of death in an organism may not be of direct interest to the philosophical question of the reasons why we humans die, and the meaning of this state of affairs. But, the physiology of death, in the first part of this book, touches in a reflexive manner upon the philosophy of biology and I intend to hash out this reflexivity, namely, to show how philosophical issues emerge once someone reflects upon the epistemology of physiological researches about death. In turn, I’ll explain the theories about why death is of direct interest to philosophy in philosophical terms, and question what they presuppose and involve for the meaning of death within biology. The consequence of such theories regarding traditional metaphysical approaches to death will be explicated. Once again, we’ll be concerned by the inaugural question that opposes death-maximalists, for whom the necessity of death holds major and essential truths about life, and death-deflationists, for whom death is not the primary thing to think about, or the primary and essential thing for life itself. But here, death as a problem will be a test case for several fundamental issues in the philosophy of biology, because it touches deeply upon the notion of fitness, which captures and measures evolutionary success.

1.8   Who Could Read This Book? For now, as it is obvious, this is a philosophy book; hence, it should be of interest to philosophers engaged by the question of death. It may enter into some genuine biological theory, but this is a consequence of the very gambit of this book: namely, the idea that real biology matters to philosophizing about death. I have tried to explain most of the scientific concepts, so that the book is readable for someone who lacks training in biology. Several boxes present more formal or technical aspects, or specific historical details; readers can skip them without losing sight of the main argument. Philosophers of biology are this book’s natural readership. They may be surprised by the history of biology in the first part, but I hope that the need for this historical epistemology will in the end be apparent. However, this book is intended also for philosophers of science, since it claims to provide general epistemological lessons. Finally, the potential readership includes biologists. Evolutionary biologists may find the chapters on evolution superficial. Nevertheless, certain epistemological and historical perspectives may be of interest to them, especially if senescence and aging are not their research topic. And even

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though they are familiar with these subjects, I hope that some analyses and perspectives proposed here, at the boundary between theoretical biology and philosophy, will be found worthy of a read. Philosophers of biology interested in death and evolution can read the second part alone, as well as biologists interested in the epistemology and ontology of their study field. Philosophers and historians interested in the historical epistemology of biology can limit themselves to the first part. This book, like many others, dreams of being “one long argument,” but can easily be split into two pieces. The boxes are addressing more technical details; they can be skipped by the readers, especially philosophers, who may be uninterested by such technicalities.

1.9  The Book’s Structure The first part, on functional biology, presents an analysis of the physiology of death in historical context. The key question here is the relation between the knowledge of death processes and the constitution of experimental physiology. The question stems from considering the fact that Bichat, held to be one of the founders of this field, wrote about it in relation to death, entitling his treatise “Recherches physiologiques sur la mort.” Chapters 2 and 3 analyze the context of Bichat’ s physiology, the main topic of the part. Chapter 4 presents an analysis of the “Recherches physiologiques sur la mort,” and shows how investigating death provides clues to life functions. The relationship between structures and functions and the difficulty of unraveling functions on the basis of evidence from the anatomy of dead bodies are the themes of this part. The last chapters examine the legacy of Bichat, especially through two French physiologists, François Magendie and Claude Bernard. The latter is often cited as the founder of experimental physiology. I’ll investigate the way in their hands death becomes an instrument of knowledge for physiology. The second part addresses the evolutionary biology of death, hence the question “Why do we animals die?” It pays much attention to the way the question has been framed in biology; that is, as a contrast between immortal cells and mortal organisms, even though the core assumption regarding cell immortality is not taken as true today. The question was raised in the late nineteenth century by the evolutionary biologist August Weismann, who started a longstanding research tradition on death in evolutionary biology. Chapter 7 will consider the way philosophy traditionally addresses the question “why death?” I will reconstitute a leitmotiv I call “providentialist

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metaphysics,” the idea that death happens because it’s the price for something else. As I said, it’s a justification for death, rather than an explanation of it. Chapter 8 examines the Darwinian idea that death could be good for the species, which is intuitive but wrong. This chapter lays the ground for the analyses that will follow, regarding current theorizing about death in evolutionary biology. It focuses on George Williams, whose theory of antagonistic pleiotropy is one of the major families of theories about death today. This is because Williams’s hypothesis allows me to put the question of death in perspective with deep conceptual issues about the target of natural selection and selection itself. Chapters 9 and 10 discuss the epistemology of these theories: what are the explananda, what are the data, and finally, how are these theories tested. In doing so, they bring to the fore findings that emerged in the 1990s about the genes underlying longevity. Chapters 11, 12, and 13 consider the ontology of death according to these theories. I examine in Chap. 11 the extent to which death is the object of an economy, because the motive of trade-offs in fitness is crucial to these genetic theories. Then, in Chaps. 12 and 13, I consider the long-standing issue of whether there is a death program (and not just stochastic processes cumulating and leading to death eventually). I’ll consider recent nonmainstream arguments in favor of these programs. This will lead me in the Chap. 14 to look at the relations between explanations of death and population structures, therefore providing an examination of the relation between sociality in all senses and the evolution of aging and death in biological populations. The conclusion draws lesson from the combined propositions elaborated in the two parts of the book. The importance of the notion of trade-off, and, ultimately, of an economic scheme of thinking, through which biological questions are addressed in terms of optimal allocation of scarce resources, retrospectively appeared as a major thread in this book, which questions the permanence of this notion in biology and philosophy, before and after Darwin, and its relevance or sufficiency for making sense of biological death.

References Ariès, P. (1977). L’homme devant la mort. Seuil. Bonner, J. T. (1959). The cellular slime molds (Investigations in the biological sciences). Princeton University Press. Bouchard, F. (2010). Symbiosis, lateral function transfer and the (many) saplings of life. Biology and Philosophy, 25(4), 623–641.

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Bouchard, F., & Huneman, P. (Eds.). (2013). From groups to individuals. MIT Press. Cholbi, M., & Timmerman, T. (Eds.). (2021). Exploring the philosophy of death and dying: Classic and contemporary perspectives. Routledge. Clarke, E. (2013). The multiple realizability of biological individuals. Journal of Philosophy, 110(8), 413–435. Elias, N. (1994). The civilizing process. Blackwell. Feldman, F. (1992). Confrontations with the Reaper: A philosophical study of the nature and value of death. Oxford University Press. Fischer, J. M. (Ed.). (1993). The metaphysics of death. Stanford University Press. Gilmore, C. (2021). What it is to die. In T.  Timmerman & M.  Cholbi (Eds.), Exploring the philosophy of death and dying (pp. 28–38). Routledge. Godfrey-Smith. (2013). Bouchard, Roughgarden and Folse III 2010, Clarke 2015. Horwich, P. (1998). Truth. Clarendon Press. Huneman, P. (2006). Naturalizing purpose: From comparative anatomy to the “adventures of reason”. Studies in History and Philosophy of Life Sciences, 37(4), 621–656. Jonas, H. (1992). The burden and blessing of mortality. Hastings Center Reports, 22(1), 34–40. Lizza, J. (2021). Defining death in a technological world: Why brain death is death. In T. Timmerman & M. Cholbi (Eds.), Exploring the philosophy of death and dying (pp. 10–18). Routledge. Luper, S. (2009). The philosophy of death. Cambridge University Press. Martínez, D. E. (1998). Mortality patterns suggest lack of senescence in hydra. Experimental Gerontology, 33(3), 217–225. May, T. (2021). Death, mortality, and meaning. In T. Timmerman & M. Cholbi (Eds.), Exploring the philosophy of death and dying (pp. 157–162). Routledge. Mitchell-Yellin, B. (2021). How to live a never-ending novela (or, why immortality needn’t undermine identity). In Timmerman T., Cholbi M. (Eds.), Exploring the philosophy of death and dying (pp. 131–136). Routledge. Nagel, T. (1993). Death. In J. M. Fischer (Eds.), Metaphysics of Death (pp. 59–71). Stanford University Press. Nair-Collins, M. (2021). We die when entropy overwhelms homeostasis. In M. Cholbi & T. Timmerman (Eds.), Exploring the philosophy of death and dying: Classic and contemporary perspectives (pp. 19–27). Routledge. Nipper, B. (2017). Legislating death: A review and proposed refinement of the uniform determination of death act. Houston Journal of Health Law & Policy, 17, 429–462. Olson, E. T. (1997). The human animal: Personal identity without psychology. Oxford University Press. Paulme, D. (1967). Two themes on the origin of death in West Africa. Man, 2(1), 48–61.

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Scarre, G. (2007). Death. Acumen. Schumacher, B., Pothof, J., Vijg, J., et al. (2021). The central role of DNA damage in the ageing process. Nature, 592, 695–703. Williams, B. (1973). The Makropulos case: Reflections on the tedium of immortality. In Problems of the self (pp. 82–100). Cambridge University Press.

PART I

How Do We Die? Proximate Causes of Death and the Rise of Experimental Physiology

CHAPTER 2

How Late-Eighteenth-Century Physiologists Understood the Living World and Their Task

In 1801, Marie François Xavier Bichat published his Physiological Researches on Life and Death (Recherches physiologiques sur la vie et la mort); his General Anatomy was printed the following year. These two volumes are evidence of major advancements in the related fields of anatomy and physiology. To understand Bichat’s physiology, and how it is central to all of his thinking, I will first survey the situation of knowledge about the living world in Bichat’s times, the late eighteenth century. Of the two major fields regarding our knowledge of organisms, anatomy and physiology, anatomy was certainly the more thoroughly formed. Since Vesalius (1514–1564), it had been understood as the description of the human body’s internal muscular, vascular, skeletal, and nervous structures, studied through dissection. In the late 1700s, Sömmerring and Winslow had published two treatises on anatomy, each attesting to a mastery of the discipline.1 Physiology, on the other hand, despite Harvey’s great seventeenth-century discovery of the circulation of blood, seemed (in the eyes of its practitioners) to be in a state of confusion, concerning such areas as its methods, purpose, and its relationship to anatomy. This disarray sometimes implied that compared to anatomy, physiology was often underrated. Some observers even mocked it as a “novel” (roman). As a result, when the Institut de France was founded in 1795 as a learned 1  Sömmerring. De corporis humani fabrica, Halle, 1794. Winslow. Exposition anatomique de la structure du corps humain, Paris, 1777.

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society covering research in all of the sciences, physiology was absent from the curriculum. In general, physiology was not taken seriously unless it was subordinated to anatomy. For example, in 1790, in a Nouveau plan de constitution pour la médecine en France submitted to the Société Royale de médecine, Vicq-d’Azyr wrote: “Anatomy can exist separately from physiology, but physiology cannot exist alone; it must be associated with the study of the human body, without which it will always wander from system to system.” But insofar as the source of anatomical knowledge was the dissection of cadavers, the life sciences seemed to be acquainted with life only in death, challenging the very definition of physiology as the study of life functions, a definition that continuously perpetuated since the times of Galen, even with slight fluctuations in meaning. In the late eighteenth century, Bichat and other French, Scottish, or German physiologists were determined to dispel this confusion, and establish the bases on which physiology could develop the way physics had, since Newton’s Principia mathematica. In this, they concurred with most of the practitioners of life science (Roger, 1963) and chemistry, which massively imported a Newtonian idea of science and methodology in their own fields. Zammito (2018) argues that upon Newtonian experimental philosophy German biology established itself and its own tradition (see also Wolfe, 2014 for the Newtonian analogy). Bichat placed physiology on an equal footing with anatomy, contending that the separation between the two, and the resulting immaturity of physiology, were an error, because “the remains of the dead were the field of the anatomist; the physiologist was left with the phenomena of life, as if the works of one were not connected to the research of the other; as if knowledge of the effect could be separated from knowledge of the agent that had caused it.” On the contrary, he continues, as Albrecht von Haller was the first to see, “the science of functions [physiology] is the goal; the study of the organs [anatomy] is the means [to reach that goal].”2 Nevertheless, the theory whereby Bichat unified anatomy and physiology in a complete science of life can only be understood as a response to a major obstacle to the knowledge of life in the late eighteenth century. For that reason, before studying Bichat’s theory, I shall outline the general contours of the problem, the most obvious symptom of which was the absence of any tradition of systematic research in physiology. 2

 Anatomie descriptive. Discours préliminaire, XXXVIII.

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2.1   Physiology and Mechanism 2.1.1   The Mechanistic Conception Since Descartes and Harvey, advancements in the understanding of the living had been governed by the concept of what came to be known as mechanistic philosophy. The discovery of the circulation of blood3 had instituted the great metaphor of the circulatory system as a machine made up of pumps and of pipes. Cartesian dualism had validated such a metaphor philosophically, by assimilating the functioning of the bodies of animals with that of a machine. As a result, Cartesianism gave rise to a mechanistic physiology. This understanding was sometimes productive, especially for explaining the processes of circulation which are in fact its paradigm. The absence of any vital principle other than these “mechanical laws” was the fundamental position of mechanist philosophy. However, Cartesian mechanist philosophy is complex, originally as well as in the hands of Descartes’ disciples: it’s at a minimum the result of two overlapping theses. The first is put forth by the Discourse on the Method (chap. V). It likens animals to machines, leaving the question of the engineer who might have designed such machines and determined their functions (God, in other words) unanswered. The Treatise on Man (published in 1662) states “These functions (...) follow from the mere arrangement of the machine’s organs every bit as naturally as the movements of a clock or other automaton follow from the arrangement of its counter-weights and wheels. (...) so that it is not necessary to conceive of this machine as having any vegetative or sensitive soul or other principle of movement and life, apart from its blood and its spirits, which are agitated by the heat of the fire burning continuously in its heart—a fire which has the same nature as all the fires that occur in inanimate bodies” (AT XI:201, CSM I: 108). According to the second thesis, mechanism means that the laws of mechanics suffice to explain the performances and formation of the living. In his treatise On the Formation of the Fetus (1664), Descartes explicitly implements this thesis in a theory of what we call epigenesis: the development of the animal from the embryonic phase by gradual additions of new configurations created by the movement of fluids in the fetus. Actually, mechanism as it was philosophically theorized by Descartes but extensively practiced by the “iatromechanist” school that followed 3

 Around 1615; Harvey published De motu cardis in 1628.

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him had reacted against and supplanted a sort of vitalism, namely, an extension of Aristotelianism that was pervasive in the Renaissance, according to which all beings have some sort of soul, are animated, and therefore alive. Roughly said, one can argue that this vitalism was conceptually based on a difficulty found by Aristotle: the soul (psuché), the life principle, is conceptualized as an entelechy (in his De Anima), but all substance (ousia) as such (and not only the living) possesses an entelechy, since it exists by itself and not in relation to something else, as it is the case of the properties, always ascribed to a substance, or the relations, which always presuppose two substances at least.4 As a result, it is easy to infer that every being is endowed with a “soul,” and many speculations until the end of the Renaissance instantiated those conceptions.5 Such a vitalism, according to which nature is alive, was attacked by mechanism. But these two opposing worldviews had one thing in common: neither makes a clear distinction between the living and the nonliving. For the former, all of nature is alive and animated by a soul, or anima, whereas for the latter, none of it is. This antagonism of two major worldviews instantiates the ontological opposition between the classical, Aristotelian natural philosophy, and the “modern,” namely, post-Galilean and Post-Cartesian, understanding of nature. It has been the object of many philosophical attempts to conciliate them—first of all, Leibniz’s rehabilitation of the Aristotelian “substantial form” in the context of a mechanistic and mathematical theory of dynamics (Duchesneau, 1982; Guéroult, 1967). There exist many scholarly debates over the actual sense to be given to Descartes’ account of mechanism, the articulation of his views on epigenesis and the appeal to the analogy with machines in order to study functions (e.g. Des Chene, 2000, Garber, 2001). They exceed the purpose of this book. Whatever the philosophical sense of those claims is, Descartes’ followers in physiology used both the machine analogy and the epigenetist view on development. We are not so much concerned with the latter here, but with the former, namely, the role of machine metaphors in physiology.  As explained by Des Chene (2000), while Aristotle’s De Anima constituted the ground for late medieval and Renaissance thinkers’ approach to the phenomena of life, these authors struggled to make sense of the plurality of “souls” proper to living beings such as animals (a vegetative, a motor, and a perceptive soul) without losing the unity of “soul.” Unity of the soul was a more urgent problem for them, as Christian thinkers, than for the ancient Aristotelians. 5  Banchetti-Robino (2020) shows how Renaissance thinkers see a kind of self-organization in all of nature. (I thank Chris Donohue for this reference.) 4

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It supported what Cunningham calls the “argument of design” (Cunningham, 2003), namely, the assumption that salient biological structures have functions, in the sense of key roles for the preservation and maintenance of life of the organisms, and that the shape of a structure would be indicative of such a role. The appeal to the machine concept, in turn, would save us from the need to understand this role in terms of a will, an intention of the organism ascribing a role to an item. And in turn the claim that all laws through which those roles are fulfilled ultimately are laws of mechanics warrants this exclusion of a will or an intention as explanatory tools. Nevertheless, the dream of a physiology seamlessly derived from physics or mechanics—possibly proper to Descartes’ metaphysics, and ultimately justified by his metaphysical views about the essence of matter (as extension) and the radical difference between thought (hence will, intention, etc.) and matter—was not endorsed in its entirety by Descartes’ followers (for instance, Boerhaave, Le Camus or Willis; La Mettrie was among the most famous ones even though he was not a real Cartesian mechanist). Most of them were doctors, and knew that in practice, material phenomena as they could understand them fall short of providing a full explanation for vital functions. For these thinkers, Cartesian mechanist philosophy—in the form of the two abovementioned theses, often poorly differentiated—would rather stand as a theoretical model or ideal standard. The aporia of mechanist philosophy was revealed in that although it was certainly a convenient way for understanding specific local mechanisms (circulation, digestion, etc.), the animal-machine as a whole eluded comprehension. In fact, during the seventeenth and early eighteenth century, no global scheme of a living being was developed by those scientists, some of them calling themselves “iatromechanists,” while others, conferring to chemistry and not to physics the status of guiding principle, were self-labelled “iatrochemists.” Gradually, the awareness therefore grew that mechanist philosophy failed to supply the structure for a science of life. 2.1.2   Georg-Ernest Stahl’s Vitalism: Opposition to a Mechanist Worldview The emergence of the mechanist worldview after Descartes raised a question that it immediately ignored: if nature as such is not alive, how can the phenomenon we customarily call “life” be defined? “Above all, I was shocked to note that in this physical theory of the human body, life, even from the beginning, was completely omitted. I could see no logical

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definition for it anywhere,”6 claimed Georg-Ernest Stahl, a physician and chemist whose contributions to the theory of the “phlogiston” have been massively influential (Kant still cites it in a laudatory manner in his first Critique), as well as his Theoria Medica Vera (1712), a major book, difficult to read and widely discussed at the time. He became arguably the first to rediscover this neglected post-Cartesian question of the nature of life (Wolfe, 2011), and to answer it in a novel way. Precisely because natural creatures in general have no soul and function according to the laws of movement alone, living things must have a soul that cannot be reduced to physical things. Classical post-Aristotelian vitalism (discussed above) viewed the natural world in terms of life, a vital force that was everywhere, in some form: buried, latent, or manifest. Stahlian vitalism conceptualized the living world in opposition to the “natural world” ruled by the laws of physics. However, for Stahl, the soul or animating force was still a spiritual entity. He theorized this force as a sort of reason (“ratio”) that steered the animal away from danger and towards what was suitable for him, independently from the animal’s awareness (see Huneman, 2008b, chap. 1; Huneman & Rey, 2007). Stahl argued for the concept of an organism, as opposed to a mechanism, characterizing its nature in this way: a set of acts that “are so laboriously born; produce, form, and coordinate themselves, and deploy mutual relationships of convenience, quite certainly in view of a specific purpose (...); and these relationships happen to be in perfect proportional harmony, physically, with the same purpose.”7 Cartesian mechanism attributed all creative power and purpose to God. The living world had no innate direction or force; it simply developed what God had planted. Stahl, on the contrary, located purpose within the living, in the form of an anima or vital force. Stahl thinks as a chemist, and chemists at this time had a major object of concern : the mixtion, or mixt. Existing things in nature are mixtions, produced and decomposed in a proper way. What is alive is made up of a special mixt, because as mixtion it would be expected to dissolve fast, whereas it keeps enduring: “living bodies have a reason of their long duration, very different, that opposes the duration of their mixtion; the latter is indeed prone to quick dissolution, and yet, contrary to its proper mode, it happens that (...) this mixtion has an incomparably longer duration to 6 7

 In “Paraenesis ad aliena a medica doctrina arcendum” (Stahl, 1831), 56.  In “Disquisitio de mechanismi et organismi diversitate”, (Stahl, 1831), 21.

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what fits its material character.” This mixtion, constantly in motion, requires an agent directing the motion: the soul. Such a soul is not a conscious, deliberate agent; Stahl distinguishes what he calls logos, namely, a reason which is the agent of life within animal bodies, from logismon, which is the reason as a conscious faculty of deliberating and knowing, a “ratiocinating” faculty. The former, as reason, provides “efficient administration of the acts of nutrition.” It is efficient in the sense that through “motions of excitation, fermentation, irritation” from within or from outside, it “achieves in a rational but non reflexive way the proper rational motions that oppose the others.” These other motions are the effects of ordinary chemistry, that tends to decompose the body. The soul opposed them through proportioned motions, because it knows the proportions under which deleterious motions alter the mixtion proper to its body, and counteract them. As Stahl writes, “the products (of reason are) shaped, coordinated according to some relations in order to reach a specific aim [survival] (…) and based on relations that correspond to this aim according to physical proportions” (my emphasis). Stahl, in order to account for the way the soul administers the body towards a continued life, against chemical deterioration, articulates notions of purposiveness and of proportionality: “achieve X” means “doing a move Y proportional to a set of moves Y’ assessed by the soul.” The difference between logos and logismon played a strategic role, since, to be conceivable, this activity of the soul has to be unconscious. Soul organizes the mixtion proper to a living body, and Stahl was one of the first writers to use the newly forged term “organism,” therefore equating life, organization, and the fact of having a specific organization underpinned by logos: “it shall suffice to establish the principle that, in the true definition of the word, the only living bodies are organized bodies” (on this term McLaughlin, 2002).8 Stahl’s thinking is often awkwardly worded and difficult to understand, and he failed to convince all of his contemporaries. Yet the question about the source of vital organization was answered by him in terms of a logical soul, and this attracted criticism by many of his contemporaries, starting with Leibniz in a set of long letters later published under the title Negotium Otiosium (translated and presented by François Duchesneau & Justin Smith, 2016). However, the concept of the organism as a body in which each part exists for the sake of the whole and the whole exists for the sake of the 8

 “Demonstratio de mixti et vivi corporia vera diversitate”, Stahl (1831), 121.

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parts, elaborated throughout the eighteenth century for natural history in particular, was, by that century’s end, the preferred concept for describing life outside the mechanist framework. After the 1750s, every theory of life required a concept of organism organization. Lamarck, for example, wrote that life was made of faculties that “result chiefly from acts of organization” (Lamarck, 1809, I, 369); according to Cuvier: “life in general assumes organization in general, and the specific life of each creature assumes the specific organization of the creature” (Cuvier, 1817, 16). Kant synthesized this movement in thought by defining organized beings in the Critique of Judgment: “An organized product of nature is one in which every part is, reciprocally, end and means” (§66) (Huneman, 2006, 2008a, 2008b). In Kant’s thought, this sentence encompasses a subtle appraisal of what it takes to be an organism, and, as such, the object of a scientific enquiry: these beings are such that their parts seem to be contingent from the mere viewpoint of physics, and, therefore, they require that we assume a concept of the whole, as a “principle of cognition” (Erkenntnisgrund) (CJ §64), in accordance with which they are understood. To take one of Cuvier’s examples, a tooth such as a velociraptor’s canine is explained by referring to its belonging to jaws, hence to the head of the dinosaur, hence it should be surrounded by incisors and molars. Those relations of constraining of the parts by a postulated concept of a whole define a kind of purposiveness that constitutes the epistemological regime of life sciences. (See Huneman, 2006, 2007, 2008a, 2008b, forth. for a systematic exposition of this view.) 2.1.3   Physiology and Classical Natural Philosophy It is easier to interpret the forms of opposition to mechanism in physiology when they are placed in the context of the development of post-­ Cartesian philosophy. This background is worth attention, if one considers that Leibniz commenting and refuting Stahl indicates its relevance for metaphysicians interested in carrying over Descartes’ legacy. Metaphysical questions here are about the nature of matter, and the inherent properties that could trigger life in a universe that otherwise would be empty of vital forces of any kind. According to Descartes, the essence of matter consisted in the extended substance (res extensa), as opposed to the other kind of substance existing, namely, mind, whose essence consists in thought, because he contended

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that bodies themselves were devoid of any inner animating force or drive. God was the source of the world’s motion, and He conserved the world by conserving the same amount of motion in it. This conservation was the basis for one of the fundamental laws of physics, the conservation of the quantity of motion. In relation to the living world, Descartes’ and Cartesian mechanist views needed a theological explanation, because if animals were machines, they had to have been built by a supreme engineer, God. The mystery of the teleological account of life, that is, for that which distinguishes the living from the nonliving, centered on God. As soon as mechanistic physiology was separated from theology, it lost some consistency. This is demonstrated a contrario by the predilection of the philosophers of the time (Leibniz, Bonnet, Haller, etc.) for Malebranchian preformationism,9 as opposed to epigenesis, to explain sexual reproduction, since preformationism focuses on God as the source of creative power. Although they approached their opposition to Descartes differently, Spinoza and Leibniz reintroduced a sort of autonomy of natural bodies into the ontology. According to Spinoza, “the actual essence” of any body is its conatus, which he defined as “its perseverance in being” (Ethics, III, 17). In other words, far from being the pure, inert res extensa, or substance, described by Descartes, the essence of the natural body contains the very reason for its motion; no longer is this motion instilled from outside by God. Spinoza does not admit any purpose in nature, even to define the living, the behavior of which is simply the result of the necessary laws of its essence. Nevertheless, the spontaneity conferred on living things by the conatus leads one to think of a sort of universal life flowing through all of nature which mingles—Deus sive natura—with the very life of God. Materialist philosophers of the Enlightenment, above all Diderot, acknowledged this affinity between Spinoza’s thought and a kind of vitalism, in the loose sense of the ascription of some form of life to material beings in general.10 9  Malebranche presented and justified his theory of preformation in Les Entretiens sur la métaphysique, la religion et la mort (1688). Xe Entretien, art. III-V. and XIe Entretien, art. VII-XII. It was highly inspired by Swammerdam seminal microscopy studies; Haller’s views on epigenesis varied throughout his career, see, e.g. Roe (1980). 10  The classical study by Vernière (1954) develops this appropriation of Spinoza’s ontology in a philosophical framework wholly alien to Spinoza himself, namely, an atheist materialism. See Wolfe (2014) for a reappraisal of Vernière’s categories, claiming that Diderot’s “epigenetist spinozism” does not fit into the classically recognized history of the progresses of epigeneticism.

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Notwithstanding the profound differences between Leibniz and Spinoza on the status of God (for one, the immanent cause of all things, producing them by the necessity of His essence; for the other, the free and wise cause voluntarily producing the essences belonging to the world which He judges to be the best), the two thinkers agreed in rejecting the Cartesian inertia of natural beings. Indeed, Leibniz edified a dynamic in which the essence of a material substance is precisely its force, which tends to be outwardly expressed in the absence of any obstacle keeping it from doing so (Duchesneau, 1982; Guéroult, 1967). Before Stahl, Leibniz was the first to apply the term “organism” to living things (See McLaughlin, 2002). To Leibniz, an organism is an infinitely well-organized machine.11 And insofar as any substance—“monad,” in his last writings—is defined by its perception of the world and its appetite, the organism is appetite and therefore desire: it strives towards an end. Finality or purpose, reincorporated into physics by Leibniz because it makes it possible to theorize the fundamental metaphysical principles of nature such as the principle of least action,12 thus becomes internal to organisms as monads. Leibniz opposes Stahl, nevertheless, in that the only difference he sees between living things and artificial ones is a difference of degree (Duchesneau & Smith, 2016; Huneman & Rey, 2007). One is an infinite machine; the other is finite.13 As a result, nature is essentially unified. Stahl, on the contrary, saw living things as being endowed with an unconscious but rational animus, governing them for the purpose of preserving them. They are in essence the opposite of inanimate things, whose laws tend to corrupt the animate. Newton, together with Leibniz and (to a lesser extent) Spinoza, has been the most influential natural philosopher of the late seventeenth century. His concept of gravitational force realized a similar rejection of Cartesian mechanism. Once again, despite serious divergences with Leibniz—evident in Leibniz’s correspondence with Clarke, where Clarke faithfully represents Newton’s views—Newton refused a universe on which motion is imprinted from outside by God. Attraction—that is, a force emanating from each body—is what causes the movement of bodies. 11  On this point, see Bouveresse (1992, chap. Vb); Smith (2011, chapter 3); Nachtomy (2007) argues that this infinite inclusion is not only a spatial inclusion, like in Russian dolls, but also a functional inclusion: x included in y should be also functionally contributing to y. What is infinite is this relation called “nestedness” by Nachtomy. 12  On this point, see Guéroult (1967), and particularly the appendix devoted to the principle of least action in Leibniz and Maupertuis. 13  See Huneman (2014) for an account of Leibniz’s views of organisms as infinitely organized machines.

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In other words, bodies are attracted to each other (objects fall downward, the planets revolve, etc.). Both scientists deeply impacted the metaphysical grounds of the understanding of living bodies after 1700. The writings of Leibniz inspired Hoffmann’s Medicina rationalis systematica (1730), which was an attempt to move away from Stahlian animism while positing the autonomy of the living (Duchesneau, 1982; on the comparison with Stahl see Ceglia (2021)). Then, with Haller, whose gigantic lifework was doubtless decisive for eighteenth-century physiology, the figure of Newtonian method came to the fore: to refrain from making hypotheses about the nature of phenomena or their primary cause, and to express the laws according to which forces act mathematically. Just as Newton observed the fact of gravitation and later gave the mathematical law for it, Haller observed the fact of irritability,14 and experimented with testing the degree of irritability of the parts of an animal’s body. The irritability quotient varied inversely to the degree of sensibility, if “sensibility” is defined as the property of a living thing to feel stimuli through a nervous system in order to transmit them to its anima. Haller rejected Stahl’s animism: he denied that any anima is controlling vital phenomena. Nevertheless, living matter has been endowed by God with irritability, a property accounting for manifestations that set it apart from the order of brute matter. Thus, ultimately, Haller is dualist in the same way as René Descartes, dividing the world into matter, brute, or living (i.e. irritable) and, on the other hand, souls (implanted in living bodies, and marked by their sensibility). But he is mechanist in the Newtonian sense,15 because he experimentally studies the laws and variations of a ­constant property—irritability—which qualifies the subject of his research (living things), without seeking to determine either the cause or meaning of these laws and variations, exactly as Newton said he did about gravity in his Opticks.16 This Newtonian ancestry is a leitmotiv, emerging again and again in eighteenth-century physiology, and even natural history in general. Buffon, who translated Newton’s Method of Fluxions into French, 14  “I call the part of the human body that shrinks when some foreign body touches it with some force the irritable part”. (Dissertation on the Sensible and Irritable Parts of Animals; by M. A. Haller, M. D. President of the Royal Society of Sciences at Gottingen. The Edinburgh review, 1756, Jan., 52–62.). Irritability chiefly characterizes muscles. 15  Roger (1963), Conclusion. 16  Zammito (2018) gives a penetrating demonstration of the Newtonian approach that framed most of posthallerian physiology in Germany. For an account of the Cartesian approach to vital processes and the way it handled the essential issue of nutrition, opening the way to the classical notion of intussusception, see Bognon-Küss (2022).

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outlined plans for a “physics” of living phenomena in his Histoire naturelle. Zammito (2018) proposes a detailed account of the “gestation of the German biology” at the same time, and views the constant reference to Newton as a structuring factor.

2.2   Vitalism 2.2.1   Haller and Bordeu Slightly after Haller’s major treatises were published emerged what has been called the vitalist school of Montpellier. Those scientists were mostly physicians—Montpellier was one of the three “facultés de médecine” at the time, together with Strasbourg and Paris. A first work was L’idée de l’homme au sensible et au moral by Lacaze (1755), but Théophile de Bordeu was the principal inspiration of the vitalist school of Montpellier, having instructed many of the doctors who worked together on the Encyclopédie (including Fouquet and Ménuret de Chambaud).17 Bordeu is also famous to have been cased as a character of Diderot’s philosophical fiction Le rêve de d’Alembert, where he champions materialist vitalism. According to Bordeu, each organ of a living thing is sensitive in its own way. As a result, in his Recherches sur les glandes (1751), he reported the secretion process in terms of discriminatory sensibility to certain elements specific to each of the glands. Accepting some substances, rejecting others, and secreting new substances on the basis of the discriminated substances that have been let in the gland enough to explain the behavior of a gland in its various environmental states and consequently, the behaviors of the organism—at least from the endocrine viewpoint, but this reasoning supposed to concern the whole organism: glands here instantiated what an “organismal part” is supposed to be and how one should account for it. As a result, a living organism was made up of a set of organs, each of which went about “its own life,” as it were, since the distinctive sign of life was sensibility. The essence of vitalism was the theory of a radical autonomy of the living, defined by the presence of an unquestionable property, sensibility. The soul or anima was no longer necessary, because the living body functioned alone, as an arrangement of elementary sensitive creatures—the organs—harmoniously assembled one on top of the other. “Life in 17  On the Montpellier vitalists see Williams (1994), Wolfe and Terada (2008), Zammito 2018 (chap. 3), Huneman (2008a, b).

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general, which is the sum of all of the particular lives, consists in a flux of regular, measured movements (...) In this way, all of the parts are causes, principles, and final causes” (Recherches sur les maladies chroniques, §3). And life, as sensibility and spontaneity, need not obey the physical laws governing the order of inanimate objects; subsequently, vital properties are essentially flexible and variable, unlike physical properties, which are standardized and constant. This plasticity and individuality or idiosyncrasy of life forces is a hallmark of vitalism at this period. Ultimately, Bordeu and the vitalists opposed Haller on a specific point: they contended that sensibility, not irritability, was the single vital property. According to Haller, brute matter was endowed with gravitation; living matter, with irritability; finally, certain animals also featured sensibility, a property that indicated they also possessed a soul that could receive information from a nervous system through the brain. Bordeu, conversely, dispensed with the intervention of the soul to understand animals: sensibility, understood as both the proper sensibility of parts to the environments, and the global sensibility of the organism, is enough to account for the proper vital behavior of a given organism. On the subject of vital properties, the crux of the debate between the schools of Bordeu and Haller therefore concerned the question of the relevance of the notion of the soul for the philosophical understanding and definition of life. It implied issues about the relations between natural science and theology, as well as commitments to either dualism or monism, that will not be discussed in depth here. Suffice to say that the physiological theses about what the essential properties of life are was embedded into a more general debate about ontology (substance dualism vs monism, materialism vs spiritualism). 2.2.2   The “Animal Economy” However, as a “biological” theory based on the claim that organs have a proper basic sensibility, the problem with the vitalism of Bordeu and his followers consisted in understanding the harmony of the organs, theorized as elementary living things. The manifestations of life like reproduction, nutrition, and movement all strive for the preservation of the individual animal, attesting to a coordinated activity apparently aimed at a goal: therefore, some harmony between the organs is necessary, to achieve the goal together. To illustrate this situation, Bordeu and then Pierre-Simon de Maupertuis famously compared it to the image of a swarm of bees, a kind of living

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thing made up of a cluster of smaller living things. Ménuret de Chambaud, the Montpellier physician and prolific Encyclopédie author, summarized this in his entry “Observation”: “A famed doctor (Bordeu) and an illustrious physicist (Maupertuis) have agreed to consider man envisaged from the luminous, philosophical viewpoint of a swarm of bees striving to cling to the branch of a tree. We can observe them crowding together, supporting each other, and forming a sort of whole, in which each living part, in its own way, contributes by the correspondence and direction of its movements to maintaining the sort of life of the whole body, so to speak, of this coordination of actions” (Ménuret, 1765). Nevertheless, the image of the swarm raises an important problem: how and why is the life of the parts related to the life of the organism as a whole? What is the primary meaning of the word “life”? Does it require organization? In that case, the components of the organization are not alive. Is it within the separate life of each part, as it’s properly the case with a bee swarm, which does not exist by itself? If so, how is the organization of an organism possible, and what does it provide? Could it be said to provide “life”—while the organization of a bee swarm does not grant the swarm with “life”? Such questions of the organism could be seen as the primary subject of vitalist investigations, once one takes the notion of “animal economy” as an organizing concept in their physiology. The organism differed from any simple material being by both its order (harmony) and the properties of its components (sensibility), and “animal economy” used to capture this double feature for Montpellier vitalists. Scholars have indeed put much emphasis on this term that is pervasive in vitalist writings of the period. They think that a major systematic presentation of the doctrine is Ménuret’s Encyclopédie entry entitled “Economie animale” (Huneman, 2008b; Williams, 1994; Wolfe & Terada, 2008). Granted, the label was used at the times by physicians of various traditions, starting with the Scottish school (William Hunter, James Monro). But arguably the French vitalists substantiated it in a specific way, using it as a framework to make sense of the problem of the life of parts vs of whole that arose as a consequence of the claim of a “vie propre” of the parts. In the French context, there was a more general scheme of “économie,” used to account for complex systems with many parts at several levels: organism, what we would call now ecosystems, and societies. The latter object required “économie politique,” a concept that involved the proper original sense of “économie”; Rousseau authored the entry in the Encyclopédie. Regarding ecosystems, the Linnaean concept of “natural

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economy” was used to conceive of the roles of various organisms, and more generally various species, in the web of nature, and the way such roles ensure the stability of the ecosystem, may be ensuring in addition benefits for the human species in a providentialist orientation.18 Thus, the point for vitalists is to understand how the phenomena of animal life—growth, nutrition, reproduction, disease—arose on the basis of this economy constituted of sensible parts connected between each other and to a milieu; in other words, by the circulation and exchange of fluids between elements endowed with a sensibility that enabled them to carry out certain actions (secretion, contraction, etc.). Ménuret defined it thus: “The animal economy is the order, the mechanism, the arrangement of forces maintaining life” (ibid.). One of the chief factors in maintaining this harmony was “sympathy,” a notion derived from the Hippocratic medical tradition, and pervasive in many writings in the Enlightenment period, in political theory, nascent political economics or moral reflection.19 Jaucourt (1765) wrote a vitalist entry about it in the Encyclopédie, echoing Ménuret de Chambaud’s articles. “Sympathy” was applied to all phenomena communicating an affinity between distant parts of the body. A vitalist doctor therefore had to trace the paths followed by these sympathies, paths that were sometimes strange, because they were devoid of visible material lines like nerves. As an epistemological result, the animal economy became a matter of observation. By separating the realm of the living from that of mechanical laws, vitalism no longer accepted 18  See Balan (1979) on the relations between animal economy and natural economy; Pearce (2010) on the economy of nature. 19  Hanley (2015) proposes the following interpretation for the pervasiveness of the concept of sympathy across eighteenth-century theorizing, which is quite relevant for our question: “Sympathy’s eighteenth-century explosion (…) is best traced to its unique status as a sophisticated philosophical response to a pressing practical challenge. This practical challenge concerned the disorientation consequent to the seismic shift in the forms of social organization experienced over the course of the eighteenth century. Most simply, the eighteenth century (especially but not only in Britain and France) witnessed a shift from traditional and more intimate forms of community to new forms of social organization; now societies of strangers emerged alongside more traditional and familiar communities of intimates. But what holds a society of strangers together? (…) It is here that sympathy emerged and then flourished, specifically as a new and creative philosophical response to the practical political problem of human connectedness in an increasingly disorienting world. Sympathy, that is, emerged as an other-directed sentiment capable of sustaining the minimal social bonds needed to realize the new social order and indeed one capable of so doing without requiring acceptance of the theistic foundations of Christian conceptions of neighbor love” (173).

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knowledge about the animal that had been obtained by applying the laws of mechanics and chemistry in order to interpret experiments. In a way, the demise of mechanist philosophy accompanied a revived emphasis on observation. “It is too far from the laws of chemistry and mechanics to those of nature,” wrote Bordeu. “Let us apply ourselves to observing” the phenomena of the organism (1751, 16). Falling back on observation is indeed directly correlated with the humbleness implied by relinquishing Newtonian methodology, so widespread in the eighteenth century, as it turned away from the ideal of seizing the remote causes. “It is certain that... the nature of the cause driving animated bodies... is entirely unknown to us,” wrote the physician and philosopher Pierre-Jean Georges Cabanis in Du degré de la certitude de la médecine (1788),20 but that was the case for all primary causes (“man knows the essence of nothing”), and mainly, this knowledge would be useless to us (“the more objects resist our investigations, and remain outside the reach of the [human] mind, the less useful they are to know”): empirical laws derived from the observation of phenomena are therefore sufficient. But the two terms, “observation” and “experiment,” were then quite distinct, and the vitalists made their preference for the former clear, as indicated above, which led to a new quarrel with Haller’s school. Bordeu’s followers, challenging Haller on the subject of observation, escalated the debate about vital properties that was already raging. Haller conducted experiments on animals. He would take a muscle, for example, and subject it to chemical and physical tests aimed at gauging its irritability. Meanwhile, anatomy could be applied to evaluate sensibility, by checking the presence of the nerves in a given organic part.21 But the vitalists thought that such experimentation deformed the animal by operating only on a part of it, and causing damage to it, which altered the normal conditions under which the 20  On Cabanis see Staum (1978); Williams (1994); Vila (1998). Cabanis was not from Montpellier but he was sympathetic to Montpellier vitalism. His major philosophical work, Rapports du physique et du moral de l’homme, echoes, by its title, Lacaze’s major treatise Idée de l’homme au physique et au moral. 21  The foreword to Eléments de la physiologie (Lausanne, 1778) insists on the usefulness of experimentation: “Animal dissection is necessary. But it is not enough to study dead animals: living ones must be opened. An inanimate body cannot move, so all movements must be sought in a living body. All of physiology is concerned with the inner and outer movements of an animated body. Consequently, to investigate the circulation of blood and its subtle movements; respiration; bone growth; intestinal peristalsis, or the transportation of the chyle, one cannot obtain valid results without sacrificing a quantity of animals. Very often, a single experiment invalidated false beliefs that had been elaborated for several years.”

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part studied would have functioned. On the one hand, experimentation could only reach a part of the organism; on the other hand, it created artificial conditions different from those of the natural animal. In fact, centuries later, neurologist Kurt Goldstein argued the same points, to demonstrate that deconstructing the nervous system into elementary reflexes could never reflect the way the whole organism functioned in its natural habitat.22 The discussion on the limits of experimentation in life sciences was somehow launched in its basic form by this controversy between Haller and the vitalists, and one should not wonder that purely biological arguments were accompanied by epistemological considerations, as illustrated by Ménuret in his lengthily Encyclopédie entry “Observation.” Here, he argued that the animal economy was more to be observed than tested by experiments. The vitalists thereby distanced themselves from another investigator of the living world, Antoine Lavoisier, who was their contemporary. His experiments on respiration had shed light on the process of combustion underlying it, and he believed it might take place in the lungs.23 As a result, the reduction of life to the material product of a chemical machine, the direction in which his research seemed to be headed, was firmly denied by the vitalists. Observation alone could respect life as life, and thus grasp the animal economy in its specificity and its totality: Ménuret’s arguments summarized the key epistemological position of these vitalist physicians. Similarly, observation was at the same time promoted as the best practice in medicine, with the advent of clinical medicine, of which Cabanis was one of the key advocates. Prior to this, medicine had been mostly nosological; in other words, it was based on the premise that illnesses were distinct entities, identifiable by certain characteristic signs—symptoms—like animal species, and that they needed to be classified. Each individual would instantiate a morbid species the same way an animal instantiates its species, and medical examination should find out this species on the basis of signs in the same way as naturalists should determine, in the face of an individual organism, and based on its visible physical properties, the species to which it belongs. “Clinical medicine” consisted in considering the patient as an individual (rather than as an exemplar of a disease), and observing the symptoms of the illness dwelling within him, in order to focus on the patient’s history with the illness. Its  Der Aufbau der Organismus (1934) (translated in Goldstein (2000)).  On Lavoisier see Canguilhem (1977); Holmes (1974).

22 23

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nosologies no longer granted a specific identity to the illness, which became a set of afflictions inside the patient’s body, the point being to diagnose the illness from all of the symptoms.24 Epistemic affinities between emerging clinical medicine (on which I will say a word below) and Montpellier-inspired medical vitalism clearly make sense of their contemporaneity, as well as the fact that often the same scientists (Cabanis, Pinel, etc.) were involved in both.

2.3   Bichat’s Dilemma I have sketched the intellectual and theoretical context in which Xavier Bichat studied, and started to practice hospital medicine and work as an anatomist and physiologist, then writing his Recherches physiologiques sur la vie et la mort; I will now reconstitute in the most general and theoretical manner the epistemic problem he inherited, within this theoretical constellation made up of Haller’s legacy, Montpellier vitalism and the emerging clinical medicine. The next chapter will therefore enter into the content of his work. In sum, Haller’s school of physiology conducted experiments, but their subject was the parts of animals, the functions of which anatomy had deduced in advance. The vitalist school, on the contrary, studied physiology through observation of the whole organism. Thus, by 1856, Claude Bernard was able to propose an experimental physiology that was no longer bound to anatomy (and inferences based upon it), penetrating inside the body with experimentation, and establishing the functional regularities which govern the life of an organism as a whole. I will claim that Bichat and, to a lesser extent, François Magendie—his continuator and Claude Bernard’s supervisor at the Collège de France after the turn of the nineteenth century—are the physiologists who made it possible to bridge this gap. To understand Bichat, we shall therefore attempt to measure his contribution to this transformation. Somehow, the status of the experiment in the production of scientific truth changed, so that the organic whole could constitute the subject of experimental knowledge, whereas formerly, the whole referred exclusively to observation, and the parts, to experimentation. 24  On this point, see Foucault (1963); Sournia (1997), who shed light on the role of the eighteenth-century chemist Fourcroy and the physician Tenon; on the role of the hospital in these epistemic changes: Ackerknecht (1967); Gelfand (1980).

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To grasp what was at stake with this transformation, we must first characterize in gross terms the problem the vitalists were grappling with, a problem which Bichat inherited. Mechanistic or even Newtonian physics did not suffice to account for life, because mechanism failed to make a distinction between the living and the nonliving.25 However, vitalism, too, was flawed by an incapacity to elaborate a science of life; in effect, the vitalist definition of life in opposition to material nature, the subject of physics, meant that life was defined by opposition to a mere existence governed by laws. Consequently, admitting no proper laws, life could not be subjected to the type of scientific intelligibility that explained matter and motion. Stahl’s animism explicitly saw physics and chemistry of brute matter, and the vital processes going on within organisms, as antagonistic; vitalists wouldn’t commit to dualism but they also rejected iatromechanism and iatrochemism, and agreed that neither the mechanics of matter nor its chemistry suffices to account for vital phenomena. In fact, most of the Montpellier vitalists were physicians and it was a commonplace of medicine that the variations in the course of the same illness in different individuals make it impossible to set down any laws for illness. And—here goes the vitalist critique—as a consequence, the known robust scientific facts regarding organisms were about the inanimate: the dead bodies dissected by the anatomist. There was in this framework no scientific knowledge of the functions, functioning and development of life, in the sense of the processes through which life is established and maintained in its environment: at best, there was an accumulation of descriptions of the animal economy, some accounts of the pathways of the sympathies, and descriptions of possible behaviors of healthy and diseased organisms. More precisely, these epistemic problems stemmed from physiology’s inability to conceive of how an organism functions, as we saw with the aporias in the theory of Bordeu. Haller and his predecessors had uncovered some partial mechanisms, but as yet, no vision of the animal economy as a whole had come into focus. True, Bordeu had postulated that sensibility was disseminated throughout the organism, in order to explain the difference between organic and inorganic. The theory of sensibility, however, provided no knowledge of the phenomena that constitute the life of the 25  Among much literature about seventeenth-century mechanism and the problem of the nature of life, see Wolfe (2011). Of course I neglect here many subtle discussions of the times, including the debates between Cartesians and Cambridge Platonicians, such as Cudworth.

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organism as a whole. To this extent, the aporia of physiology was the inadequacy of the concept of the animal economy to grasp this relationship to a purpose, this “internal purpose,” in Kant’s sense, recognized as specific to the living. One of Kant’s major claims regarding biology in his Critique of Judgment is actually that, while organisms should be understood using teleological judgments, namely, functional ascriptions, identification of adaptedness, and goal-directed embryogenetic processes, purposiveness in this context is not the “relative” or “external” purposiveness defined by intention of a designer, or utility for something else, but a specific contrivance of all parts for the sake of the organism as a whole. I use this Kantian concept here because it seems useful to characterize what was missing in the vitalist science of animal economy, and, in turn, will allow me to sketch Bichat’s challenge more easily.26 The aporia that I reconstitute here stems from the lack of an epistemic access to the animal economy in its totality. Indeed, observation provides no access to the vital processes themselves, and Haller’s experimentation revealed them but only partially and artificially. Both schools—Hallerian and vitalists—notwithstanding a common sense of the epistemic originality of the living, and a common reference to the Newtonian method of assuming basic and un-investigable essential properties, were blind to the whole system of interorganic relationships which confer purpose and life to an organism. By “purpose” here one means its drive for conservation, stability, and reproduction; Haller’s school couldn’t access it, because his physiology was subordinated to anatomy (which is basically a view of the dead body), and Bordeu’s couldn’t either, because the organs were perceived as small living entities trading and bargaining in an animal economy, like a community of citizens in a political economy, while the overall mechanism was beyond experimental access. Summarizing, there was a sense here, around 1780, that the living creature is a specific genre unto itself, since it is thought of as organized matter, but this specificity still eluded proof and knowability. That was where experimental physiology according to Bichat intervened, and I will argue in Chap. 5 that making death into an object study played a key role in overcoming this epistemic problem. 26  However, Kant’s analyses were not known by those authors; Huneman (2008b, forth.) claims that later on they will be able to make sense of those developments proper to physiology, but this is not relevant here.

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Bichat actually was a vitalist; nevertheless, all of his work tends towards establishing a science of living phenomena, which to some extent assumes that regularities if not laws can be accessed, and hold at all biologically relevant levels of the living system. We shall now see how this came about, in three steps. In the following I shall first state Bichat’s most famous theories, showing their continuity with earlier theories of physiology and medicine; next, I shall grasp the architecture of Bichat’s thinking in his Recherches physiologiques sur la vie et la mort—an architecture which gives a systematic direction to his theories and makes it possible to understand their epistemological value of innovation; and finally I’ll examine Bichat’s immediate impact upon his major followers in physiology, namely François Magendie and Claude Bernard, from the viewpoint of this epistemic architecture investigated just before.

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Lamarck, J. B. (1809). Philosophie zoologique. Dentu. Ménuret de Chambaud, J. J. (1765) Œconomie animale (Médecine). Encyclopédie, XI. Briasson, pp. 360–366. Nachtomy, O. (2007). Leibniz on nested individuals. British Journal for the History of Philosophy, 15(4), 709–728. Pearce, T. (2010). “A great complication of circumstances”—Darwin and the economy of nature. Journal of the History of Biology, 43(3), 493–528. Roe, S. (1980). Matter, life and generation. Eighteenth century embryology and the Haller-Wolff debate. Cambridge University Press. Roger, J. (1963). Les sciences de la vie dans la pensée française au XVIIIème siècle. Colin. Smith, J. (2011). Divine machines: Leibniz and the sciences of life. Princeton University Press. Staum, M. J. (1978). Medical components in Cabanis’s science of man. Studies in History of Biology, 2. Sournia, J. C. (1997). Histoire de la médecine. La Découverte. Stahl, G. E. (1831). Theoria medica vera, physiologiam et pathologiam (1712), L. Choulant (Ed.), Leopold Vossi. Vernière, P. (1954). Spinoza et la pensée française avant la Révolution. Paris: PUF. Vila, A. (1998). Enlightenment and pathology: Sensibility in the literature and medicine of eighteenth-century France. Johns Hopkins University Press. Williams, E. (1994). The physical and the moral: Anthropology, physiology, and philosophical medicine in France, 1750–1850. Cambridge University Press. Wolfe, C. (2011). Why was there no controversy over Life in the Scientific Revolution? In V. Boantza & M. Dascal (Eds.), Controversies in the scientific revolution. John Benjamins. Wolfe, C. (2014). On the role of newtonian analogies in eighteenth-century life science: Vitalism and provisionally inexplicable explicative devices. In Z. Biener & E. Schliesser (Eds.), Newton and empiricism. Oxford University Press. Wolfe, C., & Terada, M. (2008). The animal economy as object and program in Montpellier vitalism. Science in Context, 21(4), 537–579. Zammito, J. (2018). The gestation of German biology. University of Chicago Press.

CHAPTER 3

Bichat’s Theories and Their Genealogy

Bichat is known for threev major achievements in the course of his short life1: 1. In the field of anatomy, an approach that considers the body according to the texture of each anatomical tissue, and the differences in the tissues, instead of considering it according to the geography of the body and proximity. In the domain of medicine, this approach led to the idea of associating each tissue with the type of afflictions specific to it. As a result, any organic disorder refers to the identified lesion of a tissue, a fundamental idea of what came to be known as pathological anatomy. 2. In the field of physiology, the Physiological Researches on Life and Death, published in 1800 offers a definition of life that made history: “Life is the set of functions that resist death” (p. 3), and that I introduced at the beginning of this book. 3. The same work, Physiological Researches, posits a division of functions into “organic life,” in which the animal is centered on itself (respiration, digestion, etc.), and “animal life,” in which the organism relates to its habitat (sensation, locomotion, etc.). This concep-

1  He died at slightly more than thirty years old, probably from an infection he contracted while dissecting corpses, which he did every week at an impressive frequency.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_3

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tion impressed philosophers: it is referred to twice by Hegel, in Philosophy of Nature (Add. §355) and Philosophy of the Spirit (Add. §398), and by Ravaisson in De l’habitude. Comte deemed it “extremely important” to biology,2 and Schopenhauer, especially, used it extensively in supplement XX to The World as Will and Representation. It can be shown, however, that none of these ideas is entirely new in itself. Bichat’s originality lay rather in his ability to apply them to his own work within a novel epistemic architecture, which I will analyze later.

3.1   The Vitalist Definition of Life To begin with, Bichat’s definition of life built on the animism of Stahl, who had already written, “by this word Life, we must understand the conservation of an eminently corruptible body, the faculty or force with whose aid the body is sheltered from the act of corruption.”3 In his Physiological Researches, Bichat endorsed this with a typically vitalist elaboration, expressing his general conception of life: inert bodies are governed by fixed laws, but living bodies are distinguished from them by more variable laws which confer a special evolution or self-preservation upon them, whereas the laws of physics always lead to the decay of inert bodies. By contrast, the living body, exposed to continual degradation by physical forces, must have a “permanent principle of reaction” (Physiological Researches I, art. 1, §1).4 Hence, life is characterized by a principle of resistance to physical forces which tend to destroy it. For Stahl, this principle of reaction against the decaying forces of the environment’s chemistry was the immaterial soul, conceived of as a rational agent that directs the motion of the living matter in a way that computes and anticipates coming changes and counteracts them,5 so that the overall composition of the organism is

2  40e Leçon, p. 686. He adds: “Because, in principle, all acts of organic life are essentially physical and chemical, which could not be true of the acts of animal life, at least with regard to primordial acts, and especially concerning the brain and nervous functions.” 3  Theoria medica vera, Œuvres, III., 43. 4  On the constancy of the reference to the Newtonian principle of action-reaction at these times, see Starobinski (1999). 5  See above about this soul as “logos,” and Duchesneau (1982), Huneman and Rey (2007) for commentaries.

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preserved. But like the Montpellier vitalists, Bichat didn’t commit to Stahl’s dualism, he didn’t assume any soul responsible of the proper chemistry and behavior of an organism. By endorsing Stahl’s definition, Bichat advocated a position that was also shared by Cuvier, in particular, who opened his Anatomie comparée (v. I, p. 3 sq.; Year VIII) with a metaphor likening life to a healthy girl: the astonishing thing about her is that while alive, she weathers all of the weight and aggression of the world, but that as soon as she dies, these forces immediately overwhelm her.6 Importantly, this example shows that Stahl’s legacy, namely, the interpretation of the difference between alive and inert as a conflict between life and death, was shared as a major conceptual leitmotiv in various theoretical contexts freed of animism. Nevertheless, like the other authors of the time (Cabanis, Cuvier, etc.), Bichat does not put forth any theories about the nature of the vital force (“its nature is unknown,” Physiological Researches, I, art. I, §1). He simply observes the duality of the forces based on the incompatibility of the phenomena of “action and reaction” (Physiological Researches, ibid.). Opposing PierreJoseph Barthez,7 Montpellier physician inspired by Bordeu, he refuses to return to a “vital principle” or seek a “single center of all of the acts that convey the character of vitality” (Physiological Researches, I, art. 7, §1), arguing that the “primary causes” are inaccessible to human understanding, and in fact of no use in furthering knowledge: “Without knowing the life principle, can one not analyze the properties of the organs it animates?” (ibid.). Thus, physical forces continually batter life from within and without; in turn, the living thing reacts. There is a “proportion” between the action and reaction, and it varies with age: the living thing’s reaction weakens as time passes. The two types of forces, vital and physical, differ in nature: the vital forces fluctuate, whereas the physical forces, which are invariable, produce phenomena that are “always uniform” (Physiological Researches, I., art. 7, §1). For example, the “physical faculty of attraction” remains constant for a given body, whereas the “vital faculty of sensation” may be variable for the same organ (ibid.). This variability precludes the use of calculus in medicine, by contrast with physics. Epistemologically this means that whereas physicists unveil laws of nature, under the form of

6  On this point, Bichat apparently shared the conception of the Scottish Stahlians Whytt and especially John Hunter. These will be examined in §3.2.3. 7  Nouveaux éléments de la science de l’homme, 1st edition, Montpellier, 1778. On Barthez see Duchesneau 2018.

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what philosophers would now call a set of general counterfactual-­ supporting statements, physiologists can neither access robust counterfactual, such as “if organism A were heated it would do such and such” (this is what we would call the plasticity of the living: organisms’ responses to stimulation are variable (Recherches physiologiques sur la vie et la mort, 42)), nor can they claim general statements such as swans like to eat fish (this is the idiosyncrasy of the living, ibid, 44). As a consequence, when the methods of the other sciences are applied to the living, they reduce its originality: hence, the chemistry of the vital fluids is merely a “chemistry of cadaverous fluids” (ibid.). According to Bichat, this flaw is “the downfall” of the iatrochemists, like Van Helmont, as well as of the iatromechanics. Thus, Bichat, as a vitalist, clearly sees the classical epistemological difficulty of all vitalism: the lack of the vital laws. Nevertheless, refusing to abandon his plan to found a science, he concludes, “The science of organized bodies must be approached entirely differently from the sciences that are applied to the study of inorganic bodies” (ibid., p. 83). As I’ll argue, Bichat’s teachings could be read as a successful effort to work around the difficulty of vitalism without sacrificing the intention to build a self-standing science of the living.

3.2   Devising Divisions As a physician, having worked at the Hotel Dieu, trained by Desault who was one of the leading reformer of this hospital (one of the major hospitals in France, and a leading place for the medicalization of hospitals),8 Bichat wanted something more than just a conjectural medicine like the one taught by Cabanis, equipped with “practical certitudes.”9 The other two advancements (1, 3) mentioned at the beginning of this chapter were fundamental for him to attain his ambition. First of all, in Physiological Researches, he studied “the division of functions.”10 Earlier attempts had

 See Gelfand (1980), chap. 2, on Desault  Du degré de certitude de la médecine, p. 130. 10  Bichat had already written about the subject in an article on the symmetry of the organs of “animal life” for the Bulletin de la Société d’émulation, an organization he founded in 1798 with Pinel, Corvisart, and several other colleagues. Generally speaking, many of Bichat’s most important ideas appeared in the series of articles he wrote for this Society’s journal. Three essays covered questions of surgery as practiced in the tradition of Desault, whose complete writings he edited and prefaced in 1798. Two other articles are about anatomical matters, and were reprinted in his Traité des membranes. The last is the one I just mentioned. 8 9

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been made to classify the functions of the living body: for instance, shortly before Bichat’s time, a treatise by the doctor A. Louis had differentiated between the natural functions (nutrition and reproduction), the vital functions (those of the heart, lungs, and brain; when they cease, life ceases); and animal functions (sensibility and locomotion).11 Simultaneously, Cuvier also developed the subject: “Origin from reproduction, growth through nutrition, the end with a true death, such are the general characteristics common to all organized bodies,”12 while the particular functions (like the faculties “of feeling” and “of moving”), related to particular organs, characterized only one group of living things: animals. Thus, the idea of division was not at all new, and one can trace it back to the Aristotelian tradition in physiology. Bichat sought to establish a definitive system, ending the doctrinal quarrels on this point: he wanted it to be “the only real” one (Physiological Researches, I, art. 1, §1). It is significant that even though he reached nearly the same conclusions as Louis and Cuvier, he did not use the same method to determine the functions. Whereas the others based the classification of functions on the importance of the organs that carry them out (plants can live without digestive systems, etc.), Bichat—and here is the novelty—followed a principle that was more genuinely physiological and less tied to natural history, distinguishing between the functions themselves, rather than the organs, according to the type of relationship they establish. On one side, he placed functions carrying out relationships to the self; on the other side, those that deal with the outer world (a viewpoint that bears some resemblance to the concept of milieu, or habitat, the outlines of which can be found at around the same time by Lamarck).13 According to Bichat’s concepts, there would be one type of “inner” life, characterizing plants: he called this organic life, different from the “outer” life characterizing animals. “It brings everything back to his existence, exists outside itself, it is the inhabitant of the world” (ibid.); this is animal life. Then the functions subdivide easily: those of organic life as “assimilation” (nutrition, digestion, etc.) and “disassimilation” functions (absorption, secretion, etc.), and those of animal life into an “active order” (brain => senses: movement) and a “passive order” (senses => brain:

 La Nature de l’âme, Paris, 1747. The same division into natural, vital, and animal functions appeared in the Encyclopédie, v. 12, art. “Physiologie.” 12  Anatomie complète, Paris, Year VIII, t. 1, p. 10. 13  Lamarck uses the word “circumstances” to designate the habitat. 11

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sensibility) (ibid.). Precisely because he divided the functions into kinds of relation that they are themselves, Bichat could say that he had achieved “the most natural division”14: in other words, he started to establish a scientific discourse, physiology, that was perfectly compatible with its subject, the functions of life (instead of deriving indirectly from organs). From the viewpoint of history of science, this is a new way of conceiving of the traditional distinction between “vital functions” and “animal functions”—here, in terms of distinct logical kinds of relationship, namely, reflexive vs. correlational. Organisms include a sort of inner space through which they can be related to themselves.15 Within each life, one finds some of the “functions” in the sense of “major biological functions”—respiration, digestion, motion, perception. And then, each of these functions is achieved through the “functions of several organs”—the eyes see, the stomach decomposes nutriments (expressed in modern terms), etc. Those are the functions in a second sense, “local functions,” functions that the physiologist first tries to identify (“what’s the function of this organ?”) and then, analyze (“through which mechanism is such function achieved?”, and more precisely for Bichat, “which specific combination of tissues, endowed with their specific properties, is required for this function to be carried on?”; Recherches, I, 46). Functions, in both senses, are the elementary units required to analyze and understand the existence of lives and their essential relations. Thus, the bipartition of lives defines the territory of functional analysis for physiology, which is a science oriented towards functions, while anatomy is oriented towards structures and can therefore be relying on mere observations.

 Anatomie descriptive, Discours préliminaire, p. 47.  This conceptual distinction between organic and animal life has been highly praised by nineteenth-century post-Kantian philosophers. Hegel appreciated it greatly in his lectures on the philosophy of nature and turned it into a dialectical opposition between merely organic life and a life in which the animal “lives outside of its body” (in Bichat’s own terms) (Hegel, Enzyklopädie der philosophischen Wissenschaften, § 355). His opponent Schopenhauer saw it as a massive proof, through empirical science, of his own distinction between representation and will: the organic life is the will, the animal life is representation, and Bichat’s thesis according to which passions originate from the epigastrum, namely, the center of organic life (hence the life related to itself and not to any object), confirms the philosopher’s thesis about the originality of the will (Schopenhauer, World as Will and Representation, Suppl. X). 14 15

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3.3   Properties and Tissues With his theory of tissues, Bichat intended to provide a firm anatomical basis for the science he was instituting, which could settle the debates that were raging (i.e., the quarrel over irritability between Haller and Bordeu’s followers, and beyond that: the debate over the nature of the properties of life), because they were hindering the advancement of the knowledge of life. And exactly as in the case of the partition of vital functions, Bichat shifted the terms of the debate towards a novel approach, namely, the “tissues.” He can be said to have succeeded, because his conception, being widely accepted (at least, in its general outlook), became the cornerstone for studies in the life sciences up to Claude Bernard and the development of cell theory in physiology, in the latter half of the nineteenth century. In retrospect, it is thereby possible to read Bichat as one of the milestones in the development of knowledge about the localization of life. For post-Aristotelian and Galenic science, life dwelled in a soul or principle with a physical location somewhere in the body or brain, which they were determined to pinpoint; then the vitalists scattered it throughout the organs through their notion of a “proper life“; Bichat placed it in the tissues before Schwann, Schleiden, and Virchow narrowed it down to the cell, the ultimate and original element of all life.16 To understand Bichat’s role in this long knowledge-accretion process, it is important to underline the meaning and need for the doctrine of tissues in anatomy. Again here, Bichat’s conception was not entirely new. Earlier, Haller had conducted experiments in an effort to study the properties of different parts of the body (muscles, organs), and thereby differentiate between them. Bichat applied such studies to medicine: if each tissue is affected by illness in its own way, then illnesses could be identified according to the changes they caused in the tissue supporting them. This was the founding

16  On this point, cf. Claude Bernard, Leçons sur les phénomènes communs, p. 56; Canguilhem (1965), chapter entitled “La Théorie cellulaire”; Duchesneau (1982).

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idea of pathological anatomy.17 Pinel (1745–1826), whose lectures Bichat attended, had outlined the guidelines of this science in a book he published in 1797, Nosographie philosophique. He recommended that various types of phlegmasia, or inflammation, be classified according to “the characteristics of the illnesses of the organs,” whereas his entire project still belonged to the field of nosological, rather than clinical, medicine.18 In turn, Bichat’s work rather consisted of articulating a coherent framework incorporating ideas from the early pathologists, Pinel and Smyth, along with those of the physiologist Haller. The ontology of the living he established became the basis for his study of anatomy, and therefore for all of his scientific research, which we must retrace here. In his Traité des membranes, he already points out that the difference between two distant membranes is “in the form of their organization, rather than its basis” (p. 29). This implied that the organs should be classified according to their specific characteristics, instead of their surroundings and where they were located in the body. Two membranes belong together in the same class if they are observed to be identical in “outer appearance, structure, properties, and functions” (p. 30), a rule that enabled Bichat to respect the variety of membranes (whereas Haller, who also sought to study tissues, mixed them up in a single category he called “modification of the cellular organ” (p.  29)). Bichat then made a distinction between three types of tissues made up of single membranes: mucous, serous, or fibrous, and analyzed them each in turn, in his treatise. One of the innovations in the Traité is

17  Nevertheless, the most distant ancestor of this idea, barely mentioned by Pinel, was rediscovered by Othmar Keel (1979). It is contained in a book published by the Scotsman Smyth, entitled Of the Different Kinds or Species of Inflammation, and of the Causes to which These Differences May Be Ascribed (London, 1788). By inspecting cadavers—rather than by clinical examination of patients—Smyth was inspired to classify inflammations according to the structure of the membranes they affected. He viewed inflammation as a single pathological process that took on a variety of forms, depending on the tissue. Therefore, before Pinel, Bichat, and clinical medicine, the genealogy of pathological anatomy must be traced back to the faculty of medicine in Edinburgh, where Smyth taught. The key figures associated with this school were William Cullen, the brothers William and John Hunter (the latter name will come up again), and the three surgeons named Monro. But William Hunter was the first to point out that illness might be lodged in the tissue, and not in the organ (Medical Observations, 1764). The concept of analyzing disease in terms of damage to elementary tissue therefore originated with this Scottish medical school, and the Scottish Enlightenment philosophers who inspired it, Smith and Hume in particular. 18  See Foucault (1963) on the ambiguities of Pinel’s views.

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the classification of synovial membranes19 in the serous group, whereas they had previously been considered separately (III, §3). Bichat’s later works would extend this concept of tissue, developed in the study of membranes, to the whole body. Animal organization consisted of a small group of simple tissues, shared by all, “organized elements of the living economy” (Anatomie descriptive (hereafter AD), “Discours préliminaire”, p.  41). Combined in different ways, these tissues formed organs, because the unity of the various tissues made the organs “competent to fulfill” a function (ibid., 42). The whole of each simple tissue in a body is a system (the skeletal system, etc.), and the combination of elements of several systems makes up an organ. The combination of several organs working together on a function is an apparatus (digestive apparatus, etc.) (ibid.). Here, Bichat establishes the idea that there could be a ladder of organization (tissues, systems, organs, apparatus), in which the lowest rung would be fundamental and invisible, whereas the highest is the one where visible vital events occur. This conception would turn out to be essential to the life sciences, and it is echoed in the highly positivist Dictionnaire de médecine (1873) by Littré and Robin, undeniably quite distant from the vitalism of Bichat: the entry for “Organ” includes a definition of the “organized character” making it possible to distinguish seven levels of organization, starting with molecules of living matter “made up of native substances,” which constitute cells; then tissues; then systems: those “of general use” which have their own “general structure”; then organs; then the various types of apparatus; and lastly the organism itself as a whole. Essentially, each level of organization is comprised of a combination of various organized elements from the level below it, but due to the new arrangement, it possesses properties of its own and a “use” that goes beyond that of the preceding levels. Bichat listed 21 basic tissues which were cell tissue (the word “cell” had not yet acquired the meaning it later took on in cell theory); arteries, veins, exhaling vessels; the lymphatic, skeletal, and nervous vessels of animal life; the nerves of organic life; the fibrous, fibro-cartilaginous, and muscle tissues of animal life; the muscles of organic life; the mucous, serous, and synovial tissues; the glands, dermis, epidermis, and hairs. These tissues are “the subject of general anatomy; their various combinations being the subject of descriptive anatomy” (AD, “Discours préliminaire” 41, my

19  Membrane lining the inside of the cavities of movable joints and secreting a fluid (synovia) that lubricates the joint.

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emphasis). The sentence clearly specifies the meaning of Bichat’s two works of anatomy. However, general anatomy is an abstraction, he noted, because “no tissue exists in isolation.” Only descriptive anatomy “examines organs the way nature presents them to us” (ibid., 43). In a way, general anatomy is the introductory science, because it outlines the first units that are the building blocks of life. Bichat compared it to chemistry, studying simple elements, in reference to research Lavoisier had recently undertaken to establish chemistry as the analysis of simple, homogeneous bodies. However, the man of science to whom Bichat classically refers in §2 of Anatomie Générale is once again Isaac Newton. Physics and physiology, he says, are both sciences of phenomena, whereas anatomy and zoology are sciences of forms, similar to mineralogy. But clearly, our approach to the realm of the living had not yet attained the status of a science of phenomena; anatomy and natural history, the two existing disciplines most apt to provide knowledge about the living world, classify living forms but fail to explain the phenomena. While physics thanks to Newtonian dynamics realized a science that explains the phenomena, physiology is expected to provide the explanation for what anatomy and natural history describe, but is still not capable of doing it. Just as it is in Buffon, as well as in many physiologists of the eighteenth century in France and Germany (see Zammito, 2018 for a detailed analysis) the reference to Newton is therefore a requirement to go beyond these two classificatory and descriptive disciplines, to institute a type of knowledge that demonstrates what life is, how it works, so to say. For Bichat and his physiologists contemporaries, life, rather than being a form, is a function—an “animal economy”—and the point is to find a gateway to explaining this functioning.20 Correctly understood, the renovation of anatomy as “general anatomy” is a step in the right direction. 20  One often distinguishes two traditions in the science of life, one which focuses on functions, and one which focuses on forms. Actually, both are intuitively proper to living things: traits and organs have functions, living forms is maintained through time, while matter changes, at both the individual and species level, whereas physical systems merely change form. Russell (1916) proposed a history of biology articulated by this distinction; form biology and function biology were both present in Aristotle’s thought (represented by his natural history on the one hand, and his treatises on generation, on locomotion, etc. on the other hand); in the nineteenth century, Cuvier exemplified functional biology (with his “Principle of the conditions of existence”) while Geoffroy Sant Hilaire instantiated “formal biology” (through his “principle of connections”), and thus their long debate at Paris Museum d’Histoire Naturelle in 1830 was the epitome of the conflict between those two traditions (see on these principles Huneman, 2008a, ch 8; forth.). Notice that function and form biology only partially recover the two disciplines of physiology and anatomy, since Cuvier was mostly a comparative anatomist.

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Indeed, the properties that are the basis for the phenomena are the key for this approach, and they are ascribed to tissues. Just as with physics and chemistry, says Bichat, the “axiom” of physiology is “the relationship of the properties as causes with the phenomena as effects” (AG, preface, p. 36). The various sciences are similar in structure, but their content will differ: although each science has cardinal properties, those of one are not transferable to another. Mechanist philosophy had made an error when it imported gravity and impulse to physiology (AG, preface, p. 36). Therefore, Bichat insists that physiology cannot be reduced to physics, and this reason is more fundamental than the seeming lack of constant regularities in physiology, it is rather the fact of these cardinal properties involved at the grounds of the nonconstant regularities witnessed by physiologists and physicians; better yet, if physiology is sometimes forced to borrow certain laws and terms from the other science, it is due merely to historical circumstance: physics was developed prior to physiology. The latter may share some terms with physics, but in essence, it is a different science; and Bichat goes on to imagine what would have happened if physiology had been structured before physics: “I am convinced that the first would have been abundantly applied to the second: the flow of rivers would have been attributed to the tonic pumping of their banks; clusters of crystals would form due to the excitation they exert on each other’s sensibility; planets would travel great distances because of mutual irritation, etc.” (PR, I. art. 7, §1, p. 83). For the physiologist, once the specific properties of each tissue are known, it is in principle possible to analyze the way tissues combine in order to produce an organ, or in other words, a body with a given, determined effect. Thus, tissue theory makes it possible to represent how the organization of the body can produce organic life.21 But to achieve this, the debate over vital properties—that we saw raging between Haller and the vitalists—had to be resolved once and for all. To begin with, the properties of the tissues are due to the “arrangement” of the molecules (Anatomie Générale (hereafter AG), “Préface”,

21  Anatomie générale (Discours préliminaire), p. 102: “The single condition for the enjoyment of organic life is organization.”

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p. 81).22 Bichat’s vitalism is therefore quite far from animism and it also differs from classical vitalism invoking a vital principle (Barthez, for example) without specifying any emergence basis. What are these fundamental properties of life? “Sensibility and contractility: these are the vital properties” (AG, “Préface”, p. 36). The physiological division of functions then makes it possible to methodically distinguish the properties. There is an animal sensibility (in relation with the brain via the nerves) and organic sensibility (which remains confined to the organ, so that the soul is not aware of it); likewise, there is an animal contractility (seated in the voluntary muscles) and an organic contractility (which “has its principle in the organ that moves”). Each tissue possesses these properties to a certain degree. Each organ therefore has an initial amount of predetermined or potential sensibility, around which its actual sensibility continually oscillates (PR, I, art. 7, §4). This predetermined sensibility governs its relationship with the other organs: if the difference is too great, the relationship will not occur, even if the two organs are physically close to each other, in the body. This is because only two organs of similar sensibilities can affect each other. Therefore, in addition to the predetermined amount of sensibility, there is a corresponding rapport with special organs. This is how Bichat explains the selectivity of the organs of passage (larynx, membranes, lymphatic vessels) (ibid.). Vital properties account for the possibilities of exchange and circulation that constitute the “animal economy.”

 My point here consists only in emphasizing that in Bichat’s writings—as well as in his contemporaries’ treatises such as Lamarck’s works—several meanings of “organization” coexist. Bichat speaks of the organization of a tissue as an “arrangement,” not a specific organic quality: therefore, in his writing, the term “organization” has two meanings. It may refer to the organism itself (1), or the organ or the tissue (2). In each case, specific properties emerge from the organization. Interestingly, while “organized” originally indicates a partition into organs, hence into parts that have a role in a system, this new meaning (2) does not assume any roles; it’s just a specific patterns of combination. The shifting meanings of “organization,” and especially the possibility of meaning or not meaning any functional assumptions, had many effects in the debates about reductionism regarding life in the nineteenth and twentieth centuries. The reductionist stance indeed claims that organization (of an organism, thus assuming functions of parts) relies on physicochemical properties of parts, but then an antireductionist can claim that those parts themselves are organized and their organization (assuming no functional meaning) produces emergent properties, so that those properties can’t be reduced to physicochemistry. 22

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Bichat underscores the continuity between animal and organic sensibilities, since, for example, the specificity of an inflammation is to transform the organic sensibility of an organ into an animal sensibility (the subject then feels the painful limb) (ibid. §3). He therefore refines the definition of the overly vague concept of irritability, which he reduces to an organic contractility (thereby making it a notion composed of two terms). Likewise, although his concept of sensibility evacuates any reference to a soul, Bichat avoids making sensibility itself the principle of life, the way Bordeu and his followers had done. One should yet be reminded that an effort to classify vital properties is not a new idea. On the contrary, it had rather been part of the “research program,” as Lakatos would have said, of the late eighteenth-century scientists in their aspiration to a physiology of life. Hence, Barthez in his Nouveaux éléments de la science de l’homme (2nde éd. 1806), Chaussier in his Table synoptique des propriétés charactéristiques et des principaux phénomènes de la force vitale (1800–01), Dumas in his Principes de physiologie (1801), and Richerand in his Nouveaux éléments de physiologie (1801)—all of them find out two “major vital properties” and name them. The first one is the “sensibility” (Richerand, Chaussier) or “sensitive force” (Barthez, Dumas), the second one is “contractility” (Richerand), “contractile force” (Dumas), “motility” (Chaussier), “motor force” (Barthez). These authors split each of their properties, according to whether they are perceptible (sensible) or imperceptible. Bichat thus substitutes his physiological criterion of the lives for that of the difference between perceptible and imperceptible, which founded several classifications in use. Thus, the originality of Bichat’s approach lay not so much in his terminology as, physiologically, in the new principle of distinction (animal life, organic life) he stated. Although in practice, the distinction often covered the same areas as the perceptible/imperceptible division of earlier physiologists, in Bichat’s case it referred to a physiological difference, which adds on an anatomical difference that now located these properties at the level of the tissues. Anatomy and physiology are de facto inseparable by Bichat, as he intended. The field of medicine results from this unity, since the study of a tissue makes it possible to understand its disorders. Demonstrably, “all physiological phenomena are in the last instance related to these (vital) properties considered in their natural state, all pathological phenomena derive from their increase, decrease, or alteration” (AG, preface, 37, n.s.).

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Bichat thereby condemns purely empirical medicine (“devoid of general systems”), since each disease being truly the alteration of a property, “each disease has its appropriate remedy” (ibid., 46). Bichat’s intention to lay the foundation of a new science consists therefore in a search for two elementary principles: irreducible, simple tissues and ultimate vital properties. Their determination implied that anatomical and physiological considerations were combined. This combination guaranteed both the methodical nature of the science of life, and its independence from the inorganic sciences.23 To a greater degree even than Bordeu, Bichat decentralized the living: life, as a property and vital force, belongs to each tissue: the problem is “to establish the distinctive characteristics for the various tissues, to show that each has its own specific organization just as it has its own life, to prove that (this) division (of tissues) is based not on abstractions, but on differences in intimate structure” (AG, p. 14). Here, the notion of a “life specific to the organs” according to Bordeu is transferred to the elementary level of the tissue, and the imprecise idea of the “harmony” of the organs invoked by Bordeu is therefore avoided, thanks to the fact that the organs are referred back to their histological bases. The drivers of the “animal economy” become clearer and more intelligible (particularly the notion of “sympathy”). The bee swarm metaphor becomes now irrelevant: moving from the level of the organs to that of the tissues totally eliminated the conception according to which an animal is made up of elementary animals—which led to insurmountable aporias, and blocked the understanding of what an organism actually is. Yet this is not enough to supersede the antinomy between acknowledgment of vital specificity and scientific insight into the functioning of life that I explicated in the previous chapter. The genuine resolution will involve the phenomena of death and will wait for the next chapter, where the problem of (how does) death (happen) and the problem of grounding a science of life appear intertwined.

23  The reasons why Auguste Comte famously attributed the status of founder of a positive discipline to Bichat, in his “41ème Leçon” of the Cours de philosophie positive, lies in this fact that Bichat laid these foundations on simple elements (tissues) demonstrable by experiment. Comte acknowledges Bichat’s merit in having been the first to separate physiology from physics by guaranteeing it a certain scientific method, even if he rejects Bichat’s vitalism. Tissue theory is one of the two principles of Comte’s positive biology (along with the principle of the hierarchy of organisms, 41èmeleçon, p. 752).

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3.4   Bichat’s Anatomical Method The Traité des membranes provides a plan for the study of each membrane according to several criteria making it possible to determine that two tissues are identical: first, the outer appearance and form; then the texture and inner structure (here, we are at the level of anatomical observations). Next, its vital properties are tested by experiments, and the degrees of “tonicity,” “irritability,” and “sensibility” are measured. Then, one considers the function (namely, assessing the degree of vital strength possessed by the membrane, since life is spread throughout all parts of the body) and the “sympathies” characterizing the membrane (here, the question is to determine the membrane’s relationship to the “animal oeconomy” as a whole). Finally, pathological affections proper to this membrane are examined. The structure of the Anatomie générale, which generalizes to all tissues what the first treatise has set up, is analogous to this method24: each system is viewed in terms of its “organization” (internal and external); its “properties”; and sometimes (for the muscular system, for example), the “phenomena of its action”; then (which is new) its “development.” Bichat gives general indications of the means for this study: “Experiments on living animals, tests with various reagents on organized tissues; dissection; dissection of cadavers; the observation of a man in good health and a man who is ill” (AG, “Préface”, p. 1). The variety of means is notable, as well as the application of chemistry, and especially the unity of observation and intervention. Concerning chemistry, Bichat writes, “The various reagents I used served only, for me, to supplement the insufficiencies of the scalpel” (AG, p. 2). Yet, at the time, Lavoisier’s work on respiration and transpiration had recently made chemistry a possible model science for physiology, to the point that, for some, it practically occupied the role that mechanics had played in the eighteenth century. Bichat points this out in the draft of a 1798 lecture entitled Discours sur l’étude de la physiologie, aiming in fact to set up vitalist limitations on chemistry’s annexationism. Several physicians had become chemists in order to continue their research on the parts of the human body: Chaptal, Berthollet, and Fourcroy, for example.

24  “The plan consists of isolating the basic systems and their attributes and considering each one separately, as well as considering all of the various combinations whereby they form our organs” (AG, pref. 1).

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The affinities between Bichat’s reform of anatomy ultimately have to be situated within a general scientific research program, pervading various ontological domains, namely, the search for elementary elements, on the basis of the combination of which various phenomena of a given reality is constituted. It was exemplarily Lavoisier’s program of unraveling the corps purs (basic chemical elements, such as oxygen, carbon, helium, etc., in contrast with molecular compounds) that underlie chemical reactions such as combustion. A philosophical account of this program, quite influential among French scientists, was called l’Idéologie, and developed theoretical core views from eighteenth-­century sensualism and empiricism, mostly elaborated by Etienne Bonnot de Condillac (see Box 3.1).

Box 3.1  Condillac, Bichat, Pinel, and the Idéologie

In a 1946 essay, Charles Rosen linked the conceptualization of pathological anatomy by Pinel and Bichat to the philosophy of Condillac and the Idéologues (Rosen, 1946). It is clear that the analysis approach is specific to Condillac, consisting in going back to the ultimate observable properties without seeking to know the cause, and in accounting for the fact on the basis of such an arrangement of properties—this method distantly derived from Locke and Newton— inspired most of Bichat’s contemporaries in the field of physiology and natural history, as it constituted also Lavoisier’s ideal. Cabanis, for example, who played a major role in hospital reform and also in the appearance of clinical medicine, was one of the Idéologues (Staum, 1978). These philosophers claimed to be the heirs to Condillac; many of them also knew Philippe Pinel. The idea of classifying diseases according to the way they affected elementary tissues therefore seems to be related to Condillac’s legacy, even though, historically, Pinel had in fact borrowed it from Smyth.25 The very titles of his books indicate his closeness to the theoretical ideal of decomposition-analysis represented by Ideology: Médecine clinique rendue plus précise et plus efficace par l’application de l’analyse (continued)

25  As shown by Keel, see above—but one could always say that Pinel’s familiarity with the Ideologues was precisely what made him receptive to Smyth’s approach.

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Box 3.1  (continued)

(Paris, 1802) and Nosographie philosophique ou la méthode de l’analyse appliquée à la médecine (Paris, 1st edition, 1797). But perhaps the movement of ideas is easier to grasp if one takes heed of the way certain dates of publication coincide: In October 1800, just before the publication of Bichat’s Recherches physiologiques sur la vie et la mort, Pinel’s Traité médico-philosophique sur l’aliénation mentale et la manie appeared. This work is generally agreed to have opened the era of psychiatry, even though Foucault argued in Histoire de la folie that its condition of possibility occurred much earlier.26 In this Traité, Pinel aimed at classification, as he had in Nosographie philosophique, categorizing the elementary forms of mental “alienation.” He distinguished various types of insanity to be identified, based on how they affected the patient’s life—ranging, for example, from mania without delusions to idiocy, or from melancholia to dementia. The doctor had especially to know how to recognize insanity even in the absence of any signs, as illustrated by the case of intermittent mania.27 The type of madness is supposed to be reconstituted purely on the basis of the composition of signs, just as with Bichat, the tissues must be distinguished and separated from the way they appear to be mingled in apparatus and organs, according to a method similar to the Condillacian requirement for the analysis of representations as simple elements. Similarly, moreover, while Bichat decentralized life, one of the results of Pinel’s book resides in a delocalization of madness. Insanity does not affect all of the madman’s mind. Depending on the type of (continued)

26  On Pinel, alienism, nosology and their role in institutionalizing psychiatric medicine, see Huneman (2008a, 2014b, 2017). 27  On the Traité médico-philosophique and on the role of intermittent mania, as well as on the problem of classifying the types of “aliénation,” with the question of the omission of the chart showing the types of mental illness in the 1808 reprinting of Pinel’s Nosographie, see G. Swain. Psychiatry as a medical discipline.

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Box 3.1  (continued)

madness, different faculties are harmed: cognition, or memory, or will, or something else. Certain functions, like attention (Pinel, Treatise §8, p. 22), may even be “exalted” in mania. The essence of madness is in the alienation or dissociation from the self, induced in the soul. As Gladys Swain amply demonstrated, the principle of science, like the principle of the treatment of madness, is that madness is never total. However, that implies the impossibility of believing in a single principle of reason, which could then be physically located somewhere: in the brain, for example. “Can this whole set of facts be reconciled with the opinion that reason is a single principle, or resides somewhere? Then what would become of the thousands of volumes on metaphysics?” writes Pinel (ibid., p. 25). A major philosophical conclusion here is that the types of transformation affecting life, by Bichat, and the mind, by Pinel, were analogous. In the broadest way, it could be described as the application of the same principles in the approach to both the negative and the positive. With Bichat, the outlines of unity between physiology and pathology were emerging, since the science of tissues is the basis for the knowledge of both normal physiology and that of diseases, as specific anomalies in each of the tissues. With Pinel, the moral treatment of the insane was based on the observation that a “healthy” part of reason coexisted with the part that was ill. Instead of being the opposite of reason, madness could more accurately be viewed as a partial alteration of it. Likewise, for the anatomo-pathologist, diseases were no longer autonomous entities, but alterations of the normal properties of the tissues, Broussais being, two decades later, the physician who would clearly formulate this doctrine of the unity between pathology and physiology.28 On the one hand, the insane were recognized as belonging to humanity and rationality, albeit in a troubled way; on the other, disease was reintegrated into the sphere of vital activity. Beyond the reference to Condillac’s method of analysis and decomposition, and the Ideologue school, shared by Bichat and Pinel, the Recherches… by the former and the Treatise… by the latter are aligned in that they both incorporate the negative in the space of knowledge.

28  See Foucault (1963) on the role of Broussais in the establishment of anatomo-clinical medicine.

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3.5   Bichat’s Difficulties Nevertheless, none of this indicates how, in his endeavor to constitute a science of physiology, Bichat overcame the difficulty presented by his definition of vitalism in terms of the inherent variability of vital forces. Moreover, although it is true that his books in which anatomy dominates (even though anatomy is not separated from physiology) renew the science of anatomy and provide a new foundation for physiology, a major problem remains: each tissue and each organ are studied in themselves, but how does the totality of life function? True, anatomical classifications are essentially “imperfect” in the animal economy (AD, “Discours,” 50; the same organ may indeed fulfill several functions). The classifications are merely “guides.” True, the goal is physiology: but precisely, if “each order [of functions] is connected to the others in a more or less rigorous way” (AG, 115, my emphasis), if “although the functions are studied separately, their connection to each other must always be considered” in physiology (ibid.), then, how does one go from fundamental histology to a comprehensive vision of the whole of connected functions; that is, the animal economy as such? Is such a vision scientifically possible, considering the “more or less” that characterizes life function, the roles played—according to Bichat and the vitalists around him—by plasticity and idiosyncrasy in any vital phenomenon? Granted, the concept of a sensibility that would selectively govern the relationships between one tissue and the others did open a path towards an answer. But because this sensibility is a vital property, it also varies unpredictably: impossible for a science to be constituted on such unstable ground. We shall now analyze Bichat’s treatise on pure physiology, Recherches sur la vie et la mort, in order to explore how Bichat managed the jump from histology to physiology, how he dissipated what someone could roughly name the “epistemological obstacle” of vitalism. The following questions will guide us: Why does Bichat examine death? How do the various methods of investigation cited above intersect in these Recherches? And, ultimately, how does physiology intersect with anatomy? But the general project of the Recherches, and what he calls the “Recherches sur la vie,” which precede the “Recherches sur la mort,” has to be analyzed first. Later on we’ll see how the question “how is death possible and occurring?” stands at the center of the epistemic structure which made possible to overcome those epistemic problems.

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References Canguilhem, G. (1965). La connaissance de la vie. Vrin. Duchesneau, F. (1982). La Physiologie des Lumières. Empirisme, modèles et théories. Martinus Nijhoff. Duchesneau, F. (2018). Organisme et corps organique de Leibniz à Kant. Vrin. Foucault, M. (1963). Naissance de la clinique. Puf. Gelfand, T. (1980). Professionalizing modem medicine. Paris surgeons and medical science and institutions in the 18th century. Greenwood Press. Huneman, P. (2008a). Montpellier Vitalism and the emergence of Alienism in France (1750–1800): The case of the passions. Science in Context, 21(4), 615–647. Huneman, P. (2008b). Métaphysique et biologie. Kant et la constitution du concept d’organisme. Kimé. Huneman, P. (2014b). Writing the case – Pinel, psychiatrist. The Republics of Letters, 3(2). http://arcade.stanford.edu/rofl/writing-case-pinel-psychiatrist-0 Huneman, P. (2017). From a religious view of madness to religious mania: The Encyclopédie, Pinel, Esquirol. History of Psychiatry, 28(2), 147–165. Huneman, P., & Rey, A. L. (2007). Stahl, Leibniz et la controverse du Negotium otiosum. Bulletin de la Société d’Histoire et d’Epistémologie des Sciences de la Vie, 6, 214–238. Rosen, C. (1946). The philosophy of Ideology and the emergence of modern medicine in France. Bulletin of the History of Medicine, 20, 36–50. Russell, E. S. (1916). Form and function. A contribution to the history of animal morphology. John Murray. Starobinski, Jean. (1999). Action et réaction: Les aventures d’un couple. Seuil. Staum, M. J. (1978). Medical components in Cabanis’s science of man. Studies in History of Biology, 2. Zammito, J. (2018). The gestation of German biology. University of Chicago Press.

CHAPTER 4

Physiology in Bichat’s Physiological Researches on Life and Death

In the Discours sur l’étude de la physiologie, Bichat makes a distinction between two types of sciences to be applied: a “science of reasoning” and a “science of observation.” Lesch (1984) saw the first part of the Researches, where Bichat presented the theories of the division of functions and of the vital properties and forces, as the “reasoning part” of physiology. He called the second part, describing the many experiments on the heart, lungs, and brain, which were such an inspiration to Magendie and later Claude Bernard, Bichat’s “physiology of observation.”1 The remark is an accurate one, but we must nevertheless examine the relationship between these two physiologies, and raise the question of whether the latter, more adequately called “experimental physiology,” (as it will appear later on) is an investigation of death.

4.1   The First Part: “Researches on Life” 4.1.1   The Particularities of the Animal and Organic Lives Part I of the Researches is an investigation “of life.” Bichat starts from the principle of the division into animal and organic life, and follows its consequences. In the first place, he notes the symmetry of the organs of animal life, by contrast with those of organic life. This implies that animal 1

 Lesch (1984, chap. 3).

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life withstands problems and compensates for them, unlike organic life, which forms a “single system” (art. 2, §2). This symmetry is important, because “harmony is to the functions of the organs what symmetry is to their arrangement” (p.  22). The proper function of an organ of animal life—the eyes, for example—does require “the harmony” of two symmetrical organs. In the second place, organic life tolerates the irregularity in the arrangement of its organs, and this, too, contrasts with animal life (ibid., §4). For instance, variation in the shapes of heart, lungs, and brain, which pertain to organic life, is much more frequent than variation in eyes or hands, which exclusively pertain to animal life; moreover, the shape of a given internal organ will be much more irregular than the shape of the external organs such as mouth, limb, etc. Therefore, in the depth of the living thing, the vital irregularity characteristic of vitalism is already in evidence. But the difference between animal and organic life continues, when time is factored into the comparison between the two: there is a “periodic intermittence of external functions, and uninterrupted continuity of internal functions,” since in organic life, “each function is immediately dependent upon the ones that precede it” (ibid.), the circulation of the blood being “the center of them all.” Conversely, towards the exterior, it would seem that it is impossible for animal life to be maintained in constant activity; that is, in a constant struggle with the outside world; instead, it constantly needs to regenerate itself. Term by term, animal and organic life seem thereby to be opposites. The first is external, and possesses a visible harmony: symmetry. The second is hidden within; its appearance is irregular; and its harmony is also hidden, in a way, because it results not from any visible appearance, but from its function, which will require experiments to be determined. This polarity enables Bichat to structure the network of oppositions, similarities, and conceptual differences that makes up the first part of the Researches, and which we shall study in further detail later. Let us already note the antithesis between surface and depth, which proved to be fundamental to this emerging biology. At the same period Cuvier, in particular, opposed the organs carrying out vital functions, always located inside the living thing, to the organs which carry out functions that are not absolutely necessary for survival (movement, sense of touch, etc.), found on the surface. Indeed, it is true that compared to the others, vital organs need extra protection from contact with the outside surroundings, and this adaptationist approach explains for him the

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difference in locations of lungs or brain vs hands and feet, or even of arteries vs. veins.2 For organic life, continuity signifies a circle of dependency, in which all of the functions depend upon each other. Nevertheless, at this level of analysis, and in this physiology of reasoning, based on observation rather than experimentation, the principle for this dependency cannot be known. The center of animal life is the brain, because all of the sensitive nerves— those that operate in relationship to the outer world—lead to the brain. However, by contrast with the nervous system of animal life, the nervous system of organic life has no center, because it is generated by ganglia. The nerves of the life of each organ are indeed controlled by the closest ganglion.3 Again, we find the decentralization to which Bichat’s general anatomy subjected vitalism, by denying that the vital principle was located in any one organ (the brain, the liver, the spleen, etc.). Here, he shows on the organism that it is impossible for organic life—the condition for all life—to have a center. 4.1.2   Habits, Society, Passions But animal and organic life also contrast with each other in that animal life is subject to the effect of habit. “In animal life, habit modifies everything: each function, exalted or weakened by habit, seems to take on different 2  Leçons d’anatomie comparée (Première Leçon, article 3ème; Bichat’s Anatomie générale was cited just before that.). In this chapter devoted to the notion of animal economy Cuvier also criticizes “a rule which is not more exact than many others, although it was imagined by a justly famous man [Bichat]; that according to which the organs of the animal functions would always be symmetrical, while those of the vital or vegetative functions would not have this disposition. Neither of these laws is constant; cetaceans, pleuronectes, a great number of molluscs and some crabs, have non-symmetrical animal organs. Several vital organs, the gills, show symmetry in fishes; nearly all affect the same arrangement in insects; finally, many other articulate ones have them in perfect symmetry.” “Adaptationist” means that traits are primarily understood as adaptations to the environment; while making sense in a Darwinian framework (Gould & Lewontin, 1979), this notion can be extended towards biological approaches that favor adaptation and function over form, as Russell (1916) emphasized. See below, II, 5, for a development about adaptationism 3  Regarding the intercostal nerve that anatomists believed governed organic life, Bichat writes, “I think that this way is entirely false, that there is actually no such thing as a nerve comparable to the one designated by these words, that what is mistaken for a nerve is only a series of communications between various nervous centers located at different distances from each other. These nervous centers are the ganglions. Spread throughout the different regions, they all act separately and in isolation from each other” (note, p. 70, art. 6, §4).

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characteristics, depending on the various times when it operates” (art. 5, §1, p. 40). Conversely, if habit affected the functions of organic life, “a thousand causes would threaten existence every day” (art. 5, §4, p. 48), because circulation, respiration, etc., would deviate from their normal course, and therefore this argument, instantiating the kind of inference Cunningham (2003) termed the “design argument,” precludes any modification of organs of the organic life through habit-building. To us, habit is a matter for psychology, but Bichat’s physiology covers a larger field than the one we attribute to that discipline today. Examining “animal life,” Bichat comments on perception, understanding, and the passions; in other words, all the ways in which man relates to the world. “Sensation” is the basis for this relationship. Like Locke and Condillac before him, as well as most of the philosophers of the time, Bichat suggests a continual genesis of intellectual functions on the basis of sensation. Sensation causes “sentiment,” first; that is, an impression of pleasure or pain: for example, when we hear a pleasant song. Next, “judgment” occurs (art. 5, §1), and attempts to “distinguish” the harmonies and melody in the song. The sentiment can be either absolute (like the pain of an injury, the pleasure of “coupling”) or relative; that is, a function of the state of mind feeling it. A “beautiful countryside” charms the city-dweller, but not the rural person who lives there and sees it every day. This difference is basically physiological: “Everything that acts upon our organs by destroying their tissues is always the cause of an absolute sensation; the mere contact of another body on our own always produces only relative sensations” (ibid., p. 42). With sentiment, on the other hand, the mind compares the new sensation to those that preceded it—a comparison that is not at all deliberate, but is “an involuntary effect of the first impression of objects” (ibid., p. 44). The similarity between the new impression and the old ones attenuates sentiment; this is why “habit dulls sentiment”: due to repetition, the relative pleasure or pain elicits indifference. “In general, any sensation that is quite different from the one preceding it gives rise to a sentiment, worn out by habit in a short time” (ibid., p. 43). But habit has the opposite effect on judgment. To begin with, once the sentiment of pleasure or pain is dulled by habit, the mind is freer to distinguish the various causes of the sentiment, and therefore to judge. Next, this judgment improves, thanks to habit. “When sensations are repeated, when habit often brings them back, then our judgment becomes precise, rigorous; it embraces everything, the knowledge of the object that struck

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us becomes perfect, as irregular as it was” (§3, p. 46). Again, Bichat can be identified with a classic eighteenth-century theme, and when he entitles this paragraph 3 “Habit perfects judgment,” John Locke immediately comes to mind: “As it is in the body, so it is in the mind: practice makes it what it is, and most even of those excellencies which are looked on as natural endowments will be found, when examined into more narrowly, to be the product of exercise, and to be raised to that pitch only by repeated actions” (The Conduct of the Understanding, §4, p. 20). The importance of habit, or practice, makes education possible. “By gradually dulling these impressions which initially attract all of the child’s attention, habit makes it possible for him to grasp the particular attributes of the body; it thus teaches him to see, without realizing it, to hear, to smell, to taste, to touch, by successively making him descend, in each sensation, from the confused notions of the whole, to the precise ideas of the details. Such is indeed one of the great characteristics of animal life: that it needs... a real education” (Bichat, Researches, §3, p.  47). A proximity to Rousseau’s Emile can be noted, in the sense of the convergence here of a certain empiricism with the theme of the force of habit, and that of the role of education. Education, in Rousseau, also begins with the senses (II, Pléiade edition, p. 380). Especially, habit is characteristic of life, and acts from the very beginning: “Unable either to grasp things or to walk, infants need a great deal of time to form the sensations representing the objects shown to them; but by waiting for the objects to be extended or removed to some distance, so to speak, from their eyes, and to take on dimensions and figures for them, the repetition of affective sensations begins to subject them to the rule of habit” (I, 282, my emphasis). All this shows to what extent Bichat’s Recherches sur la vie are embedded within a set of themes, ideas, explanatory strategies prevalent in late-­ eighteenth-­ century physiology. Using a word by Cabanis, one can call this program a “natural history of man,” and remark that it spans across physiology and psychology. I will expand on it, because it sheds a light on the conceptual space within which Bichat’s experimental physiology constitutes itself—and this physiology, as Bichat’s famous definition of life also indicates it, paid so much attention to the phenomena of death that it provided us with the first in-depth investigation of how death occurs.

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4.1.3   Animal Life and Its Development: Physiology as a Part of Natural History of Man Organic life, spared by habit, is for Bichat from the outset what it must be; animal life, by contrast, needs to be developed. The eighth article of the Researches is therefore concerned with this development, considering first the fetus, and the natural part of this development, and next, the contribution education must make. The theme of comparison acquires a major role here: already, “sentiments” were relative and required comparison. But the outer sensation itself—of taste, color, etc.—the source of the sentiment, is in turn relative, and implies a comparison. “Every sensation assumes a comparison between the current state and the past state” (art. 8, §1, p. 117). Cold is felt in contrast to an earlier warmth. This is why the fetus, immersed in an unchanging environment, where the conditions are constant, feels no sensations, and therefore does not enjoy animal life. It is not that the fetal brain lacks excitability, but it lacks “excitation” (i.e., a minimal difference in intensity) to begin to act (ibid., p. 121). And like Bichat, La Mettrie notes, in his Traité de l’âme, that “the mind and the eyes pass lightly over things that are presented every day” (chap. X, §3, p. 162). Therefore, Bichat’s psychology must be placed within the context of the eighteenth-century French discourse on the source of our knowledge. For Condillac, the comparison of sensations gave access to ideas.4 For Rousseau, “when one imagines, one merely sees; when one conceives, one compares” (Emile, II, 344); and La Mettrie notes “Every judgment is the comparison of two ideas that the soul knows how to distinguish from each other” (Traité, chap. X, §10, p.  172). In L’Histoire naturelle de l’homme, Buffon points out “No matter how strong it is, any sensation that is isolated and entirely without connection to other sensations will leave no trace in our mind; while it is our soul that establishes these relationships with things, through the comparison it makes between them; it is the soul that forges the links between our sensations, and weaves the fabric of our existence with a continuous thread of ideas.” Comparison, in a way, is the essential act in eighteenth-century theories of knowledge, 4  For example, Traité des sensations, 1755, 4th part, chap. 6, p. 246: “How his ideas [of the inanimate statue he postulated] go from particulars to generality”; and in the 3rd part, chap. 3: “The difference between colors will necessarily make us notice the borders or limits separating two colors, and therefore will give us an idea of figure” (p. 170).

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insofar as it is the vehicle whereby sensation, and the disorder of impressions, are referred to intellectual functions and their order. Theorizing animal life (and especially the way it’s realized in human beings, since the first part of the Recherches mostly focuses on humans), Bichat clearly belongs to this context, even though he writes that sensation itself is the product of a comparison. The harmony of the organs and the accuracy of intellectual functions: all of that comes slowly, thanks to education (ibid., §3). Just as with Rousseau, and Condillac before him, psychology is, at the same time, the genesis of the functions, and is backed up by a theory of learning. From this perspective, Bichat examines what is added to nature to model the animal life of man—in other words, society (§4: “Influence de la société sur l’éducation des organes de la vie animale”).5 The division of labor is the most important result of life in society. For the individual, this means the obligation to exercise one or several organs at the expense of the others. “Society exerts a remarkable influence on this sort of education of the organs of animal life; it expands the arena of some; shrinks that of others; and modifies them all” (art. 8, §4, p. 130). Indeed, “the habit of acting perfects the action,” so that man living in society possesses certain organs that are highly educated—those he is accustomed to using—and others that are comparatively inept. “It is therefore manifest that society partly reverses the natural order of education of animal life” (ibid., §5, p. 133) writes Bichat, closer than ever to the Rousseauian inspiration. However, Bichat’s proof is based on a trade-off law he states later: “A given amount of strength has been distributed in general to this [animal] life; and the amount must always remain the same, whether it has been evenly or unevenly distributed; as a result, the activity of one organ necessarily assumes the inactivity of the others” (ibid). This is why the man who channels all of his physical strength into a single activity, for the sake of society, will be weak in other ways. But organic life is also subject to this trade-off, as attested by certain phenomena. For example, “if one kidney is affected, the secretion of the other doubles” (ibid., p.  135). Finally, “all of the functions together 5  Certain Rousseauian themes are noticeable, particularly the idea that man is denatured by social life, and his lifespan shortened: “We live with excesses... we abuse animal life, circumscribed by nature within limits that we have broadened so much that they surpass its duration” (art. 10, §1, p. 159). Current findings in the debate over comparative life expectancies for Europeans and “savages” can be found in Duchet (1971, 448, n. 202). The issues of lifespan will generally be treated in Part II of this book.

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represent a sort of circle, half of which belong to organic life, and the other half to animal life. The vital forces seem to flow through these two halves successively” (ibid., p. 136). This also provides us with the reason why society, which makes us live outside ourselves and therefore abuses animal life, shortens our lifespan: if my animal life is spent to excess, my organic life will obviously shrink by just as much (art. 10, §1, p. 159).6 This “law of the education of organs of animal life” again attests to the epistemological ambition to constitute physiology as a science. Indeed, it can be seen as the position of an invariant prior to the study of the phenomena of life. Throughout these considerations, Bichat inherits reflections by eighteenth-­ century physicians about the conflicting relations between health and social life. George Cheyne’s English malady (1733) is paradigmatic here: the English doctor in this famous book considered nervous affections (forms of hysteria and hypocondria) that mostly affect women of high society, and also writers or scholars, and speculates that the way of life of those people make them subject to such diseases. Medicine, later in the century, both in France and the UK, made a major use of this conceptual scheme in which leisure, scholarship, nervous susceptibility, illness, and mental condition are intertwined—for instance, the “vaporous diseases“ or vapeurs, typically instantiating such kinds of diseases, were of interest among physicians at the time (Vila, 1998). After the essays on the development of both lives, Bichat goes on to their “natural end” (art. 10). He specifies that animal life is the first to die (§1), and reviews Haller’s conceptions according to which the functions cease, one by one, until the heart stops living. “Little by little, strength abandons each organ” writes Bichat summarizing Haller’s view (160), and the heart dies the last. Haller notes: “It may be said to occur when the powers gradually decay, first of the voluntary muscles; then of the vital muscles, and lastly of the heart itself” (Prima linea physiologue, 1747, trad. W. Cullen, Edinburgh, 1786, §972). The first section of the Researches seems almost to be an anthropological study of man, guided by the distinction between the two types of life. 6  One of the first problems of physics was indeed the search for an invariant, with the Cartesian principle of the conservation of the quantity of motion, later contested by Leibniz, and the “vis viva controversy” that ensued, concerning the nature of this invariant. When, closer to Bichat’s time, Lavoisier founded modern chemistry, he established the law of conservation of mass, the invariant, making it possible for him to write equations that quantified chemical reactions.

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While the distinction between those types is novel, as I emphasized it, regarding his considerations about animal life, Bichat clearly belongs to the age of Locke, Condillac, and especially Rousseau. But he also brings to mind the philosopher-doctor Cabanis, whose Rapports du physique et du moral chez l’homme is perhaps even closer to the first part of Bichat’s Recherches, in the way it links philosophy and medicine. The essence of Cabanis’s theory here is the continuity of the body and mind, of the physical and psychological: “sensibility” is a universal property that occurs as feeling and sensation in the “moral” side of human being, but as a vital property on its “physical” side. The doctor and philosopher are identical, in a way, because physical disturbances cause mental ones, and vice versa: bodily diseases may derive from mental failings (the passions, etc.).7 The notion of sensibility as the essence of life, a concept we saw with the vitalists, enables Cabanis to connect life in general to the human brain, the physical center of conscious sensibility. Sensibility, unconscious to the physical, conscious to the psychological, remains the unique essence of human life. But the particularity of the first part of the Researches is its insistence on the distinction between the two lives, more than on the mind/body duality, which does not overlap with the animal/organic distinction. Since this overlap does not exist, Bichat can examine the two dimensions of what is ordinarily attributed to the human mind, the intellectual and the emotional, in a chapter entitled “On the Moral in Both Lives” (art. 3). Intellectual function belongs wholly to animal life, since the reasoning and understanding functions rely on sensation; on the contrary, emotional function—and this is the innovation Bichat is introducing—is wholly assigned to organic life. Bichat goes on to point out that all of the organic functions (digestion, circulation, etc.) are affected by passion: for example, fainting from fright; reddening with shame; or wasting away with sorrow. However, the same degree of passion leaves intact the functions of animal life (understanding, thinking, etc.) (ibid., p.  58). Likewise, by contrast with the functions of animal life, passion does not obey the will. Reciprocally, certain passions, pains, and disorders, are due to “lesions on the stomach, liver, spleen, intestines, etc.” (ibid., p.  61). Consequently, passion truly does belong to organic life.

7  See Huneman (2008) about the way this natural history of man made possible a specific approach to mental illness by French “alienists” such as Pinel.

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In that case, why have the passions always tended to be associated with human relationships, that is, with the “animal life”? To explain this illusion, Bichat must account for the influence of the passions on animal life despite the fact that they belong to organic life (art. 3, §3) and, in particular, on the organs of animal life, like facial expressions, etc. So in the case of some passions anger makes the blood circulate faster, and arrive in great quantities in the brain: this supplemental load explains the nervous agitation that accompanies wrath. More generally, borrowing the pathways of the sympathy connecting the organs, passion, which is centered somewhere in one of the organs of the organic life, determines the effect on certain organs of animal life. It is thus outwardly expressed by facial expressions, tears, laughter, gesticulations, etc. “What happens with the passions is similar to what we observe in the diseases of the internal organs, which sympathetically induce spasms, weakness, or even the paralysis of the muscles of locomotion” (ibid., p. 66). Once passion exists, and is centralized in an organ of organic life, it will produce effects upon the animal life, just like any other condition of organic life.8 Whereas Cabanis spoke of the continuity between the physical and mental, to point out the unity of man and make it the subject of a single philosophico-medical science, Bichat sees the influence of organic life on animal life as the key to the phenomena of intertwining physical and mental states, characteristic of human existence. On that basis in particular, he understands the notion of character. “Our outer acts form a picture: the background and outlines of it are animal life, but organic life is what colors it with the hues and shades of passion. And these hues and shades are character” (ibid., §4, p. 70). This explains why our character is fixed and involuntary, why it always leaves an identical imprint on our acts, no matter what we do. Assigning passions to organic life was a pivotal moment in the construction of Bichat’s medical philosophy, or philosophical medicine. In his World as Will and Representation, Schopenhauer saw it as the essence of Bichat’s contribution, because it adds weight to his own philosophical theory according to which a fundamental distinction must be made between pure will and consciously willed choices. Schopenhauer was eager 8  “What does it matter whether the irritation of the stomach, the liver, etc. is caused by a passion or by some material cause? Sympathy arises from the condition, not from the cause that produced it” (ibid., p. 67).

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to find convergences between contemporary scientists’ views and his own philosophical conceptions; in this case, Bichat seemed to him to be at the closest from his understanding of passions as manifestations of the will (taken in a very specific sense, exposed in his treatise). Schopenhauer wrote concerning Bichat: “His reflections and mine mutually support each other, since his are the physiological commentary on mine, and mine the philosophical commentary on his, and we shall be best understood by being read together side by side. This refers particularly to the first half of his book entitled Recherches physiologiques sur la vie. He makes the basis of his explanations the contrast between organic and animal life, corresponding to mine between will and intellect.”9 Indeed, one of the crucial points of Schopenhauer’s doctrine consists in distinguishing the conscious, deliberate will according to which we make choices, assimilated with intellectual knowledge—from the Will (Wille) that is the essence of everything, remains unconscious, and is objectified by the beings of nature. If passions, which are recognized as conditions of the will, belong to the order of organic and therefore unconscious and subterranean life, then will itself must not be essentially conscious, and the will we experience is only a manifestation of the essential will, which is what Kant called the “thing in itself” and saw as unknowledgeable. Speaking of Bichat, Schopenhauer writes, “His result is that la vie organique est le terme où aboutissent, et le centre d’où partent, les passions.10 Nothing is better calculated than this admirable and thorough book to confirm and bring out clearly that the body is only the will itself embodied (i.e., perceived by means of the brain functions, time, space, and causality). From this it follows that the will is primary and original, but that the intellect, on the other hand, as mere brain-function, is secondary and derived” (ibid., p. 972). The investigation of physiology, in retrospect, seems to confirm the investigation Schopenhauer was engaged in for his philosophy. The German philosopher also recognizes the theory of the freedom of the will in relation to the intellect, in Bichat’s idea that organic life is based not in the brain (the center of animal life, hence of intellect for Schopenhauer), but in the ganglia (ibid., p. 960). Regarding Schopenhauer, Bichat may be one of the best examples of Schopenhauer’s strategy of legitimizing his philosophy using parallels in 9

 Supplement XX to vol. 2 of Le Monde comme volonté et représentation, PUF, p. 970.  “Organic life is the terminus of the passions, and the center from which they originate.”

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current science; inversely, it also shows more generally how much Bichat’s science resonated with philosophical questionings of the times, even though no philosophy of science was distinctively required.

4.2   Bichat as Anthropologist This first part of the Researches is therefore linked to an ideal of Enlightenment physiology according to which this science, in its broadest extension, would ultimately be a science of human nature—an anthropology. The Researches belong to a body of texts that share a philosophical background drawing on the ideas of Rousseau, Condillac, and Locke, as we saw. It would include the Rapports by Cabanis—doubtless the most exemplary in terms of the idea of physiology it advances—but also Buffon’s Histoire naturelle de l’homme, Pinel’s Traité médico-philosophique sur l'aliénation, the second Mémoire pour servir à l’histoire naturelle de l’homme by La Mettrie (entitled Traité de l’âme),11 the third part of Lamarck’s Philosophie zoologique, and even certain pages of Kant’s Anthropology from a Pragmatic Point of View. This is why the investigation of processes that are literally physiological in these texts is accompanied by a discourse on the conditions of human life, on the use of his intellectual faculties, on the relationship between the animal and the intellectual, between the natural, the social, the legal and the civil, and finally on education.12 While for us there are two disciplines here (physiology vs anthropology or philosophy), for these authors there was only one conceptual space, within which overlapping disciplines were elaborated which shared concepts, questions, and methods. For the anthropology of Bichat and Cabanis, among others, insofar as it is a unified theory of physiology and psychology, the idea of “temperament” was central. Temperament is halfway between the physical and the mental: it is inborn, and therefore involuntary, but at the same time it is 11  In 1751, La Mettrie’s Histoire naturelle de l’âme, originally published in 1745 (condemned and publicly burned in 1746) was reprinted under this title in his Mémoires. 12  In the Rapports du physique et du moral de l’homme, 1811, OC, VI, p. 30, Maine de Biran points out after Bichat the “great laws of habits, the exclusive properties of organized machines, the periodicity of vital or animal functions, of wakefulness and of sleep, of growth or wasting away,” and notes, on habit: “the same habit that imperceptibly erodes, alters, and erases the passive sensation and all of the subordinate faculties that originate in it serves on the contrary to perfect, enlighten, or develop the perception of the mind (...)” (ibid.).

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visible in a person’s thoughts and deeds. Generally, the authors of the time distinguished various types of temperament: bilious, phlegmatic, choleric, sanguine, etc. In Bichat’s writings, “temperament” is a manifestation of organic life that affects animal life. “Usually, the characteristics of such and such a temperament are such and such a modification of the passions, on the one hand, and on the other, of the condition of the viscera of organic life, and the predominance of such and such a function. Animal life is almost always foreign to the attributes of the temperaments” (art. 6, §2, p. 61). In other words, temperament derives from the initial and immutable characteristics of the individual’s organic life, characteristics that are therefore buried deep in the flesh. According to Kant’s Anthropology from a Pragmatic Point of View, “physiological knowledge of man investigates what nature makes of man” (p. IV), which suggests the perspective of a natural history of man (what nature makes). This perspective actually defines the study of man outlined by the body of late eighteenth-century writings to which the Researches belong.13 It goes beyond the schisms between the various metaphysical theories espoused by these authors (materialism for Lamarck and Cabanis, dualism for Buffon, etc.). We have seen how Bichat’s Physiological Researches on Life fits into this anthropological effort, which in the eighteenth century ascribed them an object finally identical to life Buffon and Cabanis were studying. Buffon investigated it from the angle of the history of humanity intertwined with the history of nature,14 and Cabanis from the viewpoint of a doctor-philosopher confronted with ills which are above all related to the lifestyle of a period, rather than of a single individual. In a nutshell they shared the view that human life is caused by society to deviate from nature, and restored to itself by education; 13  According to the perspective adopted in relation to man, this anthropology could be qualified as either naturalist or medical, the two paradigmatic texts being Cabanis’ Homme au physique et au moral, for the former and Buffon’s Natural History, book on “Man,” for the latter. The naturalist anthropology of the eighteenth century (see Duchet, 1971) cites human history, and therefore mobilizes the savage/civilized duality. Medical anthropology uses the healthy/ill opposition. Both types of discourse may agree on the theme of the corruption of man by civilization. 14  On this point, see Duchet (1971), particularly p. 226 sq. “L’anthropologie de Buffon”; on the related project of an anthropology based on conjectural history, undertaken concomitantly by Scottish philosophers such as Dugald Stewart, see Garrett (2003).

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profoundly swayed by passions which may alter it to madness; amenable to a natural history which would be simultaneously psychology, physiology, medicine, and pedagogy, studies which would embrace it in its relationship to itself as well as in its relationships to others; and in the thickness of the times that have brought it to what it is.

References Cunningham, A. (2003). The Pen and the Sword: Recovering the Disciplinary Identity of Physiology and Anatomy before 1800  – II: Old Physiology—the Pen. Studies in History and Philosophy of Biological and Biomedical Sciences, 34(1), 51–76. Duchet, M. (1971). Anthropologie et histoire au siècle des Lumières. Maspero. Garrett, A. (2003). Anthropology: The ‘original’ of human nature. In A. Broadie (Ed.), The Cambridge companion to the Scottish enlightenment (pp. 79–93). Cambridge University Press. Gould, S. J, & Lewontin, R. C. (1979). The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London. Series B, Biological Sciences 21, 205(1161), 581–598. Huneman, P. (2008). Montpellier Vitalism and the emergence of Alienism in France (1750–1800): The case of the passions. Science in Context, 21(4), 615–647. Lesch, J. E. (1984). Science and medicine in France, the emergence of experimental physiology, 1790–1855. Harvard UP. Vila, A. (1998). Enlightenment and pathology: Sensibility in the literature and medicine of eighteenth-century France. Johns Hopkins University Press.

CHAPTER 5

Bichat’s Experimental Physiology in the Recherches (Part 2): Death as an Epistemic Facilitator

In this chapter I will focus on the second section of Bichat’s Recherches physiologiques sur la vie et la mort, which is about death. Those investigations indeed consist in unraveling the various processes through which death follows from the alteration of one basic organ (heart, lung, brain), through the use of various experimental devices he designed for this purpose. After having situated it in its narrower and wider context—namely, the evolution of the scientific conceptions of death and, more generally, the shifting attitudes towards death in early Modern Europe (and especially France)—I will analyze its content, insisting on the way Bichat establishes a specific experimental and discursive structure likely to produce physiological knowledge. Rather than the particular views he defends on death, this analysis considers the matrix through which some knowledge is produced, that concerns death and also life, and that allows Bichat to answer major questions with which his physiology is concerned, and for which no answer can be given by observation or usual experimental methods at the time.

5.1   Conceptions of Death and Sensibility to Death: End of a Dualism The second part of Bichat’s work, Recherches physiologiques sur la mort, seems to uphold a different discourse than the first one, aimed at a sort of observational of physiological functioning, in the style of contemporary natural history; its similarity with the works referred to previously—namely, © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_5

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works by Buffon, Barthez, Bordeu, Cabanis, or Crichton—is much less certain. The influential historiographical perspective adopted by Lesch (1984) has seen it as an experimental physiology, laying the groundwork for later advances by Magendie and Claude Bernard, in contrast to the first part of the book, Recherches sur la vie, whose optic was inherited from the past: Cabanis, Buffon, and so on. Before arriving at an understanding of this heterogeneity, I must first analyze these Recherches sur la mort, linked to the Recherches sur la vie by just one element, which is Bichat’s originality, among all other authors to have conceived of a physiological anthropology, namely, the division drawn between the animal life (la vie animale) and the organic life (la vie organique). In order to grasp the significance of this extensive investigation into how brain-death leads to death of the lungs, or how heart-­death leads to death of the whole, and so on, one must first place it within a tradition of thought. Of course, Bichat’s idea, according to which each tissue type has its own particular life, entails the possibility for each organ to be conceived of as comprising a specific way of dying, thereby allowing him to examine what impact the death of a given organ would have upon the others. In the text, however, what we find is a conception of death as a process linking several specific organ deaths, namely, death of the lung, the brain or the heart. This triad is still dominant in current attempts to determine and define death: while brain-death is currently the major criterion for death,1 lung and heart are the two other targets of the dying process, as attested by the President’s Commission that ushered in 1981 the influential set of criteria for death mentioned in Chap. 1. Thus, one sees that the structure investigated by Bichat kept some permanence and stability when it comes to death in physiology and medicine. But death as a process embodies a particular conception that represents an endpoint in a historical progression which should be now recalled. In line with the Christian conception of a dualism between body and soul, enhanced by the Aristotelian concept of the soul as the very principle of life, death was long considered to be precisely the separation of soul from body. However, as Philippe Ariès points out, “during the first millennium, death was conceived of not as a separation of soul and body but as a mysterious slumber of the indivisible being” as it awaited the Resurrection.2 This was followed by a certain individualization of death, particularly evident in various guides to “dying well” distributed under the title of artes 1 2

 See Chap. 1 for the issue of the variety of criteria.  “La famille dans les testaments et les tombeaux,” in Ariès (1977), p. 148.

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moriendi.3 Dying was instantaneous and death was the state of the body with no soul. But with the end of various sorts of Galenic or Aristotelician animisms, instantiated by iâtromechanism and the physiological theories I surveyed in Chap. 2, physicians were able to consider things differently. Thus, there emerged in the first decades of the eighteenth century a tradition of research on death which saw it as an internal working of the living being: wear and tear of the solid organs through friction, obstruction of fluids through solidification and thickening of the vessels—all notions advanced by Haller in his Principles of physiology (1755), and which will be pursued up to now, as it will be examined in Part II. Buffon stressed this point too in a chapter of his L’Histoire naturelle de l’homme entitled “De la vieillesse et de la mort” (“On old-age and death”), but the same idea can be found in Maupertuis’ letters and was also adopted by Lamarck in his Philosophie zoologique. 4 Here death is primarily a process, not a state; it begins almost with life itself, arises from within. To be precise, death is but the result of this (living) work. As Buffon writes, “we begin living by degrees and we finish dying just as we begin living” (Buffon, 1749, II, 153). The same scientific conception may take part in a global picture of the evolution of western experiences of death when we compare it to how people’s view of death has evolved, as described by Philippe Ariès. Following a period where the tragedy of death was concentrated into the very moment of dying, where the key issue was whether salvation or  On this point, see chapter 5 of Ariès (1977), entitled “Gisants, priants et âmes,” which examines the evolution of funerary monuments through the Middle Ages, thus retracing the development that led from death in slumber (requies in pace), informal and experienced as a social event, to a more individual kind of death, the correlate of a personal soul, separated in death from the body. 4  “We feel the beginnings of decline in youth itself. Even in that fruitful period, the solid elements of the body grow, the canals through which the humors pass are narrowed, the smaller vessels fill up. […] But when these causes continue to operate, so as to harden the body’s matter, to lower its irritability, and to increase its mass of earth, it is not possible for decrepitude not to overcome” (Haller, 1786, § 963, 970). “In the nature of things, [death] is therefore but the final nuance in a preceding state” (Buffon, 1749, II, p.  151). For Maupertuis, see Lettre XIX, 1752, Oeuvres, II, pp. 342–343. In the Enyclopédie by Diderot and d’Alembert, Ménuret de Chambaud writes in the entry “Vie” (1765): “Physiology demonstrates how the machine is destroyed little by little, there being no possible way to prevent it by any remedy whatsoever.” See also slightly later: “Every living body is inevitably subjected to death; for the very characteristic of life [...] is to bring about, after some certain amount of time [...], a state in the organs which finally makes the accomplishment of their functions impossible” (Lamarck 1809, II, chapter 1). 3

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damnation would follow, there developed an attitude of “reticence” towards a death whose permanent immanence the Church was beginning to emphasize. In the sixteenth century, “modern man began to experience a reticence towards the moment of his death. A reticence never expressed, probably never fully thought through. This determined a trend towards a demeaning of this formerly honorable moment.”5 This in turn explains why life as a whole began to be penetrated by the feeling that death was at work within it: “Death was thus replaced by mortality in general, which is to say that the sentiment of death, formerly concentrated into the historical reality of its hour of arrival, was now diluted into the total mass of life, thereby losing all of its intensity.”6 By this account, mechanist models describing death as wear and tear were able to lean on this new attitude Western humans had adopted towards death. Nevertheless, this novel scientific conception of death, resulting from the mechanist tradition, was only able to spread—albeit in a profoundly modified form—thanks to a final global transformation in historical sensibilities, a transformation that overcame Christian dualism and brought forth the concept of “apparent death.”7 Indeed, the custom of burial directly after death was to be challenged by Winslow in 1740 in a paper on the “uncertainty of the signs of death” that combined scientific observations of corpses apparently coming back to life with cases taken from folkloric accounts. His translator and distributor, Bruhier, later set out on a crusade against “precipitate burials in a french 1742 text entitled Dissertation sur l’incertitude des signes de la mort et l’abus des enterrements et embaumements précipités.” It was indeed discovered that observed death was not necessarily death at all; a return to life was possible. From this arose the fear of being buried alive, which spread swiftly in the second half of the eighteenth century. Ariès sees apparent death as an indicator of the rupture in traditional sensibilities towards death, which comprised a familiarity and resignation with respect to fate: “Up until then, society had intervened with full force to maintain the reassuring traditional familiarity death was framed in. Fear of apparent death was the first confessed, acceptable form of the fear of death.”8 Before, while a human fear of death may indeed have existed, “this dread never stepped over the threshold of the unspeakable, the inexpressible. It  Ariès, (1977), II, p. 26. See also Brown (2015) on the genesis of this attitude.  ibid., p.26. 7  On this point, see Milanesi (1989), and, on Winslow and signs of death, Gorini et al. (2018). 8  Ariès (1977), II, p. 120. 5 6

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was translated into soothing words, channeled into familiar rites.”9 But this fear finally made its way into the realm of the imagination,10 and then, “over the course of the seventeenth and eighteenth century, the frantic fear spilled out of the imagination and penetrated experiences of reality, in conscious and spoken feelings, in a nonetheless limited, banishable form, not encompassing the entire myth, in the form of the apparent death and the dangers faced should one become one of the living-dead.”11 And so, between the instant of apparent death and that of true death, a space extended out which science would interpret as the absence of certain functions. The article Mort from Ménuret de Chambaud in the Encyclopédie by Diderot and d’Alembert in 1762 took note of this change: death was no longer a matter of instantaneous separation but rather the progressive, yet sometimes reversible, extinction of various functions. Vitalism—in the form of Bordeu’s doctrine of the “proper lives” of organs—allowed for the conception of a progressive death, for if life is the sum of the specific lives of several organs, then the death of the whole body results from the death of the individual organs, yet the life of an organ may continue after the life of the whole has ended. Those two meanings of the word “life” (of organs, and of the organism) lead to two meanings for death (even if, in Ménuret’s article, his identification of life with a property such as irritability would render inexplicable the persistence of life signs in the cadaver following the irreversible end of life).12 Thus, the notion of a process-death, advanced by mechanist thought, takes on a new interpretation within the framework of vitalism, one that makes room for the new concept of the “apparent death.” Bichat clearly joins himself to this line of thinking, albeit with certain radical modifications specific to his own project: his essential concern being the rejection of the life/death dualism. In a way, the Recherches about various processes of death represent the culmination of this movement, which was imposing a new conception of death upon our collective knowledge and a new attitude towards death upon society (e.g., the transformation of funeral practices: later burials, distancing of cemeteries, etc.), while at the same time they inaugurate something else, as I’ll show now.

 Ariès, (1977), II, p. 114.  ibid., pp.76ff. 11  ibid., p. 115, my emphasis. 12  Ménuret’s model involves two important steps: first circulation stops, then irritability also, marking the definitive death. For a study of these texts, see Milanesi (1989), p. 174ff. 9

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To this extent, making sense of the difference between life and death is one of Bichat’s objective throughout the whole book. The distinction drawn in the first part of the book (“Recherches sur la vie”), between “vital properties” and “tissue properties,” avoids the error of seeing vital signs in phenomena such as the twitches or bleeding of a cadaver. In the Article 7 therein, Bichat indeed distinguishes sensibility and contractibility from those “tissue properties” possessed by every “part [made of] organic tissue” (i.e., having the potential to live, hence possibly parts of dead bodies) yet which do not depend on the vitality that is in them. Those latter properties notably include “extensibility”—the distension of tissue under some “foreign influence”—which Bordeu, Barthez, and Haller had wrongly classified with the genuinely organic properties, being therefore unable to make sense of strange phenomena occurring within recently dead bodies. Such a property distinction thereby endowed the notion of apparent death with an intelligibility and clarity that was lacking in earlier conceptions. These had always suffered from a level of morbid fascination—whether in the case of early eighteenth-century doctors, for example, Garmann (De miraculis mortuorum, Dresden, 1709), still marveling at the idea of life in the cadaver, or in the case of Ménuret, struck with wonder at “irritability” manifested in the corpse after true death. Thus, the discriminating role played by death is discernible in this first part of the Recherches: it is the filter through which the “tissue properties” of a body part can be identified, that is, those which persist either after death or after removal of the part from the body (which is to say, after the death of the part). But death displays another discriminating function in those “Recherches sur la vie”: it provides a criterion for differentiating the functions and organs of the organic life from those of the animal life, since the former are extinguished some time after the latter. Leaning on the division of the animal life from the organic life, Bichat is therefore now able to precisely characterize apparent death: such lapse of time refers, scientifically, to the interval between the death of the animal life (reversible) and the death of the organic life.13 The distance between the deaths of these two types of life accounts for the interval that constitutes “apparent death.” To be precise, this distance between the end of the animal life and the end of the organic life is to be identified, strictly speaking, only in experiments where the death of the brain, center of the animal life, will lead to that of the other organs. But even though Bichat’s other experiments on dying processes in  See Recherches, part II, art. 1, § 1, p. 165.

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the “Recherches sur la mort” (as we’ll see below) begin before the end of the animal life, the fact remains that only the distance of this end from that of the organic life justifies attributing a lapse of time to the phenomenon of dying. Analysis of the organic life per se therefore becomes possible by experimentally studying the processes which take place during this interval. The experimental approach was harshly criticized by the vitalists because of the modifications it superimposed on animals and the unnaturalness of reactions it may occasion through suffering; here regains its importance.14 Indeed, if the animal life is no longer an element of interest, since the interventions occur when it has almost ended, then any traumatizing or sufferance-inducing experiments the animal undergoes that would strike at its animal sensitivity are of little matter, since the animal life is no longer the center of concern. We see also here how, despite their differences in tone, within the Recherches, the “Recherches sur la mort” connects to the “Recherches sur la vie”: through its distinction of two types of life, the latter informs the status that is to be determined for “apparent death,” this determination being the object of the analyses which make up the former.

5.2  Life and Experiments on Death As expected, the “Recherches sur la mort”, second part of the Recherches, is wholly focused on death and initially draws a distinction between accidental death and natural death. Furthermore, insofar as it treats accidental deaths, it deals only with violent death, that which arises abruptly following a disturbance, as opposed to death from disease.15 Indeed, since disease is an “intermediary state between health and death,” it cannot be imitated, and even if it could be, this might lead to no enlightenment at all since disease involves a modification of the vital laws.16 For these reasons, Bichat proceeds by imitating violent death, grounding his postulates in animal experimentation. As Milanesi (1989) notes, in contrast to Ménuret or Barthez, Bichat narrowed his scope to a single type of death—that is, violent death. Epistemological progress is thus to be obtained through a reduction of the questions asked. 14  On vitalism in the eighteenth century, experiments and methods, see Williams (1994); Reill (2005). 15  Recherches, part II, art. 1, § 1, p. 164 16  Recherches, part II, art. 1, § 1, p. 164

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In his Discours sur l’étude de la physiologie, Bichat had already begun to respond to vitalist criticism by pointing out that experimental uncertainty is not absolute: it concerns those experiments—Haller’s would be an example—which target a single organ or property, since in these cases one should expect inter-individual variation. But this leaves in principle the way open to experiments involving several organs. Experiments, Bichat indeed says, are “uncertain when they choose vital forces as their object,” forces that would be tested upon one organ, on which point he evokes contradictions inherent to some of Haller’s experiments on the dura-­mater. Conversely, robust, “sure” (certaines) experiments can be conducted—even if they do “demand extreme precision”—on phenomena involving several organs: digestion (we could mention Lazare Spallanzani here), asphyxia, or the mutual influence of the various secretions (experiments such as those conducted by Bichat himself). On the subject of such experiments, Bichat laid out methodological rules that predate those Claude Bernard would stipulate some 60 years later: the use of an animal control, the consideration of the animal’s state, multiple repetitions of the experiment, and so on. In the Recherches, death is the sequence of the partial deaths of several organs, primarily the heart, the brain, and the lungs, since “every sudden death begins by the interruption of the circulation, the respiration, and the activity of the brain” (p. 167). The “Recherches sur la mort” set itself the task of understanding how each particular organ death leads to (“influences,” to use Bichat’s own terminology17) that of the others and, ultimately, to the end of life itself. Reflecting this, his text is split into three principal sections: the effect of heart-death on the death of the other organs, then the effect of brain-death on the same, and then onto the effect of lung-death. In this, Bichat places himself within the expanse of apparent death, thereby isolating his aims from the continuist conception of death of Haller, Maupertuis, and Buffon, as was already evident from his decision to consider only violent death. Death is no longer the effect of vital wear and tear across one’s whole existence, but rather a new process all of its own. In Bichat’s work, the cause of death is never studied in and of itself; what counts is how, once one organ has ceased functioning, the others are affected. Thus there is a discontinuity or a gap between life and death which begins from the moment the first organ has been struck. This is a fact, a datum, regardless of its causes—by proceeding in this way, Bichat is able to identically deal with diverse forms of death: asphyxiations, blackouts, drownings, and so on.  For a systematic computer-assisted investigation of Bichat’s terminology, and the rôle played by the word and concept of “influence” therein, see Di Palo (2005). 17

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At this precise point the threads of knowledge, active experimentation, and death get woven together: the experiment triggers the death of an organ, consequently revealing the process of death to the eye of the observer. Yet what this process genuinely reveals is the inverse order of the inter-organ dependencies that make up the vital function. Concretely, if death of the “black-blooded heart” (i.e., venous) causes arrest of the “chemical phenomena of the lungs,” then it is clear that the former maintains the latter (“Recherches sur la mort,” art. 3, § 1). Experimental analysis of death—by a process of cancellation, nullification or knocking out—reveals the sequence of inter-organic conditioning that constitutes life. It enables us to see, for example, that, just as the lungs combine chemical and mechanical phenomena (e.g., respectively, combustion and contraction of the intercostal muscles), so there is a corresponding division between venous blood and arterial blood conditioning each other (“Recherches sur la mort,” art. 3, § 2). Several experiments are sometimes needed in order to demonstrate a dependence. For instance, although the heart may be shown to die just after the brain, whether or not the dependence between them is direct would still remain to be proven (“Recherches sur la mort,” art. 11); yet simple observations (e.g., the heart is not the center of the voluntary movements) coupled with experimentation (e.g., irritation of an open animal brain having no effect on the heart) show that stimulation of the brain does not always result in an effect upon the heart; therefore the death of the former must kill the latter via the intermediary of another organ, namely, the lungs. Yet this still leaves open the question of whether it is the arrest of the chemical or the mechanical pulmonary phenomena that specifically act as intermediary. The answer to this is given in article 10 of the “Recherches sur la mort,” where it is shown that the mechanical lung phenomena depend upon an element of the animal life, the nerves, which, by extension, means that they depend directly upon the brain. In this sense, each experiment is designed to test, and in general to refute, a hypothesis; often the result of the experiment is binary: life or death. The variability of the vital forces, as he conceives of them, rendered indeed any attempt to establish a quantitative science of the phenomena quite pointless. This is why Bichat’s experiments establish no measurements (as Haller’s experiments on the vital properties of organs had done) but instead result in binary responses: yes/no, life/death. In our modern eyes, this distrust of the quantitative may sound obsolete: is not today’s medicine wholly occupied with the measurement of variables? Pulse, tension, glycaemia, and so on, some values of which are taken to indicate good health, are values that medical regulation of the organism is directed at keeping

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constant. Nevertheless, for Bichat the significance of these variables in the case of vital phenomena is not a fixed one, since each “normal” value is dependent upon the context and even the individual’s characteristics. Hence Bichat’s intent to favor binary variables as target of its experiments makes a clear sense in regard to idiosyncrasies and plasticity of the living— the latter understood as a case of context-dependence.18 Each experiment led in the “Recherches” more specifically consists in severing the link between a source organ and a target organ: if the latter continues to function, then it proves that the supposed dependence is not a real one. This schema can also be made more complex by the introduction of a ternary element: with respect to the mechanical lung phenomena, Bichat puts forward the hypothesis that the control exerted by the brain may be relayed by the first ganglion. But severing the connection between the brain and the ganglion does not change the appearance of the lungs: the ganglion in question is therefore not a relay (art. 11). Each experiment thus gives rise to the idea of another one, which would either confirm or clarify the first. For example, lung-death through asphyxiation converts venous blood into arterial blood, provoking brain-death (art. 7); but what about the other organs (art. 8)? Bichat thus sets a tap into the tracheal artery of a dog, connected to a second, asphyxiated dog whose “black blood” (venous blood) is channeled into the first with a variable flow. The tap enables the experimenter to observe that, during the asphyxiation, when it is closed so that air can flow, the blood rapidly regains its red coloring, indicating that the “principle” of red (i.e., arterial) blood runs directly from the lungs into the blood.19 Conversely, when the tap is left open, death overcomes the brain, the nerves, then the organs of the animal life, and lastly the rest of the organism. This demonstrates that black blood is incapable of sustaining the animal life and that this then kills the 18  Canguilhem (1991) clearly showed how each living being lays down its own norms in accordance with its own lifestyle, its own environment, and so on, such that one same value, a pulse of 40, let’s say, would not have the same significance for an office worker as for a marathon runner. In this sense, when Bichat considers life to be irreducible to measurement, by reason of its great variability, his thought remains close to that of the physician and the physiologist. Or rather, on this specific point, his vitalism is not a strong and outdated metaphysical claim but rather the recognition of the context-dependence inherent to vital phenomena studied by the physiologist. 19  As a result, this part of the Recherches has implications for the practice of resuscitation. Moreover, it was around the same time that first-aid societies for drowning victims first appeared in Paris (Milanesi, 1989). The reversibility of apparent death and its conditions had become a topic of study.

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organic life, whereas the heart seems able, autonomously, to continue functioning longer on black blood alone than the other organs. That also confirms Bichat’s idea that blood sustains life in two ways: by its “movement”20 and by its “nature.” Now he is able to more precisely affirm that this second way is reliant on the “principle of red blood.” The two actions are, one mechanical, the other chemical; by accounting for them as one, Bichat unifies mechanistic physiologist theories with the theories of the iatrochemists (those physicians who thought that life basically resolved into specific chemical processes, rather than mechanical laws or vital principles (see Chap. 2)), while simultaneously revealing their respective failings. Further on in the text, he states that death via the lungs or the brain leads to an arrest of the chemical action, whereas death by the heart puts a stop to the mechanical action (art. 12). Thus, the reason why the establishment of experimental physiology should involve investigations into death now becomes clear. Experiments on the vital properties of one organ make no real sense in light of the fact that the vital forces of an organ are, by essence, variable, as Bichat argued in the “Recherches sur la vie,” in accordance with many vitalist authors of his time; knowledge of histology, while certainly essential, cannot be expanded into an understanding of how all the organs live, let alone the organism as a whole. When physiology reaches the level of tissues instead of organs, as Bichat does, anatomical deduction (from organ to function), once warranted by the design argument (Cunningham, 2003) and championed by Haller, cannot be the physiologist’s proper method. But death is a process of sequences, as brought to light by physiological experimentation. These death-inducing sequences are, for their part, unvarying, whereas the vital forces can vary in each of the organs that participates in such sequences. Among the variety of natural conditions of death, Bichat writes, “the sequence of the phenomena [by which death occurs] does not vary.”21 This sequence is the invariable element upon which a science of the living can be constructed, since, as we have already seen, such sequence reveals the dependency connections between the organs. Those connections are the very process of life, invariable despite the plasticity of the vital forces. As soon as the body dies, such connections no longer exist, whereas 20  For instance, blood stimulates the brain by the impact of its arrival via the carotid arteries (art. 2). Bordeu had already articulated the same conception in Bordeu (1751): “These tremors are communicated by way of undulations to the extremities of the nerves, which latter communicate with all the parts” (§ 129, p. 199). 21  Recherches.., p.364.

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in life they are imperceptible, since all interrelated phenomena occur simultaneously. Experimental examination of the death process turns into chronological sequences (e.g., cessation of the mechanical lung phenomena leads to arrest of the chemical lung phenomena, “Recherches sur la mort,” art. 5) the logical sequences that make up the living being (e.g., the mechanical lung phenomena conditioning the chemical lung phenomena). Death has the effect of stretching out time and presenting, spatially and temporally, the invariable logical connections between the phenomena which make up the organism yet cannot be “seen” in life because of the simultaneity and depth of natural organ functioning. It is therefore in the second part of the Recherches called “Recherches sur la mort” that Bichat overcomes the pitfalls of vitalism as described in Chap. 2 and establishes a science specific to the living—namely, experimental physiology—made possible by providing it with its own specific vital object: these very logical sequences. Only death can bring such “sequences”—which the Anatomie générale had always wished to have “in view”—into apprehensible proximity.22 This death is studied, as we have just seen, by means of several inter-­ linked experiments. It can only be understood through the study of several localized approaches: asphyxiation for lung-death, blackout for brain-­death, and so on. This multiplicity acknowledges the fact that there is not only one death-inducing sequence, and therefore not only one organic axis of dependence. Rather, the dependencies are reciprocal and multilinear, such that multiplying the experimental approaches will enable them to be described. On the one hand, each of the three sections of the “Recherches sur la mort” (brain-, heart-, and lung-death) is made up of subsections (in which one particular link between two of these organs is studied); on the other, each of them, once the results of the subsections have been put into sequence, constitutes a specific sequence, independent of the other two. As an important epistemological result, the object of physiology cannot be described using a unilinear account of cause/effect relations; several sequences are rather needed. When, while discussing the effect of lung-­ death on that of the heart in the Article 6 of the “Recherches sur la mort,” Bichat provisionally indicates (as a precursor to the demonstration to follow in article 8) that “black blood” (venous blood) cannot “nourish” the organs, he inserts a methodological note to the effect that physiological problems are “a circle whereby something must always be assumed, then to be proved thereafter,” just as it “is from the sequence of questions concerning  Recherches... p.116.

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circulation that results the impossibility for the solution of one [sequence] to lead by necessary consequence to the solution of all the others” (my emphasis).23 If death does open the way to a scientific approach to knowledge of the functioning of the organism as a whole, then this could actually not occur through a purely deductive method but only as part of a circular theory, where each reconstruction of an inter-organ conditioning would have to presuppose the others. One can see here an instance of the concept of “organism,” according to which every part is both cause and effect as Kant famously formulated it in the Critique of Judgment (§65)—a concept that at the same time distinct elaborations in various disciplines such as embryology or comparative anatomy concurred in constituting, and whose first philosophical account was precisely proposed by Kant in the German context.24 For Bichat, advancing via the study of death is necessary in order to understand the networks of conditions that penetrate the organism so that it might live. Granted, many scholars have emphasized the apparition of the word Biologie (in French or German) in 1800, independently by authors Burdach, Treviranus, and Lamarck,25 noticing that this emergence indicates something regarding the science of life—namely, the project of a science of living things as such, of their development, organization and functioning, instead of a set of disciplines ranging from natural history to medicine through botany and physiology, for which the living was not an object by itself. Here we see that Bichat’s project of a physiology participates to this move towards a scientific framework devoted to the understanding of organisms as functional  Recherches..., p.228.  Huneman (2008b, forth., 2017) investigates the multifaceted genealogy of this concept of organism, that Kant captures as a kind of circular causality (parts are both effects and causes of the whole, which therefore causes itself and its part, a circularity that the concept of “self-organizing” attempts to formulate in the second part of the Critique of Judgement). Connections between the french vitalist context and the German embryology and comparative anatomy have been lengthily described by Schmitt (2006), Huneman (2008b, forth.), Corsi (1988), Duchesneau (1982), Sloan and Lyon (1981), Sloan (1995), and most recently and exhaustively Zammito (2018). 25  McLaughlin (2002) emphasized an earlier occurrence in a treatise by the physician Hanov, though its meaning is less decisive therein.The present section is just a partial contribution to the question of the “emergence of living things as such,” from the viewpoint of experimental physiology. In no ways it pretends to exhaust this question; some of the major contributions include for example Zammito (2018), which explicitly addresses the German context, here almost untouched. 23 24

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systems whose functioning relies on circular conditioning—and that such project essentially stems from a new approach, both conceptual and experimental, to the phenomena of death. Even though significant scholarship has been devoted to the emergence of biology as an autonomous science, this contribution, and the role played by death as an object study in this story, has been quite overlooked, and one of my major endeavors here consists in exposing it. This can be verified from a closer look at the contents of the Recherches.

5.3  Sequence-Schemata Article 1 of the “Recherches sur la mort” is dedicated to death in general. Three sections follow it, dedicated successively to heart-death, lung-death, and brain-death, with each one divided into four articles as follows: the articles corresponding to 4n – 226 deal with the effect of heart-death, then lung-death, then brain-death (according to the section) on, respectively, the brain, the lungs, and the heart; the articles corresponding to 4n – 1 deal with the effect the deaths of the three principal organs, relative to each section, have on, respectively, the heart, the brain, the lungs; the articles corresponding to 4n deal with the effect the deaths of the focal organ in the section have on the other organs; and lastly, the articles corresponding to 4n + 1 describe how these organ deaths lead to the death of the whole organism. Each article in this last set must therefore sum up the partial studies undertaken in the first three from its section. It sets out a complete death-­ inducing sequence linking together all the organs and sums up the partial sequences identified between the arrests of each organ’s various activities. To give an example of a partial sequence: “1/ interruption of cerebral activity; 2/ extinction of all animal life activities; 3/ consequent arrest of the mechanical phenomena of respiration; 4/ suppression of chemical phenomena and the coloration of the blood; 5/ penetration of black blood into the fibers of the heart; 6/ weakening and arrest of activity of these fibers.”27 The summary articles thereby unveil a death sequence that is also an essential chain in inter-organ conditioning, such that, taken together, all 26  The numbering tries to give a view of the formal structure of the “Recherches sur la mort.” But given that the first article is about death in general, the account of experimental works starts at article “2”; hence this somehow strange numbering. I estimated that naming the rank of each article would not convey the kind of systematicity that structures the work. 27  Recherches..., part II, art. 11, § 2, “On the death of the heart by that of the brain,” p.343.

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these summary articles constitute a respectably complete schema of the internal functioning of the organism. Of course, certain specific sequences, such as the conditioning of respiratory chemistry by respiratory mechanics within the lungs, reappear in every summary article, but each time within the assembly of different partial chains of conditioning. More specifically, the first general sequence is28 heart → brain → lungs (article 5); the second, lungs → heart, but also lungs → brain; the third, brain → lungs → heart. First to be remarked is the particularity of the lungs, which give rise to two distinct sequences, corresponding to the empirical fact that most sudden deaths begin in the lungs (article 6). We then notice that these three sequences, as relations of dependence, can be read in succession, which is to say that there is a circularity to the conditioning of organic function. The organization of the living, as described following experimental examination of the death processes, can thus be superposed onto the circularity of methodology Bichat set out in the above cited note. This, at least, is visible in the structure of the “Recherches sur la mort.” We see therefore how the second part of the physiological investigations, the “Recherches sur la mort,” levels the epistemological obstacle raised by the first parts, the “Recherches sur la vie,” when it advanced the idea of a vitalist physiology. Thanks to its examination of death, it can produce an initial scientific understanding of vital functioning that will serve as a framework for the experimental research. The vital phenomena are circular and therefore closed in on themselves. In this way, Bichat had grasped a fundamental singularity of the living, one that later biology would develop through the concepts of regulation, feedback loops, and cycles (Krebs cycle, ATP cycle, etc.): living beings function in a circular manner, in contrast to material nature which is conceived of as a linear process, having neither beginning nor end. As we saw in the previous chapter, referring to Kant’s Critique of Judgement, the circularity of the living corresponds to its very organicity: the parts are simultaneously the cause and the effect of the whole. Similarly, when Cuvier as a comparative anatomist writing contemporaneously to Bichat pronounced the “principle of the conditions for existence” stating that each part of the animal has a form determined by all the other parts, which ultimately relies on the contribution it makes to the viability of the organism in its environment,29 here too we find a schema of circularity (Cuvier, 1802, 1817).  I abbreviate “heart-death conditions brain-death” using “heart → brain.”  For a classical statement of the principle, see “Discours sur les révolutions du globe” in the Prologue to Recherches sur les ossements fossiles des quadrupèdes. 28 29

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In fact Cuvier stood in close connection to Kant’s formulation—having himself studied in Germany, at Halle, with professors influenced by the teachings of Kant—and his principle instantiated to some extent Kant’s concept of organism as a circular and causally closed totality.30 Insofar as it is circular and closed in on itself, a given organism possesses an individuality through which it stands against and relates to its environment. In the present analysis, Bichat’s “Recherches sur la mort” develop, from the standpoint of physiology, a way to experimentally address the circularity of organisms that parallels the approach led by Cuvier at the same moment, which mostly relied on the method of comparisons between extant species (comparative anatomy). In a way, understanding death allows Bichat to step into this circularity of the living, the observation of which constituted the first part of the Recherches sur la vie et la mort.

5.4  Organs and Functions Is this opening of vital circularity the only conceptual connection between the two moments of Bichat’s book, the “Recherches sur la vie” and the “Recherches sur la mort”? To the extent that the focus of the former was turned more towards functions (with the problem of their division) and the latter towards the sequences of the organic activities, we expect that the relation of the functional to the organic represents another intended connection within the book. Indeed, by studying the sequences of death, the “Recherches sur la mort” also analyzes how the two lives distinguished in the “Recherches sur la vie” (animal life and organic life) are linked together in nature. To this effect, each type of life must have a corresponding organ. Bichat establishes this as he progresses. Indeed, while the brain is the principal organ of the animal life, since it commands the nervous system, and the heart that of the organic life (as indicated by the classical fact—recalled in the first part—that the heart is the last to die in a natural death), the “Recherches sur la mort” reveal the role to be attributed to the lungs: these are the seat of both mechanical and chemical phenomena, the former governed by the nerves and thereby connected to the brain, hence pertaining to animal life, whereas the latter

30  Huneman (2006, 2008b, forth.) develops an analysis of the Kantian foundation of Cuvier’s principle for comparative anatomy and paleontology.

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pertains to the organic life since it is independent of the animal nerves: “This is why the existence of the lungs is just as tightly linked to that of the brain [...] as that of the heart.”31 Respiration is therefore a “mixed function” (ibid.), an intermediary between the animal life and the organic life; the lungs mediate these two lives (which also explains the singular nature of the lung-death sequence, as seen above). In the reality of the body, the twofold functional schema of the first part of the book (organic/animal life) thereby corresponds to a threefold organic schema centered around the lungs, this latter correspondence implying that the “Recherches sur la mort” also reveal the sequence that connects the two classes of function. The first article of the “Recherches sur la mort” indeed notes that the “mode of influence, link between the two lives” is situated between the brain (for the animal life) and the lungs and heart (for the organic) (article 1, § 1, p. 166). In this, it indicates that finding the relation between the two lives is the aim of the investigation, or to be more precise, that this relation matches exactly with (and is constituted within) the circular interaction of the lungs, the heart, and the brain. As Bichat puts it in this formula: “The action of one of these three organs is essentially necessary to the action of the other two.” Speaking of the two lives, Bichat writes: “Although a host of characters distinguishes them, their principal functions are nevertheless linked together in a reciprocal fashion” (ibid.). While the first part of the Recherches, about “Life,” analyzed these differences, the second part— about “Death”—aims to retrace the reciprocal link or sequence between the two lives via the experimental examination of the organic process. This unity between the two parts of the book is marked by repeated use of the concept of “influence”: in the first part, the organic life influences the animal life (this is the secret of the passions); in the second part, the death of an organ influences the death of the others. This voluntarily indeterminate term highlights the specificity of biological causality: less linear than circular, less determined than plurivocal, from the beginning to the end of the text, this causality occupies the horizon of Bichat’s investigation. Yet the phenomenon of death precisely lends itself to such a loose or vague concept of causality since, in light of the fact that its investigation aims to

 Recherches..., Part II, art. 10, § 2, p. 330.

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retrace an etiology along the combined paths of anatomo-pathology, clinical approach, and statistics, it can only provide an account of influences that have by themselves no decisive causality as Fagot-Largeault (1989) has shown (§ 7.3.6, p. 370).32 Thus, while the “Recherches sur la vie” looks to humans—to such an extent that some like Albury saw it as a medical anthropology—we that the second part, since it is experimental, proceeds by considering superior animals, in order to get into the very materiality of the body and the organic relations underlying the distribution of functions, as these had been traced out in the first part. In this, by furnishing it with an organic reality, the “Recherches sur la mort” confirm the legitimacy of the physiological partition conducted in the “Recherches sur la vie”; it is as though Bichat, in his desire to transform physiology into a science, were tracing a reverse path from death to life in accordance with the “Recherches sur la vie”—a reverse path none of the other turn-of-the-century savants who subscribed to the same project of a “natural history project of man”33 would ever have suspected. By constructing the book in this way, anchoring the knowledge of life and its functioning within the experimental investigation of death, he makes the physiology of life appear in a radically different light. And, undoubtedly, on this point again we can identify a proximity between Bichat and Pinel, since the latter also broke the boundaries of eighteenth-­ century anthropology in his Treatise by placing the possibility of becoming mad at the core of man-as-subject.34

32  Indeed, Fagot-Largeault remarks that “a hundred and seventy-six years after Bichat, the causes of sudden death have barely changed,” and underlines the enduring stability of the “explanatory examination schema” as first established by Bichat (§ 5.1.5, p. 260). 33  As Cabanis named it, a project to which the first part of the Recherches aimed to contribute. As mentioned in the previous section, Cabanis (1802) is the main example of such anthropology. See Williams (1994) and Huneman (2008a) for an account of the project of a “natural history of man” under these naturalistic lines, and Staum (1978) for a specific analysis of Cabanis’ views—which differs, because of the focus on medicine, from the earlier anthropological projects such as Buffon’s, anchored in natural history in general; and more generally, Wolff and Cipolloni (2007) on anthropology in the Enlightenment. 34  On the role of the possibility of being mad in Pinel’s advances towards psychiatry, see Huneman (2008a, 2014).

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5.5  Interpreting the “Recherches sur la mort”: A New Understanding of the Living 5.5.1   Physiology, Anatomy, Pathological Anatomy We can see that for Bichat anatomy and physiology (respectively, the study of organs and the study of functions are inseparable), because they both revolve around experimentation and death, that is, the notion of deathinducing organic sequence-schemata. Anatomical deduction (namely, deducing the function of an organ from the anatomical consideration of its shape) and tissue-based experiments are no longer the unique methods for physiology, which is precisely the novelty here.35 If certain traces of an anatomy-centered knowledge do remain in Bichat’s work, then they are the remnants of a tradition that had not yet died out but that are given no place in the infrastructure of the new scientific complex Bichat was constructing with experimental physiology and histology. This infrastructure takes form through the relation between life, death, and experimentation, which itself relies upon the triplicity of organs, functions, and sequence-­ schemata. Bichat’s own works on anatomy, along with his conception of a pathological anatomy, are a testament to this. The fact that the various tissues are characterized by properties (as demonstrated in the “Recherches sur la vie” after the Anatomie générale) is so that they can participate in sequences with other tissues and thereby accomplish given functions.36 And insofar as these tissues are “organic elements,” organ-death, as studied by the physiologist, relates back to their specific morbid affections. Knowledge of diseases therefore involves knowledge of how the causal tissues are affected (and not mere knowledge of the symptoms),37 hence medical knowledge too, like modern experimental physiology, drew the objects of its study from consideration of death. This is the very sense of the famous declaration from the “preliminary discourse” of the Anatomie 35   About the methods of seventeenth- and eighteenth-century physiology, see Duchesneau (1982). 36  We noted earlier the selective role played by the sensibility of a tissue. 37  This is at least the case for diseases that attack a given organ, rather than those that attack “the general habit of bodies” (Anatomie pathologique, p. 1), even if the former are the more numerous (Anatomie générale, “Discours préliminaire,” § 7). Among the latter, Bichat places “essential fevers.” It was Broussais who, after a long dispute, managed to move fevers into the set of local affections some twenty years later, thus completing the triumph of pathological anatomy (Broussais, 1832; see Foucault 1963, ch. X).

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générale: “What is observation if we do not know where the ill resides? […] Open up some cadavers, whereupon will dissipate the obscurity that observation alone could never have dissipated.”38 Of course, localism—namely, the idea that pathologies have a cause to be thought in precise anatomical localisation—has a history that long predates Bichat (himself citing Morgagni),39 but it could never have grown to the extent that pathological anatomy went on to in the period following him, for the simple reason that it never so deeply and coherently undertook a configuration of our scientific understanding of the living wherein the truth of the vital phenomena arose from examining the processes underlying death.40 This configuration, let it be stated again, had the capacity to reconcile vitalism—which, for Bichat, is simply the term given to the stance that the science of living beings can be an autonomous one—with the claims of a positive knowledge and a rational medical science,41 something the earlier vitalists could never have formulated. The epistemological coherency of experimental physiology, histology, and pathological anatomy can thus be observed in this introductory declaration from the Anatomie pathologique of 1805: “It is advantageous to discover the connection between the cadaverous phenomena and those which preceded them” (p. 9). Should we wish to represent the relations in Bichat’s work that link general anatomy—taken as the theory of original properties and tissues— to physiology, then it could be useful to turn to the difference Judith Schlanger describes between what is “founding” and what is “constituting” a science42: general anatomy founds Bichat’s science because it contains its first principles; physiology provides it with the tools and attitudes that will enable this set of principles to get a handle on real phenomena and thus give rise to an understanding of the processes involved, thereby constituting it. In a certain sense, this founding/constituting duality can  Bichat (1801), p.99.  He who “created the science of pathology” (Anatomie pathologique, p. 3). Morgagni’s De sedibus et causis morborum dates to 1761. In stark contrast to Bichat, his diversification of the affections was primarily organ rather than tissue based. For an account of his work, see Ghosh (2017) an Zampieri (2012). 40  See footnote above. 41  Earlier nosographies had seen themselves as either descriptions of essences or else guides for practitioners, Cabanis being an example of the latter (Cabanis, 1788, § 4). Conversely, Bichat demanded the same status of invariance in the results of his pathological anatomy as in the objects of his experimental physiology: “A nosography based on the affection of the organs would necessarily be invariable” (Anatomie pathologique, § 3). 42  Schlanger (1971), p. 174. 38 39

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be found in the Recherches themselves, in the relation between the two parts of the text, as we have just analyzed them. 5.5.2   Concepts and Institutions Constituting a science therefore implies the production of concepts which are not only mental representations but also “handles” on the object to be understood. In this sense, constitutive scientific concepts are only fully intelligible when examined in light of the practices and institutions through which they ultimately also become techniques. Thus, Bichat’s physiology made use of the institutional transformations of his time (see Box 5.1). Box 5.1  Hospitals and Experimental Physiology

The reorganization of medical teaching around 1780–1790 took its cues from the teachings of the College and Academy of Surgery, in particular that at Hôtel-Dieu, reformed by Pierre-Joseph Desault from 1785 onward. Desault established the “clinical surgical lesson” consisting of an operation, a case history of the patient, and, when fitting, an autopsy aimed at discovering the nature of the disease at hand, its “location” and the pathological changes it had brought about.43 Surgeons were therefore able to infuse medicine with a specific sense of touch and the palpation of bodies, dimensions which were to be central to the new clinical school.44 But they also brought with them a technical know-how, without which the “experiments on living animals” would not have been possible, as Lesch (1984, ch.3) has previously underlined in reference to the experimental devices conceived by Bichat in the Recherches. (continued)

43  Gelfand (1980), p.  124. The author provides a detailed analysis of the Paris medical school where modern anatomo-clinical medicine was born. He shows how it borrowed certain particularities, pertaining to both the institutionalization of surgery and to surgical teaching, from the Royal Academy and College of Surgery. These institutions, dating to the first half of the century, were an extension of the Saint-Côme and Paris Academies for barbersurgeons, unified by the king in 1656. For a general overview of the changes within medicine at the period see Brockliss and Jones (1997). 44  For a first and pioneering analysis of the role surgeons played in the rise of clinical medicine, see Temkin (1977).

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Box 5.1  (continued)

Desault, in particular, was one of the first to have confrontations with ecclesiastical hospital staff when he demanded a medical rather than an ecclesiastic management of hospital business. He ultimately won his fight, thereby setting down the modern concept of the hospital as a place of healing rather than a hospice (Brockliss & Jones, 1997; Gelfand, 1980; Weisz, 2006). But the hospital was also the place where different potential treatments for the same affection were put to trial. The keeping of registers and calculation of statistics, indicators of the number of deaths and recoveries for a given disease under a given treatment, became the instrument that enabled group tests of diverse, competing treatments to be conducted on a population of patients.45 The hospital had now begun to produce medical knowledge of its own, not forgetting that, as the theater for the clinical surgical lessons, it was also the forum par excellence for teaching. Foucault (1963) showed how, in becoming an anatomo-clinical medical practice, medicine began to accrue even more knowledge about the individual. “It was when death became epistemologically integrated into the medical experiment that disease was able to detach itself from its contra-nature status to become embodied within the living body of individuals. […] From the establishment of death within medical thought was born a medicine that presented itself as a science of the individual.”46 We can use this perspective to revisit certain teachings from Bichat’s Recherches. Indeed, we saw that the second part of the book established models, short “death stories” that plot the sequences through which death overcomes the individual. In the same way, in the first part, the concept of temperament—a concept specific to all eighteenth century anthropological physiology—exposes how human life is diffracted through the multiplicity of individual human beings. Life and death are always singular, but they can be known because they fit into types: a particular temperament, a particular “death story.” It is a kind of physiological typology, reshaping medicine into a knowledge of singularity. (continued)

45  For a careful investigation of these new techniques and how they came to pervade medicine in the first decades of the nineteenth century, see Ermakoff (2012). 46  Foucault (1963), p. 200.

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Box 5.1  (continued)

Of course, medicine has always, as Aristotle put it, treated “this man here” rather than “mankind”: but the price to be paid for this is the “empirical,” speculative, conjectural aspect of this “art.” Now, in the modern hospital, two practices upon the individual suddenly come together: the medical art and the monitoring of mortality tables, first begun in the sixteenth century to record variations in populations of individuals (rate of death according to age, gender, etc.). Bichat’s project was to constitute medicine and physiology as sciences; this transformation required, as we have seen, a configuration in which death was integral to knowledge. But by drawing up particular models of death, short stories, he allows medicine to conserve its knowledgeof-the-individual character while also freeing it from empiricism and conjecture. By their very possibility, such stories tend towards the notion of the “case,” which was emerging from within the nascent hospital practice consisting in a twofold analysis of the individual: a “case” was an individual touched by an illness, an individual who had undergone either surgery or perhaps even death, the subject of a sequence of events that ultimately gave rise to a “case history” to be retraced as part of the clinical surgical lesson 47; a “case” was also an element in a set of cases similar in some given way, dissimilar in others (treatment, antecedents, operations, etc.), in other words, a variation in a population of similar individuals that was to be recorded in the register of the hospital.48 We discover just such a twofold object in the short death stories found in the “Recherches sur la mort”: at once a variation on the theme of violent death and also a narrative sequence, a twofold dimension that clearly prolongates the two dimensions of hospital practice, the combination of case histories and the construction of therapeutic and pathological sets of comparable cases. A text of pure physiology, propped up by animal experiments, the second part of the Recherches, the “Recherches sur la mort”, nevertheless reflects many facets of the then emerging reality of the hospital institution.

 For a parallel analysis of the notion and use of “case study” and “case history” at the same time by Pinel, when he contributes to establish psychiatry as an autonomous medical discipline, see Huneman (2014b). 48  On the administrative practices in hospitals at the times, see Weisz (2006), Brockliss and Jones (1997). 47

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Educated for two years at the school of the great anatomist Marc-­ Antoine Petit in Lyon, Marie François Xavier Bichat was initially a surgeon, a student of the most celebrated surgeon of the period, Pierre-Joseph Desault (Bichat’s first publications were works on his mentor), who he later succeeded as the surgeon-in-chief of the Hôtel-Dieu. However, surgeons in France at the time of the Revolution underwent a remarkable change in status: socially speaking simple artisans, they rose to become the equals of doctors. When the Revolution decided to bring reform to the domain, it closed the Schools and Academies dedicated to medicine but not the Academy of Surgery, thereby creating a situation where surgeons were called upon to play a role in the evolution of medicine.49 Thus, the notion of pathological anatomy demands that it be linked back to Bichat’s surgical training.50 Bichat himself indeed stresses the decisive role played by surgery when he makes the following remark in the preface to Desault’s Oeuvres complètes: “I am no longer engaged with surgery, except insofar as it is an essential base for all medical knowledge, an important means of analogy in a multitude of difficult cases, and a guide without which medicine would often proceed at random” (my emphasis). The fact that Philippe Pinel—although being the acclaimed author of the Philosophical nosology, which was the clinical guide for generations of physicians after 1790 (Pinel, 1797)—was never fully able to understand the scope of pathological anatomy, insofar as it condemned nosological medicine as a mere classing of disease-entities is certainly related to the fact that he was a doctor and not a surgeon. In other words, for Pinel, one of the masters of the physicians who created the “école clinique de Paris” (Ackerknecht, 1967; Weisz, 2006), to know was to see, to draw up tables of symptoms and ultimately tables of diseases: Pinel could not conceive that the truth might be found at the tips of a touching approach, in the palpation and manipulation of wounded flesh. Before the times of Bichat and the “école clinique,” the classical doctor’s business was with immaterial, invisible entities—diseases— and his craft was to track their visible signs51; the classical surgeon’s business was lesions, to a greater or lesser extent exterior, material, palpable. Thus, in parallel to the diseases of the doctors, there was a “surgical concept of 49  Sournia (1997). On the Academies and Faculties of Medicine that were closed, the creation of a corps of “officers of health,” the abolition of corporations and, by the same measure, the granting of medical diplomas, as well as on the re-opening of the Paris and Strasbourg Schools of Medicine, see Foucault (1963), ch. III and IV; Ackerknecht (1967). See also Gelfand (1980). 50  Quoted by Gelfand (1980), p. 186. 51  About what “Observation” meant for early eighteenth-century medicine, see Singy (2006).

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disease,” of which “medical diagnostic and pathological anatomy formed dependent parts,” and which “found its fullest expression at the end of the eighteenth century in Desault’s school at the Hôtel-Dieu.”52 Because he began as a surgeon, Bichat was able to accord all due importance to the idea that there was a correspondence between lesion and disease. Smyth, a physician from the Edinburgh school from whom Pinel had undoubtedly borrowed the idea (Keele, 1979), was paradoxically closer to Bichat, since he elevated pathological anatomy to the status of principle, rather than including it within nosological medicine, by casting lesions as supplementary symptoms. But he too, although a clinician rather than a surgeon, nevertheless belonged to a milieu populated by surgeons. The De sedibus ... by Morgagni (1761), illustrious forefather of pathological anatomy, owes much to the structure of the Padua School of Medicine at the beginning of the eighteenth century, where “doctors and surgeons were not separated as rigidly as elsewhere.”53 To generalize, this Padua school, the Edinburgh school a little later, and the Paris school following the Revolution all present an analogous structural particularity: the proximity maintained between doctors and surgeons. Yet in each case, the idea of a pathological anatomy was advanced in these places. It was Bichat, however, who, by integrating it into a new type of knowledge of living beings, one that manifested the coherency between anatomy and physiology which we have endeavored to analyze here, was in a position to make it a linchpin of medical knowledge, the pivot between consultation and hospital, pathology and physiology—in such a way that the status of medicine and the conception of disease would later be transformed. It is clear that the institutional metamorphoses hospitals were undergoing during the same period represented a decisive historical difference between Bichat and, before him, the Padua or Edinburgh schools. In this sense, Bichat’s physiology manifests the re-internalization of the structural changes of the hospital and of medicine (the place of surgery, the use of registers and statistics in the hospital, now become a place of healing and knowledge) into a conception of the living and the establishment of a route to its intelligibility. Far from the history of ideas being determined and explained by general history, we see here, in the example of Bichat and his contemporaries (see Box 5.2), that the real and undeniable autonomous conceptual development presupposed a sort of internalization of its socio-historical conditions (in this case, changes in the status of medicine, of surgery, and of the hospital).  Gelfand (1980), p. 183. On the Padua school, see also Porzionato et al. (2012).  Porzionato et al. (2012).

52 53

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Box 5.2  Bichat and John Hunter

These remarks about surgery and the new physiology find support in what another member of the Edinburgh School of Medicine, John Hunter, had developed a little before Bichat on the basis of strikingly similar considerations and, more precisely, in relation to surgical classes. A student of William Cullen, 54 doctor, author of A Treatise on the blood, inflammation, and gunshot wounds (1794) and Lectures on the Principles of Surgery, credited with a not insignificant contribution towards comparative anatomy, made possible by the large collections of organs and various animals held in a museum founded for just that purpose (Cross, 1981), John Hunter, like Bichat, conceived of life as a special force, always struggling against the material nature that leads it towards death. Like many of his contemporaries, he attributed vital properties to the vital elements, which he viewed as irreducible to mere matter. He saw two orders within animals: that of the organs, each of which fulfills a function in the animal economy, and that of the vital parts which make up the animal—flux and vessels—, each of which has its own “power of action” and the combination of which constitutes, in a certain sense, the basis of the animal economy while also accounting for sympathetic phenomena. Ultimately, what we get is something analogous to Bichat’s general anatomy as I described it above. Furthermore, Hunter too thought that disease was not a foreign entity but, like Bichat and especially—although later—Broussais, rather an alteration in the actions and parts of the organism. Pathologies are “the perversion of the natural actions of the animal economy” (Hunter, 1835, 211). In this sense, he imagines a coming together of physiology and pathology not too far removed from the union Bichat would go on to establish. In particular, he carried out autopsies in order to understand the internal lesions that explain disease. (continued)

54  Cullen was an important figure of the Scottish Enlightenement, and a friend of David Hume. See Clayson (1993), and Demeter (2021), who argues that Cullen instantiated a method of philosophical chemistry inspired by Newton’s Optick rather than Principia, which was influential upon Hume’s method in moral philosophy.

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Box 5.2  (continued)

Death, in a way, is a divisible and explicable process. With the disease that precedes it, it becomes a source of knowledge for physiology, notes Hunter :“[we] are also obliged to Disease for many of our hints on the animal economy, or for explaining the actions of parts, for the wrong action of a part often points out what the natural action was” (Hunter, 1835, 220).55 In comparative anatomy, monstrous forms shed light on the inter-dependencies between organs, since their natural correlation leads to actions that are rendered impossible in the monster. Monsters, disease, death: these negative dimensions of life now possess the resources of a certain knowledge, the outline of which cuts across the double axis of teratology and pathological anatomy. The proximity of this to Bichat’s conceptual apparatus should now be clear (the essential difference of course being the experimental dimension of Bichat’s physiology, where for Hunter the science of the living was directly related to comparative anatomy, which places him closer to the interests of Cuvier at the same period).56 However, institutionally speaking, the two authors were writing in similar surroundings, as regards the relation between medicine and surgery present in their respective environments. It seems as though the very injection of surgery into medicine opens the way to a medicine and a physiology for which positive knowledge about life itself (rather than about disease in particular) can be acquired only through a confrontation with death as a process (Bichat) or with the dysfunctions inherent to monstrosity (Hunter): in a word, with what philosophers such as Hegel would soon call “the negative”.

55  These few elements would lead us to count Hunter’s writings among the principal building blocks in the formation of Bichat’s own thought. However, the present section is less a historical account of Bichat’s intellectual formation, than an epistemological inquiry about the role played by death in the establishment of experimental physiology. It’s much more an archaeology of the conceptual space of physiology, than a history of physiological doctrines— “archaeology” naming here the relations of conditioning and incompatibility between concepts, discursive elements, and experimental designs, rather than the causal history of influences, teachings and break-ups. The precise difference between Foucaut’s analyses— who famously used this term—should become clear throughout the book. 56  On the relations between physiology and comparative anatomy in Hunter, and for an assessment of the historical meaning of his work at the crossroads of natural history and biology, see Cross (1981), which was the main inspiration for this Box.

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5.6  The Specificity of the Living According to the Nascent Experimental Physiology Bichat’s legacy was adopted in separate elements: the pathological anatomy by Broussais and his “physiological medicine,”57 by François Laënnec,58 and by the entire École Clinique in Paris; the physiology by François Magendie (1783–1855), exemplified by Magendie (1809) and its many references to Bichat, Félix Legallois, and their disciples until Claude Bernard. The diversity of the works involved, sometimes even their contradictions, can obscure their relevance to one and the same organization of knowledge; both traditions are, by their origin, related to an identical form of intelligibility of living beings, centered around the positive epistemic power of the dying body. In what way then, as a result of this intelligibility, do the life sciences at this period and in this configuration distinguish themselves from the other sciences? Through death, the living being is laid open to our understanding without any departure from the vitalist framework, and this is precisely how experimental physiology was born. Death is therefore anchored in life, it is that very extension of life through which knowledge can gain access to it. This may seem to contradict Bichat’s explicit position, which plainly opposed the vital forces and the physico-chemical, death-inducing forces, the latter continuously struggling against the former, the former constantly changing their physical laws, as the “Discours sur l’anatomie générale” tells us, and as Stahl initially formulated it. Physics and chemistry are the death within the living, even as they contribute to its functioning, as Bichat among others says in the “Discours” when he stresses the necessity for physiology to include knowledge of the physical and chemical laws: without this, physiological experimentation, which makes use of 57  For Broussais, all disease had to relate to an organic lesion, which in final analysis was generally an irritation that could be cured using either bleeding or leeches. His medicine gave rise to a uniform therapeutic, a system, like the earlier “Brown system” which identified as the root of all disease either an excess or a lack of force (“asthenia”). Moreover, unlike his peers, Broussais was first a military doctor, something which hindered him from initially identifying medicine and clinical practice, as could be found at the École Clinique in Paris (Laënnec, Bayle, etc.) which he would later vehemently criticize. See Brockliss and Jones (1997) about these episodes and their context. 58  Author of the first ever classification of tissue alterations, in one of his classes in 1803 and then in the 1812 Dictionnaire de médecine, though perhaps he is most known for his 1815 Traité de l’auscultation mediate.

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physical and chemical means, would be impossible. But precisely because life is resistance to death, it is in some way subordinate to it and ultimately condemned to die, since death is its very condition. Pushed to the logical extreme of its own implications, the vitalist definition weaves death into the very essence of life. This explains why the vitalist expression of an irreducible difference between gross body and living body boils down to the affirmation that the specificity of the living is to die, combined with its ability to override life through disease. “The history of the phenomena in which the vital forces find their natural type leads us, as a consequence, to the history of the phenomena wherein these forces are altered. But in the physical sciences there is only the first story: the second is nowhere to be found. […] It is in the nature of the vital properties that they be exhausted.”59 Bichat’s work consisted in fleshing out this structure until it became a thick bundle of epistemological relations capable of upholding experimental physiology. Notwithstanding formal similarities, his definition of life as a “set of functions that resist death” can therefore not be equated with the definitions of Stahl or Barthez, who championed the idea that life is a constant (and deemed to failure) fight against death as chemistry. The reason for this is that Bichat’s definition accounts equally for vital resistance as for, on a more profound level, the anchoring of vitality in death, but also for the possibility of knowledge this mortality thereby constitutes. Correlatively, the autonomy of this science of the living, compared to the science of nature, stems from the mortality that gives it its rigor yet which belongs, in the strongest sense, to organized beings.

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Staum, M. J. (1978). Medical components in Cabanis’s science of man. Studies in History of Biology, 2. Temkin, O. (1977). The role of surgery in the rise of modern medical thought. In The double face of Janus (pp. 493–507). Baltimore: John Hopkins University Press. Weisz, G. (2006). Divide and conquer: A comparative history of medical specialization. Oxford University Press. Williams, E. (1994). The physical and the moral: Anthropology, physiology, and philosophical medicine in France, 1750–1850. Cambridge University Press. Wolff, L., & Cipolloni, M. (edS.). (2007). Anthropology of the Enlightenment. Stanford: Stanford University Press. Zammito, J. (2018). The gestation of German biology. University of Chicago Press. Zampieri, F. (2012). Da Morgagni alla patologia molecolare. Teorie e modelli dell’anatomia patologica. Libraria Padovana Editrice.

CHAPTER 6

Life and Death in Experimental Physiology After Bichat

Bichat’s experimental physiology constructed a new framework for knowledge, life, and death. The only way for us to evaluate its resiliency, and to assess my claim about the constitutive role played by the focus on death and death processes within this epistemological structure, is by examining what became of it in subsequent decades. Continuing Bichat’s research, François Magendie—a professeur of physiologie at the Collège de France in Paris, and the master of Claude Bernard who as young student was préparateur (namely, research assistant) for him in this setting—made some structural transformations to the new experimental physiology. These I shall review, along with the features that remained constant. But I shall focus my scrutiny on Claude Bernard, in particular. He wished to be viewed as the inventor of experimental physiology, and his achievements and originality are undeniable. It appears from what precedes, however, that when one wants to pick up one it was Bichat who laid the basis for this physiology, and overcame some of the conceptual obstacles that were hindering its development. Let us first resituate Claude Bernard in a tradition that, through Magendie, connects him to Bichat, with whom he is in constant discussion. Then I will measure the gap that separates Claude Bernard from the founder and evaluate the meaning of experimental physiology as a mature science, as well as the changing role death played within it. This will eventually confirm the

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crucial role of death as object study constituted through novel epistemological features elaborated by Bichat’s Recherches (experimental devices, sequence-schemata, etc.)

6.1   François Magendie and Bichat At the Collège de France, Bernard describes François Magendie—whom he assisted at the beginning—as a “rag-picker of facts”: a pure empiricist, naturally suspicious of any theoretical elaboration. Pursuing the experimental direction Bichat had given to physiology, Magendie arrived at important discoveries, like the distinction between the functions of the ventral and dorsal roots of the nervous system, one being motor and other sensory. Nevertheless, Magendie expressed strong reservations about Bichat’s theory of “vitalism,” as I will detail it now. Magendie effectively asserted that in the end of the analysis, “nutrition” and “action” are the only phenomena common to all organisms (e.g., the kidney secretes urine, the liver secrets bile, etc.). But there is no point in seeking to reduce these phenomena to the principles of physics, of gravity, inertia, and so on: it is and must be sufficient to recognize vital existence as such. As for the vital properties, before discussing their nature, it would have been better to begin by cataloguing the physical properties of living tissues (Précis élémentaire de la physiologie, I, p. 27),1 thus rejecting the usual way of formulating the question, which assumes that a few properties are common to all livings qua living. In contemporary terms, Magendie’s science proceeds in a mostly bottom up way, while physiology of the Montpellier vitalists as well as Hallers physiology embraced a more top-down view, where the properties of the living are a priori fixed and then ascribed to individuals (organs, tissues). To see vitality expressed as different properties, depending on different organs, is already a too risky inference. Magendie thereby challenged two pillars of Bichat’s vitalist theory: first, against what Bichat took from Stahl, even though the properties of the living are irreducible to chemical and physical properties, this does not mean that there is any struggle between the two orders of phenomena.2 1  One of Magendie’s important books is Leçons sur les phénomènes physiques et chimiques des vivants, Paris, 1842. 2  Magendie contended that the vital properties had been “romanticized” and even that “philosophers had anthropomorphized molecules” (Précis, p. 30).

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Secondly, the supposed analogy between vital properties and gravity— advocated by both Haller, Bichat, and the Montpellier vitalists—misses what is essential: that is, the mathematical laws of gravity given by Newtonian science. It is essential because science is about detecting regular correlations rather than unraveling hidden natures: paradigmatically, the glory of Newton does not consist in having “discovered attraction,” but in having “established that it acts as a direct function of the mass, and inverse of the squared distance” (Précis, 15). But the vital properties are indeed not subject to any quantitative laws.3 Sensibility in general and insensible fibrillary contractility suffice to describe the phenomena of life, and even these two properties are merely pragmatic assumptions, not facts. Finally, wary of sinking into the “novel of physiology,” Magendie was driven to confining his science to the level at which the phenomena are accessible to our senses. Ultimately, the subject of physiology is the visible effects of vitality, the primary causes of which are assuredly beyond understanding. “All the phenomena of life, then, may be comprehended under nutrition and vital action; but the concealed molecular motions that constitute these two phenomena are not amenable to our senses, and it is not upon them that our attention should be fixed; we ought to study only their results, that is, the physical properties of the organs and the perceptible effects of vital actions, and endeavor to discover how they both concur in the general effects of life.”4 Magendie was utterly pragmatist: the metaphysical issue of the separate nature of life is not even addressed, and physiology should proceed in a bottom-up way, based on data that the physician would have gathered. It is therefore more rational to say that we don’t know anything about the substance of what behaves in physiological and biological way, and just describe these behaviors, the regularities we can observe, and relate them to chemical and physical regularities involved in them and manifest experimentally. Therefore, Magendie defined physiology as the study of functions, rather than of vital properties or anatomical parts. He divided the functions that mediate the individual’s relationship to the world into two categories: nutritive and generative—which fits Bichat’s template, although it should be noted that for Magendie, the “nutritive” function is life itself: in other words, Bichat’s organic life.5 Magendie proceeded by experimentation.  Ibid., p. 34.  Ibid., p. 37. 5  The other author to whom Magendie refers is Cabanis (see Temkin, 1946). 3 4

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In an important essay, William R.  Albury points out that although Magendie borrowed Bichat’s experimentation method, he plunged it into a radically new context, freeing physiology from anatomy by his indifference to tissues themselves.6 Albury relates this conception to that of Cuvier who, a little earlier, moved the science of the classification of living things (natural history) to the investigation of life itself (biology).7 From this perspective, Bichat belongs to eighteenth-century science, and Magendie brings physiology up-to-date with Cuvier. The essence of this reasoning is that although it is true that Bichat used experimentation in his Researches, the experiments were never more than confirmations of suggestions derived from observation: experimentation as “an extension of observation” (Albury, 1981). For Albury, in other words, Bichat, like the school of Montpellier, thought that life must at first be observed as the phenomenon of a whole—this is what he does in the first part of the Researches, while in the second part, he conducts experiments, like Haller, to know the parts. This is where according to Albury Magendie broke away from Bichat, by asserting that experimentation provides both adequate access to the functions of life and a pathway for exploring new questions. “The methodological opposition between Bichat and Magendie arises not from a difference in experimental techniques (rudimentary as opposed to sophisticated techniques), nor from differing metaphysical conceptions of life (vitalism as opposed to mechanism, or spontaneity as opposed to determinism), but from the perspective of the experimental investigation (an investigation of observation as opposed to an investigation of experimentation)” (Albury, 1981). Clearly, these discussions consisting of separating the Ancients from the Moderns, and attributing to one or the other (Haller, Bordeu, Bichat, Magendie, Claude Bernard, Cuvier, etc.), the glory of having discovered new epistemological continents could go on indefinitely. We shall therefore accept Albury’s reasoning as it is: from his point of view, Magendie is the father of modern experimental physiology, just as Cuvier is described as “the father of modern biology.” Nevertheless, although Magendie may have established the investigation procedure for research in experimental physiology, it seems to me that all of Bichat’s work was necessary to build the foundation for Magendie’s theory. Experimentation according to 6  “Magendie held that the functions themselves should be the focus of physiology, not the properties and activities of anatomical parts, be they organs or tissues” (Albury, 1981, p. 90). 7  Obviously, here Albury draws on Les Mots et les choses by Foucault.

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Bichat is doubtless an extension of observation, and the second part of the Researches may obey the endeavor to define physiology as a natural history of human beings developed in the first part (and specific to the latter half of the eighteenth century, cf. supra, chap. 3, §1.5), as Albury demonstrates. However, it is also true that Bichat elaborated all of the following: the possibility that experimentation might be the key to the interorganic processes making life alive; that death is what mediates life as an act and the knowledge of this life; and the spread through time and space of knowable vital processes, thanks to experiments on death. I therefore eventually reject Albury’s thesis, because it overlooks what’s mostly original in Bichat’s physiology, namely, the shift towards a study of death as the gate to experimental knowledge of organic circularities. Without Bichat, the theory of pure experimentation in physiology could not have been reached. Looking back from the present day, the two authors, Bichat and Magendie, form a fairly cohesive couple, spawning the implementation of new concepts, techniques, and theories. If the two are compared, Magendie’s radical novelty is always detectable, but only because Bichat, earlier, achieved a paradigm shift that made Magendie’s new ideas thinkable.8 In any case, Magendie departs from Bichat by dispensing with a multitude of vital properties in order to explain the diversity of vital phenomena organ by organ. According to Magendie, these effects can be understood by the simple fact that they are the result of differences in the organization of the bodies: “the phenomena whereby the presence of vital force is manifested in bodies are always directly related to the organization of these bodies,” so that “when the vital force animates a body with a given organization, it will produce given phenomena” (Quelques idées sur les phénomènes particuliers aux corps vivants, 1809). Regarding the role of death, Magendie therefore gives up Bichat’s commitment to a metaphysical opposition between the living and the non-living, and would not subscribe to his definition of life as forces joined against death, even though the experimental apparatus of physiology he’s using inherited Bichat’s project of a physiology; according to him, this statement would go far beyond what our observations and experiment allow us to claim. Nothing authorizes us to make any principled 8  A similar relationship links Pinel and Esquirol as the fathers of modern psychiatry, if Gladys Swain’s 1976 analysis is applied.

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differences between the metaphysical forces that support the physiological properties and behaviors, and the physical forces that explain the natural phenomena investigated by physicists. Actually, the apparent irregularities, variations, and unpredictability that we see in the case of physiology and pathology could perfectly be ascribed to a lack of understanding, observation, and information from our side, with no need to attribute these properties to the natural forces themselves. We can only hope that progresses in our observations and experiments will ultimately bridge the gap between the degree of completeness of our knowledge in physics, and the current state of physiology. Yet epistemologically Magendie was not exactly a pure behaviorist or phenomenist. He admits some “forces” that are involved in living phenomena, and that are manifested each time a biological phenomenon happens, since he acknowledges that there may be an unknown force acting within living bodies. However, he refuses, against what he sees as vitalism, to ascribe to them some distinct properties (such as plasticity, etc.) that would make them proper to the living realm, and therefore view them as ontological entities that instantiate a specific and independent ontological realm. Instead, he conceives of these forces as pure unknown references of designations that we make in specific contexts of scientific descriptions. We just label “vital force,” he says, “an unknown cause of the phenomenon of life.” We have to recognize these forces, because they are supporting the constant connections between phenomena that we can identify through experiments and observations, and because we need them to turn the pure establishment of connections into useful relationships of causality. This brings to the borderlines of determinism: certain conditions produce certain effects. The specific nature of the vital force separates us from it; but insofar as the diversity of its effects are due to the diversity of the organizations it touches, this force is devoid of characteristic predicates. As a result, there is absolutely no logical need to call upon a force that differs from physical forces—since nothing makes it possible to prove that the assumed irreducibility of the effects of this life force to the effects of physical laws is not also the result of the uniqueness of the organization of living bodies. By speaking of a “vital force,” Magendie suggests a hypothesis that is irrelevant, in view of the principle that he has just formulated. Nevertheless, he continued to mention it. Claude Bernard took a decisive step when he eliminated the concept of force, as I will show now, since his novel concept of the milieu intérieur, or internal environment, stripped the physiological discourse of its last vitalist trappings.

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6.2  Claude Bernard’s Critiques Bernard’s criticism of Bichat goes beyond simple polemic: it plays a primordial role in the conceptual and methodological apparatus whereby Claude Bernard wished to redefine physiology as an experimental science. For this reason, in order to understand this critique, and to assess the extent to which the epistemological connection between death as object study and the possibility of physiology—elaborated by Bichat as a first framework for experimental physiology—persists in later physiology, we must first retrace the conditions in which Bernard developed it, in his “general” writings: the Introduction à l’étude de la médecine expérimentale, published in 1865 (IME); the posthumous Principes de médecine expérimentale (PME) of 1867; and the Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux (LPC), published in 1878. First of all, notice that Bernardian physiology embodies a reaction against the medicine of his day that had been promulgated by both Bichat and Cabanis. Medicine was a descriptive art, the art of the clinical “eye” and the instinct for a remedy that might be adequate, but was never certain. In this medical tradition covering half of the nineteenth century in France, the physiological doctrine of the flexibility of vital forces supported an empiricist definition of medicine as an art, a concept dating back to Cabanis.9 Bichat’s promotion of pathological anatomy could only agree with this clinical attitude, based on sight and description, since it opened an immense field to descriptive orientation by founding the knowledge of diseases on the detailed perception of lesions to tissues. Bernard’s methodological books, fully dedicated to undoing this structure (rather than elaborating a general epistemology—their title target “experimental medicine” and not “biology” or “science” even though they are often read as treatises on the methods of science), are impossible to understand without the background of this institutional practice of medicine, defined by the conjunction of vitalism, clinical empiricism, and pathological anatomy. For this reason, the critique of Bichat is important to Bernard. However, that does not necessarily mean that in the field of physiology, Bernard was entirely free of the imprint left by Bichat. Instead, what happened is rather that experimental physiology and anatomical/clinical 9  “In medicine, nearly everything depends on the doctor’s gifted eye and instinct; certainties can be found more in the sensations of the artist himself than in the principles of the art.” (De la certitude de la médecine, pp.129–130, my emphasis).

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medicine, the two traditions derived from Bichat, became irreconcilable, for Claude Bernard, as I’ll argue now. 6.2.1   Critique of Anatomical-Clinical Medicine Opposing clinical empiricism, Claude Bernard aimed to make medicine a science derived from physiology, itself a strict experimental science based on the principle of the determinism of phenomena, and therefore oriented towards the knowledge of the conditions for the phenomena of life and making it possible to act on these conditions. This determinism, according to which given conditions necessarily produce given phenomena, is the only invariable postulate of science (IME, p. 83), since it makes science possible. Claude Bernard is indeed credited to be one of the first author systematically using (in French) the word “determinism” and, philosophically speaking, to shift away the meaning of this term from the ideas of determination, in the sense that any event is determined regarding all the parameters that describe it—“determination” being an abstract concept possibly defined in relation to God, as Leibniz or Spinoza would use the word, or Kant talking of the “principle of complete determination”10— towards the ideas of causation and prediction, as current scientists employ the word. Yet Bernard had another notion of determinism, distinct from determinism as a principle for the science of all nature—namely, “determinism” in the sense of “mechanism”, when for example he talks about “the determinism of glycogenesis in the liver” (Gayon, 2006). Both notions are causal: the “universal” determinism means roughly “same causes, same effects” and is an apriori postulate of science; the “determinism” as a local concept, as in the example, is a posteriori and names a particular series of causal chains whose intertwining produces the phenomenon to be explained. According to the viewpoint of determinism, no vital forces of any kind are therefore necessary to account for the regular and necessary connections established by experimental physiology. “Vital phenomena are not manifestations of a principle free and independent. One cannot grasp this inner living principle, isolate it and act on it. On the contrary one sees vital acts having constantly as conditions some external 10  Critique of pure reason (“Dialectics of pure reason,” Chapter 3, sect. 2); see Allison (2003) on this. Bernard takes déterminisme from the german Determinismus, as Gayon and Petit (2019) indicated it, but endows it with a causal rather than theological meaning.

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physico-­chemical circumstances, perfectly determined and capable of hindering or allowing their appearance.”11 Bernard’s determinism succeeds in getting rid of Magendie’s deflated vitalism. Interestingly, the arguably metaphysical principle of general determinism—and its connection to the idea of le déterminisme de, as a target of experimental research—permits the elimination of this other metaphysical idea, the “unknown forces” or the vital forces, that from Bordeu to Magendie, through Barthez or Bichat, a whole tradition of physiologists postulated. Universal determinism implies, in addition, that the difference between pathological phenomena and physiological phenomena is the conditions and not the nature of the processes involved—“the pathological condition creates nothing” (PME, p.  133)—which is the justification for deriving medicine from physiology. This identity of the physiological and the pathological, one of the principles of Bernardian science,12 was inspired by research on intoxication and poisoning. It gave the coup de grâce to nosological medicine after the critiques by Broussais, and earlier by Bichat. Throughout his lifetime, Claude Bernard continued the research he began in 1846 on the action of toxins and, in particular, carbon monoxide poisoning. Moreover, he showed that, rather than inducing novel phenomena, toxins merely cause a disturbance in the functions: “The poison did not create new organs, new pathological functions; it only disturbed the functions” (PME, p. 139). Since, to Bernard, “the activity of poisons parallels the activity of disease, in every way” (Leçons sur les effets des substances toxiques et médicamenteuses, p.  129), there is no qualitative difference between disease and health. The same physiology operates, but the conditions differ: namely, there is a poison present. But toxins are not only mimicking the process of disease: Bernard suggested that certain diseases might be produced by endogenous secretion of a poison, especially by the nervous system.

11  Claude Bernard, Leçons sur les phénomènes de la vie communs aux animaux et aux végétaux, tome II (Paris: Germer Baillière, 1879). 12  Claude Bernard may have encountered an explicit statement of this principle in Comte’s writing, under the name of “Broussais’s principle” (Cours, p. 695 sq.), even though Comte extends it to sociology. Such a principle yields “a sort of spontaneous experimentation, which inevitably results from a judicious comparison between various abnormal conditions of the organism and its normal condition” (ibid.), and which replaces physiological experimentation, of which Comte was extremely wary.

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A second experiment, the one for which Bernard is famous, validated this parallel between physiology and pathology: it is the discovery of the liver’s glycogenic function.13 Ever since Claude Bernard himself described the experiment in 1859, in a chapter of the IME, we know how he understood that the liver produced sugar, after he happened to find sugar in the vena cava of a fasting rabbit. Thus, diabetes was no longer the appearance of a glycogenic function in the body, but the amplification of a function that already existed. At some point, summarizing those researches the Leçons de physiologie expérimentale appliquées à la médecine, lectures that were delivered in 1854–1855, intended to demonstrate the unity of physiology and pathology by shedding light on the processes leading to diabetes. These lectures describe both the pathway of sugar in the organism and the essential role it plays, by promoting the fermentation that prevents the “chemical indifference,” which would be harmful to regenerating vital tissues.14 They reveal the role of the nervous system in the production of sugar, and by that token, Claude Bernard can produce diabetes by modifying the conditions of the nervous system: “You have therefore seen the phenomenon of diabetes produced before your eyes by a simple lesion of the medulla oblongata.” Finally, just like a lesion of the liver, either a nervous system disorder—like the one simulated by the effect of curare or a reflexive action, by excitation of another organ like the lung—can produce diabetes.15 6.2.2  The milieu intérieur and the Critique of Vitalism However, so to depart completely from contemporary medical opinion, Bernard had to attack the vitalism supporting physiology. And universal determinism of phenomena indeed ruled out exceptions: “regardless of the nature of the vital force, we can say that it is the same as brute forces in that it, too, is chained to material conditions determined by laws in its manifestations” (PME, p. 125). The idea of explaining illness by lesions to a vital principle, as Barthez did,16 is as absurd to Bernard as explaining the weakness of a battery by lesions to electricity (PME, p.  168). Even 13  Quite precisely, the gluconeogenesis of the liver, that is, the ability to secrete blood sugar from chemical substances, rather than what is called “glycogenesis,” that is, the storage in the liver of glucose ingested in the form of a glycogen. 14  Lesson 12, p. 255. 15  Lesson 15, p. 305. 16  Discours sur Hippocrate, p. 35.

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speaking generally of a force makes no sense, because it is an unknown unless “the relationship of a movement to its cause” is specified (IME, p.  107). In this case, the force is the name of the determinism to be known.17 The point is simply to seek the relationships between conditions and phenomena in life, not to search for “the essence of diseases or the cause of life” (ibid. p. 107). Had Bernard been satisfied with that, he would simply have reverted to a classically mechanistic explanation to replace vitalism: “In fact, life as considered by the physiologist and doctor is only a mechanism” (PME, p.  12). But he had to account for the apparent spontaneity and self-­ conservation of vital phenomena, which seem to cast them apart from brute matter and its physics and chemistry, an appearance that supported Stahl’s animism and the later vitalist arguments in favor of the plasticity an idiosyncrasy of the living. To do so, starting in 1851, he developed the concept of the milieu intérieur, or internal environment, which provided a general framework for his investigations of detailed phenomena.18 He understood this environment as an intermediary between the organs and external environment, protecting the organs from being directly affected by the outer world. In ways which obey ordinary laws, the internal environment maintains stable conditions inside the organism, the conditions of hydration, pressure, and temperature necessary for life (IME, p. 119). It consists of “all the fluids circulating” inside the organism (ibid., p. 105) and is “produced” by the organism itself (ibid.). The more evolved the organism, the more complex its internal environment, thereby making it relatively independent of the outer world: for example, the higher mammals’ temperature are not determined by temperature variations (at least within certain limits). Moreover, variations in 17  Bernard, although critical of Comte, did read his works. This type of rejection of the concept of force occurs in the positivist literature that had such a pervasive influence on French medicine in the years after 1850, in particular through the Dictionnaire de médecine by Littré and Robin published in 1865. However, in a book Robin published in 1873, Anatomie et physiologie cellulaires, we find a statement about force similar to Bernard’s: “That which physicists and philosophers study in abstract terms, commonly designated general forces of nature, are qualities inherent to all matter, whether they are considered as a mass or as molecules. It is impossible to separate the two. It is important to be able to define this expression precisely, by describing the type of conditions under which the activity of the raw or organized matter is taking place” (p. 161). 18  On the history of this concept in Claude Bernard’s thought, see Grmek (1973).

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the internal environments (blood, lymph, juices, etc.) account for the variations in “vital manifestations” (ibid.). The milieu intérieur buffers the animal against the variations—within some range—of the external environment and therefore accounts for the appearance of independence towards its environment that characterizes living organisms, and that seems to increase as one considers more and more complex organisms. Thus, while the milieu intérieur is constituted and functions according to the same physical and chemical laws governing inanimate matter, its mediation produces the impression that the organism does not obey these laws, and that it fluctuates in an idiosyncratic, plastic, and indeterminate manner, justifying the vitalists’ calls for a singularity of the life sciences and possibly their reluctance to quantitative and nomothetic approaches. However, this impression vanishes as soon as the activity of the milieu intérieur, mediating between external physical conditions and vital manifestations, is taken into account by the physiologist (IME, p. 103). Hence the life sciences can and must adopt the “experimental method” (namely the rules and principles of which are stated in the Introduction), which derives from the universal principle of determinism, and debunks all vitalistic commitments, such as the ones made by Montpellier vitalists or even Bichat about the variability and plasticity of the living. However, these sciences must never lose sight of the specificity of their subject, that is, the way it is governed by what one could call a mediated determinism. For our daily experience, the word “life” signifies indirectly the expression of the physical reality that is the milieu intérieur, whose mediation is not visible, and whose functioning and constitution pertain to the physiologist’s perspective. In a way, with this concept of the milieu intérieur, presented in the Introduction as his own construction, Claude Bernard had solved what I labeled above Bichat’s problem: how to reconcile physiological autonomy (and therefore the uniqueness of life) with the scientific method. By Bernard, this induces a critique of general terms from biology and physiology: “There is absolutely no objective reality in the words life, death, health, illness. They are literary expressions that represent to the mind the appearance of certain phenomena” (ibid., p. 108). Contrary to this appearance, life is “the result of contact between the organism and its environment”; its conditions are “neither in the organism nor in the external environment, but in both at the same time”; and to speak only of life is “an abstraction: a force that appears to be outside matter” (ibid., p. 117). As for the determined vital phenomena, they are the result of the contact

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between the internal environment and organic elements (ibid., p. 119).19 Finally, this concept of milieu intérieur provides a framework for understanding diseases that go beyond the anatomical/pathological problem of the lesion, “a morbid, physical-chemical alteration of the organic environment alone being capable of bringing on the morbid phenomenon that occurs in the absence of any earlier lesion of the tissue, simply through an alteration of the milieu” (IME, p. 198, n.s.). Through the milieu intérieur, all the parts of the body communicate with each other. The blood carries nutrients and oxygen, digestive juices are released, and so on. Thus, the milieu intérieur ensures the organism’s organicity: it is the “harmony” Bordeu sensed between all of the organs endowed with their own life. In the organism, “experimental medicine must see a whole made up of a considerable number of smaller organisms, each of which has its own specialty, living inside a milieu intérieur” (PME, p. 11). The physiologist, when considering a living thing, keeps in mind that “it forms an organism and an individuality,” and that this is what makes his science different from that of the chemist, who breaks down and separates phenomena. Thanks to the milieu intérieur, the ultimate anatomical elements—the cells—are nourished and protected, as if this environment had been constructed “for the cells” (LPC, p. 358), with all of the complications that characterize it, in the most complex species, such as the nervous system, glands, digestive apparatus, and so on.20 In other words: “Life resides in the elements: all the rest is merely mechanism. The organs taken all together are only an apparatus built for the purpose of conserving the elementary properties” (Leçons de physiologie opératoire, Leçon 14, p.  303). The various systems (nervous, circulatory, etc.) are necessary when the living thing exceeds a unicellular creature, because “how could elements located deep within, far from the external environment, receive its stimuli?” (ibid., p.  304). As we saw, both Bichat and Cuvier assigned to organs a vital importance proportional to how deeply located they were in the body: thus, Claude Bernard’s milieu intérieur extends their intuition, insofar as it expresses the need to mediate a contact between the essential organs and the outside. 19  Already, Comte had emphasized the reciprocal action of the environment and the organism (see 40e Leçon, p. 678). 20  Grmek notes that Bernard’s concept of the “milieu intérieur” and Virchow’s “cellular pathology” were being elaborated at about the same time (Virchow, Cellularpathologie, Berlin, 1858). Bernard learned of Virchow’s work in March 1859. (On all of this, see Grmek, 1973, p. 127, and also Holmes, 1974, Canguilhem, 2008, chap. “Cell theory.”)

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As we see, in order to define these basic “elements,” Claude Bernard refers to the cell theory being developed by Theodor Schwann21 and then Rudolf Virchow (1821–1902),22 even if he is suspicious of Virchow’s cellular pathology due to the fact that it invokes specific diseases (bringing it closer to Pasteur), and thereby deviates from the identity of normal and pathological. At the same time, the milieu intérieur is created “by the cells”23 and therefore is simultaneously means and goal, in the sense that “the goal of all vital mechanisms is to maintain the unity of the conditions for life in the internal environment” (LPC, p. 122). The properties demonstrated by the organs and their functions must therefore be understood in this sense; that is why considering the shape of the organs alone, or their composition, would not suffice to understand their function, realized in this continued circular relation between elements and the whole: experimentation is necessary. Made up of the liquids in which the organs are bathed, maintaining them in conditions that are favorable to life, the milieu intérieur relies chiefly on the circulation of the blood, which carries the nutritive substances needed by the cells. But there are two types of circulation, general and local (through the capillaries); the general circulation sends and receives blood throughout the organism, and thereby connects each of the organs “to the whole,” whereas the local circulation ensures local distribution of the blood depending on the organs, and thus adapts the nutrients delivered to the tissues concerned.24 This duality thereby makes the internal environment a system that simultaneously produces organic integration and the independence of the organs. Once again, this concept of milieu intérieur was based on specific experiments. First, in 1851, in his report on “the influence of the great sympathetic nerve on sensibility and heat action,” Bernard proved that the nervous system acts on the body’s internal temperature to correct variations. Nerves therefore have a governing function over the whole organism, correcting local variations. Bernard thereby provided one of the first  1839: the cell established as the smallest constituent unit of any living thing.  1855: every cell is derived from a cell. 23  This circularity is also reflected by the blood, an essential element of the internal environment: “Blood is made for the organs, but it is also made by the organs” (Leçons... sur les liquides, I, leçon 3, p. 45). See the preceding chapter, on the role of circularity in the concept of organism. 24  Leçons sur les propriétés physiologiques et les altérations pathologiques des liquides de l’organisme, p. IX. 21 22

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major insights into the organism’s self-regulating activity, to use a term that was invented after his time.25 By the same token, he made the nervous system the essential agent of this regulation. As a result, in pursuing a “research program” guided by the concept of the milieu intérieur, he revised the antiquated conception of vital heat (traditionally considered to be one of the signs of life). The Leçons sur la chaleur animale published in 1871 show that this heat, “demonstrated by a conflict between the internal space and the external temperature” (10), is not produced by any ordinary combustion mechanism, contrary to what Lavoisier thought. This was proved when cutting the great sympathetic nerve increased heat without increasing combustions in the blood (ibid.). Consequently, “calorific phenomena are the expression of chemical metamorphoses accomplished in the intimacy of the tissues” (138), and thus heat action is related to nutrition and “is not a function of a special organ... but a general faculty belonging to all tissues” (193): since all the organs participate in this production, “a regulatory mechanism has to intervene here”; it will be the nervous system (201), appearing here as a major global regulator.

6.3  The Novelty of General Physiology According to Claude Bernard In what I’ve detailed, Claude Bernard seems to be quite far from Bichat’s physiology: vitalism is eliminated, the very notion of life is suspicious. Bernard salutes Bichat for having carried out a “decentration” of life (LPC, introduction) or, in other words, for having “brought physiology to a specific field where it was possible to follow and localize the phenomena of living bodies, by associating them to the elementary properties of tissues as effects to their cause.”26 But this back-handed compliment is also a way of bidding farewell to Bichat, since Claude Bernard intended to dispense with the distinction Bichat held dear, between physical and vital 25  In the course of his research on respiration, Lavoisier, occasionally hailed by Bernard as the man who introduced disciplined chemistry to physiology (e.g., in the Rapport sur les progrès de la physiologie), had anticipated these observations. He wrote of “three principal regulators,” respiration, perspiration, and digestion (Mémoires sur la respiration, III, 46). Nevertheless, Lavoisier is not Claude Bernard, and these concepts belonged to a mechanism or chemicalism, so to say, that left hardly any place for physiology as such—which Bichat in fact opposed. 26  Rapport sur les progrès de la physiologie, p. 6.

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properties. When Bernard speaks of those who came before him, Bichat and Lavoisier, he is aware he is writing about the prehistory of physiology as a science, whereas he himself is the first to write its history. This distancing from the past is reflected elsewhere: in the very direction Claude Bernard wants to give to physiology itself. Bichat was still linked to the hospital, where he taught, and thereby to the medical field; as a result, he principally wrote a human physiology, the anthropological dimension of which we have reviewed. We know that Claude Bernard wanted to see medicine begin at the hospital and end in the laboratory.27 There, the science could turn away from man and explore a general physiology, which would study the phenomena of life “common to both animals and plants,” as Claude Bernard outlined it, in his last book. For “plants and animals live identically, but function differently” (LPC, p. 151). General physiology according to Claude Bernard merges two traditions of knowledge about the living world: one derived from medicine and the other from natural history. It encompasses the project Lamarck had put forth, under the name “biology.” To this respect, it is significant that in 1848, with Léon Robin, Théophile Rayer, and others, Bernard was one of the founders of, and then an active contributor to, the Société de biologie. Robin drafted the presentation of the society, published under the title “Sur la direction que se sont proposés les membres fondateurs de la société de biologie pour répondre au titre qu’ils ont choisi.”28 The role of positivism in this plan for biologie must not be forgotten. According to Auguste Comte, the limitation of physiology to the human—inevitable at the time—was ultimately what led Bichat to neglect the organism’s dependency on its environment. Hence, he erroneously gave a vitalist definition to life, in terms of a struggle (Comte, 40ème Leçon, op.cit., p. 679). Claude Bernard fulfilled the Comtian wish by extending physiology to the entire realm of the living. This broader view was made possible by the discovery of glycogenesis, because it showed that animals did not need to draw sugar from plants, but could, like plants, produce it themselves. A general unity of vital functioning thus replaced the old scheme of animal dependence on plants, themselves drawing on soil, air, and sunlight for the substances they need  On this point, see Canguiilhem (1968).  “On the direction adopted by the founding members of the Society of Biology to comply with the title they have chosen”) in Comptes rendus et mémoires de la société de biologie, I (1849). 27 28

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to synthesize the elements animals later extract from them.29 Claude Bernard thereby eliminated any external purpose from natural history— external in the sense of what Kant called “relative purposiveness”, namely, organism or species A is here for/in the sake of organism / species B: a living organism “works for itself, not for others” (ibid., p. 148). In the lectures of 1864, Sur les propriétés des tissus vivants, Bernard went back to Bichat’s classification system of lives and tissues. He differentiated between three types of classification: zoological ones, those established for humans, and those of general physiology. He notes that although Bichat’s division between the organs of animal life and those of organic life is valid for “physiology specific to humans and livestock,” it cannot be applied to general physiology, because certain animals are exceptions to the rule. The hearts of fish, for example, do not possess the striated muscle fibers characteristic of animal life (p. 105 sq.). The Bernardian biologization of physiology therefore consummates the break from Bichat which began with the critique of vitalism. Thus, in the same context, Bernard denied Bichat’s claim that the heart, lung, and brain are essential organs, because “an infinite number of lower animals live without lungs, without brain, and without heart.”30 Here, Claude Bernard adopts the viewpoint of comparative anatomy, which was able to demonstrate that several different organs are capable of carrying out the same animal function: respiration is not necessarily linked to the lung, and so on. To this extent, it appears that by Claude Bernard, Bichat’s physiological teaching is confronted by the tradition of comparative anatomy and morphology, initiated by Cuvier—comparative anatomy who was held by Comte as the major principle for life sciences discovered in the nineteenth century, together with Bichat’s idea of tissues (Cours de philosophie positive, 40th lecture). Nevertheless, had Bernardian science broken away completely from the structure of knowledge about life set up by Bichat?

29  Nevertheless, this unity of life, accurate at the cellular level, is no longer valid today in terms of organic processes, which often differ between animals and plants; especially, reproductive processes diverge, as well as the kind of development proper to plants vs. animals. However at the inferior levels of cell physiology, a general unity still exists and is investigated. 30  Leçons de physiologie opératoire, p. 93. With regard to the problem of life and death in particular, Claude Bernard’s writing is constantly in discussion with Bichat, around his Physiological Researches. In Bernard’s Notes détachées, he reminds himself of a plan to “Analyze Bichat on life and death” (p. 162).

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Another possible interpretation could be advanced here, which appeals to the more recent concept of “embodiment.” “Embodiment” means the fact that minds are not wholly separate from the physical world but in situation realized or instantiated in a body which is to be characterized as “their body.” The idea may be illustrated by Husserl’s or Merleau Ponty’s idea of “proper body” (corps propre) or Leib, namely, bodies that are to be distinguished from material bodies since they are bodies as lived by a consciousness, or an in-the-world being (to use phenomenologists’ phraseology). But it’s more general, and is used in cognitive sciences to contrast with brain-oriented theories, and the computer analogy as it’s pervasive in cognitivism. Philosophically, embodiment means that a body is somehow coextensive with a subjectivity and reciprocally (Huneman & Wolfe, 2017). As Smith (2017) indicates: “To speak of embodiment by contrast is always to speak of a subject that stands itself variously inhabiting, or captaining, or being coextensive with, or even being imprisoned in, a body. The subject may in the end be identical to, or an emergent product of, the body—that is, a materialist account of embodied subjects may be the correct one. But insofar as there is a philosophical problem of embodiment, the identity of the embodied subject with the body stands in need of an argument and cannot simply be assumed” (p.2). “Animals are embodied” means that besides the relations between their body and the environment, there exists a level of subjectivity, thus of reflexivity, through which this relation is possible. “Organic life” as a relation of the organic body to itself (according to Bichat’s concept) exactly realizes such reflectivity, hence the subjectivity, therefore it is what “embodiment” means.31 Thus, reading Bichat, one can argue that “embodiment” here designates, first, organic life as—in phenomenological terms—what differentiates any living body (including plants) from mere bodies: a space of reflexivity; and second, the articulation between organic and animal life, which makes it possible for the animal to be an embodied agent behaving in the world. The inquiry about the relations between organs of animal life and organs of organic life, as it is led in the Recherches, underpinned by the discovery of sequence-schemata that the study of death processes reveals, is a physiological window into the way organism-­environment relations are somehow mediated by organic life; thus in the present terms it’s an exploration of the embodiment proper to the mammals investigated.  The idea is developed in details in Huneman and Wolfe (2017).

31

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Thus, Bernard’s concept of milieu intérieur could be seen as an additional extension of Bichat’s idea of vie organique. As we saw, the exact mechanism (in Bernardian terms, le déterminisme) that governs animal functioning and behavior is not a strict relation between organism and the external milieu, but a double relationship, between organs and their milieu intérieur, and then between this milieu intérieur and the external environment. To this extent, the variables describing the trajectories of each organ are not directly affected by the modification of environmental variables, that is, the milieu intérieur somehow buffers them against external extremes and rapid changes likely to be met by the organism. The milieu intérieur functions exactly as a space of relations of the organism with itself, which supports and mediates its relation with its environment. Hence it can then easily be understood as an operationalizable way to understand what Bichat called vie organique. In this sense, the milieu intérieur can be seen as a figure of animal embodiment, inherited from Bichat’s physiological bi-partitioning of lives: a version of it that can be can be analyzed regarding its composition and potential alteration as a specified mix of liquids, and thus addressed by the tools of chemistry (toxicological analysis, etc.), which is a way through which Bernard intends to make experimental physiology more rigorously scientific, and therefore overcome Bichat’s vitalism, as I’ll consider it now.32 By considering the way in which Bernardian physiology transforms or perpetuates features from the epistemic structure of physiology Bichat’s Recherches set in the beginning of the century, this will allow us to analyze the relationships between life and death in the idea of general physiology presented by Claude Bernard.

6.4  Life and Death in Claude Bernard’s Work 6.4.1   The Experimental Approach To decide whether Claude Bernard truly broke away—as he claims—from the type of knowledge instituted by Bichat’s Researches, our first task is to examine the particular conditions in which Bernard developed his science. Another of the themes in his famous experiments, along with the discovery of glycogenesis in the liver and the effect of cutting the great sympathetic nerve, was his investigation of the effects of curare and various other poisons, and notably research into the mechanism causing carbon  See Grmek (1973).

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monoxide poisoning. The remarkable thing about these experiments is that the object of knowledge is simultaneously the instrument of scientific production of knowledge. This feature is quite characteristic of Bernard’s work: the vital mechanisms he discovers are used as means to uncover other vital phenomena: results and research are continually interacting. For example, before he had found the exact mechanism whereby carbon monoxide prevents red blood cells from fixing oxygen, Claude Bernard used the substance as a reagent to determine the mechanism whereby tissues absorb oxygen. Likewise, once he had learned how curare acts to paralyze the body (it neutralizes only the motor nerve), he used it as an instrument to analyze the nerves. Since the poison leaves the muscle intact, Bernard’s experiments demonstrated that motor nerves and muscles have independent properties (Rapport..., p. 33).33 More generally, in addition to curare, the poison strychnine, which acts on the sensitive nerve alone, could be applied, as well as potassium cyanide, which affects muscle fibers. These three toxins, targeting three different systems, were used as investigative instruments. The fact that the toxic effects are local and extremely precise made it possible to study organic function when the poison is administered, at a much more accurate level than mere observation. “The localization of the toxic actions permits us to follow the mechanism all the way into the organs.”34 The reason Bernard focused so intensively on investigating toxic action is that the knowledge it yields can then be used as an instrument to find out more about general physiology. Sometimes, as was the case with strychnine, it can be applied even if the details of the poison’s mechanism are still unknown. When possible, Claude Bernard used toxins as instruments. A lecture delivered to the French academy of sciences in 1856 explicitly outlines this form of knowledge: “I should like to draw the attention of physiologists to the sort of physiological analysis of organic systems that can be carried out using toxic agents (...) Considered in this way, these substances are truly reagents of life which, carried by the torrent of circulation to every point in the organism, exert their action on certain tissues, isolating them and leading to death by a mechanism that designates the physiological role of the tissue that they affect. With these agents, one can study the death of organic systems, 33  “This effect of curare makes it possible to use it to analyze the properties of motor and sensitive systems, and to find out whether muscular irritability and sensitive irritability are two distinct orders of phenomena” (Leçons sur les substances toxiques, lesson 16, p. 311). 34  Leçons sur les substances toxiques, p. 52.

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rather than the death of organs, the way Bichat did. This study is a source of great interest from the viewpoint of general physiology” (my emphasis). Here we again find the structure of the science of life as it emerged from the work of Bichat: the grasp, through experimentation, of the processes leading to death yields knowledge of vital connections. It is notable that Bernard mentions a difference in level—no longer organs, but organic systems (muscular, nervous, etc.), a term that, in fact, refers to the conceptual framework of Bichat’s anatomy. This similarity would suggest that this project belongs in full to the realm of thinking unlocked by Bichat’s Researches. And indeed Claude Bernard, despite the whiggish tone of his discourse, identifies this conceptual space as the home of his own explorations when he expresses the experimental imperative of physiology by writing: “to learn how animals and humans live, it is essential to see a great number die, because the mechanisms of life can only be revealed and proved through the knowledge of the mechanisms of death” (IME, p.  150, my emphasis). Claude Bernard achieves Bichat’s intention by insisting that anatomy be “subordinated to physiology,” since the former includes only “passive mechanical elements” of life, whereas the latter conceives the “active elements” that cause it to function (IME, p. 158). Now, experimental physiology thereby does two things: identifying functions—for example, the glyconeogenic function of liver—and finding the mechanisms that implement such functions. A Bernardian function is actually a more fine-grained instantiation of the sets of necessary conditionings that Bichat intended to unravel through his “Recherches sur la mort.” A mechanism implementing a function is often established through the same method Bichat systematically elaborated: disturbing or killing some of the tissues putatively involved in the realization of the function, identifying the downstream effects of the intervention, and finally summing this information about the effects of the controlled disturbances in order to reconstitute the mechanism (Grmek, 1973). For current-day philosophers of science, what appears with this methodology that is deployed constantly from Bichat to Bernard and is centered on the role of death, instantiated either by physiological or toxicological interventions, is the following: many philosophers follow Glennan (2017) or Craver and Darden (2013), who convincingly argued that scientific explanations mostly consist in unraveling mechanisms responsible of the explanandum. Such mechanisms, when it comes to life itself and the functioning of physiological systems are identified via an investigation that produces death of

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the organisms through interventions on subsystems of various levels (organs, by Bichat; nerves and then cells, by Claude Bernard). 6.4.2   The Characterization of Life and Its Relationship to Death To measure the degree to which the structure of physiological knowledge about life requires a conception of it based on death, we must now examine the principles ruling Claude Bernard’s general physiology. Despite his critique of the term “life,” by asserting the specificity of physiology Bernard could not avoid speaking of “life,” and attempting to determine its originality. This is how the Leçons sur les phénomènes de la vie communs aux plantes et aux animaux (LPC) had to begin, how it does justice to their title. First, according to Bernard we must set aside the definitions of life, for it is impossible to formulate a definition for natural things that are already known (LPC, p. 25). Moreover, Bernard shared the common convictions of medicine at the time—namely, the positivist beliefs of De Blainville and then Comte—that it is impossible to separate life from the physical organization underpinning it and that therefore life is the result of this physical organization.35 We find the same assertion in Robin’s writing: it is true that phenomena like animal heat or heredity, which are not linked to any organic apparatus, are specifically vital, “results of vitality,” that cannot be reduced to mere physics. However, Robin is careful to define “irreducible”: “here, it is intended from the biological point of view; that is, they are irreducible as long as one does not rise all the way to the theory of molecular movements of matter in general.”36 The definition of “life” in the Dictionnaire de médecine as “the dynamic attribute of organized substance” (Littré and Robin, 1865, p. 1673) is another example of this positivism. For De Blainville, the living body “is not a machine”; it is nevertheless, as matter, subject to the general laws of all bodies (Cours de physiologie, 1, pp. 30). De Blainville’s student Auguste Comte extended this approach by making life a harmony “between the living thing and the 35  For de Blainville, see the Cours de physiologie of 1829, where he wrote: “It was therefore a mistake for physicians and physiologists to argue that the phenomena of living bodies had to be studied independently from the properties of native substances. This error led them to attribute special forces to life, as if it would simplify a phenomenon to sequester it from its surroundings.” 36  Anatomie et physiologie cellulaires, ou des cellules animales et végétales du protoplasma et des éléments normaux et pathologiques qui en dérivent, Paris, 1873, p. xvi, n.s.

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environment” (“40e leçon,” p.  676), in order to reject the opposition Bichat had established between living and inert. Comte’s conception announced Claude Bernard, who was largely inspired by it. However, for Comte, death is only a break in an equilibrium, and he therefore ignores the constituent bond Bichat established between life and death, even though Bichat is a major reference for his positivism in biology. Although the definition of life is meaningless, as Bernard states in accordance with many of these authors I discuss, one can and must nevertheless “characterize living bodies in comparison to inanimate ones” (LPC, p. 32, n.s.). Bernard stated the following characteristics of life: organization,37 generation, nutrition, evolution (meaning individual growth and development), and “decline and death.” Bernard saw development, which he called “evolution,”38 as “the most remarkable trait of life” (ibid., p. 33). Nevertheless, nutrition could also be seen in this light, because “nutrition is the continuation of generation” (Rapport, p. 130). Nutrition is also fundamental, “the cause and purpose” of organization (Rapport..., p. 307). Here we see the modern physiologists voicing an idea that had already been expressed by the naturalists of the century before, and then by Magendie. But, as we have seen, the nutrition process does not involve the direct absorption of nutrients by the organism. Actually, they are subject to two movements, or transformations: first they are broken down, or destroyed, and then they are repaired or assimilated. The latter processes enable the organism to integrate the nutrient principles essential to its various tissues. Nutrition also compensates for the living thing’s expenditures of energy (to employ a term that is slippery in the context of the Bernardian lexicon). As a consequence, “there are two orders of phenomena within the living thing: phenomena of vital creation, or organizing synthesis; and phenomena of death, or organic destruction. (...) In a living

37  The physical and chemical arrangement of substances from which vital properties result, which are not the “physical-chemical properties of organized matter” (33). 38  Bernard respects here the ancient use of the word; “evolution” meant development, especially in the context of preformism where it means the unfolding of a germ. But it came to signify, with Darwin, the transformation process of species, hence populations, and not individuals. Nowadays only species evolve, individuals develop. This lexical precision was unknown to Claude Bernard. See Richards (1992) for an account of the shifting sense of “evolution.” On the interrelation between nutrition and generation, a conceptual scheme that Bernard mostly inherited see Bognon-Küss (2019).

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thing, everything is created morphologically, is organized, and everything dies and is destroyed” (LPC, p. 40).39 This idea of a two-part movement was not entirely new. It is also found much earlier, in Stahl, then in Haller and Lamarck.40 It brings modern physiology to the notion of metabolism, composed of anabolism (Bernard’s “organic synthesis”) and catabolism (his “organic destruction”). Yet Claude Bernard’s interpretation of the relationships between life and death was entirely unheard of. Actually, only “the evolutionary synthesis is the part that is truly vital” (ibid.); the other order of phenomena is purely physical and chemical: in fact, it does not cease after death (lesson 4). According to the former use, the syntagm “evolutionary phenomena” should be understood here as developmental or seemingly life-long embryogenetic phenomena. Therefore, life as a whole is composed of phenomena of both life and death, braided together so tightly they cannot be undone. “The existence of all living plants and animals, summarizes Bernard, is maintained by these two essential and inseparable orders: organization and disorganization.” Moreover, “any manifestation of a phenomenon in a living thing is necessarily linked to an organic destruction,” since any functional accomplishment requires the consumption of organic matter—especially since Claude Bernard had pinpointed life processes in the elementary level of the organism. Thus the sight of life is nothing more than the sign of death: “Life is death” (p. 41). Claude Bernard presents this as the truth intrinsic to Bichat’s work: in the Bichatian conception of life, he says, “it is true that life is only death, and we are constantly sliding towards death by the very fact that we are alive” (PME, p.  242). But we must evaluate the distance between this Bernardian rooting of death in life from the conception pointed out in eighteenth century science (Haller, Buffon, etc.), in which death is a 39  The author indicates that in the glycogenetic function, for example, there are two steps: first the starches are synthesized as glycogens, and then the glycogen is broken down into glucose. 40  “The vivification accomplished by the soul... constitutes a veritable mechanical and physical action, being accomplished: 1. By relying on perpetual and involuntary elimination of matter that is used up and rotting; 2. By receiving new matter that is absorbed and assimilated to the corporeal substance... That sums up the nutrition function” (Stahl, Theoria medica vera, Œuvres, III., 482). See Haller, op. cit., §957–959; Lamarck, op. cit., II, chap. 1, §5, p. 322). Also, in the Dictionnaire de médecine by Littré and Robin, the entry on “nutrition” reads: “Nutrition, hence life. An elementary property of organized bodies, characterized by the continual dual movement of combination and decombination, presented without self-destruction, by the anatomical elements of both animals and plants.”

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process of erosion consubstantial with life: Bernard by contrast is actually speaking of distinct physiological actions. Moreover, to him, death is not a negative consequence of life, but simply the other side required for the accomplishment of every vital function. The French physiologist operates in the new conceptual space opened by Bichat—quite different from Buffon’s—which made this perspective shift possible. True life is the silent synthesis continually recomposing the burnt tissues. “Life is creation,” Claude Bernard writes in the Introduction, and this aphorism seems to contradict the earlier one. But such a creation is invisible. In life, we see only death. Especially, it is impossible for us to know the inner workings of life. In this very specific conception of the singularity of life, the insight offered to physiology, as a knowledge of the functions, is death in the heart of life. Vital creation, present in all phenomena of development, remains opaque to us, in particular because experimentation has no traction on these developmental phenomena. For Claude Bernard, not only, in accordance with Bichat’s teachings, is life always known on the basis of death, but beyond Bichat’s view, life itself is irreducibly linked to death. The bond between the two is so strong that the knowledge of life eludes us. All that we can understand is that life and death are indissociable on the specifically vital basic level, that of “organic elements.” For example, the carbon monoxide experiment showed that it is the alteration and decay of the bond between the red blood cells and oxygen atoms that makes it possible to feed the tissues and thereby sustain life—and that carbon monoxide poisons them, precisely because it stabilizes these lesions.41 Life lives on the elementary deaths within it, deaths whereby Bichat had been able to propose as objects of knowledge the interfunctional dependencies that make up the organism. This interplay of life of the organism and death at elementary level is a major advance in biological knowledge, and we’ll witness it later on in the course of this book.

6.5  The Two Pathways 6.5.1   Creation, Evolution’s Directive To understand Bernard further, one should however specify the limits of biological knowledge. For Claude Bernard, the processes of organic destruction can be understood. These are catalytic actions, as the french  Leçons sur la chaleur animale, p. 176.

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chemist Berzelius called them. But here, the catalyst is specific to life: it is a ferment. The three types of organic destruction—fermentation, putrefaction, and combustion—are all ultimately forms of fermentation, which “therefore characterizes life chemistry.” As for organic creations, one should clarify the previous assertion that they were inscrutable: they are either chemical—that is, local renewal of cells—or morphological, that is, constituting the general form of the living thing throughout the phases of its development. The chemical renewal of cells can be understood by science, because the products that are created can be reproduced in the laboratory, although the chemist must use a process other than the one that occurs in life: “The chemist can make the products of life, but he will never make its tools” (LPC, p. 227). Morphological synthesis, however, goes beyond the realm of science, because it is not ordered by physico-chemical determinism. That does not mean that it belongs to another order of causality, but it “translates a hereditary influence whose influence (sic) we would not know how to erase” (ibid., p. 32). Thus, morphological synthesis mostly relies on inheritance, namely, on the fact that fundamental forms of the organisms are just inherited from ancestors—primates or earlier mammals, when it comes to humans. Forms circumscribe another kind of laws, besides laws of physiology as some toxin-based (among others) investigations reveal them. As a result, on the highest level of generality, “life is a conflict” (66), between determined material conditions and these vital “laws,” which “are derived by atavism from organisms which the living being continues.” Such view constitutes the least known conception by Claude Bernard, mostly developed in his attempts towards a theoretical biology—namely, LPC and the Rapports—in principle likely to be detached from the guidelines of his physiology, and includes interesting philosophical assumptions regarding laws, causation, or time. These laws, in themselves, have indeed no effectiveness in reality: only the physical-chemical determinism can “manifest” them. Nevertheless, this determinism does not “engender” life (Rapport... p. 156); on the contrary, it carries out the “development directive” (consigne d’évolution) which, by itself, does not aim at a goal but represents the history accumulated in the egg. The information in the egg is “an organic formula that sums up the being from which it proceeds, and of which it has preserved the developmental conditions” (ibid., p. 148). “The vital force directs phenomena that it does not produce, and physiological agents produce phenomena that they do not direct” (LPC, p. 51). The phenomena of organic creation “characterize life,” but the only thing that

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makes them possible is their physical and chemical destruction. Without this destruction, hence the pervasiveness of death at all physiological levels, no hereditary organic formula for life would be manifested. Epistemologically speaking, only the physical and chemical conditions of physiological phenomena can be known, because experiment makes it possible to attain them. According to the logic extracted from Bichat, this implies that life will be attained based on death, and finally as death, but a death that, instead of being different from life, is actually its most intimate condition. However, the only suitable knowledge of the “development directive (consigne d’évolution)” is a description, and as a result, this directive can never be a scientific subject (namely, and explanation along the lines of experimental method). Thus the sort of dialectics that characterized methodological discussions about specificity of life and emergence of vitalism in the eighteenth century—namely, experiments versus observation (Chap. 2)—resurfaces now, within the complete theory of life exposed by Claude Bernard, under the form of this contrast between experiments and description This contrast underlines a striking difference between Claude Bernard and his contemporary Charles Darwin. Leaving aside a growing scholarship, one can roughly not that Bernard was aware of but never accepted the works of Charles Darwin, which plausibly connects to this difference between descriptive and experimental explanatory science I just mentioned. On the one hand, Bernard is led to acknowledge that history is the specific property of the living organism, that the very regularities of this organism are related to heredity. But on the other hand, the structure of the science he is establishing forbids him from thinking that heredity can be the locus of a knowledge. The population thinking approach adopted by Darwin and Mendel could not appear to be scientific, to Bernard—a scientist to whom statistics were only a conjectural method, because statistics only designs rough means or variances and can’t capture the variation proper to living phenomena—whereas his work culminates in something that we could now recognize as a requirement to take such an approach: Bernard’s “consigne d’évolution”—where évolution means development— could be understood by a present-day reader unafraid of anachronisms as a precursor of our “genetic programs.” But the most interesting convergence here is the fact that this “directive” is seen by Bernard as inherited, namely, as a result of evolution (in the modern sense—he says “atavism”), which for him stands out of reach of our science.

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6.5.2   Bernard’s Hesitations and the Conflict Between Morphology and Physiology The question arises: with regard to Bichat’s well-entrenched vitalism, has physiology achieved its independence, even though the laws of life escape its grasp? Hesitations of the sort are constitutive of Bernardian physiology. As we said, Bernard’s aim was to apply the scientific method to knowledge of the physical and chemical conditions that are manifestations of vital phenomena, even though they do not produce them. If this is so, something about life eludes science, contrary to what we’ve been told—nothing less than life’s very laws, since the “laws” guiding the construction of the organism are epistemologically inscrutable. The 1867 Rapport assigns physiology to find the expression of these “organotrophic” laws. The object is not the laws that are common to all matter, but “the organotrophic or vital laws characterizing living things. The physiological laws are the very laws of organization” (180). This contradiction to the Leçons and the doctrine of the two orders of phenomena, morphological and physiological, is not accidental; it is inherent to the very structure of the Bernardian program. For even though Bernard has previously stated that the specificity of life must escape from its procedures, being established on death, and yielding knowledge of the work of death in the living, his program aims at scientifically knowing life. This contradiction occurs on two levels. (a) A controversy surrounds the attribution of the term “life”: exactly what is alive, the matter itself, or its organized form? In other words, is life in the protoplasm or the cell? At this time, when cellular theory was new, the question was widespread. Charles Robin answered categorically: life is a correlate of organization, and ­therefore of organized matter.42 Claude Bernard shared the idea that the properties of life are the result of a molecular arrangement. He, too, considered that protoplasm itself was life, since it possessed contractility, the ability to feed itself, and to reproduce. It is “the only living, working matter” (LPC, p.  192). However, Bernard did later qualify this comment by adding that protoplasm is not a living creature, since it lacks a shape. Hence, “there is no 42  The vital properties are “living matter, amorphous or shaped” (Anatomie et physiologie cellulaires, p. 168); “the hypothesis according to which the form is the essential and fundamental characteristic of the organizational status is false” (ibid., p. 246).

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way to explain morphology on the basis of a property of protoplasm” (ibid., p. 293). The thought of the consigne d’évolution kept the physiologist from identifying life merely as organized matter, because he also had to do justice to shape. ( b) Life is évolution, or development. “The guiding idea of this vital evolution is that part of embryonic development which is essentially related to life and belongs neither to physics nor to chemistry” (IME, p. 143). One of Bernard’s Pensées asserts, “Everything is evolution... There is no single period that characterizes a creature or phenomenon in an absolute way.” Yet Claude Bernard never published an experiment or research about the development of a living thing, precisely because his scientific method did not apply here. This contradiction was lifted to some degree with the development of experimental embryology by Roux, His, and then Spemann, at the turn of the century.43 At that point, consigne d’évolution became accessible to experimental knowledge. For Claude Bernard, however, the impossibility of experimental embryology was related not so much to technical insufficiencies as to a principled position: for him and against his contemporaries doing Entwicklungsmechanik (study of “developmental mechanics”), the field of embryology, as a primary manifestation of the consigne d’évolution, refers less to the individual than to the historical layers of the lineage of its ancestors, and it is impossible to conduct experiments on the past, which can only be described. From his perspective, even if the instruments necessary for experimental embryology were available, the research could only reach the ultimate, extreme, minimal, most current point of a reality that is literally metaphysical, because it embraces both the future and the most remote past, and even though it is incapable of being enacted in the physical order, it nevertheless governs the physical processes of life. To understand the Bernardian ambiguity in the definition of physiology, which is simultaneously the science of life as an absolute reality, and a science inherently unable to seize the essence of life, it seems that we must underscore the fact that Bernard’s conception of life ties together two late eighteenth-century scientific traditions approaching the study of life, from the works of Bichat and Cuvier.  On these embryologists, see Bolduc (2021).

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We have seen how Claude Bernard’s physiology behaves within the framework of the physiological knowledge elaborated by Bichat. But the term “morphological,” which Bernard applies to describing the syntheses related to the “development directive,” derives from an entire field of research that opened up when Cuvier constituted (or heavily contributed to the constitution of) “comparative anatomy.”44 In this field, several advances occurred that made up the cradle of Bernard’s idea of consigne d’évolution. On the one hand, Geoffroy Saint-Hilaire (1772–1844) had elaborated a program for “morphology,” a science that would seek how all animals fulfilled a single plan for their shape, modified according to precise rules of transformation.45 On the other hand, Von Baer (1792–1876), in particular, linked embryology and comparative anatomy by stating the fundamental rules for the development of animal morphologies in a descriptive embryology.46 Noticeably, the German master of physiology Johannes Müller (1801–1858) was Von Baer’s student.47 To put it very concisely, one can say that in this type of knowledge, the living creature is constituted as a scientific object based on the description of its genesis and of the possibility of coordinating the genesis, as a series of successive stages, linked to each other but also heterogeneous, with a series of animal forms connected to each other by orderly relationships of opposition and transformations bearing on organic elements. In both Von Baer’s embryology and in transcendental morphology, the connection to the field of comparative anatomy is the gateway to a knowledge about life based on the origin of the living individual. Claude Bernard’s hesitation in the very definition of the purpose of physiology reveals the coexistence of two distinct types of knowledge about life at the source of his thinking: the experimental physiology derived from Bichat (clearly predominant) and a biology less identifiable with the name of a single scholar but nevertheless perceptible in the writings of Geoffroy Saint-Hilaire and a cluster of German embryologists or morphologists.  On Cuvier, see Daudin (1920, 1923), Ospovat (1978), Huneman (2006, 2008, forth.).  Ospovat (1983); Rehbock (1983). Geoffroy Saint Hilaire conflicted with Cuvier on the very notion of biology and comparative anatomy, the latter instantiating a function-oriented biology while the former instantiated a form-oriented biology—see Huneman (2006a) on their differences—but it’ s not relevant for the present argument. 46  On Von Baer see Balan (1979); Ospovat (1978) explains how Von Baer’s embranchements fuels Geoffroy’s idea of morphology, which gave rise to transcendental morphology. 47  On Müller see Lenoir (1981, 1982). 44 45

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In his plan for a general physiology—that is, the transformation of physiology into biology—it is clear that Claude Bernard, a French physiologist, would have to confront the second tendency and, in the tensions internal to his work, reveal the heterogeneity that separates it from the first school. For it is not so much a question of two methods, but rather two paths whereby life becomes an object of knowledge, in such a way that, at first view, the understanding of “life” wavers in the gap between the two. On the one hand, the way a living thing functions as a whole can be examined by scientific method, in light of the creature’s death; on the other, the essence of life is distilled in a descriptive discourse clinging as closely as possible to the transition from non-life to life, a discourse in which the life form becomes intelligible when its individual history is elucidated. Or: on the one hand, a knowledge from the actual functioning of the organism tied at its foundation to death and experimentation; on the other, a knowledge strung between the “poles” of history, origin, and description. In his effort to edify a general physiology that could conjoin these two epistemological structures to reflect a coherent image of life, Bernard was compelled to suggest a vantage point that is necessarily equivocal for whoever analyzes it in a philosophical light.

6.6  Conclusion In this first part, I intended to consider the “how-question” regarding death, from the viewpoint of an inquiry about the conditions and genealogy of experimental physiology. It claimed that the epistemic problem of vitalism, outlined in Chap. 2, is handled by instituting experimental devices that address death as a process, and make into scientific objects the sequence-schemata unraveled by various sub-researches in Bichat’s Recherches on death. Thus, I wanted to analyze the epistemic role played by death in the structure of a major aspect of what Mayr (1961) called “functional biology,” namely, experimental physiology. My historical enquiry, here, about Haller, Bichat, and other vitalists, didn’t pretend to provide a survey of how death occurs, but to cast a light of the way such science constituted itself as a scientific knowledge, and, by so doing, emphasize the continued role played by death as what I call “a epistemic facilitator.”

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This is the reason why, more than a study of Bichat’s Recherches, I intended to explicate the connections between Stahl, Bichat, and Claude Bernard’s physiologies, in order to show that notwithstanding the major theoretical shifts occurring through these figures—shifts that led to a more contemporary idea of physiology, given that often Bernard is credited to have established modern experimental physiology, as well as major conceptual frameworks for addressing regulation and nutrition—this epistemic role of death stands as an ongoing thread here. The conclusion of those analyses doesn’t enrich traditional philosophical issues about death—its meaning, its demarcation, its status regarding the essence of humans, and so on, as reminded in the introduction—by a reference to biological death, in the sense of what biology knows about death. To some extent, many of these questions may be affected by the question “what is death,” as explained in the Introduction—but much less by answers to “how does death occurs?”. And precisely what I argued here is that this latter scientific question, when one examines the genealogy of scientific responses that have been given to it, contributes to answer another philosophical, historical, or epistemological question, namely, “how has a knowledge of life as functioning been possible?”. This question may in turn be relevant to the general epistemological issue “how is a knowledge of life itself possible—given the vitalist dilemmas that we met in the second chapter?” But the present investigation, followed up to Claude Bernard’s theory of the “two syntheses,” opened up in the last paragraph onto an insight into evolutionary theory. Granted, the epistemic structure of experimental physiology, mounted on the epistemic set-up conceived by Bichat for studying accidental death processes, displays views on the functioning at all levels, including the level where some “main” functions transversal to at least many major lineages are instantiated (skin, cells, etc.). But such a structure faces major difficulties conciliating this physiological knowledge with an enquiry about the reasons why the organismal functioning and functions happen in the first place. Remember, for Bernard the “morphological synthesis,” first realized by embryogenesis but then constantly applied throughout life, traces back to an “development directive” inherited by the species. Evolutionary theory thus appears as what precisely addresses the question of the “development directive,” even though Bernard didn’t make the connection by himself. Epistemologically, his position exactly prefigures what Ernst Mayr will theorize almost a century later in his famous piece “Cause and effect in

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biology” (Mayr, 1961), by introducing, as I said in introduction, the difference between functional biology as a science of proximate causes and evolutionary biology as a science of ultimate causes. Bernard’s “general physiology” overlaps with or even covers the former field. But Mayr’s argument targets the precise issue exposed by Bernard. He starts by mentioning that a “genetic program” explains the behavior of an organism and its development. This answers questions about how does an organism develop and function. But then he turns to the question: “why is this the case?”; that is, “why does the organism has such a genetic program?” And answering such question requires to consider evolution, and mostly natural selection. What Mayr calls in terms of the 1960s a “genetic program” seems very close to the notion of a directive guiding the development of an organism and its morphological syntheses, conceived of by Bernard. And arguing that this program requires an evolutionary explanation is an argument similar to Bernard’s claim that the “development directive” is rooted in inheritance, and that its explanation calls for considering history of the species. Thus, the question of a physiology of death, which plays this epistemic facilitator role as extensively described above, leads to an evolutionary question about the “Consigne d’évolution,” in Bernard’ words, or about the evolution of development, in current terms. In this way, my enquiry into the genealogy and structure of nascent experimental physiology, and the role death played in it, led to evolutionary biology. When one is interested in the overall structure of biological science, the reference to evolution therefore naturally emerges, unsurprisingly since, as the famous saying by Dobzhansky noticed it, “nothing in biology makes sense except in the light of evolution.” This is why I now turn to evolutionary biology, in order to assess the way the issue of biological death is handled since Darwin’s theory. Within evolutionary biology, why questions are asked: “why do elephants have horns?”, “why are chimps aggressive?”, or more generally “why these genetic programs in such species?” But interestingly many of the features that one takes for granted, as definitional of life itself, have been progressively been questioned by evolutionary biologists. For instance, most of the multicellular organism species are sexual species— and often, in lineages, branches that witness reversion to asexual reproduction don’t last long. Since the 1950s, evolutionary biologists won’t take this as given, and ask why is it the case.

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Even the most obvious fact of biology, namely, organisms—living things are organisms, unless they are unicellular organisms—is a major question for evolutionary biology. Since Dawkins (1976) hypothesized that genes were the targets of natural selection—and not organisms—so that it becomes puzzling why genes only exists bundled into nucleus or mitochondria of cells, generally within organisms, many biologists asked : “why organisms?”, “why are biological individual organisms?” Leo Buss published The Evolution of the Individual in 1987, which questioned the emergence of a definitional characteristic of organisms like us, namely, the sequestration of the germ-line. Evolutionary biology thus provides a framework for asking the question “why organisms?” To the same extent, death ceases to be taken for granted, as just a fact of life. Evolutionary biologists can, and did, address the question: “why death?” The second part of the book will now tackle such question from an evolutionary point of view. Here, the target of the enquiry is not so much an epistemological issue regarding biological knowledge, as this first part of the book dealt with. It’s a much older concern about explaining why do we—and, more generally all living creatures—have to die and, prior to this, do we even have to die? I’ll start the next part of this book by framing this philosophical question, and some answers that it received within the philosophical tradition; this will allow me to show that the occurrence of Darwinian biology provides us with a radically new philosophical perspective on such question and, then, examine this perspective in details.

References Albury, W. R. (1981). Experiment and explanation in the physiology of Bichat and Magendie. Studies in the History of Biology, 1, 47–131. Allison, H. (2003). Kant’s transcendantal idealism. Yale University Press. Balan, B. (1979). L’ordre et le temps. Vrin. Bognon-Küss, C. (2019). Between biology and chemistry in the Enlightenment: how nutrition shapes vital organization. Buffon, Bonnet, C.F. Wolff. History and Philosoph of Life Sciences, 41, 11. Bolduc, G. (2021). Préformation et épigenèse en développement. Naissance de l’embryologie expérimentale. PUM. Canguiilhem, J. (1968). Études d’histoire et de philosophie des sciences concernant les vivants et la vie. Vrin. Canguilhem, G. (2008). Knowledge of life. Fordham.

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Craver, C., & Darden, L. (2013). Mechanisms in biology. University of Chicago Press. Daudin, H. (1920). De Linné à Lamarck. Méthodes de classification et idée de série en botanique et en zoologie (1740–1790). Paris. Daudin, H. (1923). Cuvier et Lamarck, les classes zoologiques et l’idée de série animale (1790–1830). Paris. Dawkins, R. (1976). The selfish gene. Oxford University Press. Gayon, J. (2006). Les réflexions méthodologiques de Claude Bernard: Structure, contexte, origines. In Bitbol, M., & Gayon, J. (Eds.), L’épistémologie française 1830–1970 (pp. 231–251). Presses Universitaires de France. Gayon, J., & Petit, V. (2019). Knowledge of Life Today: Conversations on Biology. ISTE/Wiley. Glennan, S. (2017). The new mechanical philosophy. Oxford University Press. Grmek, M. D. (1973). Raisonnement expérimental et recherches toxicologiques chez Claude Bernard. Droz. Huneman, P. (2006). Naturalizing purpose: From comparative anatomy to the “adventures of reason”. Studies in History and Philosophy of Life Sciences, 37(4), 621–656. Huneman, P. (2008a). Montpellier Vitalism and the emergence of Alienism in France (1750–1800): The case of the passions. Science in Context, 21(4), 615–647. Huneman, P. (2008). Métaphysique et biologie. Kant et la constitution du concept d’organisme. Kimé. Huneman, P. (forth.). Life Sciences, Kantianism, and the Concept of Organism. Routledge. Huneman, P., & Wolfe, C. (2017). Man-machines and embodiment from La Mettrie to Bernard. In J. Smith (Ed.), Figures of embodiment (pp. 241–276). Oxford University Press. Lenoir, T. (1981). The Göttingen school and the development of transcendantal Naturphilosophie in the romantic era. Studies in the History of Biology, 5, 111–205. Lenoir, T. (1982). The strategy of life. Teleology and mechanism in Nineteenth Century German biology. Reidel. Mayr, E. (1961). Cause and effect in biology. Science, 134, 1501–1506. Ospovat, D. (1978). Perfect adaptation and teleological explanation. Studies in the History of Biology, 2. Rehbock, P. (1983). The philosophical naturalists: Themes in early nineteenth century British biology. University of Wisconsin Press. Richards, R. (1992). The meaning of evolution. University of Chicago Press. Smith, J. (ed.). (2017). Figures of embodiment. Oxford University Press. Temkin, O. (1946). Materialism in french and german physiology of the early nineteenth century. Bulletin of the History of Medicine, 20, 322–330.

PART II

The Ultimate Causes: Why Do We—and All Others Creatures—Die? And What Should the Answer Do to Philosophy?

CHAPTER 7

A Providentialist Metaphysics and the Traditional Economics of Death: Mortality and Individuality

In all organisms, large and small, the life cycle is essentially irreversible, starting from birth, and going through some (reproductive) maturity towards death. For a long time, the philosophical tradition attempted, if not to explain this irreversibility, at least to capture its meaning; more recently, biology, be it physiological, molecular, or evolutionary, has suggested various explanatory theories. These theories are difficult to integrate into the philosophical tradition and, in fact, often deviate radically from it.1 In the past, in seeking a justification or validation for the fact of death, philosophical discourse put forth an argumentative logic pointing out that the negativity of death was merely the confirmation of a negativity already at work in life. As Aristotle said in his Metaphysics, the living die because

1  This part of the book is about current evolutionary biology. During the writing of the book, science continued its advances. As a result, some important literature has been published or I noticed it, only when the bulk of this manuscript was already written, or sent to reviewers. However, I chose to take them into account and add a few discussions. This concerns first of all Pierre Durand’s book The evolutionary origins of life and death (University of Chicago Press, 2021)—even if his foundational work on “programmed cell death” was already reported and discussed here—some advances in epigenomics on aging processes as well as several important position papers on the biology of aging by prominent researchers in the field. Later on, I took note of some convergence between their statements and the results of my inquiry.

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they live—but then, death fulfills what is negative in life. Seen in this light, death is not starkly negative, because in a way it realizes this negativity that is inherent to life; thus it completes life. To make sense of this completion, the categories essential to understanding life are implemented in what I will here call the providentialist conceptions of death. These are based primarily on the categories of totality and individuality, since those two categories are metaphysically mandatory in order to account for living organisms. Those can only be understood through the concept of totality: on the one hand, because a living thing maintains a specific relationship between its parts—most deeply analyzed by Kant in his Critique of Judgment—according to which the whole cannot be deduced from the sum of its parts; and, on the other hand, organisms are individuals, that is, they display an indivisible singularity or unity. The individuality question and the totality question will be considered in the following discussion, although the first part has already dealt with the question of totality, since Bichat’s experiments investigating death addressed the question of the relation between the life of the whole organism and the interrelations of the parts. The same question of the relation between parts and whole will emerge later on, in the form of the relation between the death of the whole and the death of some parts, exactly as in Bichat’s model, but reformulated at the level of the cells. For the moment, I will focus on the individuality issue, namely, the relation between death and individuality, since it is the core of what I will present as the providentialist metaphysics of death.

7.1   The Providentialist Metaphysics To start: for Hegel, death sanctions individuality; the individuality of the living organism separates it from the universal or the species; its very being is a contradiction between the universality of its concept and its own singularity, so it eliminates itself and dies. The disparity between the finitude [of the animal] and universality is its original disease and the inborn germ of death, and the removal (Aufheben) of this disparity is itself the accomplishment of this destiny. The individual removes this disparity (hebt sich aus) in giving its singularity the form of universality; but in so far as this universality is abstract and immediate, the individual achieves only an abstract objectivity, in which its activity has become deadened and ossified, and the process of life has become the inertia

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of habit; it is in this way that the individual brings about its own destruction (es sich aus sich selbst tötet).2

For Schopenhauer, in the paradigmatic metaphysics of death entitled “Supplement XLI to The World as Will and Representation,” the death of an individual creature cannot properly be conceived if one remains within the individual’s point of view. One must adopt the perspective of the whole species, which entails the following: To this, however, as was already mentioned above, it is essential, just because it is will to live, whose whole nature consists in the effort after life and existence, and which is not originally endowed with knowledge, but only in consequence of its objectification in animal individuals. If now the will, by means of knowledge, beholds death as the end of the phenomenon with which it has identified itself, and to which, therefore, it sees itself limited, its whole nature struggles against it with all its might. Whether now it has really something to fear from death we will investigate further on, and will then remember the real source of the fear of death.3

Considering this totality, death is only one aspect of the existence of life as such. According to this viewpoint, the individuality of life is only an appearance,4 related to what Schopenhauer calls representation, which implies the principle of individuation. Hence, biological individuality is bound by time and must therefore die. In this sense, it implies death, but for Schopenhauer death is not related to the essence of things. The negativity of death does not attain the essence of the will to live, or rather the essence as the will to live (since, for Schopenhauer, the essence of things is the “will,” and the World as Will and Representation constitutes the argument supporting this thesis). It is related instead to the inessential individuality, a correlative of the phenomenality of time and space in its representation (1231). While the objective, the species, appears as indestructible, the subjective, constituted by the simple consciousness of oneself in these individuals, seems to be of the briefest duration and doomed to an incessant destruction,  Philosophy of Nature, §375.  World as Will and Representation, 1229. 4  “Appearance” is to be taken in the Kantian sense, as a translation of Erscheinung, since Schopenhauer starts with the Kantian distinction between Ding an sich and Erscheinung. 2 3

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to come out as many times from nothingness, by an incomprehensible process. But, in truth, it is necessary to have a very short sightedness to be misled by this appearance, and not to understand that, even if the form of the temporal duration is appropriate only to the objective, the subjective, i.e. the will, present in all, and with it the subject of the knowledge, where the subjective is represented, must not be less indestructible. (1231)

As it stands, even though Hegel and Schopenhauer in general disagree on many things, they both argue that there is a tension between living individuals and the viewpoint of the universal to which they pertain, be it the species, or what Hegel calls the Concept. Death results from this tension and to some extent, such an argument justifies death. Even though the individual sees death as a kind of scandal, the viewpoint of the universal shows that it is legitimate. There is something inevitable in the fact of death because it is rooted in the essential contradiction, finitude, or deficiency of the living individual. I call this conceptual scheme “providentialism,” because it is strictly analogical to the justifications of evil and pain grounded on an appeal to divine Providence. Augustine’s City of God, in explaining why the destruction and rapes that occurred after the fall of Rome into the hands of “barbarians,” exemplifies this idea: human subjects feel that this is evil but there is a divine justification, which shows that those events had from the viewpoint of God a beneficial side. Of course, in classical metaphysics, theodicy represents the perfect realization of this appeal to Providence. Leibniz’s Théodicy intended to explain that this world is the best among all possible worlds, so that what from our partial and limited standpoint sounds terrible finds a justification in terms of the consideration of the best of all possible worlds, from the divine standpoint. For instance, negative events are in fact nothing, because they are merely an absence of a positive reality, and the economy of the whole world makes it necessary that such lacks happen; otherwise, because of complex compensations between possible causes and effects, the total sum of the positive reality in the whole world would be lower, and then our world would be such that better worlds exist, so that God—omnipotent and good—could not have chosen it. In such a theodical logics, death occurs as such a negative thing because within the overall economy of the various positive realities in the world, the best possible world should include it. Here I claim that within the philosophical tradition, there exists a pervasive view of biological death relying on this notion of divine

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Providence—even though Hegel or Schopenhauer do not call for any common idea of God, so that providentialism somehow gets secularized. But the logic of the argument is always the same. What matters is that death is justified because it achieves something, or more precisely, it pays or compensates for something. To some extent, Aristotle’s claim that the individual has to die because it is alive was a very simple and minimal form of such an argument: life has a cost, which is death. The providentialist metaphysics of death functions as an economy. Philosophers diverge about what has to be paid, what is the currency, and how the cost is calculated, but the logic of the argument is generally the same: individual organisms are in debt to something, this debt has to be paid, and death is the cost. Thus, there is a metaphysical justification for death, which can be seen at the same time as Providence and as economics. It is providentialist because death is not there for nothing but serves a higher goal—for instance, according to Hegel, death is the last moment of the dialectics of nature, through which the living individual overcomes its finitude as a living creature and reaches existence as a spirit (therefore opening the “philosophy of the spirit,” the last stage of philosophy). And it is economics in the sense that death is understood as the price paid for something which is faulty: an inadequacy, a debt, a lack of completion. Each version of the scheme may emphasize one or the other aspect of such an argument linking universality, life, individuality, finitude, and death (in the following, for the sake of brevity, I will often simply refer to “Providentialist scheme”). The overall argument can be seen as a form of teleology, but emphasizing the notions of Providence and of debt is important to specify the kind of justification that is at work here, as well as the way later developments in evolutionary biology will be radically disruptive.

Debt in Mythical Justifications of Death

Even though I know all limitations of comparisons between myths and philosophy, I’d like to quote here one of those myths on the origins of death compiled by Denise Paulme, that I cited in introduction. It is a story collected by a Swiss anthropologist, Zemp in 1963, heard among the Dan people, in the western part of Ivory Coast. The motive of the debt is salient here: (continued)

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(continued) Zra made Death; but formerly Death was in the bush and did not come to the villages. Men did not die. A hunter 1 day went into the bush. In those times Death was in the bush and killed only game. The man was a very good hunter. In the bush he found some fire on which Death was cooking meat. Nobody had seen Death until then, but the hunter met him. Death told him: ‘well, you have seen my game, so you have seen me! You are a hunter, I am a hunter. We are fellow hunters!’ The man stayed with Death for several days. Death gave him some meat, he thanked Death and brought some meat back to his village. But he did not know he was in debt. One day Death came to the village to ask for payment. He said, ‘repay your debt’. The hunter said, ‘why, was not the meat a gift? Was it a loan?’ Death answered, ‘I was in the bush. You came, you collected all my meat. Today you must repay me.’ The hunter said, ‘all right, take one of my children.’ And Death thereupon caught his child, saying, ‘I have come to you. You are in the village, you did not know I was in the bush. I killed game in the bush, you came and took away my meat and when I asked for payment, you would not pay?’ (Paulme,5 1967, my emphasis)

Epistemologically, this providentialist argument is not an explanation of death, but rather a justification of it: death has to be there, because something proper to individual life has a cost, and has to be paid. No causal process, nothing that could scientifically answer the question “why death?”, is proposed. Death is “natural,” meaning that it is an intrinsic property of the living individual even though it may seem to happen to her; understanding it does not consist in finding a cause, but showing how it fits either in the grand scheme of nature, or, as more theologically minded philosophers used to do, in the grand scheme of God. At the time of Hegel and Schopenhauer, philosophers had the project of a “philosophy of nature,” and such a Naturphilosophie became a major philosophical trend after Goethe, with a major impact upon the life 5  Denise Paulme was one of the first major Africanist anthropologist; this is taken from her Frazer lecture, later published in the journal of the Royal Anthropological Institute.

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sciences, which at this time started to emerge (Richards, 2001). This idea of a philosophy of nature meant that philosophy does not itself engage in the science of nature, which is mostly mathematized and observational or experimental, but reflects on these sciences in order to find out the meaning of the systems of laws discovered, often inductively, by the scientists. I called it a “hermeneutics of nature” (Huneman, 2006b), and the providentialist scheme of understanding death perfectly fits into this endeavor, which consists in putting distinct established empirical facts within a single, metaphysically justified framework. But this does not mean that such a scheme would be absent in any scientific attempt to make sense of death, even after Darwin.

7.2   Providentialist Metaphysics, Individuality, and Death in Biology: Darwin and Weismann 7.2.1   Biology, Geosciences, and Chemistry: Using Providentialist Schemes of Death According to Hegel or Schopenhauer, whose reasoning could constitute the most modern form of the argument, that which has a cost, ultimately paid by death, is the individuality of the living, which as such is lacking, wanting, finite. This deficiency of the living individual has to be compensated, and death occurs for this reason. Hence, death is not a bad thing that just happens: it is not exactly a mere event, since it stems from the inadequacy between the living individual and something universal. Undoubtedly, such an account of death owes some of its appeal to the imaginary categories of debt and accounting. Schopenhauer again highlights this scheme, arguing that death is the price to pay for sex, that the individual organism born of the union of the two sexes has to die: Life presents itself as a problem, a task to be worked out, and therefore, as a rule, as a constant conflict with necessity. Accordingly, everyone tries to get through with it and come off as well as he can. He performs life as a compulsory service which he owes. But who has contracted the debt? — His begetter, in the enjoyment of sensual pleasure. Thus, because the one has enjoyed this, the other must live, suffer, and die.6

6

 The World as Will and Representation, Supplement XLV, p.1329. Emphasis is mine.

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This quote is telling because it ties together the issue of the account of death and the justification of sex, and I will indicate below (Chap. 8) that these two problems entertain parallelisms in evolutionary biology. For now, the metaphysics of death indicates an essential bond between death and individuality. It is notable that the bond is common in biological thought up to Darwinism and even beyond. Eighteenth-century theories of natural economy, like those of Linnaeus, Huber, or Cuvier, represented death as a set of scales held by God, with the old on one side and the young on the other.7 Linnaeus’ economy of nature is a model for these conceptions in which nature is seen as economy on a universal scale. The death of the individual serves to promote the survival of the species: while Hegel insists on the inadequacy between the individual and the human species as a universal concept, natural historians mostly focus on the way death contributes to the flourishing of the species as an eternal class of individuals—the emphasis is put either on the providentialist or on the economic side of the metaphysical argument I sketched previously. What is important to note here is that such a providentialist account of death in natural history still pervaded up to Darwin. Darwinian thinking repurposed this scheme in an evolutionist perspective. Seen from this viewpoint, the idea of the struggle for life facilitated the thought that in addition to contributing to the survival of the species and to population regulation, the death of individuals actually improves both species and populations. A providentialist metaphysics of death was easily grafted onto Darwin’s evolutionism. It was even more hospitable to the idea that sexual reproduction was a valuable factor in diversity, hence variation, and therefore provided opportunities for improving natural selection. Thus, within a Darwinian framework, the old link between death and individuality could survive: living individualities have to die—in other words, death is justified—because their death contributes to the future benefit of the species or its descendants. In particular, death alone would give the diversity induced by sexual reproduction the possibility of spreading. Like sex, death participates in a providential economy prevailing over all of nature, according to the cycles of biological evolution itself. This is not a thorough historical reconstruction, but some references suffice to show that the providentialist reading of death pervades natural

7

 See Linnaeus (1982). For Cuvier see Pearce (2010).

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history around the times of Darwin. In England, as analyzed by Hamlin (1985, 1986), and in Germany and Sweden, the notion of cycles of nature, approached through chemistry, allowed naturalists and chemists such as Alexander Müller, the Swedish naturalist; Justus Liebig, the German chemist; or James Johnston, the Scottish chemist, to conceive of the death of individuals as fulfilling a role within an eternal cycle of the transformation of biological matter into novel materials for other living creatures and their milieu. For them chemical cycles were “typifying the Creator’s wisdom and goodness in establishing a beautiful, bountiful, healthful, and self-sustaining world” (Hamlin, 1986, 135). No doubt that Darwin, like all biologists, was aware of this chemical theodicy that, like Johnston, saw “death as a glorious participation in natural cycles, in which” borrowed molecules “were freed for utilization in new life” (ibid 138).8 The death of individuals is a necessary episode in this “wonderful circulation of nature” praised by Müller (cited in Märald, 2002) that embraced not only natural beings but also societies via agriculture and industrial chemistry. Interestingly here, the providentialist account of death, mostly exemplified at this period by the project of a hermeneutics of nature, pervaded geosciences and organic chemistry. 7.2.2   Darwinizing the Scheme: Weismann, Soma, Germen, and Death In biology, August Weismann in the late nineteenth century elaborated what later came to be called “Neo-Darwinism.” His theoretical views relied on Darwin’s evolutionary theory, but focused on the issue of inheritance. He clearly separated the Lamarckian component of Darwin’s thinking, what Darwin called “the use or non-use of organs”—which was an additional cause of evolution, yet (for him) less important than natural selection—from the theory of evolution itself. His experiments on mutilations in the lineages of mice, in which he let 901 mice across five generations emerge intact from mutilated parents, had convinced him that no modification induced within the lifetime of an organism could be transmitted to its offspring.

8  Marlin explicitly introduces the concept of Providence as the theological root of these cycles according to the authors examined. I am grateful to Sébastien Dutreuil for these references.

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Because nothing from the life of the individuals heritably passes onto their offspring, Weismann forged the crucial distinction between germen and soma, or somatic and germinal cells, in order to make sense of this fact that heredity is untouched by the life experiences of individuals.9 He proposed this theory in an 1882 text precisely about death and lifespan, Ueber die Dauer des Lebens (“About the duration of life”), which argues that the lifespan in each species derives from a specific articulation of soma and germen. Localizing inheritance in cells, Weismann sees the difference between what happens during the life of the individual, namely, learned experiences, body modifications, and so on, and what is transmitted, as a difference between two types of cells, the somatic ones, which make up the individual body but can’t survive the organisms—and the germinal ones, which are the same as what is received from the parents (hence the ancestors) and therefore can persist indefinitely beyond each individual body (Weismann, 1889). This “sequestration of the germ line,” as we say now, is characteristic of most animals; however it is a major evolutionary innovation—some organisms like Botryllus Schlosseri, a colonial ascidian tunicate, lack this sequestration—and it evolved several times independently. At the same time, in the early twentieth century, another theory explaining death, more widespread among physiologists than among naturalists, was based on observable differences in lifespan between species, a fact that was also topical for Weismann’s writing on the duration of life. This theory posited that the reason for these differences must ultimately be related to the reason for death itself. After Rubner (1916 - see Ferrucci et al. 2012 on this history), the gerontologist Raymond Pearl, writing in the 1920s, wanted to attribute this reason to differences in metabolic rate: mice have shorter lifetimes than elephants (even though the size/lifespan correlation holds between species rather than within species) because, due to their lower weight, they burn their calories more quickly (Pearl, 1922, 1928). This theory was based on an intuition that “he who lives fast dies sooner.” For our purposes, the point is that this theory also fits into a scheme of “vital bookkeeping,” in which death is the price paid for the benefit of life. It is similar to the providentialist metaphysical concept justifying the end of life with a calculation of profits versus losses, as Pearl’s own formulation

9

 See, for instance, Winther (2001) for an analysis.

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puts it: “The somatic death of higher organisms is simply the price they pay for the privilege of enjoying those higher specializations of structure and function.”10 Yet, the lifespans of animals like birds and bats—who live fast but seem to die later than other larger mammals—contradict the predictions made by Pearl’s “rate of living” theory (Austad & Fischer, 1991). However, by contrasting immortal germen and mortal soma, Weismann opened a new theoretical space, which frames the question of why we die through its need for an evolutionary answer. His own answer is consonant with the general scheme of the providential metaphysics of death: individuals die so that the species itself can be perpetuated. Death is, once again, the cost of individual life: when germen and soma are not distinguished, cells can persist indefinitely, and therefore not die; inversely, the sequestration of the germ line entails that, in organisms that are not unicellular, mortality is the price of the possibility of complex individuality. Weismann’s view of death therefore instantiates again, for the first time within Darwinian biology, the providentialist-economic scheme for justifying death that I outlined above. At the same time, his account is not a purely metaphysical justification considering logical properties (individuality, species, universal, etc.) but also targets actual biological structures, the soma and the germen, which are sets of cells. Broadly put, his account merges the justifications of death that philosophers traditionally forged often using a providentialist-economic interpretative grid with a biological explanation, focusing on biological entities and their causal effects. Granted, the individual pays a price by dying, but this debt is understood in novel terms. The soma is a living individual, while the germen never exists as an individual: in sexually reproducing individuals it only provides what is needed for making up the new zygote, while in asexual creatures it is indefinitely reproduced. And the soma dies, while the somehow immortal but never-existing-as-an-individual germen can persist indefinitely. This merging of justification and explanation has two major consequences. First, by figuring the essential finitude or inadequacy of the living in terms of the heterogeneity between soma and germen, it sets the question of death in relation to the cell theory. Individuality appears as

 Quoted by Medawar, Uniqueness, p.30.

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multicellularity—which for Weismann requires the sequestration of the germ line—while cells are by definition replicable; hence they are never individuals. The price of individuality becomes the price of complex multicellularity as opposed to single cells. Even though the providentialist scheme will fade out, as I will explain in the next chapters, this formulation in terms of unindividualized and immortal cells vs. mortal multicellular organisms will constitute for a very long time the context of the biological question of mortality. More generally, the version of providentialist metaphysics that permeates Darwin and all pre-Modern Synthesis Darwinism calls upon Weismann’s difference between the temporary soma of the individual and the eternal germen. The cells of the individual’s body—his soma—die: this is the price paid for sexual reproduction, that is, the union of his germen and that of another individual. This reference to sexual reproduction echoes Schopenhauer metaphysics, in which death appears as the price paid by the individual for such reproduction. But the connection here is biologically understood. Sexual reproduction broadens the diversity of germinal lines and variation within a given species. In this way it increases not only the abilities of the species to adapt but also its potential to give birth to varieties with even more efficient traits. In return, since sex requires the division of soma and germen, the soma—hence the individual—cannot survive forever. Individuality, sexuality, and mortality are the trinity supporting a sort of theodicy of the living, as reinterpreted by an emerging Darwinism. Second, the providentialist reading in Weismann’s terms concentrates on two biologically concrete terms: the individual organism and the species. The economic scheme here consists in a trade-off between the species and the individual—and even though the reference to the opposition species-individual within a theory of mortality is far from original, Weismann’s reading is new in connecting it to the soma—germen difference (since the germen ties the individual to its species). For our question, this will have longstanding consequences because from Weismann on, the idea of death evolutionarily interpreted points to the notion of the “good of the group.” But this implicitly engages what will be later known as “group selection,” and the investigation of biological

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death will therefore be tied to the debates on group selection, as the next chapter will show.11 7.2.3   Death, Individuals, and the Good of the Group Along these lines, the immortality of the germen, according to Weismann, implied that the immortality of the soma was useless, and could therefore be swept away by natural selection. This selection was assumed to have been the case in the past. Such an idea opened the door to questioning the emergence of mortality in living species. If the soma was more or less “disposable,” as it would come to be labeled later (see Chap. 10), then the various types of death—due to old age, or to the end of life after spawning, like certain species of salmon, and so on—should be variations on the same theme, namely, the relationship between germinal eternity and somatic representatives. The causes of these variations should logically be found in evolution: Weismann was thus the first to think that natural mortality had evolved driven by natural selection.12 And this idea is framed both by him and generally in terms of the “good of the species.” Individuals age and finally die because otherwise the species could not persist: resources would

 But even more generally, this division between soma and germen is crucial for biology because it carries the possibility of distinguishing the history of a lineage and the history of the individual. Modern evolutionary biology—namely, the Modern Synthesis that some people sometimes call “Neo-Darwinism” (e.g., Walsh, 2015)—relies on a sharp distinction between inheritance (namely, the transmission of traits through generations within a species) and development (namely, the process that goes from the zygote to the reproducing adult). This distinction can be easily built on the separation between germen—hence, inheritance, since the life of the individual organism is not concerned—and development. Current evolutionary biologists face a growing challenge especially from evolutionary biologists of development, who advocate the role played by developmental processes in the generation of heritable variation, and the patterns of variation, which in turn fuel evolution (Huneman & Walsh 2017; Müller, 2017). One should therefore notice that this foundational challenge in today’s evolutionary biology can be traced back to a conceptual pair that was elaborated when the question of the reasons for death first emerged. Yet, as I will show in the next chapters, the Modern Synthesis stepped back from the providential metaphysics of death to which Weismann still subscribed. 12  Even though Weismann fell into the vicious cycle mentioned earlier, because he insisted that elderly individuals with worn tissue were useless to the species and could be eliminated—which presumed that the tissue was necessarily worn, and therefore that “senescence” occurred, and hence that the fact of death was already established. See Weismann (1882). 11

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not be enough. Often, this providentialist idea is formulated in terms of the cycle of life where the dying young individuals allow for new individuals to start over, hence instantiating an eternal loop of life and death through which the species itself can exist indefinitely. In a book called The Evolution of Death, which examines recent changes in death and lifespan mostly among humans, the biologist Sydney Shostak writes that “by lubricating life’s cycle, death greases the way to better life. Moreover, life cycles with the best lubrication shape future generations” (Shostak, 2006, xii). The death of the individual improves the life of following generations: once again, a justification of death, which here constitutes the background of an investigation of the changing patterns of death among humans. This idea of natural selection aiming at the good of the species is a longstanding misunderstanding of Darwinian selection, which explicitly targets individuals. However, it was pervasive in Darwinian thinking before the 1960s, especially when biologists were considering ecology. One of the major treatises in twentieth-century ecology, Principles of Animal Ecology, written by Clyde Allee, Thomas Park, Alfred Emerson, Orlando Park, and Karl Schmidt, elaborated a very influential frame of thinking in which ecological communities and ecosystems were thought of as organisms—a leitmotif in ecology since Frederick Clements in the 1920s (Eliot, 2005)—but understood as an effect of natural selection, in the same sense as organismic cohesiveness was promoted by individual natural selection (Huneman, 2019a). This view was largely supported by the major evolutionists of the Modern Synthesis, notably Theodosius Dobzhansky, who wrote a laudatory review of it (Dobzhansky, 1950) in the Quarterly Review of Biology, and Sewall Wright, arguably the main influence on the authors, who are often referred to as the “Chicago school of ecology” because they worked and met at the University of Chicago, where Wright was the leading evolutionary biologist. This line of thinking led to the influential book by Vero Wynne-Edwards (1962). Here, he argued that animals such as mammals or birds would exercise self-restraint in their consumption of resources in order to let the group flourish rather than die. His book is mostly remembered for triggering the critique by George Williams that provided one of the most insightful analysis of natural selection and selectionist explanation. In his 1966 Adaptation and Natural Selection, Williams argued that all apparent adaptations at the level of the group are actually a reflection of adaptations at the level of the individual; natural selection does not act at the level of the group or the species but of the individual or even the gene—this last

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claim being the first formulation of the thesis that made Richard Dawkins famous, namely, genic selectionism or “the selfish gene” (Dawkins, 1976). But dying resembles self-restricting consumption, if one looks at such species-level or group-level selection appealed to as its explanation. It therefore comes as no surprise that one of the biologists who massively rejected this view of death as being “good for the species” was precisely George Williams, the champion of individual selection, the subject of the next chapter. 7.2.4   Facing Difficulties of All Sorts Because the concept of debt tends to align so well with providentialist theories of death and aging, whether they fall into the rate-of-living category favored by physiologists, or that of Darwinians like Weismann, it has been easy for thinkers to ignore the many fallacies underlying them. For example, they often tend to omit the fact that aging should include certain selective advantages, immunity-related at least, and perhaps behavioral—the old have learned the dangers, know how to react, and so on. More decisively, saying that death is caused by the fact that the old must “make room for the young” already presumes that there are old and young—whereas one of the only ways to define old age is as an increase in the probability that one will die at a given age.13 Aging therefore presumes this death for which an explanation is sought, and the providentialist dogma apparently goes around in circles. Thus, even leaving evolutionary biology aside, the intuitively attractive idea that death is here for the good of the species faces a major logical shortcoming. However, the influential Weismannian account faced another, empirical drawback later on. In the 1920s, when Alexis Carrel asserted the immortality of cells from multicellular organisms that reproduce regularly, the contention—whether or not it was a matter of experimental error or fraud—was, in any case, profoundly coherent with such a vision. Because cells that replicate identically—that is, cells without individuality—do not 13  The very definition of “old age” is conceptually fragile. The English language makes a valuable distinction between aging, meaning simply a number of years, and senescence, which means an increase in age that results in weakness, decline, and so on, according to measurable parameters. Aging does not necessarily imply senescence, as unicellular creatures can indicate to us. Therefore, senescence signifies a greater proximity to death. In this sense, the investigation of death is also an investigation of the source of senescence.

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know how to die, they earn immortality. Here, Carrel was navigating upstream, from conclusion to premise, with the Hegelian reasoning that the individual must die. Fifty years later, by establishing reproductive limits for most cell families, Leonard Hayflick demonstrated that biology does not conform to this framework. This experiment is reported in Hayflick (1996): basically, it was a reversal of the interpretation of a fact. One surely knew then that cultured cells died, but since those of Carrel had survived, biologists assumed that these cell deaths resulted from human errors in the laboratory. Hayflick and his team showed that the opposite was true: the laboratory error had originated with Carrel. Hayflick mixed two lines of human cells, female and male fibroblasts, and fed only the female line with new cells; nevertheless, in every case, only the male line died out, after 50 divisions. This was proof that under natural conditions, a cell ends up dying. Hence today, the providentialist link between the individual and death, framed in terms of the good of the species, is undergoing a thorough rethinking. Since the 1950s, when the study of evolutionary biology was placed within the framework of the Synthetic Theory (founded on the principle that Mendelian heredity and variations fuel the mechanism of natural selection), Darwinian conceptions of death have changed radically. As we shall find, this change implied the understanding that genes constituted a substrate for heredity, but also that genes or genotypes could influence several genotypes at the same time. Then, starting in the 1960s, thanks to the discovery of the structure of DNA in 1953, the rise of molecular biology made it possible to understand the relationships between the physiology of the organism and its cellular components. The very idea that a wrongly assumed cell immortality was linked to the irreversibility of the life cycle of individual organisms in a providentialist manner was disrupted entirely. We shall approach each of these aspects in turn. Recent biological theories on mortality—the result of new findings in evolutionary biology and molecular biology—challenge the general understanding of death that pervaded philosophy and biology, as I have just described in these two chapters. Starting in 1952, Peter Medawar and then G.C. Williams suggested hypotheses, called, respectively, the theory of the “mutation burden”14 and that of “antagonistic pleiotropy.” By so

 This would be the proper name, since accumulated mutations are deleterious in later life. It has come to be named “mutation accumulation theory” and in the following I will follow this use. 14

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doing, they forced us to rethink the differences between intrinsic and extrinsic or accidental death, and between the life and death of the parts— cells—and the whole organism, two distinctions that structure theorizing on death. The rest of this book will examine this rethinking in all its dimensions.

References Austad, S., & Fischer, R. (1991). Mammalian aging, metabolism and ecology: Evidence from the bats and marsupials. Journal of Gerontology, 46, 47–53. Dawkins, R. (1976). The selfish gene. Oxford University Press. Dobzhansky, T. (1950). The science of ecology today. Review of Principles of Animal Ecology by W. C. Allee, Alfred E. Emerson, Orlando Park, Thomas Park, Karl P. Schmidt. Quarterly Review of Biology, 25(4), 408–409. Eliot, C. (2005). Method and metaphysics in Clements’s and Gleason’s ecological explanations. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences, 38(1), 85–109. Ferrucci, L., Schrack, J. A., Knuth, N. D., & Simonsick, E. M. (2012). Aging and the energetic cost of life. Journal of the American Geriatric Society, 60(9), 1768–1769. Hamlin, C. (1985). Providence and putrefaction: Victorian sanitarians and the natural theology of health and disease. Victorian Studies, 28(3), 381–411. Hamlin, C. (1986). Robert Warington and the moral economy of the aquarium. Journal of the History of Biology, 19(1), 131–153. Hayflick, L. (1996). How and why we age. Ballantine Books. https://en.wikipedia. org/wiki/Ballantine_Books Huneman, P. (2006b). From the critique of judgement to the hermeneutics of nature: Sketching the fate of philosophy of nature after Kant. Continental Philosophy Review, 39, 1–34. Huneman, P. (2019a). How the modern synthesis came to ecology. Journal of the History of Biology, 52, 635–686. Huneman, P. (2019b). Revisiting Darwinian teleology: A case for inclusive fitness as design explanation. Studies in History and Philosophy of Science Part C, 76, 101188. Huneman, P. (forth.). Life sciences, Kantianism, and the concept of organism. Routledge. Huneman, P., & Walsh, D. (Eds.). (2017). Challenging the Modern Synthesis. New-York: Oxford University Press. Linnaeus, Von C. (1972). L’économie de la nature, transcripted J. Biberg, transl. B. Jasmin, introduction C. Limoges. Paris: Vrin. Linné, C. (1980) L’équilibre de la nature, Limoges C. (ed.), Vrin.

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Märald, E. (2002). Everything circulates: Agricultural chemistry and recycling theories in the second half of the nineteenth century. Environment and History, 8(1), 65–84. Müller, G.  B. (2017). Why an extended evolutionary synthesis is necessary. Interface Focus, 7, 20170015. Paulme, D. (1967). Two themes on the origin of death in West Africa. Man, 2(1), 48–61. Pearce, T. (2010). “A great complication of circumstances”—Darwin and the economy of nature. Journal of the History of Biology, 43(3), 493–528. Pearl, R. (1922). Biology of death. Philadelphia. Pearl, R. (1928). The rate of living. London. Richards, R. (2001). The romantic conception of life. University of Chicago Press. Rubner, M. (1916). Machinery of metabolismë. JAMA: The Journal of the American Medical Association, 66(24), 1879. Shostak, S. (2006). The evolution of death. Why we are living longer. SUNY Press. Walsh, D. (2015). Organisms, agency and evolution. Oxford University Press. Weismann, A. (1882). Ueber die Dauer des Lebens. Fischer. Weissmann, A. (1889). Essays upon Heredity. Clarendon Press. Winther, R. (2001). August Weismann on Germ-Plasm variation. Journal of the History of Biology, 34, 517–555. Wynne-Edwards, J.  C. (1962). Animal dispersion in relation to social behavior. Hafner.

CHAPTER 8

The Evolutionary Synthesis’ View of Death: Peter Medawar, George C. Williams, and the Riddles of Senescence

8.1   A Biologist on Selection and What Apparently Resists Its “Paramount Power” George Williams may be an exception in American evolutionary biology. His contributions are numerous and range from the conceptual elucidation of natural selection that I cited to the notion of maladaptation and the limits of adaptation as foundations of evolutionary medicine (Nesse & Williams, 1994), the explanation of sex and, naturally, the explanation of aging and death. His questioning can be seen as an exploration of what Darwin termed “the paramount power of natural selection,” meaning at the same time that its causal effects are pervasive across the whole domain of living things, and that its explanatory capacities are tremendous. Why is Williams an exception? As Depew (2011) underscores, while the Modern Synthesis emerged from the conjunction of British and American biologists—the British population geneticists J.B.S. Haldane and Ronald Fisher, the zoologist Julian Huxley, and the population geneticist Sewall Wright from the US, as well as the zoologists and botanists Leylard Stebbins, Ernst Mayr, George Gaylord Simpson, Theodosius , working in the US (Cain, 2009; Huneman, 2019a; Smocovitis, 1992)—it included two quite different styles. The notable controversies between Wright and Fisher on the target of selection illustrates this divide: Fisher concentrated on the “additive effects of alleles”—which anticipates Dawkins famous “gene’s eye view,” according to which selection doesn’t act on organisms © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_8

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but merely on alleles, since only these wholly replicate from one generation to the next.1 A biologist from the University of Chicago, Sewall Wright, in turn, argued that natural selection targets entire genotypes, not alleles, since the fitness effects of the interactions between alleles (epistasis, pleiotropy2) are crucial and cannot be neglected in the models (even though Fisher would argue that these effects are averaged away because of the size of the population, and the recombination at each generation in the case of sexual reproduction). This rough characterization of the divide3 indicates the parting of the ways between Fisherians, widely represented at Oxford and Cambridge, with younger figures such as Anthony Edwards or more recently Alan Grafen (who together disagree on many things)— and Wrightians—who included Dobzhansky, the above-­ mentioned Chicago school in ecology, and so on. It indicates that in the UK a focus on genes and adaptation—possibly inherited from the focus put by English natural theology on adaptations, which was so influential on Darwin through Paley’s Natural Theology—pervaded evolutionary biology. In turn, organicism and attention to within-species diversity was more proper to the US brand of the Synthesis (Depew, 2011), even though in the post-1960 generations one finds in the US hybrid figures such as Lewontin, or Gillespie, who is more selectionist, and in the UK Charleston or Barton, who are not pure Fisherians. In this sense, George Williams, the American biologist who mostly worked on selection and formulated the first justification for the gene’s eye view, is indeed an interesting exception.4 But this exception makes sense, precisely, as a reaction. Williams not only strongly reacted to Wynne-Edwards’ theory of group selection. As he recounted, as a young biologist he attended a lecture by Alfred Emerson, the world expert on termites and colonial insects, and one of the first to introduce the notion of homeostasis as characterizing insect colonies. Emerson was possibly the major writer of the section on 1  Actually, it has even been argued that Fisher’s most important contribution from his viewpoint, the Fundamental Theorem of Natural Selection, enunciated in his Genetical Theory of Natural Selection (1930), and stating that the increase in mean fitness of a population caused by natural selection is always positive—makes no sense except by appealing to a form of Dawkins’ genetic selectionism (Okasha, 2008). 2  Pleiotropy is the action of an allele on several traits; epistasis is the conditioning of just one trait by several alleles at several loci. 3  On Fisher vs. Wright see Gayon (1998), Plutynski (2006), Winther (2006). 4  I thank Arvid Argren for having pointed out to me the singular situation of Williams here.

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“Ecology and Evolution” in the Allee et al. (1949) treatise, including the parallel between organisms and ecosystems as targets of selection. When Williams heard group selection being so much invoked by Emerson to explain aging and death, he decided that this was blatantly wrong, and should be refuted—otherwise, he said, biology was not worth doing.5 This inspired his theoretical work, whose breadth, as I emphasized above, can be seen as a systematic investigation of the explanatory power of individual selection, whose assimilation to Darwin’s notion of selection he justified in his book on natural selection. What is striking indeed here is that Williams focuses on facts that seem so intuitively bad for individuals that they could not result from this selection that “scrutinizes” any small variations for the good of the individuals, as Darwin said, namely, sex, maladaptation, and death. “Natural selection should ordinarily proceed towards lengthening life, not shortening it,” he wrote in his seminal 1957 paper on senescence. I will first review the theoretical underpinning of this view of selection, recalling Williams’ arguments and evidence, and then will focus on his view of death, and how, concurring with the conception of the immunologist and Nobel Prize winner, Peter Medawar, it contributed to frame the current theoretical evolutionary thinking on aging and death.

8.2   Why Would We Have Sex and Die? Sex and death have been intertwined for various reasons, and not only because their mix provides the best recipe for a romantic movie or a bloody thriller à la James Ellroy. Many myths about ancient origins invent answers to the questions “why do humans die?” and “why are there two separate sexes?” The biblical Fall exemplifies the becoming-mortal of human beings, while the infamous myth of Plato’s Symposium, narrating a pre-­ originary world where humans were sort of huge symmetrical balls with eight legs, metaphorically explains sexuation: the Gods cut each of these pre-humans in half, each of whom is now devoted to finding their “sister half” (or as we say, “soul mate”).

5  Interview by Carl Zimmer, Science, 2004: “[Emerson] said growing old and dying is a good thing,” Williams says. “We’ve evolved to do it so we get out of the way, so the young people can go on maintaining the species.” “I thought it was absolute nonsense,” says Williams.

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Sex and death are comparable because both of them seem bad for the individual; hence one wonders why natural selection didn’t get rid of such detrimental features. Regarding death, its being opposed to the interests of the individual is quite obvious; regarding sex, think of an asexual female: she would pass on 100% of her genes at each generation, while an ordinary sexually reproducing female would at the same time pass on only 50% of her genes, due to the statistical laws of gamete segregation. Hence— assuming the disposition to reproduce is somewhat slightly heritable—in the long run the asexual female will take over the whole population. Yet most of the metazoan species are sexually reproductive species; when, within a lineage, an asexual species emerges, it does not persist long enough generally, and is always superseded by the other, sexually reproductive species. This phylogenetic pattern is proper to sex and constitutes part of the enigma of sex for biologists (e.g., Michod & Levin, 1988). Sex and death therefore do not seem to be needed there because of selection being an improvement of “individuals,” as Darwin thought. On the contrary, individual selection should have somehow got rid of sex and death or prevented their existence, in the basic Darwinian viewpoint. However, selection at the level of the group or the species may provide an answer here. As we saw, death can be good for the group, and be selected as such. Sex is a mechanism by which the genetic materials of two individuals of two different types are exchanged; because of mixing in meiosis, the offspring is genetically different from its two parents. Hence, assuming a low mutation rate, a class of offspring of several couples of sexually reproducing parents would be more diverse than a class of offspring of asexual individuals. If the group is more diverse, it has more chances to include a “good” variant in case the environment changes. In this way sexual reproduction confers an advantage on the whole group (as compared to a group of asexuals) and therefore should be favored by natural selection at the level of the group. But George Williams, as we saw, was a strict Darwinian: he thought that natural selection operates only at the level of individuals. Why is this the case? Without wanting to summarize a text as rich and complex as Natural Selection and Adaptation, consider that Williams’ constant concern is parsimony: an explanation should be relevant and not too onerous, in terms of principles and causes involved. Natural selection itself is not to be mentioned in any biological explanation: some traits are here just because of the physical effects of chemical and physical laws given initial

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conditions. As Williams ironically says, no natural selection is needed to explain why flying fish fall back into water after they have jumped instead of staying in the air, which would lead to certain death and harm their reproductive chances; the force of gravity is explanation enough. Thus, only traits that cannot be explained by the usual theories in physics and chemistry require selectionist explanations. The same reasoning holds for group vs. individual selection. Saying that groups of antelopes have been selected to run fast because the mean speed of the group is higher than the speed of their predators is too onerous an explanation: the mean speed of the group derives from the addition of the speeds of all the individuals. The “principle of selection within a group,” he writes in his paper on senescence and death, “is simpler and more applicable” than group selection (1957, 399). Because individual selection alone can account for the speed of the group, no additional processes, such as selection at the level of the group, should be appealed to. To this extent, all purported cases of group adaptations, as the effects of selection targeting groups, have to be reinterpreted in the less onerous terms of individual or genic selection. This is what his 1966 book establishes. Sex and death being two major cases of explanations ordinarily appealing to group selection, Williams’ work implied that for epistemological reasons other explanations should be found. About sex, for example, he argues that sex in complex organisms with low fecundity, such as vertebrates, does not need to be explained by selection in general because it is a constraint inherited from their ancestors (in the sense that, given the many features that have been built on this property, no variant including asexual reproduction would be a viable variant). He thinks that it cannot be suppressed, even though it is maladaptive (in the sense that other forms of reproduction would ensure more offspring, or more genes passed on to future generations.) As to other lineages, sex emerged as a result of individual selection, for various advantages, and varieties of sexual reproduction (anisogamy, hermaphroditism, etc.) can be envisaged as strategies for optimally passing on genes to individuals in the next generations. His conception of the reasons for death, however, were elaborated at the end of the 1950s, and rather fueled his theoretical reflection about natural selection that followed from it. His 1957 paper was written shortly after the formulation of one of the first modern, non- group selectionist theories of death, formulated by Peter Medawar in The Uniqueness of the Individual; here Williams explicitly criticizes Allee et al.’s (1949) view of

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group selection explaining senescence (p. 399), because they postulated a selection at the level of the group that would favor senescence, whereas selection at the level of the individual is enough.6 The neo-Darwinian theory of death, said Medawar, aims to explain both the process of senescence in the individual and the “form of the age-­ frequency distribution of death” as related to natural selection.7 But according to him, death was not selected as such by natural selection. Instead, it is caused by the accumulation of certain genes whose lethal effect occurs only after the individual reaches a certain age. At this age, well beyond the average reproductive age, selection is no longer operative, because chances are that the individual would already have been eliminated by predators and more generally by life in the wild. Basically, this theory develops a simple principle at work in Darwinian theory, noted by Haldane and then by Simpson,8 according to which “the changes an animal may undergo after it has ceased to reproduce are never directly relevant, and in most cases are quite irrelevant, to the course of its evolution.”9 In other words, this means that all of these statements (about the theory of death, and this holds beyond Medawar also, as we will see) derive from the hypothesis that “natural selection will so act as to enforce the postponement of the age of the expression of those factors that are unfavorable.”10

6  Even though the demise of group selection is important to understand those theories of death, and Williams explicitly dismisses any appeal to group selection in evolutionary explanations, more recently a few variant concepts of group selection have been introduced and some of them may be considered again in models of senescence; but they are not the same “advantage for the group” theories that Williams rejected. I’ll address them in Chaps. 10, 11, and 14. Durand’s recent book on life and death (Durand, 2021) devotes chapter 15 to the “evolution of life and death and group selection,” and finds “ironic” that “such a controversial topic” as group selection proves important for “two of the most important biological processes—the origins of life and death” (159). 7  Medawar, Uniqueness, 34. 8  Tempo and Mode in Evolution (1944), p.183, cited in Uniqueness. 9  Uniqueness, p. 34; here, Medawar should have qualified the term “evolution” with “of its species,” since this is a point he moreover insists on later: the (genetic) compositions of populations are what evolves; the theory of death presents the same epistemological difficulties as evolutionary theory (in this case, that of the unity of evolution). 10  Uniqueness, 67. Here, the increasing age means “aging,” above all, and therefore does not necessarily imply senescence. This distinction is essential to understanding how the consequences of the hypothesis can explain death and therefore senescence, as shall be seen.

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8.3  Mutation Accumulation and Antagonistic Pleiotropy: Framing the Evolutionary Conception The latter claim about selection and age is supported by the following thought experiment: assuming there are simple, immortal creatures—what Mangel (2002) called Darwinian demons, in a clear allusion to “Maxwell’s demon”—with a given reproductive output and a fixed risk of death, we could expect that over a given interval in time, due to the very fact that the eldest are exposed to deadly risk more often, there would be more deaths among the old than among the young. As a result, at a certain point in time, there will be more young than old, and therefore more descendants-ofyoung than descendants-­of-old. Again, in this case, the old are not more “senile” than the young; the only difference is a greater probability that they will have survived a deadly accident in the past, since they would have been exposed to the risk of such an accident for a longer time. As a result, says Medawar, “the contribution that each age class makes to posterity decreases with age.” Importantly, this does not assume that the fertility of an individual decreases with age; it might be constant, but, given that the older the individual is, the higher the chances she will have already died, old individuals will be fewer in the population and their offspring will therefore be fewer than the offspring of the youngest. As George Williams will later say, there is “a cumulative probability of death” which “would produce a decline in reproductive probability because the probability of reproduction at any age is proportional to the probability of surviving to that age” (Williams, 1957, 401). Under these conditions, if a gene appears that promotes younger individuals by displaying its effects at an earlier age, it will spread more easily, because the age class of the young have more offspring. Any gene that strengthens the youngest, stimulates their reproduction, and takes effect early in life would therefore have more chances of spreading than a gene that takes effect later. By the same reasoning, any gene that inhibits reproduction or ends lifespan, and takes effect early, would quickly be eliminated by selection, compared to an identical gene that takes effect later. Or, as Medawar puts it, we witness both the “precession of positive genes” and the “recession of negative genes” (Uniqueness, 39). Hence, as a consequence, the later in life a gene’s effect is expressed, the slower its rate of control by natural selection will be, since the individuals carrying it will be older and therefore, at a given moment, will have fewer offspring, no matter what—as if they were less visible to natural selection. Ultimately, deadly

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genes that take effect early will be eliminated, but others will not. Deleterious mutations taking effect late in life accumulate—“mutation accumulation” is the principle of this view of death, and has usually been labeled in this manner in subsequent studies. The mortality of individuals can therefore be explained as an effect, albeit an indirect one, of natural selection; indirect in the sense that it is not directly selected for itself, unlike traits referred to as “biological functions” (Neander, 1991), that is, those which directly increase the chances of survival and reproduction. This was the major rationale behind Medawar’s groundbreaking theory of senescence and death and more generally the Darwinian take on intrinsic death. To show more precisely how death has evolved, Medawar proposes a thought experiment. Consider a population of immortal individuals with a fixed yearly reproduction rate. For instance, think of a population of test tubes in a laboratory—inanimate objects, with a stable daily probability of being broken—and assume that the test tubes reproduce, rather than being replaced at a fixed rate by the laboratory staff. According to the former a priori argument, in a given population, after a while the contributions to the next generation are mostly done by the youngest tubes. Suppose that some mutations affect the tubes, and entail their breaking at a definite time, and are then transmitted to the descendants. Now compare mutations X that induce breaking after n timesteps, and mutations Y that induce breaking after m timesteps, with m >> n. Take p such that n < p < m. After p timesteps, among existing tubes, none will be tubes produced at time 0 with mutation X (since p > n), some will be X mutants produced at i > 0, and tubes with mutation Y emerged at time 0 will still have descendants, whose descendants will be much more represented in the population (since neither these tubes nor their descendants have reached their expiration date m). Because most of the tubes at generation p + 1 will be produced by younger tubes, and because most of them will have mutation Y rather than mutation X, chances are that at generation p + 1 most of the test tubes will be carrying mutations Y. Now, if b is the age at which half of a population of test tubes produced at the same time is broken, one sees that for a given n and m, the value of b plays a role in determining the fraction of tubes carrying X mutations and Y mutations in the population, since it determines the amount of X and Y tubes that are still present at p. Thus, the smaller b is, the quicker mutation X will decrease in frequency in the population (respective to mutation Y). Intuitively, b gives a measure of the time when natural selection is most active. This reasoning is the sketch of Medawar’s “mutation accumulation”

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argument, which states that mutations whose deleterious effects occur later will tend to accumulate in a population, and that the intensity of this accumulation is determined by the chance of being destroyed by the environment. The result is that most organisms carry many of these mutations and therefore accumulate factors that contribute to higher chances of death later. Since the increase in chances of dying by itself defines senescence, this argument theoretically explains the evolution of senescence. Notice that in this model, it cannot be said that selection only operates after reproductive age since reproduction occurs initially at any time. On the contrary, the model will also account for the emergence of a reproductive period and a post-reproductive period.11 In effect, in the population of test tubes, we saw that in principle, the fertility of the young test tubes would be favored. This implies that eventually an optimal reproduction age r (occurring mainly early in life) will emerge. In this sense—as the reasoning proceeds—mutations X having a deleterious effect at n > r will tend to be passed on to the descendants since organisms that express those deleterious effects will already have reproduced, and hence they will have ceteris paribus as many descendants as their counterparts without this X mutation. Hence the notion that the strength of selection declines with age; and this is all the more relevant when organisms experience a period when they don’t reproduce, since all mutations having effects at this time may remain in the gene pool, because selection does not “see” them. (However, it should be also noted that in the wild, most animals (including sponges) do not exhibit a “menopausal” or post-reproductive phenomenon12—and do not seem to senesce, even though (see next chapters) we now know they do.) Such a model can be tested empirically. When the pressure of deadly risk heightens, natural selection responds by shortening an animal’s lifespan so that lethal genes are eliminated or expressed late in life. John Maynard Smith and Steven Rose successfully performed this type of experiment using Drosophila, and then Steven Austad tested the hypothesis on opossums. Austad modeled his experiment on Medawar’s theory that in an extremely dangerous environment, a high rate of accidental death resulted in selection declining as age increased.13 Thus, many harmful genes remain active, because they may only be expressed after the 11  “The existence of a post-reproductive period is one of the consequences of senescence; it is not its cause” (Uniqueness, 58). 12  On this point, see Austad, How We Age, ch. 7. 13  How We Age, 111.

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individual has reached reproductive age and hence are always passed on to descendants. So, when the opossums were moved to a nearly predator-free setting (Sapelo island, off the Australian coast), the expectation was that the effect of natural selection would last longer into old age. According to this hypothesis, harmful genes that begin acting late in life would be filtered out, leaving only harmful genes that are expressed even later in life. As a result, average lifespan would increase: indeed, that is what happened.14 Since part of the following chapter will be devoted to the experimental corroborations of evolutionary views of death, I will not expand on this here, but I wanted to indicate that these models and theories are not deprived of empirical evidence.15 As a consequence, and most generally, the essential mortality of life thus seems to be nothing more than a trait that is indirectly selected, a side effect. Its indirect selection is triggered by the increasing probability of accidental death as time goes on. From the standpoint of evolution, potential “accidental” death controls the appearance of essential, “internal” death. To quote Medawar once again, “the ‘force of mortality’ has been moulded by a physical operator that has the dimensions of time × chance.”16 Internal death results from the external. It has absolutely no autonomy and is in fact almost “more accidental” than accidental death, because the intrinsic death can evolve only in relation to chances of dying, hence extrinsic mortality.

8.4  Enters Indirect Natural Selection: “Antagonistic Pleiotropy” In this context, Williams’ “antagonistic pleiotropy” view is an evolutionary theory alternative to Medawar’s “mutation accumulation,” although it is neo-Darwinian too. According to G.C. Williams,17 genes with a lethal effect are possibly maintained by natural selection because at an earlier age, they  Austad (1993); on earlier experiments involving flies, see Rose (1991).  Bowles (2000) criticizes Medawar’s thought experiment as inaccurate because test-tubes are identical, and their crashing is only one kind of event, while real organisms are different, learn, and can be destroyed through very different processes. But Medawar does not intend to be realistic at all; the point is to have a very abstract model that shows how senescence can evolve. To some extent, it’s as unrealistic as key models in population genetics such as the Fisher-Wright model, but expressed in a verbal way. 16  Uniqueness, 36. 17  “Pleiotropy, natural selection and the evolution of senescence,” Evolution, 1957, 11, 398–411. 14 15

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provide a selective advantage: here (like in Medawar’s theory) death is not selected for as such, but as a collateral effect of other traits (in this case, the reproductive benefit of lethal genes at an earlier age). This thesis actually results from one of Medawar’s examples, where he shows that a gene that increases reproduction but shortens lifespan will be selected over a normal gene that does not affect lifespan (this is still due to the period when natural selection is active, namely early in life).18 The decisive trait here is reproductive age rather than age at death, which somehow derives from the former (this relation will be analyzed in the next chapter). And Williams admits Medawar’s reasoning that even in the absence of senescence, and even if fertility remains constant, the age class of the old individuals will produce fewer offspring than the age class of the young individuals; hence the force of selection acting on the former class is much lower than the force of selection acting on the latter. Thus we don’t even need to assume that there is a reproductive period here (see Box 8.1 on formal aspects). What drives senescence and ultimately death is not selection itself, but rather its decreasing intensity, that is, what Haldane had called “the shadow of selection.” “Pleiotropy” means that a gene affects several traits at the same time, and these effects are the various factors in the formula Williams borrowed from Wright (see Box 8.1). This notion has been known in the wake of

Box 8.1  Medawar, Williams, Wright, Fisher

While Medawar was inspired by Fisher’s idea of reproductive value, Williams’ paper elaborates on Sewall Wright’s simple formula for the “selection of a gene with mixed effects on fitness” : W = (1 + S1) (1 + S2)...(1 + Sn) where Si is the advantage associated to the effect i of the gene; Williams decomposes Si then into two factors, the magnitude and direction (positive, negative) of the effect mi, and the “proportion of the total reproductive probability influenced by the effect,” pi. Thus, W becomes: W = (1 + m1p1 ) …(1 + mipi)…(1 + mnpn). The probability term pi proves crucial because if the advantage of a trait concerns only a small amount of the possible offspring that the individual can produce in its lifetime, which is measured by this probability pi, the total contribution to fitness due to this effect will be (continued)  Uniqueness, 64 sq.

18

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Box 8.1  (continued)

very small. And the effect of this simple formula is that, the earlier an effect mi occurs, the higher is pi, the proportion of total fitness affected by mi. Therefore, if the indexes i are ordered by the chronological happening of the effects on fitness, a gene G, where positive effects mi are concentrated at the earlier period, described as i < j, will be selected against a gene G′ whose positive effects mj, even higher than the positive effects of G, are concentrated in the later period described as j > i. “The selective value of a gene, as Williams summarizes, depends on how it affects the total reproductive probability,” (410) and genes with early effect affect their probability much more than genes with later effects, since the chances of dying from external mortality increase when the considered period of time increases. transmission and population genetics, and it plays a major role in evolutionary biology; as recalled, the extent of pleiotropy and its role upon mean fitness intergeneration change is at the heart of major controversies among authors in the Modern Synthesis (e.g., Wright vs. Fisher, but also Fisher vs. Hogben when it comes to measuring heritability). “Antagonistic” means that the effects of the two traits upon fitness are of opposite vectors—for instance, one will reduce it, the other will increase it. But fitness is, as indicated, a mix of survival and reproduction, and the exact measure in which a gene has antagonistic effects is hard to determine. Yet the phrase “antagonistic pleiotropy” is expressive enough to capture what goes on in the model proposed by Williams for the evolution of intrinsic death. The antagonism between early fitness increase and fitness decrease late in life concerns values of an abstract measure of evolutionary success—fitness—whose exact nature fortunately does not concern us here. (But see Chap. 11.) Given that in any case fitness is ultimately measured in terms of the representation of a trait-class or an allele-class in later generations, it has directly to do with the number of descendants of an individual endowed with this allele or trait.19 To this extent, early life fitness increase can easily be realized as an increase of the number of 19  See Orr (2009) for a clear presentation of several meanings of fitness, even though philosophical critiques could be raised against the view.

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offspring of this individual compared to others individuals who lack the focal gene; late-life effect can be seen as either a decrease in fertility later in life, or as a decrease in life expectancy. Considering the latter option, “antagonistic pleiotropy” as hypothesized by Williams would mean that, from the viewpoint of selection, genes that increase chances of reproduction but decrease prospects of survival would do better than genes that don’t hamper survival or even extend it. In this sense, an example of antagonistic pleiotropy was recently given by Metcalf et al. (2020), showing that a strong immune response to early infections confers a selective advantage because it favors the prospect of early reproduction, and therefore it can be retained by natural selection, even though it will hamper late survival since it induces an increased risk of inflammation. And in the sword tail fish, Xiplophorus Cortezi, the oncogene Xmrk provides to its bearers a selective advantage in size, hence for mating and reproduction, while it increases the later risk of melanoma (Fernandez & Bowser, 2010). These examples supplement a long list of examples, but those given by Williams are such that he mostly deduces the antagonism from the data. For instance, in Drosophila melanogaster, although the two laboratory mutants at the black and speck loci increase longevity, they are rare in nature; hence Williams deduced that they should involve a fitness cost earlier in life. It is to be noted that Williams does not need to single out cases of antagonistic pleiotropy; his argument is partly a priori. “Pleiotropy in some form,” he says, “is universally recognized,” as there is no reason that all effects of a gene should be equally beneficial or harmful or should be expressed at the same time. Hence antagonistic pleiotropy should happen, no matter what we already know about genes. Actually, one can understand the phrase “pleiotropy in some form”—as Williams puts it—in several senses here. It may mean that a gene conditions two distinct phenotypes, but it also may mean that the gene conditions one phenotype whose effects on survival and reproduction change along the life cycle. Williams describes this imaginary example as “a mutation arising that has a favorable effect on the calcification of bones in the developmental period but which expresses itself in a subsequent environment in the calcification of the connective tissues of arteries” (1957, 402). Here, the gene can be seen as a gene for one trait, “calcification”; but the developmental trajectory affects different somatic environments to this trait, which makes it at distinct periods into two distinct phenotypic patterns, the calcification of bones and the calcification of arteries. These

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patterns have opposite fitness effects. Here, the mutant gene indirectly favors reproduction because it favors the chances of survival at the reproductive period, but it does not involve what behavioral ecology calls an “investment” in reproduction and parental care. So pleiotropy is most generally defined as the change of phenotypic expression for a gene, due to the change of “somatic environment,” which in turn comes with the passing of time. When this change implies a change in the sign of fitness from positive to negative, then senescence evolves. Williams’ reasoning does not stop here. Natural selection is expected to select against the calcification of arteries since it decreases fitness, so it is expected to evolve mutations that would suppress this latter effect. But the fact that the force of selection declines with age, as we have seen, renders this expectation unfulfilled. “Complete suppression [of the arteries’ effect] would probably never be realized” (ibid). In this sense, Williams identified two opposite “forces” at play when it comes to senescence: the “indirect selective force” that increases “the rate of senescence” by “favoring vigor in youth at the price of vigor later on”; and then the selection counteracting this price, which selects directly for mutants counteracting senescence, and which, as we saw, is never wholly successful. He deduces the interesting conclusion that the rate of senescence will be determined by the ratio of these two forces, one directly selective and one indirectly, and therefore will depend upon species and their ecological environments (which determine selective pressures). The old intuition that organisms living faster—growing and reproducing fast—die earlier (see above Chap. 7) here acquires a new justification. Senescence is related to genes with effects early on, hence genes involved in morphogenesis. Therefore, the rate of senescence is intrinsically tied to the pace of morphogenesis. “Conditions that favor rapid morphogenesis should also favor rapid senescence, not only by reducing the time required to reach maturity but during the adult stage as well” (ibid., 409). So, if development towards maturity is slowed down, individuals will live longer. Williams gives the example of an eel that lives for 55 years in captivity, where conditions for spawning (hence reproduction) are absent, whereas in the wild it lives ten years. The significant difference manifests the connection between slowing development and extending life. But, as is often the case with evolutionary theorizing, the feature to be explained, here senescence, also plays a role in subsequent evolution, including the evolution of factors that conditioned its emergence. Such circularity of the explanandum and the explanans has been seen in the case

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of mutation rate, robustness (Wagner 2005), diversity (Huneman, 2019d), or exemplarily, sex,20 and naturally characterizes evolution: features that evolve are part of the ecological and genetic context of what can further evolve, and therefore causally condition it, and hence contribute to explaining it. Precisely in the case of Williams’ antagonistic pleiotropy, this circularity stems from the fact that senescence, once it has evolved, is constantly counteracted by natural selection, according to the “two forces” model—namely, selection indirectly favoring senescence and directly favoring genes that expand lifespan, and hence decrease the senescence rate. Thus, a given pattern of senescence conditions selection for and against mutations that affect aging or reproduction. A noteworthy consequence is the evolution of menopause, which is an extremely rare phenomenon among animals.21 Because senescence, as a general deterioration, affects the reproductive system, says Williams, selection will favor caring for children rather than engaging in “increasingly hazardous pregnancies,” and will fix genetic mutations going in this direction. “Menopause (…) may have arisen as a reproductive adaptation to a life cycle already characterized by senescence, unusual hazards in pregnancy and childbirth, and a long period of juvenile dependence” (1957, 408). This notion of menopause has been developed in recent times by researchers who put forth the so-called “grandmother hypothesis,”22 according to which menopause has been selected for allowing for the care of grandchildren; not having children allows time to help daughters or sons with their offspring which, in the end, after two generations, increases the total number of grand-offspring as compared to those who raised their own, often frailer offspring, born in their later years. This view implies kin selection, absent from Williams’ paper. But it conserves Williams’ intuition

20  Williams (1975) on sex mostly intends to explain the evolution of sexual reproduction but also considers eventually how genetic recombination, characteristic of sex, in turn influenced evolution. 21  Beyond humans, species that experience menopause are kinds of whales: narwahls, plus killer whales, short-finned pilot whales and beluga whales. 22  This modern hypothesis has been foreshadowed as often by Hamilton (1966): “the 15 or so years of comparatively healthy life of the post-reproductive woman is so long in itself and so conspicuously better than the performance of the male that it inevitably suggests a special value of the old woman as mother or grand-mother during a long ancestral period, a value which was for some reason comparatively little shared by the old male” (37).

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that menopause is somehow part of the reproductive life.23 This allowed him to state a major conclusion of his hypothesis, namely, that there should be no “post-reproductive” period (since menopause extends towards the end of life). In effect, since no system should age faster than others, selection counteracting senescence should synchronize the deterioration of the reproductive systems with the decay of all other systems, therefore preventing any post-reproductive period. Seeing his view as a hypothesis likely to be tested, Williams made some predictions in his paper. The link between extrinsic mortality and rate of senescence is a key element to be tested: “Cumulative adult mortality is the primary reason for the decline in reproductive probability with the passage of time” (1957, 404). Thus environments where mortality is higher should, as in the case of mutation accumulation, see faster senescence. Williams argues that this prediction is realized by mentioning a case that will be often central in the discussions, namely, that of birds versus mammals. It was well known that even though they have comparable life cycles, birds live longer. Many like Comfort (1956) used to explain this difference by a difference in physiological organization. However, for Williams, who was starting a tradition of empirical research, “the evolutionary cause of the low rate of bird senescence is that birds can fly” and are therefore “less liable to predation.” This is confirmed by the fact that the birds who live the shortest amount of time are the ostrich and the emu, which are birds that walk. Inversely, the bat, a flying mammal, lives longer than many same-size mammals, fulfilling the theory’s expectations.24 Finally, turtles are longer lived than other reptiles, and this fits the prediction that the highest chances of surviving predators, due to their 23  Interestingly Hamilton (1966) in his attempt to formally state Williams’ and Medawar’s theories, considers that birth in species doing parental care “should be considered to occur (…) at the age at which the offspring becomes independent” (14). 24  However, regarding their extraordinary longevity among mammals, bats were the objects of another account that focuses on their extreme tolerance to viruses. This led them to evolve mechanisms that protect against inflammatory reaction, while the accumulation of inflammation is held as a major proximate cause of aging. Such mechanisms restrain the deleterious effects of the cumulated activity of immune systems. A cascade of effects seems to alter all the “hallmarks of aging,” namely, pathways that promote aging, and therefore yield their special longevity. See review in Gorbunova et al. (2020) who write: “We speculate that bats exceptionally high exposure to viral pathogens forced them to develop ways to co-exist with viruses rather than to fight them. Bats are unique among mammals in the size and density of their colonies, and in their ability to fly long distances, a trait that further increases pathogen exposure.”

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shells, decreases the rate of senescence. In the same way, this hypothesis predicts that in many species, such as humans, males and females will not have the same life expectancy since males suffer a higher extrinsic mortality, because of differences in behavior. An important aspect of Williams’ theory is that it also explains the difference between aging in multicellular organisms and in bacteria or unicellular in general. A condition for the theory is that organisms should have a soma, since pleiotropy is defined by the changing effects of changing somatic environment. Some don’t have this, either because they are unicellular, or because their life cycle does not allow a clear separation between germ and soma. Later on, Leo Buss (1987) authored a seminal monograph on the emergence of the sequestration of the germinal lineage, and actually not all organisms feature this separation that is familiar to us; this work initiated a research program in the evolutionary explanation of biological individuality (Maynard-Smith & Szathmary, 1995; Michod, 1999). For Williams, without such sequestration, so without a soma, there would be no aging and eventual death.25

8.5  Ecology, Evolution, and Physiology: The Novel Territory of the Question About Biological Death As a consequence of the primacy of external death in accounting for intrinsic death, hence senescence, the ecological environment appears to play a major role in determining how and why individuals of a given species die. Realizing this fact opens a research field in ecology, namely, the investigation of the ecological determinants of senescence in various ecological settings—and, reciprocally, the role played by the senescence patterns of various species as well as the intraspecific differences in senescence with respect to the ecological dynamics and the maintenance of biodiversity (see Bonsall & Mangel, 2004; Mangel, 2002). Thus, after evolutionary theorizing, ecological theories took over the question of death and 25  This is for him also valid for cells that are relatively autonomous parts of organisms, such as erythrocytes or macrophages. Erythrocytes, which live indefinitely, might appear prima facie very adaptive; however this adaptive advantage would be so very small that “genes favoring erythrocyte senescence might creep in because of other advantageous effects they might produce.” Later on, as explained below, this idea of unicellulars unable to senesce will be refuted.

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senescence, seeing it both as an explanandum (“why senescence?”) and an explanans (“how do senescence patterns affect communities’ ecology?”), in the same way as evolutionary views address both the factors accounting for senescence and then the effects of senescence in evolution. For instance, Hulbert et al. (2004) found a striking example of this ecological moulding of senescence: in flies, reducing the temperature decreases the accumulation of damage (somatic or not) within their organism, which entails that when it’s cold flies grow old more slowly. In this context, the journal Functional Ecology recently published a special issue (edited by Gaillard & Lemaître, 2020) about an “integrated view of senescence in nature.” This followed another special issue of the same journal in 2008 about “the evolutionary ecology of senescence,” which was, according to the editors, “intentionally biased towards investigations of senescence in natural conditions and/or non-model species” (Monaghan et al., 2008). Advances in the evolutionary biology of aging, as the 2020 editors note, have moved from the question “Do wild animals display reproductive and actuarial senescence?” towards, after the 2000s, “sophisticated methods analyzing longitudinal datasets over long time scales.” As Gaillard and Lemaître write, senescence is “an integrated dynamic evolutionary process that both shapes life-history variation within individuals, among individuals within populations, and across species [it’s an explanans], and responds to life-history variation [it’s also an explanandum]” (Gaillard & Lemaître, 2020, 5). Ecologist Robert Holt in a 1996 paper about “Demographic constraint in evolution” developed the idea that ecological and evolutionary phenomena are affected by senescence. The paper does not consider a causal relation between senescence and an ecological phenomenon but, interestingly, a parallelism between them: both are explained by the same process. Besides senescence in an age-structured population, Holt considers “niche conservatism,” namely, the fact that on evolutionary time species tend to conserve niche features. In both cases an asymmetry is the explanation: young/old asymmetry defines the “age-related selection,” as Williams said, since the force of selection decreases with age; and in ecology, considering a source-sink structure, namely, the generation of variants of a species somewhere (source) and their going elsewhere (sink), the stronger selective pressures are on the source rather than on the sink, and decrease once one progresses towards the sink. Therefore, viable individuals will remain closer to the source, exactly as individuals in their life history tend

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to be better reproducers when young. Avenues of research based on this tentative synthesis are still underexplored As I will indicate in the next chapter in more detail, much of the evidence that shapes our understanding of death and senescence now comes from ecological studies. The question of senescence moved from a framework defined mostly by physiology and demography to an integrated framework involving evolution, ecology, and, as we will see, molecular genetics (which is not the bulk of molecular biology, for sure). This conceptual landslide signals the importance of the evolutionary take on senescence in the biology of death. Box 8.2  Hamilton and the “Moulding of Senescence by Natural Selection”: Formalizing Williams and Medawar

An alternative version of this same book would start by focusing on William Hamilton’s seminal paper that is so entitled. Hamilton made some of the major advances in evolutionary biology in the second part of the twentieth century by conceiving of the ways selection works in social contexts, and especially how it is possible that it can favor altruism, namely, behaviors costly for the actor and beneficial for others. Altruism, like sex and death, as I already mentioned, should be counterselected, so something complex is at stake in the fact that altruism pervades all clades. Williams conceived of kin selection and inclusive fitness, two concepts that capture the action of selection at the genic level, in order to make sense of altruism and cooperation. These two notions will appear again later. Like Williams, besides altruism, Hamilton was interested in the enigma of death and senescence. His 1966 paper intended to make mathematical sense of Williams’ and Medawar’s ideas about the declining force of selection. There, he quantifies the ‘force of mortality’ and its increase, by capturing them through measures of evolutionary success. Hamilton explains that he aims at a “general approach to the problem of assessing how the age at which a gene acts affects its influence on fitness.” (1966, 14). Previous attempts at understanding senescence were right in focusing on the differential effect of natural selection on age classes, but the measure of this (continued)

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Box 8.2  (continued)

difference was too simplistic because it assumed a stable population. However, the value of an offspring—namely, according to Fisher’s views on fitness, its chances of itself reproducing—always depends upon the size of the population, because in a smaller population it will fare better ceteris paribus because of lesser competition, so if it increases or decreases, the value of the timing of the offspring varies: “early births are worth more than late in an increasing population, and vice-versa in a decreasing one.” Hamilton therefore aims at formulating in the most general context the effect on fitness of the action of a gene depending upon the age it is expressed. Fisher’s reproductive value, considered by his predecessors as a measure of this effect, is not correct because it overlooks the fact that many individuals with gene x to be expressed at age a will not survive until a. Hamilton shows that, to take into account the differential fitness effects on age classes, the Malthusian parameter (also forged by Fisher), which is the estimation of the growth rate of the class under focus, is better than the reproductive value. It allows him to compute the ‘expected reproduction beyond age a’, which is what Williams called ‘reproductive probability’. Hamilton finally derives, for fecundity and for mortality, the form of the effect on fecundity (respectively survival) change at age a upon fitness. These functions s and s′, given l and m functions of survivorship and fecundity respectively, and r meaning the Malthusian parameter, are: s  x 

 e l  y m  y  ry

y  x 1

s   x   e  rx l ( x ) (Using terminology by Rose et al. (2007)). As a conclusion, these general mathematical analyses of the force of selection show how that, in accordance with Williams, even if there is no mortality and no aging, senescence tends to evolve: “It is striking to find that even under these utopian conditions selection is (continued)

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Box 8.2  (continued)

still so orientated that, given genetical variation, phenomena of senescence will tend to creep in. The form of wa (..) [expected reproduction beyond a] discussed earlier, shows unequivocally that any mutation causing an improvement in early fecundity at the expense of an equal detriment later will give a raised Malthusian parameter, so that the mutant form will gradually come to numerical preponderance in the population; and if we allow any incipient incidence of mortality we likewise see that selection will favor resistance to it at early ages to a certain extent at the expense of greater vulnerability at later ages.” (1966, 25). These two functions are what Hamilton will first call the ‘forces of mortality’; these formulations allow “the evolution of the curve of force of mortality,” to be generated; as he puts it: “It is continually being “nibbled” from above, the nibbles representing the spreading of more or less age-specific advantageous mutations through the population. They may be closely age specific or they may involve a lowering of the curve along a strip of considerable length. Following each nibble the whole curve, after more or less delay, makes a small ascent. The delay corresponds to the period of increasing population: the ascent to the coming into operation of the Malthusian checks to increase. The nibbling takes place fastest at the left-hand end of the curve and towards the right-hand end finally with infinite slowness at the age where reproduction ends. The greater the speed with which nibbles occur the sooner they can be succeeded by others.” (Hamilton, 1966, 36) Hamilton’s paper was much more mathematized, though its mathematical apparatus was quite inelegant, and did not immediately take over population genetics. However, beyond its major theoretical importance as the first formal expression of the notion of the shadow of selection, later advances in evolutionary genetics about death and senescence relied on it. In the 1980s, the British biologist Brian Charlesworth was spending his postdoc years at the lab of Richard Lewontin, already a very influential population geneticist. Lewontin was, together with Richard Levins, Robert Mc Arthur and Eugene Wilson, among those who in the late 60s–70s intended to reframe (continued)

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Box 8.2  (continued)

evolutionary biology on firm mathematical bases. In this context, Charlesworth started where Hamilton had left off and published a series of papers about the variation of fitness across age classes, and then evolution in age-structured populations, summarized in his Charlesworth (1980). From the theoretical viewpoint, he reformulated Hamilton’s theories properly (e.g. Charlesworth, 1993), and with Hughes, Charlesworth and his former student Michael Rose, he designed quantitative genetics experiments to test predictions from these hypotheses. Historically speaking, many of the researchers specializing in death and aging, who will be discussed later in this book, started with this group, in a sort of evolutionary descent from Hamilton. The riddle of senescence is so intricate that many of them spent decades working on it. Michael Rose wrote his book on the evolution of aging in 1991 (Rose, 1991). He worked closely with Caleb Finch, who became another major biologist working on death and aging. They edited a seminal special issue that became a book in 1994, and Finch alone wrote a landmark book in 1991. Prominent names in population genetics and ecology such as Peter Abrams, Robert Ricklefs or Nicholas Barton who started their careers in the 1990s also devoted some time to thinking about the theories of senescence. Steven Austad worked with Rose and set important experiments; like Finch in his later works, he took into account the major advances in molecular genetics of aging that I’ll consider in Chaps. 12 and 13. Relying on this group, and often linked with them through mentoring or postdoc supervision, Linda Partridge, Jacob Moorad, Daniel Promislow, Annette Baudisch among others belong to a younger generation of researchers who partly worked on senescence. To this lineage of experimental or theoretical population/quantitative geneticists or behavioral ecologists one should add a lineage of biologists who were mainly concerned with cellular and molecular biology and what it taught us about aging. This is another tradition, which besides Leonard Hayflick, who shattered our ideas about the death of unicellulars, includes Russian biologists such as Mikhail (continued)

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Box 8.2  (continued)

Blagoskonny or Sergei Skulachev, who focused on the notion of aging programs, and then a tradition of researchers who unraveled the riddles of programmed cell death, as I will discuss at more length in Chap. 12. Since the present book is a philosophy book, it will not consider the fascinating aspects of the sociology of research groups who worked on these issues—small groups and, as one will notice by a glance at the references, just a few people—but I wanted to give here a snapshot of the social evolution of the field.

8.6  Conclusion: Charting the Shadow of Selection To sum up, a proper understanding of natural selection according to Darwin—the foundational theory on the basis of which modern biology elaborates its explanations—asserts that selection is beneficial to the individual, not to the group or species (contrary to a popular understanding of the theory). Hence death, a phenomenon that obviously goes against the interests of the individual who dies,26 cannot be explained in any simple way by natural selection. It is unthinkable for any proper Darwinian to resort to “the good of the species” or of the group to explain it. Neo-­ Darwinian biologists thus invariably refer to the level of the individual, which is liable to be subject to natural selection. The alternative between Medawar and Williams is then situated between a death that is co-selected as a mutational burden, and therefore by virtue of an absence of selection of lethal or late-in-life deleterious genes, and a death that is co-selected because these particular genes stimulate positive effects at an earlier age. Such an alternative is a crucial one in the frame of current evolutionary theories of why we age and die. Medawar ascribes death, finally, to the absence of selection, while Williams sees it as a by-product of selection— selection is the cause at stake and Williams explicitly writes that it “produces a declining vigor (senescence) during adult life” (1957, 410, my emphasis). To this extent, evolutionary approaches to death concur in shifting the essential meaning of death from intrinsic mortality towards 26  Both from the viewpoint of survival, and from the more modern viewpoint of reproduction, because dead individuals do not reproduce any more.

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extrinsic contingent mortality, thus challenging the providentialist metaphysics of death that governed the traditional philosophical questioning on death, as we have seen. Medawar and Williams shared a core view about the variation of the intensity of selection with time; the framework in which their insights will be developed into rival accounts, as I will explain in the next chapter, is called “life-history theory” and is the theory of the changing investments of fitness during life. And Williams was well aware of the proximity of his views to Medawar’s—since he acknowledged that Medawar saw that senescence could “result from processes that have effects favorable early in life but have cumulative bad effects later.” Yet Williams says that according to Medawar “linkage and pleiotropy” were involved in this combination, while in fact linkage should play no role. However, a major difference consists in the fact that Medawar at some point hypothesizes a particular senescence process in a group of organisms, based on a regular sequence of organs’ failures, while for Williams evolution should imply that no such common pathway to senescence exists. The reasoning is the following: suppose some tissues or cell types age faster than others because genic effects affect them with deleterious effects. Then the direct selection countering senescence will target those effects, and favor mutants that reverse the deleterious effects; eventually, all cell types and organs will have the same deterioration rate, and equal chances of failing. “Natural selection will always be in greatest opposition to the decline of the most senescence-prone systems” (1957, 406). This goes against many physiological conceptions of senescence that have been central in gerontology, namely, that one or few systems—hormonal, or immunological—drive aging, which represents a “logical impossibility” (note the strong wording). While Medawar agreed with traditional physiological views of aging, the evolutionary conception defended by Williams stands in stark contrast, because it renders obsolete the question of finding the main aging mechanisms. As I indicated above, it only retains the notion that “rate of living” conditions the rate of senescence, justifying by a reference to declining selection the intuition that supports this idea. However, more generally, Medawar’s and Williams’ approaches instantiate, in general, alternative hypotheses that the evolutionary biologist can ask regarding any trait: is it directly selected—and for what exactly? Or is it a by-product of selection? Or an effect of no selection, a neutral trait? Because death and aging are approached by theories based on the two latter options, one sees that these issues bring to the fore the structure of

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evolutionary theorizing, centered on one of the most puzzling features of life itself, namely, death: recall Bichat here, “living beings are those who get sick and die.” These two theoretical options may both be contributing an explanation to the phenomena, or each of them may explain a side of the phenomena, or each of them may explain the phenomena or an aspect of the phenomena within a specific lineage or clade or family. Those questions will be at the center of the rest of this book. As I will have several occasions to highlight it, this Modern Synthesis conception of death and aging, split between the selectionist and the less selectionist views (Williams’ and Medawar’s) would constitute the framework of the theorizing for the next decades, even though experimental, mathematical, and molecular tools will allow for an impressive amount of findings, and many sophisticated elaborations. This ramification and enrichment would constitute the field of “aging research” into a flourishing domain, which integrates a massive amount of evolutionary theorizing, and occasioned the emergence of many research journals such as Nature aging or the Aging research review. The epistemic and theoretical structure and content of the field will be considered in the following chapters. In a nutshell, however, here are the main experimental and theoretical developments that occurred in the field since the Modern-Synthesis-style accounts by Medawar and Williams: • Particular genes have been identified as lifespan expanders in model organisms • Unicellulars and cells in general have been seen aging • Programmed cell death has been demonstrated in multicellulars and then in unicellular eukaryotes and prokaryotes • Single cell methods allowed tracking senescence processes within cells, especially at the molecular level • Genomics uncovered methods to capture and describe gene networks of all sorts (Protein-Protein Interactions, Gene Regulatory Networks (Davidson, 1986), etc.) including genes and protein networks involved in individual and species-typical lifespan • Systems biology more generally allowed for a systematic understanding of metabolic “aging pathways” • Focus on epigenetics and on microbiota, through tools accessing epigenetic changes in gene regulation and metagenomics (i.e., sequencing all genes present in a given sample, no matter what species are there), delivered novel insights about aging processes

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Clearly some of these advances pertain rather to the mechanisms or proximate causes of aging and death; however they are often straightforwardly tied to evolutionary questions: after all, antagonistic pleiotropy is about which genes influencing longevity. Yet, as we’ll see, they will not radically challenge the main theoretical positions explained in the present chapter, focused on the notion of a shadow of selection. I’ll consider most of these advances in the following chapters. As we’ll see, they will not radically challenge the main theoretical positions explained in the present chapter, focused on the notion of a shadow of selection. A Semantic Precision

Antagonistic pleiotropy (AP) and mutation accumulation (MA) are, depending on the contexts, alternatively ‘accounts’, ‘hypotheses’, ‘theories’. Defining their exact epistemic status could be a sharp exercise in the philosophy of science, but I think that even though they are built around a core idea, the precise definition of each is given by the way it is used. When one infers from AP (resp. MA) predictions that are then tested is a ‘hypothesis’; when it is given as a general explanation of facts related to aging and death, including some hypotheses likely to be tested regarding several species or populations, AP (resp. MA) is a ‘theory’. When the context is unclear, or when AP or MA is contrasted with other alternative ideas regarding death, I would call it an account. Those notions are overlapping and there is some flexibility in the uses; I’ll try to adhere to this terminology, but there will be some vagueness.

References Allee, W.  C., Park, O., Emerson, A.  E., Park, T., & Schmidt, K.  P. (1949). Principles of animal ecology. W. B. Saunders Company. Austad, S.  N. (1993). Retarded senescence in an insular population of Virginia opossums (Didelphis virginiana). Journal of Zoology, 229, 695–708. Bonsall, M. B., & Mangel, M. (2004). Life-history trade-offs and ecological dynamics in the evolution of longevity. Proceedings of the Biological Sciences, 271(1544), 1143–1150. Bowles, J. (2000). Shattered: Medawar’s test tubes and their enduring legacy of chaos. Medical Hypotheses, 54(2), 326–339. Buss, L. G. (1987). The evolution of individuality. Princeton University Press.

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Cain, J. (2009). Rethinking the synthesis period in evolutionary studies. Journal of the History of Biology, 42(4), 621–648. Charlesworth, B. (1980). Evolution in age-structured populations. Cambridge University Press. Charlesworth, B. (1993). Evolutionary mechanisms of senescence. Genetica, 91, 11–19. Comfort, A. (1956). The biology of senescence. Churchill Livingstone. Davidson, E. H. (1986). Gene Activity in Early Development. Orlando, FL: Academic Press. Depew, D. (2011). Adaptation as a process: The future of Darwinism and the legacy of theodosius Dobzhansky. Studies in the History of Biology and the Biomedical Sciences, 42, 89–98. Dobzhansky, T. (1950). The Science of Ecology Today. Review of Principles of Animal Ecology by W. C. Allee, Alfred E. Emerson, Orlando Park, Thomas Park, Karl P. Schmidt. Quarterly Review of Biology 25(4), 408–409. Durand, P. (2021). The Evolutionary Origins of Life and Death. University of Chicago Press. Eliot, C. (2005). Method and Metaphysics in Clements’s and Gleason’s Ecological Explanations. Studies in History and Philosophy of Science Part C: Studies in History and Philosophy of Biological and Biomedical Sciences 38(1), 85–109. Fernandez, A. A., & Bowser, P. R. (2010). Selection for a dominant oncogene and large male size as a risk factor for melanoma in the Xiphophorus animal model. Molecular Ecology, 19, 3114–3123. Gaillard, J.-M., & Lemaître, J.-F. (2020). An integrative view of senescence in nature. Functional Ecology, 34, 4–16. Gayon, J. (1998). Darwinism’s struggle for survival: Heredity and the hypothesis of natural selection. Cambridge University Press. Gorbunova, V., Seluanov, A., & Kennedy, B.  K. (2020). The world goes bats: Living longer and tolerating viruses. Cell Metabolism, 32(1), 31–43. Hamilton, W. D. (1966). The moulding of senescence by natural selection. Journal of Theoretical Biology, 12(1), 12–45. Hayflick, L. (1996). How and why we age. Ballantine Books. Hulbert, A. J., Clancy, D. J., Mair, W., Braeckman, B. P., Gems, D., & Partridge, L. (2004). Metabolic rate is not reduced by dietary-restriction or by lowered insulin/IGF-1 signalling and is not correlated with individual lifespan in Drosophila melanogaster. Experimental Gerontology, 39, 1137–1143. Huneman, P. (2019a). How the modern synthesis came to ecology. Journal of the History of Biology, 52, 635–686. Huneman, P. (2019b). Revisiting Darwinian teleology: A case for inclusive fitness as design explanation. Studies in History and Philosophy of Science Part C, 76, 101188. Huneman, P. (2019c). The multifaceted legacy of the human genome program for evolutionary biology: An epistemological perspective. Perspectives on Science, 27(1), 117–152.

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Huneman, P. (2019d). Between explanans and explanandum: Biodiversity and the theoretical unity of ecology. In Casetta, E., & Vecchi, D. (Eds.), Biodiversity. Beyond the Species Approach (pp. 269–296). Springer. Mangel, M. (2002). Environment and longevity: Emergence without interaction, multiple steady states and stochastic clocks. Evolutionary Ecology Research, 4. Maynard Smith, J., & Szathmáry, E. (1995). The major evolutionary transitions. Freeman. Metcalf, C. J. E., Roth, O., & Graham, A. L. (2020). Why leveraging sex differences in immune trade-offs may illuminate the evolution of senescence. Functional Ecology, 34, 129–140. Michod, R. (1999). Darwinian dynamics. Oxford University Press. Michod, R., & Levin, S. (Eds.). (1988). The evolution of sex: An examination of current ideas. Sinauer. Monaghan, P., Charmantier, A., Nussey, D.  H., & Ricklefs, R.  E. (2008). The evolutionary ecology of senescence. Functional Ecology, 22(3), 371–378. Neander, K. (1991). Function as selected effects: The conceptual analyst’s defense. Philosophy of Science, 58, 168–184. Nesse, R., & Williams, G. C. (1994). Why we get sick: The new science of Darwinian medicine. Times Books. Okasha, S. (2008). Fisher’s fundamental theorem of natural selection—A philosophical analysis. British Journal for the Philosophy of Science, 59(3), 319–351. Orr, H. A. (2009). Fitness and its role in evolutionary genetics. Nature Reviews Genetics, 10, 531–539. Plutynski, A. (2006). What was Fisher’s fundamental theorem of natural selection and what was it for? Studies in History and Philosophy of Biological and Biomedical Sciences, 37(1), 59–82. Rose, M. R. (1991). Evolutionary biology of aging. Oxford University Press. Rose, M.  R., Rauser, C.  L., Benford, G., Matos, M., Mueller, L.  D. (2007). Hamilton’s forces of natural selection after forty years. Evolution, 61(6), 1265–1276. Smocovitis, V. B. (1992). Unifying biology: The evolutionary synthesis and evolutionary biology. Journal of the History of Biology, 25(1), 1–65. Wagner, A. (2005). Robustness and evolvability in living systems. Oxford University Press. Williams, G. (1957). Pleiotropy, natural-selection, and the evolution of senescence. Evolution, 11, 398–411. Williams, G. C. (1975). Sex and evolution. Princeton University Press, N.J. Williams, G.  C. (1966). Adaptation and natural selection. Princeton University Press. Winther, R.  G. (2006). Fisherian and Wrightian perspectives in evolutionary genetics and model-mediated imposition of theoretical assumptions. Journal of Theoretical Biology, 240(2), 218–232.

CHAPTER 9

Epistemology of Death (1): Goals and Evidence

There are more than three hundred theories of death now; some are very hypothetical; others are supported by some experiments or observations (Gavrilov & Gavrilova, 2002). Most include models that are sophisticated and much more complex and wide-ranging than what the experimental facts can back up. However, evolutionary theories still can be grouped into three general families: the MA (Medawar’s view), the AP view, and a third, more recent view, the “disposable soma theory” (Kirkwood, 1977), which is closely connected to antagonistic pleiotropy, as I will explain below. Those theories and models instantiate the major conceptual shift through which, as I explained in the last chapter, extrinsic death—due to the contingencies of life in a hazardous environment, defined by interactions with predators, alliances with mutualists, and exogenous environmental variables such as climate, salinity, pH, acidity—is explanatorily and logically prior to intrinsic death (namely, senescence). As encompassing distinct models, the theories differ not only in what they say about death and predict about it, but in what exactly—about aging and death—they focus on. They also differ in terms of the actual or possible tests and evidence gathered in their favor. Finally, they differ in terms of the hypotheses they make regarding the causes or processes that produce the general fact (MA or AP) seen as an explanans for death and aging. In this chapter and the following I will successively address those questions, which constitute what one could call the epistemological territory of the theories of death. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_9

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9.1   What Are the Objects of Enquiry? The Equivocations of “Aging” and “Death” Until now, I have not made any distinctions between death, aging, and senescence as the focus of theories of death. Of course, these are different things, and, strictly speaking, not all of them are explained by a given model or theory. However, they are related, and in order to explore the epistemology of the biology of death, one must first make precise the explananda that are involved. Granted, one is here essentially concerned by death, but death, aging, and senescence are connected in complicated ways, not only because their definitions are different, but also because the entities of which they are properties—organisms, species, lineages—are not always the same. 9.1.1  Senescence Senescence is by definition connected to death, since what first characterizes it is an increase in the probability of dying along time. Since Medawar and Williams, this is what biologists often measure; when they want to test theories about the role of extrinsic mortality as a selective pressure, they ask: “does this increase or diminish when extrinsic mortality is loosened?” Some authors address this phenomenon, which they call “actuarial senescence,” and distinguish it from “reproductive senescence,” namely, a decrease in fertility with age, a distinction that is natural when one deals with life history traits, which can affect survival or fertility. Besides this statistical aspect, senescence has a more mechanistic aspect—namely, a measurable deterioration of physiological functions. For instance, Monaghan et al. (2008) define it as an “inevitable, irreversible accumulation of damage with age that leads to loss of function and eventual death.” The fact is that such deterioration is always the result of the alteration of many organs, and can happen in many ways—like Bichat’s circuits of death, but in a more gradual and slow manner. But senescence also includes processes that do not decrease fitness, such as the emergence of gray hair in mammals. Thus, this physiological deterioration encompasses many processes, which, with regard to humans, are summarized in the table proposed by Clark (2002) (Table 9.1). The first, statistical aspect is also sometimes called “demographic” aging, and evolutionary explanations would explain it simultaneously with physiological aging, by pointing out the increase in mortality figures per

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Table 9.1  Changes proper to physiological senescence (After Clark, 2002) Parameter

Change

Size

Height and weight decrease in both men and women, especially after age 60, due mostly to losses of muscle and bone Gradual diminution in metabolic rate after age 30 Loss of subcutaneous fat; appearance of wrinkles, pigmentation. Graying of hair at all body sites; loss on top of head; some facial hair may increase. Nails thicken Some thickening of heart muscle, but no obvious diminution of pumping function in undiseased heart. Resting heart rate unchanged. Widespread cardiovascular disease after age 50; the leading cause of death in both sexes Kidney, lung, and pancreas functions diminish. Atrophy of skeletomuscular system; bone and joint problems Female reproductive function ends at menopause; male function compromised as testosterone levels drop after age 50 or so Vision impairment in both sexes. Hearing, smell, and taste affected; more pronounced in men. Sense of touch only modestly affected Gradual decrease in T-cell responses; increase in autoimmunity; increased susceptibility to cancer Loss of brain cells; shrinkage of brain; physical response to stimuli slowed; learning and memory impaired; some degree of senile dementia common after age 70

Metabolism Skin and hair

Heart and cardiovascular function Organ physiology Reproductive function Senses Immune function Neurobiology

age class due to the late-life deleterious effects of the alleles hypothesized by both theories. But one can also imagine that they are two different things: a particular evolutionary model accounting for the demographic statistical aspect, while another model would account for a specific deterioration process. Such decoupling is illustrated by the following consideration: in principle, some organisms may even just increase very steeply in the probability of their dying after some point, which makes physiological senescence very quick. That would be the case of salmon, who die shortly after reproduction, which comes at a certain period. This is an extreme case where after one reproduction death happens (but given that in general there is no post-reproductive period, senescence almost occurs after reproduction stops). Only demographic senescence is supposed to be explained in this case. If mutation accumulation (MA) is the proper account of death, then the lethal genes that accumulate within the population may differ according to individuals, resulting in a huge diversity across the processes of

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deterioration. On the other hand, once statistical senescence is explained by antagonistic pleiotropy (AP), then the genes whose deleterious effect impact organisms late in life are selected for their effects on survival or reproduction early on. Hence they go to fixation in the population (i.e. their frequency reaches 100%) with their “downside” effects therefore fixed in the same way; finally the deterioration processes would be less variable than in the MA case, and would be directly accounted for by the model of senescence. Yet, a difficulty with senescence understood statistically is that isolating such a process is not easy. In many vertebrate species, the probability of death drops just after birth, then increases and reaches a peak at the reproductive age. Among humans (essentially in males) the interval around 20 years is characterized by a high level of death, often due to accidents, drugs, insane behavior, etc. Then the curve plateaus for a while and subsequently decreases (exact figures vary according to countries); after getting back to the pre-20 years level, the curve of the probability of death slowly increases, and at a later age again increases very quickly (see below §2 on these curves). If one sees any increase in mortality probability as senescence, then one would consider the short period before the plateau as senescence, but then it would be followed by a reversal of senescence, a stasis and some years after a restarting of senescence (see Diagram 9.1). This whole scenario counters the very idea of senescence, which connotes an irreversible and unique process. Such difficulty shows how a mere statistical concept of senescence, of demographic aging, is not satisfactory. It must be complemented by a sense of physiological decay, which, however, is rather problematic, as we saw in the case of salmon. Some authors addressed this difficulty by focusing on this phase of the early decrease in the chances of death after birth, which is almost universal. They call it ontogenescence (Levitis, 2011), and consider that it is an evolved feature of animals. The question therefore—in a way parallel to the case of senescence according to the two major families of theories—is whether this phase is evolved by selection, or as a by-product of selection, or whether it is itself part of a process of selection (a hypothesis that is not considered in the case of senescence). I address this issue below. 9.1.2   Aging, Death, and the Contrast Classes Aging may be understood as the equivalent of senescence. Monaghan et al. (2009), among many others, see both as mostly synonymous, but

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Diagram 9.1  Rough sketch of a mortality curve in European countries. When zoomed in, a peak of mortality appears around 20 years of age. The period before the plateau could be considered as a senescence phase if this is merely statistically defined as a simple increase in the probability of death

prefer to use senescence, which clearly does not include developmental processes, unlike some uses of “aging.” Others follow the seminal papers and see aging as the mere passing of the days while senescence is a process involving deterioration, loss of fertility, and increasing chances of dying. For reasons of ease, however, I will use the two terms as synonyms, except when a different use is specified. Since aging by definition leads to death, explaining aging is part of explaining why death. But many other aspects of death are not directly explained by the evolutionary explanations of aging: not only, of course, the mechanism of sudden death, but, from an evolutionary viewpoint, the across-species differences between lifespans. This is why “death” seems to be the most encompassing explanandum. In any case, “explaining aging” does not mean a single thing. Philosophers of science often characterize explanations in part by their contrast classes. Asking “Why X?” is never a complete question, but is always, implicitly “why X rather than Y?” Those “than Y” implicit clauses are called contrast classes. One question about aging is “why do some organisms age rather than not age?” For a long time, unicellulars were believed not to age, in the sense that their probability of dying remains the same, and their physiological processes don’t decay—and I indicated that this was crucial in the formulation of the problem of mortality and the providentialist scheme in biology.

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An apparent answer here to this question, leaving aside any Darwinian viewpoint, is that the fact that not having a multiplicity of cells (and the complex interactions between them), which characterizes unicellular organisms, saves them from problems affecting those interactions, and hence from an increased probability of dying. In contrast, and still from a non-Darwinian viewpoint, the simple use of their organs and cells by multicellular organisms, as well as the somatic mutations that accumulate in each cell lineage generation after generation, indeed increases their probable disconnection (from others) and (internal) decomposition. Time fosters aging, understood then as the increased probability of dysfunction and then death. However, such a non-Darwinian view cannot be taken for granted. Cells have evolved very pervasive molecular mechanisms of DNA repair, as well as many other kinds of maintenance and repair systems at all levels. This holds also for whole organisms: DNA, cells, tissues, and sets of cells— organs. Actually, robustness—namely, the property of overcoming perturbations and maintaining one’s functional state—is a key property of organisms (Kitano, 2004), it is universally realized across the living realm, and it has evolved mostly by natural selection (Huneman, 2018). Williams began his 1957 seminal paper on AP by targeting the “wear and tear” views of death and senescence, seeing them as a major obstacle to our understanding of death. Look, he says in substance, machines get old and have to be fixed, but sometimes they cannot be fixed. However, contrary to this scheme of slow deterioration because of activity that we’ve seen emerging in Buffon’s thinking, the deterioration of machines through use is not like the alteration of organisms, because they should have the means to repair themselves, given that, unlike machines, they are self-­ formed. They evolved such complex systems to produce their own development as multicellular entities that it would be indeed surprising if they were not able to repair themselves to some extent, since repair is much simpler than development. “An organism,” Williams writes, “produces itself by a morphogenetic process. It is indeed remarkable that after a seemingly miraculous feat of morphogenesis a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.” And actually, unicellular systems do that, as Charlesworth (2001) reminds us: “Unicellular organisms, such as bacteria, which propagate simply by binary fission, and the germ lines of multicellular organisms, have been able to propagate themselves without senescence over

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billions of years, showing that biological systems are capable of ongoing repair and maintenance and so can avoid senescence at the cellular level.” So, the most general question about death can be traced back to asking why did these repair systems not evolve such as to prevent death? It suffices to say here that the mere view of mechanical degradation is in general not a satisfying account of senescence and death. We will later get back to this question, since both MA and AP intend to answer it. For the moment, I want to compare the question “why do they age rather than not?” to another explanandum, namely, “why is aging occurring in this species at such a rate, rather than at another rate (possibly proper to another species)?” The rate of aging is indeed the explanandum for a set of models that intend to account for the difference in the ways organisms from different clades or species do age—namely, the rate at which their vital functions as well as their fecundity are hampered over the course of time. Among others, Ricklefs (2008) addressed differences between birds and mammals, since all observations show that, while they have similar metabolisms, mammals age more quickly than birds on average. In such studies the measure of the rate of aging is not trivial. Barton and Partridge (1993) write: “A fundamental problem is that death rates do not give a reliable indication of state, because they ignore fecundity. Selection acts on the product of survival and fecundity, and does not distinguish between them. In principle, either factor alone can therefore evolve an arbitrary pattern of increase or decrease, even when their product shows the decline characteristic of senescence. In reality, both may be affected by aging, and in ways that are not independent.” What we want to measure is therefore a compound of survival and fecundity, and the rate of increase of this compound is what we label “rate of aging,” but how is the compound calculated? Senescence is composed of actuarial and reproductive senescence, as we saw, but their combination does not obey a self-­ evident rule. Intuitively, something decays in the course of life for most organisms. However, physiological functions and reproduction are not the same. Once again, fecundity and survival should be considered together, and their decline should be assessed at the same time, in order to measure a rate of aging and therefore compare various species in this regard. Otherwise, models according to which extrinsic mortality increases the aging rate could not be tested, especially by comparing species.

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Barton and Partridge (1993) examined the usual measures of aging, and showed that it is not at all trivial to forge a measure that captures all the required features of aging in any species. They propose that “reproductive value,” a Fisherian definition of fitness, could measure the rate of aging better than survival chances, as Charlesworth (1980) was doing when he provided the first rigorous formal treatment of evolution in an age-class structured population. Fisher’s “reproductive value” is given by: 



v  x   l  y  / l  x   m  y  e  x

r x  y

dy

where, r is the asymptotic rate of population growth, which in many cases could be taken as zero (l(y) and m(y) are respectively longevity and fecundity at time y). The “reproductive value” gives the expected number of descendants that will be produced by an individual of age x over the rest of its lifetime, given that it has already survived to that age. It is therefore a measure taken prospectively from each age of the potential of the organism to produce further offspring, which is the evolutionarily relevant indication of the state of the organism. This reproductive value changes along time, but if we want to compare the rate of aging between two species, we need to look at the curves representing reproductive value. The comparison is easy if the two curves are not crossing—the higher one represents the higher rate of aging. But if they do cross, it is more difficult to decide which aging rate is faster. Recently, Galipaud and Kokko (2020) even questioned the notion of “aging” by distinguishing the “demographic age,” which is the time since an organism appeared in the population, from what they call the “A-age” (inspired by Aeoji, the hero of a Japanese legend who was born at 3 years of age), which measures the degree to which somatic mutations made it to the gamete during the gamete formations. In some cases the initial zygote may be more or less “fresh,” considering these mutations. In many plant species, or species that are not the most usual metazoans, decoupling A-age and demographic age is not rare. While many biologists now decouple the “chronological age,” measured by watches and calendars, and the “biological age,” measured by various indicators at the cell of organism level, especially epigenetic ones (see below), this theoretical notion of A-age, whose extension goes beyond mere animals, diversifies the univocity measures of age. In this case, because just measuring the age of an organism is ambiguous, the question of measuring the rate of senescence becomes trickier.

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9.1.3   Lifespans and Life History Besides death, statistical senescence, and aging, another major explanandum of these theories is lifespan. Of course explaining death directly explains the fact that organisms have a finite lifespan; and explaining senescence implies that life deteriorates towards a final point, and that, since such deterioration is explained, the endpoint is explained. However, why a particular lifespan holds in one species, and another lifespan holds in another species,1 is another question, and does not even arise once we know why organisms have to senesce. That lifespans are indeed as various as death is a universal phenomenon (almost; see below). Some examples illustrate this: eagles live 14–20 years, oysters 1–3 years; bees of the species apis mellifera live 6 weeks when they are workers but the queen lives 8 years. And in the ant Lasius niger, the workers live 1–2 years while in captivity the queen can live up to 28 years. At least 25 species of birds have lifespans of over 40  years. One of the records is held by Pinus Longaeva, which has been ascribed a longevity of 5062 years (it is said to be non-senescent, which raises issues that will be addressed later).2 Among teleostei—a family of fish, although “fish” is not a scientifically well-formed name for the lineage—the American gizzard shad (Dorosoma cepedianum) lives 6 years in the wild. Brown trout (Salmo trutta) often live to about 6 years of age but some can live up to 38 years. Variability is the key word, both between families and (to a lesser extent) within lineages: “bats live three to fivefold longer than rodents, parasitic wasps which attack the same host show marked variability in survival and, similarly, mollusks (an invertebrate phylum of over 130,000 species) show patterns of senescence varying from centuries (e.g. clams) to months (e.g. sea hares)” (Bonsall, 2006). Evolutionary theories of death simultaneously answer questions about death, lifespan, and senescence; however, their focus is often different and they cannot be taken as competing altogether for the same explanation of the same phenomenon. In any case, whereas the general question of 1  This is, for example, the title of a paper by Kirkwood, who elaborated the Disposable Soma Theory, a major account of death and senescence addressed below (Kirkwood, 1992). 2  The database AnAge records information and bibliographical references about the longevity of different species (mainly animals) https://genomics.senescence.info/species/. Started by Joao Pedro Magalhaes, it concerns especially mammals, fish, and birds, indicating a bias in our extant studies, possibly due to differences in interest but essentially to the facility of observation.

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senescence was (inaccurately) framed—since Weissmann at least—in terms of “unicellulars are immortal vs multicellular organisms are mortal” (see above, Chap. 7), here the variety of lifespans calls for a range of sophisticated and species-specific explanations. Since the 1990s, the framework for such questions about lifespan, and more generally senescence, is called “life history theory.” This approach is an important aspect of evolutionary genetics, and of “behavioral ecology,” namely the explanation of the behavior of organisms in an evolutionary perspective. Behavioral ecologists consider behavior in a very general sense of the term: not only conscious and deliberate sequences of actions—what we often call “behavior” (see Dretske, 1996 for a discussion)—but more generally, any regular sequence of moves from an organism that can be identified and does not seem to derive from an immediate application of the laws of nature. For instance, the size of a tree’s leaves are an object of study in behavioral ecology—even though of course trees are not conscious or even cognitive agents, and their being “agents” in the first place is contentious.3 But, the size of the trees’ shadows are not an object of study, because of course they directly derive from the laws of optics and physics.4 Behavior is, in a sense, biological traits simpliciter. Behavioral ecology questions them as strategies5—each behavior realizes a strategy, which is hypothesized as a selected strategy, that is, a strategy that has been maintained by natural selection because it provided a fitness gain over all other extant strategies. Hence, the actual trait is the strategy that, by maximizing fitness, proved to be optimal in the given environment. Fitness can be seen as the expectation of a probability distribution of offspring, and, when testing the predictions of a model, is measured by measuring a proxy such as caloric intake, metabolism speed, etc. Two clarifications should be given here. First, as made clear by Reeve and Sherman (1993), the major question in this area is the maintenance of a trait, not its origin. When environments change, it is very possible that a trait that evolved as an adaptation for environmental demand X, becomes most adapted for new environmental demand Y, and this optimizing the answer to Y explains its maintenance. The textbook example is the 3  On the use of the notion of “agents” in biology in this context, see Grafen (2006), Huneman (2019b, 2020), Desmond and Huneman (2021). 4  On the emergence of behavioral ecology, Grodwohl (2019). 5  On behavioral ecology, see Krebs and Davis (2001).

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feathered wings of birds, which indeed are an adaptation for flight and are maintained for this reason, but probably originated as an adaptation for thermoregulation (Gould & Vrba, 1982). Second, fitness can also in this context be “inclusive fitness,” as defined previously—a measure of fitness properly adequate when traits under focus are involved in strategic interactions. That is to say, their fitness payoff depends upon what others do—hence the process at stake is better modeled as kin selection than as natural selection generaliter (Hamilton, 1964; West et al., 2007; Birch, 2017). Now, “life history theory,” considers not only a given strategy at a given time—for instance, being aggressive in an interaction, or having large leaves, or foraging for a given time (all these being classical instances in behavioral ecology studies)—but also the major question as to how organisms transform their resources into fitness during their whole lives. Therefore, organisms face “decisions” about how to best invest their resources in various activities during their lifetime in a given environment. Having a few or many offspring, having them seasonally or continuously, choosing to have a small or a large variance in offspring at each breeding season, etc., are basic life history questions.6 The major issue here is, basically, the best allocation of resources—and from this very general viewpoint, reproducing but also helping its offspring, ceasing to reproduce, or even dying are facts that should be explained by natural selection, provided that there is some heritability in these behaviors (which is a very plausible assumption). Notice that with a very low heritability, selection may still lead traits to fixation provided that the selective intensity is strong enough.7 In 1947, in one of the first major works of behavioral ecology, David Lack studied the number of eggs laid in a nest. He shows first that natural selection acting at the level of individuals rather than group selection best explained the facts—here, the clutch size ranged between 3 and 5 in most of the bird species, and, second, that optimality considerations regarding a trade-off between various environmental demands constituted the best model for addressing the question of the maximal amount of eggs such that adding one egg to the clutch finally decreases the chances of survival the whole nest? Answering this question predicts, for Lack, the expected clutch size, which is met by the facts. Hence, behavioral ecology could account for a key “decision” organisms take regarding their number of offspring. 6 7

 See Stearns (1992) for an extensive presentation of life history theory.  Among many presentations, see Huneman (2015).

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Contemporary to Lack, The Principles of Animal Ecology (1949) (Allee et al., 1949) elaborated a sophisticated theory according to which a form of group selection acted on communities and regulated population numbers.8 In 1947 and then in Lack (1954), Lack defined a major alternative to this view, an alternative that will soon after (especially after Williams’ devastating critique of Wynne-Edwards a decade later) become the orthodox view. LaMont Cole, in a 1954 seminal paper, developed the idea that the whole life of an organism can be understood as the deployment of a sequence of actions (birth, reproduction, death) that can be more or less fructifying of the initial resources (Cole 1954). Differences in such sequences characterize ecological differences between species—for instance, “one of the most significant of the possible classifications of life histories rests on the distinction between species which reproduce only once in a lifetime and those in which the individuals reproduce repeatedly.” He “proposes to employ the term semelparity to describe the condition of multiplying only once in a lifetime, whether such multiplication involves fission, sporulation, or the production of eggs, seeds, or live young,” and iteroparity when organisms reproduce several times in a lifetime. This distinction holds for plants and animals alike (e.g. salmon are semelparous, primates are iteroparous9). From then on, explaining the diversity of species, which has always been an explanandum of Darwinian biology, should not only be explaining the diversity of forms and functions, but also the diversity of “life histories.” “Living species,” Cole writes, “exhibit a great diversity of patterns of such life-history features as total fecundity, maximum longevity and statistical age schedules of reproduction and death.” Death and lifespan are clearly understood as life history features whose diversity should be evolutionarily understood. And, Cole adds, “corresponding to every possible such pattern of life history phenomena, there is a definitely determined set of population consequences which would ultimately result from adherence to the specified life history. The birth rate, the death rate and the age composition of the population as well as its ability to grow are consequences of the life history features of the population.” Thus, the ecological dynamics of the population, namely, its expansion, regulation, or extinction, are affected by these life history traits, which include lifespan. 8 9

 On this Chicago school of ecology, see, among others, Huneman (2019a).  Even though botanists prefer to talk about annual/biannual vs perennial plants.

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This first hint towards what Stearns (1992) called “life history theory” entails that even the lifespan of an organism can be part of a strategy, which can be seen as falling under natural selection. Cole had already written that “it is to be expected that natural selection will be influential in shaping life history patterns to correspond to efficient populations” (Cole, 1954, 134). Life history traits, as they will be soon called, should be included within the domain of behavioral ecology, the science of organismal adaptations: “In other fields of comparative biology it is usual to examine individual characteristics and to regard these as possible adaptations, and [I] believe that life history characteristics may also be profitably examined in this way” (ibid., 135). Williams’, 1957 paper carried on the program set by Cole, focusing on the phenomena of death and specific lifespans. In the case of antagonistic pleiotropy, the questions related to death (senescence, death, lifespan) indeed fall under the umbrella of life history theory as a subfield of behavioral ecology. However, Medawar’s MA model isn’t so tied to this domain, because here the explananda considered are not directly part of selected strategies, they are rather the flipside of the life history traits as evolved by natural selection, the proposed explanans being rather the effects of the lack of selection—selection shadow, as Haldane said in 1941—than of selection itself.

9.2  How to Gather Evidence About Death and Senescence? All multicellular living beings die and almost all senesce. But, as already noted, they do this differently, and those differences are relevant for an evolutionist. From an epistemological viewpoint, then, how is it possible to address those questions and corroborate the explanatory hypotheses that have been designed? I will now examine various sets of evidence that have been collected in order to forge and assess various hypotheses about senescence and death. There are three general sources of data that count as evidence for any hypothesis and that, prior to any hypothesis, triggered the quest for explanations about death and senescence. First, observations on humans—including mortality curves—other animals and plants; second, experiments on physiology, cell biology, and now molecular biology; then modifications of the environment of animals and plants as well as comparisons between various species in distinct environments—especially captivity vs wild environments—or between populations.

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9.2.1   Humans and Curves In a paper that formally connects in mathematical terms Medawar’s and Williams’ accounts of death to classical population genetics, Brian Charlesworth, who extensively modeled population genetics and tested such hypotheses in the 1980s, writes: It is probably not without significance in this connexion that the death rate in Man takes a course generally inverse to the curve of the reproductive value. The minimum of the death rate curve is at twelve, certainly not far from the primitive maximum of the reproductive value; it rises more steeply for infants, and less steeply for the elderly than the curve of reproductive value falls, points which qualitatively we should anticipate, if the incidence of natural death had been to a large extent moulded by the effects of differential survival. (Charlesworth, 2001)

This quote points to another interesting fact, namely, the role played by the curves representing mortality and fecundity in human beings. I will first address thoroughly the heuristic and evidential roles of mortality curves and, in general, of actuarial representations. Of course when it comes to death, death rates, and lifespans, human beings have been the most studied species, and for the longest time (but not for the largest number of generations). Information on lifespan in humans has accumulated since the eighteenth century, especially because of the need to gather the most realistic data on populations in order to set up insurance policies. This development in the human sciences comes with the shift towards “populations” as an object of political consideration in political governance.10 That has been famously analyzed by Foucault in Surveiller et punir, and a significant example of this shift occurs when Rousseau in his Du contrat social wonders how to measure the degree to which a nation correctly functions, and answers that the criterion is when its population thrives. Mathematicians at the same time developed statistics and probability theory, as illustrated by the major advances made by Bernoulli. To this extent, many of them—among them Babbage and De Moivre—looked at the life tables and attempted to find out the proper mathematical function that would express the time series manifest in these tables. This was a longstanding endeavor: Forfar (2006) surveys about 15 of such laws  See also Coleman (1982).

10

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formulated before the 1980s. Possibly the most important or fruitful was the so-called Gompertz law.11 The British mathematician Benjamin Gompertz attempted to capture the shape of the curve of the probability of death related to age, resulting in a curve called the Gompertz curve or function. Gompertz was an actuary and a fellow of the Royal Society; he used tools from contemporary probability theory to make sense of what the extant life tables, used by emerging insurance companies, were saying. But where De Moivre later imagined constant mortality rates, Gompertz assumed that there is an exponential increase in death rate related to age classes. The importance of his “law” (which, epistemologically speaking, is less a law of nature than a mathematical formulation of a phenomenological regularity) consists in involving for the first time an exponential factor in its formulation. Succeeding attempts to model death rates would integrate this insight. As a sign of its importance, the Gompertz law has been recently analyzed by biologists, often involved in the study of biological death (Olshansky, 2010; Olshansky & Carnes, 1997; Ricklefs & Scheuerlein, 2002). It is considered to still be at the foundation of actuarial theories. The 1825 paper provides concrete examples of the computation of an insurance premium based on the model Gompertz proposes. It used data from actuarial life tables from Carlisle and Northampton, as well as referring to data from the Equitable Society. Gompertz’s equation tells us for each age class, how many individuals as a proportion of the class are expected to die. It expresses the rate of mortality as a function of age. The Gompertz curve is based on a sigmoid function and can be expressed by

G

m  x   a  e bx

Kirkwood (2015) comments: “where m(x) denotes the mortality rate at age x, and a and b are constants.” In essence, the equation represents a force of mortality that increases progressively with age in such a manner that log m(x) grows linearly. The term b might be said to describe the “actuarial aging rate,” in that its magnitude determines how fast the rate of dying will increase with the addition of extra years. Another expression can be mx = m0eγx where m0 is the initial mortality rate experienced by 11  The first one was published in 1825—later Gompertz refined it in subsequent publications, but that does not change what is essential for us.

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young adults and γ is the exponential rate of increase in mortality rate with age. Visually, the Gompertz curve starts to increase very slowly, and at some point increases very rapidly. Then, for the old-age population, the rate of death quickly decreases, and asymptotically tends to some value. An improvement on Gompertz’s law is due to William Markehan. In 1860,12 he remarked that Gompertz didn’t mathematically decouple those two ranges of causes in an adequate way, namely, between those that are age-dependent and those that are age-independent (the “chance, without a predisposition to death” according to Gompertz.) The law becomes therefore m(x) = mo +aeγx, but, as Ricklefs and Scheuerlein (2002) note, the added parameter (being mo) still refers to a rate at youth, hence may not be as age-independent as expected. Epistemologically, Gompertz’s approach also instantiated an idea of what causes aging: “Contemplating on this law of mortality, I endeavored to enquire if there could be any physical cause for its existence.” And the answer is: “It is possible that death may be the consequence of two generally coexisting causes; the one, chance, without previous disposition to death or deterioration; the other, a deterioration, or an increased inability to withstand destruction.” Together with the general support for the approach—many life tables being able to yield the same function13—this was the reason why Gompertz saw his formulation as a “law of human mortality.” One should first note that Gompertz was not alone at this period in trying to anchor statistical descriptions in the assumption of a generating process, composed of some essential causes and some anecdotal causes. At the same time, Alfred Quêtelet’s L’homme moyen, which is a seminal work for statistical analysis, attempted to capture the pattern of the distribution of several human properties. Quêtelet was expecting normal laws, because he thought that two sets of causes were at the basis of the distribution— essential causes that would yield a value close to the mean, and then accidental fluctuations, responsible of the distribution of the normal laws. The central limit theorem would explain why the accumulation of small

12  Gompertz (1860), “On the law of mortality and the construction of annuity tables”. The Assurance Magazine, and Journal of the Institute of Actuaries. 8(6): 301–310. 13  “I derive the same equation from various published tables of mortality during a long period of man’s life, which experience therefore proves that the hypothesis approximates to the law of mortality during the same portion of life.” (my emphasis)

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accidental causes deviating from the essential tendency that underlies the property results in a normal distribution.14 Thus, importantly, the attempt to make sense in mathematical terms of the data gathered by those who established the life tables traces back to a principled distinction we made earlier between intrinsic and extrinsic mortality. Gompertz needed to decouple these two kinds of death, senescence being the process that underlies intrinsic deaths, while extrinsic mortality appears as a sort of noise, what he calls “chance.” Gompertz’s law has been very influential both in statistics and actuarial practices, and in physiology; it inspired Raymond Pearl in his attempts to model life expectations in terms of a logistic law, which is of the same family as sigmoid functions and the Gompertz function, and to extend it via his dietary restrictions experiments (see Chap. 5). Philosophically, Gompertz’s allusion to “deterioration, or an increased inability to withstand destruction,” is expressed in the formula by the coefficient of the exponential term. Hence, the curve connects physiology (physiological decay) with demography; or, as Ricklefs and Scheuerlein (2002) put it, in Gompertz’s law, “the increase in mortality rate over the initial adult mortality rate measures the aging-related decrease in physiological function in demographic terms.” Here, the mathematics intends to capture through the demographics a physiological trend, sometimes called the “force of mortality,” which underpins a process that, as physiological, affects individuals. The “law” is fundamental—and deemed to be a law by Gompertz and some of his followers such as Olshansky and Carnes (1997)—because it captures something that happens within individuals but is not visible as a cause, only through its effects. Olshansky (2010) opposes Gompertz’s search for a “law of mortality,” which he supports, to the mathematical search for a “model” of mortality that would be neutral regarding underlying causes, and would consist merely in curve-fitting, even though the “cause” that Gompertz’s law supposedly captures would itself require an evolutionary explanation. In A Means to an End. The Biological Basis of Aging and Death, William R. Clark insightfully surveys all those processes that occur in us while we age, and which taken together are seen as a fact of senescence. But, he adds 14  On Quêtelet see Ariew (2007). The theorem of central limit, a key statement in probability theory, states that when a random variable is an aggregate of random variables with the same mean and variance, a normal distribution. This theorem has been essential in the epistemology of measurement (e.g. in astronomy) since the nineteenth century.

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“none of these processes is the cause of aging; they are all the result of the aging process” (Clark, 2002). However, this process is not as obvious as the signs. For Gompertz, it could be at least measured not in the individuals themselves, but at the level of a population, through the mathematics that properly expresses the law of the relevant time series. Clark’s “aging process” as the cause of all the signs of senescence is Gompertz’s “increased inability to withstand destruction,” which was captured by him, or at least measured, as a coefficient. The cause and effect of death are therefore epistemologically inscribed in an articulation between physiology and demography, and the latter expresses the former, through the use of mathematical formulae. Evolutionary approaches will be the last side of this epistemic structure: they intend to shed a light on this “cause of aging itself,” and not only to measure it. But because it can be measured (through the coefficient a in (G)), it can be the focus of predictions taken from evolutionary models. In other terms, it can be part of a hypothesis testing protocol. Gompertz’s function captures various sets of data regarding human lifespan and mortality; its robustness has been established through decades. In Fig. 9.1, one sees how the curve, based on the Northampton data used by 1000.0

India, 1900 Mexico, 1940 Sweden, 1949 United States, 1900 United States, 1940 United States, 1950

500.0 200.0 Deaths/1000/Yr (All Causes)

100.0

Gompertz, Northampton, 1825

50.0 20.0 10.0 5.0 2.0 1.0 0.5 0.3

Jones, 1956

0

Fig. 9.1  Gompertz law

10

20

30 40 50 Age (Years)

60

70

80

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Gompertz, also matches other data sets from distinct countries and times. This function had the further interest of making connectable the data gathering achieved by actuaries for decade—especially because of the needs felt by insurance companies—and the evolutionary theories of death proposed by Medawar and Williams. As Olshansky (2010) notes, he was led to evolutionary theorizing by his own initial work in actuarial tables—“the declining force of natural selection from evolution theory corresponds perfectly with the rise in mortality observed by the actuaries, a phenomenon that one would expect in a genetically heterogeneous population. The stochastic component to senescence also contributes to the expected rise in age-specific death rates as a function of time. Thus, the evolutionary theory of senescence provides a plausible explanation for why a law of mortality should exist.” Indeed, the two phases of the Gompertz curve match easily with the two periods that evolutionists detect in the life cycle related to the force of selection, namely, the effect of selection and the shadow of selection, past the reproductive peak (Fig. 9.2, from Carnes et al., 1996) Postreproductive period

Reproductive period

Reproduction

50% Selection

0%

High Effectiveness of natural selection

Cumulative reproductive success

100%

Prereproductive period

Low

0

Lifespan

Human

15

Age (years)

50

Fig. 9.2  Match between Gompertz law and decline in selection intensity (After Carnes et al., 1996). Notice that they consider a post-reproductive period where Williams thinks there is none; however, he counts parental care for grandchildren, especially in humans, as reproductive, which is not the case with the present authors, hence the discrepancy

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Cumulative survival: S(t)

1.0

Human

0.8 Beagle

0.6 0.4

Mouse

0.2 0.0

100

300

500

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40

700 900 Age at death, mouse (days)

1100

3000 4000 5000 Age at death, dog (days) 60 80 Age at death, human (years)

1300

1500

6000

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7000

120

Fig. 9.3  Mortality curves in several species compared. (After Olshansky, 2010)

The Gompertz law has been used for many types of increases that it can model adequately: the growth of individuals, the growth of tumors, or other applications in economics. Regarding senescence, it is powerful enough to capture the growth of many species other than humans. This generality is an additional and strong reason some biologists think that the Gompertz function indeed expresses a natural law. Yet the true generality of the law is not visible at first glance: one has to somehow normalize the data to show what happens. But what does “normalize” mean? Olshansky (2010) explains that when one considers mortality in general no common pattern emerges; however, “when intrinsic mortality schedules of different species are compared on a uniform timescale, they should overlap.”15 If extrinsic mortality is indeed put aside, then the patterns of mortality rates compared to age classes across many species do match (Fig. 9.3). “All of the scientists from Gompertz to Pearl failed in their effort to verify the law 15  Then he goes on: “We refer to these age patterns of mortality linked to reproduction as a mortality signature that applies individually to each species. Since the environment within which most species arose was hostile, with a high force of extrinsic mortality, it stands to reason that the response to that environment would be equivalent across species.”

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of mortality because they relied entirely on a comparison of total mortality within each species. Total mortality is contaminated by deaths that are unrelated to ageing” (Olshansky, 2010). But if many species fall under this quasi-law, not all do (many more species have been investigated since the Carnes et  al. paper in 1996). This means that another way of using the Gompertz function consists in identifying patterns of senescence in the species where they occur and patterns of non-senescence elsewhere. As Kirkwood (2015) writes, “the application of the Gompertz model as a yardstick continues to serve as a means of determining whether or not ageing, as it has been conventionally recognized, is a feature of a species’ life history.” But, as Olshansky and Carnes write, “numerous statistical distributions have been shown to characterize reliably the age pattern of the dying-out process” (Olshansky & Carnes, 1997, 11). Even if the Gompertz law is the most used of these distributions, the so-called Weibull distribution presents some advantages (Jorgen Weibull is a Swedish economist who, recently, proposed major contributions on inheritance; he is quite sympathetic to evolutionary approaches). This distribution has two parameters instead of one in the Gompertz law, which characterizes the rate of aging; its formula is: mx  m0   x b

“b is a dimensionless parameter, characterizing the shape of the curve relating mortality rate and age; α determines the magnitude of the mortality rate at any given age for a particular value of b” (Ricklefs & Scheuerlein, 2002). Ricklefs (1998) indicates that it fits some populations of birds better than the Gompertz function. Later, he used these findings to propose that “factors that influence the rate of aging in natural populations” are a selective response to variation in the initial mortality rate of the species, and therefore that AP or MA not only explains senescence, but also a balance between the effects of metabolic “wear and tear” along existence and “genetically controlled mechanisms of selection and repair.” But independently of the theoretical question of the fit between distributions (Gompertz and Weibull being among the best-performing ones) and data points about lifespan in various species, what appears from the use of those distributions to compare species is an interesting difference between the evolutionary and mechanistic causes of death that Ricklefs explains as follows: senescence may result in part from the accumulated effects of cellular wear and tear on the individual associated with life itself (Finch, 1990). However,

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differences in the maximum potential lifespan among organisms with similar metabolic rates suggest that the rate of aging may be modified by biological processes that are under genetic control and subject to evolutionary adjustment (Rose, 1991; Charlesworth, 1993). For example, sparrows can live 15 years while rodents of similar size rarely attain a third of that age under ideal conditions. This contrast suggests that wear and tear related to rate of living cannot fully explain the variation in rate of aging in natural populations (Holmes & Austad, 1995). (Ricklefs, 1998)

In effect, biologists, like most famously, Raymond Pearl, tended to interpret the Gompertz law as resulting from a pattern of cumulative use, via metabolism, of the tissues, cells, and body parts (“wear and tear,” in Ricklefs’ phrase). However, the differences between species, given the same metabolism rate, indicate that other causes are at stake in determining the different rates of aging. This is the room for the evolutionary explanations we are concerned with here. Epistemologically, it means that explaining aging requires being able to decouple those two sets of causes, mechanical ones— due to physiology, but not evolved—and those which are there because of evolution. The fact that differences in Gompertz’s or Weibull’s parameters allow one to make this difference in general does not imply that it’s always possible to decouple these two sets of factors in a particular case. Charlesworth (1994) states that a major issue in the biology of death concerns whether there are “universal mechanisms of aging”; such an issue emerges precisely by considering the general validity of the Gompertz distribution, and then the variations in the parameters that this distribution allows one to identify (even if the profile of the distribution is often the same). That hints toward the possibility of universal mechanisms locally instantiated, and that is the basic hypothesis for evolutionary research on death and aging. The Gompertz law is useful to start with in detecting a pattern and looking for explanations, in that the usual strategy in scientific explanation consists in first establishing the pattern of a phenomenon—for instance, a distribution—and then, looking for a cause or mechanism likely to explain this pattern. Thus the Gompertz law is useful because of its quasi-­ generality, but it’s also useful because of what it misses. a. The two extremes of the curves are anomalies. (a1) First, the two extremes of the curve actually misrepresent the data: as Gaillard and Lemaître (2020) write: “Only a few organisms, if any, display a Gompertz-type age-specific mortality from birth to the oldest age.”

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The initial part is the mortality excess after death; the last part is what is often called the “centennial plateau,” namely, the fact that very aged people (above 90) see their aging rate decline or become steady. This phenomenon is intriguing since it does not seem to derive from the trajectory of the mortality curve; Mangel (2002) labelled it an “emergent property,” using a phrase that is familiar to philosophers of mind dealing with explanatory irreducibility.16 Various explanations have been given for these facts, which are crucial for public health and the speculative programs of “lifespan improvement” among humans. The centennial plateau is to be found in many species, including nematodes or drosophila (while 100 years may of course not be the age for this plateau, the pattern is a steady rate of aging at the extremity of the curve). “In both Gompertz and Weibull models, rate of mortality continues to increase, at an accelerating rate, with increasing age. Empirical studies of large populations of flies and humans have shown, however, that a plateau in mortality rate may be reached in extremely old age” (Ricklefs, 1998, 27). Granted, some authors doubt that the centennial plateau is real: they see it as an artefact of the data-gathering, just noise in the data (Newman, 2018). However, if it is a real fact—the jury is still out on Newman’s claim—one has to think of an accounting process, and here its existence would be enlightened by the statistics of extreme values (which present extreme variances): “the distribution of survival at the highest ages most likely reflects the variation inherent in statistical extreme-value distributions” (Kirkwood 2010). Gavrilov and Gavrilova (2001) elaborated a “reliability theory” of aging that derives the plateau as a consequence of its assumptions (see below Chap. 11). Closer to Williams’ AP, Hamilton (1966) produced a more general formal framework to think of the decrease of the force of selection with age. Switching from Fisher’s reproductive value to the Malthusian parameter (see Box 8.2), he allows researchers to demonstrate that after a period, the decrease of the force of selection asymptotically tends to zero. The function s, which measures the fitness effects of genes in function of ages, decreases exponentially and at some point, “since genetic effects at very advanced ages are equivalent with respect to their effects on fitness no differentiation between ages is expected to evolve” (Rose et  al., 2007, 1269). Simulations run by Rose and colleagues in this paper, which assesses Hamilton (1966) 40  years later, indeed show that “late-life 16  “Leveling of the mortality rate is an emergent property without interaction between members of the population, each of whom experiences mortality according to a different Gompertzian curve.” (p. 1067)

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mortality plateaus can evolve as a consequence of natural selection in age-­ structured populations alone, without any special suppositions.” (Ibid) Possibly distributions other than Gompertz’s (e.g. Weibull’s distribution) fit this phenomenon better. But a set of explanations is still available. Challenging Hamilton’s view, which focuses on the variation of the force of mortality, others advocate the explanatory role of individual heterogeneity. “If the population comprises a set of individuals who differ in the inherent robustness or rate of ageing, the frailest individuals tend to die soonest, leaving the most robust individuals to predominate at the oldest ages. In such a scenario, it is possible for a late-life mortality plateau, or even a decline, to be seen at the population level, even if the various individuals that comprise the population all experience an increasing probability of dying with advancing age” (Kirkwood 2010; see also Vaupel et al. 1979). In contrast to Rose et al.’s simulations, this heterogeneity theory has been corroborated on an experimental population of nematodes (Chen et al., 2013). (a2) As to the first part of the curve, some biologists identified the initial high rate of mortality, which decreases until reproductive age, as a specific phenomenon that they call “ontogenescence” after Levitis (2011). They consider that it can be explained by a reference to natural selection. In his very exhaustive paper, Levitis assesses possible explanations. The interest in this initial portion of the mortality curve, which is a drastic decrease, is indeed recent, coming long after Medawar’s hypothesis in 1957. Ontogenescence is a “population-level phenomenon in which the death rate of each cohort tends to decrease with increasing age between conception and maturity,” and all vertebrates experience it, as well as insects, brown algae, red algae, and many green plants (see Box 9.1).

Box 9.1  The Riddle of Ontogenescence

Explanatory hypotheses are multiple: ontogenescence may be selected for, because by this method the less promising offspring (in terms of potential transfer to resources to the kin) die without themselves generating poor quality offspring; it may also be a product of selection, such that “if selection for growth is strong enough, a risky developmental pattern that increases growth rate but decreases protection against mortality may be favoured over a slower and more protected path.” (ibid). (continued)

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Box 9.1  (continued)

A third explanation appeals to by product selection. “If mortality is strongly size-dependent, it should decrease with age while the organism is growing, not because the early concentration of mortality is advantageous, but because it is unavoidable when individuals start out small and vulnerable.” Another hypothesis evokes by-product selection: there are many mechanisms involved in the life of an organisms, and chances are that the ones whose mechanisms can’t function together will die earlier, in such a way that early life sounds like a test of these mechanisms and their harmony. The fact is that in order to function the organisms need all of these tested mechanisms: if it is an adult, chances are that these mechanisms function—by definition—so that its mortality rate is lower than when it is very young. Hence, ontogenescence. None of the latter hypotheses is exclusive (the first one problematically calls for group selection which, as we have seen, has been put aside). Levitis conceded that they can work together, each of them being more prominent in a specific clade or lineage. However, not only the first stage of life, before the reproductive period, stands apart from most data and common models, but the start of the senescent period, where mortality begins its increase, may be postponed, as it has been progressively indicated by researchers. Gaillard et al. (2017) have shown that in mammals the reproductive period precedes the moment mortality starts its steep increase by several years. b. The Gompertz pattern is not wholly universal. (b1) Second, as I said, many species do not conform to the Gompertz or Weibull distribution, even if they are not the norm. Data about various animals and plants have been synthesized in Jones et al. (2014), and show that things are even more complex than theoreticians have thought. In Fig. 9.4 the curves start from reproductive age. Contrary to the usual patterns represented by the Gompertz law, “several species’ mortality declines with age and, in some cases, notably for the desert tortoise (Gopherus agassizii), the decline persists up to the terminal age.” Hydra are also nonstandard animals since Martinez (1998) has suggested that they display negligible senescence and apparently an indefinite lifespan. But what is

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25.0

Homo sapiens (Japanese, in 2009)

Legend

Homo sapiens (Swedish, born in 1881)

Mortality

22.5

Fertility 20.0

Humans

Trees

Other mammals

Other plants

Other vertebrates

Algae

Survivorship

Invertebrates

17.5

Leucopsar rothschildi (Bali mynah)

Fulmarus glacialoides (southern fulmar)

Homo sapiens (hunter gatherers)

Poecilia reticulata (guppy)

15.0

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0.01 15

5.0

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Daphnia longispina (water flea)

Orcinus orca (killer whale)

Years

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Months

2

38

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Papio cynocephalus (yellow baboon)

Panthera leo (lion)

Years

81

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Macrotrachela sp. (bdelloid rotifer)

33

1

Capreolus capreolus (roe deer)

2.5

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5.0

59

4

Days

48

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Caenorhabditis elegans (nematode worm)

Cervus elaphus (red deer)

Years

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Pan troglodytes (chimpanzee)

Pediculus humanus (human louse)

2

Days

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Drosophila melanogaster (fruitfly)

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2.5

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5.0

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Days

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Apus melba (alpine swift)

Ceratitis capitata (Mediterranean fruit fly)

Ovis aries (Soay sheep)

Years

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Cygnus olor (mute swan)

Days

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Hypericum cumulicola (hypericum)

Microtus oeconomus (tundra vole)

2.5

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Pinus sylvestris (Scots pine)

3

Days

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Crocodylus johnsoni (freshwater crocodile)

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Accipiter nisus (sparrowhawk)

Marmota flaviventris (yellow-bellied marmot)

Months

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Lacerta vivipara (common lizard)

Geonoma orbignyana (geonoma palm)

Years

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Borderea pyrenaica (borderea)

Ulex minor (dwarf gorse)

Years

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Ficedula albicollis (collared flycatcher)

7

Years

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Rhododendron maximum (great rhododendron)

2.5

0.01 1

0.1

34

5.0

Years

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2

6

Years

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Hydra magnipapillata (hydra)

Parus major (great tit)

Years

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Pagurus longicarpus (hermit crab)

6

Years

27

1

Atriplex acanthocarpa (armed saltbush)

Years

5

5

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14

0.01 1

Rana aurora (red-legged frog)

Haliotis rufescens (red abalone)

2.5

0.1

0

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Years

4

0

Paramuricea clavata (red gorgonian)

Centuries

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Laminaria digitata (oarweed)

Viburnum furcatum (viburnum)

Years

9

7

Quercus rugosa (netleaf oak)

Years

17

3

Gopherus agassizii (desert tortoise)

Years

11

0.01 1

Avicennia marina (white mangrove)

2.5

0.0

0.01

0.1

5.0

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1

1

Agave marmorata (agave)

Cryptantha flava (yellow cryptantha)

2.5

0.0

0.01

0.1

5.0

0.0

0.01 1

Rupicapra rupicapra (chamois)

Survivorship

Standardized mortality and fertility

0.0

0.1

0.1

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Years

44

14

Years

66

1

Years

8

27

Years

177

12

Years

64

3

Years

123

0.01

Age

Fig. 9.4  Mortality and fertility curves in relation to age, in numerous species. (After Jones et al., 2013)

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striking is that, beyond the current Gompertz-style mortality pattern, when one plots mortality and fertility against age, three facts appear: –– in some species, the mortality increase is much less steep than in the usual Gompertz-like mortality pattern; –– in other species, mortality does not increase with age, and fertility does not decrease, but remains almost constant (tundra vole, yellow bellied marmot); –– in some species, mortality even decreases with age and fertility increases (desert tortoise, oak, white mangrove). These curves are important because they allow one to distinguish two characteristics of senescence: lifespan, and the speed at which some level of mortality is reached starting from reproductive age; and also the steepness of the curve, be it linear, concave, or convex. Authors call those two traits, respectively, “pace of life “and “shape of mortality.” Pace and shape seem to be independent features of senescence. These data also show that there is no correlation between length of life and degree of senescence. Actually, current research has definitively decoupled lifespan and senescence, and given up the idea that the maximal longevity in a species could be informative of the nature of senescence in that species: “age at death by itself does not measure senescence” (Monaghan et al., 2008). Importantly, there is no straightforward difference between animals and plants in this respect—both happen to belong to the three categories I indicated. Yet, phylogenetic relatedness seems to have some role in the order of species (..) as shown by taxonomic clustering of mortality, fertility and survivorship patterns. All mammals are clustered in the top part of Fig. 9.4, whereas birds are somewhat more scattered, from the Bali mynah in the first row to the great tit in the seventh row. Amphibians and reptiles are found in the lower half of the panel, with flat mortality shapes and almost no overlap with mammals. In contrast, invertebrates are scattered across the continuum of senescence, with bdelloid rotifers and water fleas sharing the mammalian mortality pattern. The plants in our sample tend to occur lower in our ordering (Jones et al., 2013).

But many plant species can enter into dormancy, which changes many things since the species can “wait” for a proper moment to flourish, by decreasing both the “metabolic cost and physiological costs associated

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with harsh environmental conditions” (Lemaître & Gaillard, 2020) that it faces. Hence senescence is delayed and will happen later on.17 Thus, while Charlesworth could claim in 1994 that “despite this diversity, we can observe an almost universal life-history pattern: that of senescent decline in survival and reproductive performance with increased age after reproductive maturity” (Charlesworth, 1994, 13), the situation now looks much more complex. The review of lifespans across species however met important critiques. Orzack and Levitis have shown that claims about non senescent species such as hydra are vastly dubious, because the statistics don’t wait for eventual life termination, so that they can’t establish any absence of mortality increase. It would be as if one doesn’t wait for complete lives of humans and finally claims that some of them live indefinitely. “To this extent, entire lives (or nearly so) must be measured in order to make a claim that the agespecific mortality rate does not eventually increase human data were censored so as to include mostly uncompleted lives, one could also infer that humans have a 5% chance of living for hundreds of year” (Orzack and Levitis 2019). However, even though the details of the lifespan statistics for various species are contested, the works cited in this paragraph provide us with the novel knowledge that there are clusters of patterns of aging across animals and plants. Based on the various cases reviewed, biologists indeed distinguished three general patterns of aging, and this is enough to complexify the question of an evolutionary account of senescence. To sum up, there are at least three great families of aging as represented by Baudisch and Vaupel (2012): positive, constant, and decreasing senescence (Fig. 9.5). The question raised for theorists is the sufficiency of the evolutionary frameworks (AP, MA) to account for these three general varieties of mortality patterns, even if most of the known organisms fall under the most classic, Gompertz-like pattern, the one that seems to best fit with the evolutionary accounts. To make sense of these three families, life history should focus not only on early versus late life and the effects of selection, but “on all the difficult choices an organism must make in allocating limited resources to competing needs over its lifespan” (ibid., 618). 17  Importantly, as Salguero-Gómez et al. (2013) remarked, the senescence studies are far less developed in plants than in animals. “The current landscape of research into whole-plant senescence appears rather deserted. This is surprising, because declines in whole-plant fitness with age have obvious consequences for all branches of plant biology.” This is a fact, despite the increasing interest in the last 5 years. See Roach and Smith (2020) for a review of the current research.

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Fig. 9.5 The three types of senescence patterns (from Baudisch and Vaupel (2012))

Jones et al. (2013) suggested then that what contributes to an explanation of these differences are, first, phylogenetic constraints,18 and second, specific features allowing some species in a clade to escape the typical mortality patterns of the clade.19 The striking diversity of patterns across the phylogenetic tree in any case invites us to look away from the characteristic human senescence pattern, because within these figures “humans, especially modern humans, are extreme outliers.” 9.2.2   Producing Evidence About Death: Comparisons Two major sources of evidence can support our theorizing about biological death. The first, indicated by the current phylogenetic picture, is the comparison between species (which assumes observations). The second is 18  “Primitive traits related to the bauplan of species may have a pivotal role in determining patterns of ageing. In fact, the evolutionary conservatism of mechanistic determinants of ageing has been highlighted by genetic studies” (Jones et al., 2013). 19  “It has been suggested that asexual reproduction, modularity, lack of germ-line sequestration from the soma, the importance of protected niches, regenerative capacity, and the paucity of diverse cell types, may facilitate the escape from senescence in some clades” (Ibid).

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experimental practice, given that senescence and death have been the object of numerous experiments since the work of Bichat. As Auguste Comte argued at the time that modern comparative anatomy, embryology, and experimental physiology originated, biologists mostly rely on these two sources, comparisons between species (or—as we would add now—populations in different environments) and experiments.20 An examination of experiments as evidence will be done in the next chapter; here I survey the way systematic comparisons can constitute evidence.  omparing Senescence Patterns C Some comparisons are introduced, as I said, through the curves plotting population mortality or chances of death against age. Common patterns between species or clades, or different patterns, along with the range of common patterns, constitute important evidence for theories of death, since differences in death, lifespan, rate of senescence, or shape of senescence, can therefore correlate to phylogenetic and ecological differences between species. As we have just seen, one of the major advances in the last two decades regarding our knowledge of death indeed comes from the establishment of the many different patterns of mortality across species, focusing not only on lifespans, but also on the shape of aging. Comparisons can now be multiple, and they are precious for this reason. Comparisons are to be made between species and between families (clades, lineages). “The observation that many of the more active mammals, including bats and carnivores (as well as birds), have relatively low rates of aging for their body size (Austad & Fischer, 1991), yet relatively high rates of metabolism, throws further doubt on the hypothesis that aging is a simple byproduct of metabolism. The comparative data suggest, therefore, that the consequences of oxidative damage for aging-related mortality are controlled by other processes subject to evolutionary modification” (Ricklefs, 2010). Here, those differences where metabolism similarities would suggest that a metabolism-based theory of aging is sufficiently explanatory indicate, once again, the relevance of an evolutionary view of aging, because metabolism alone, as advocated by Pearl, would not make such a difference. Ricklefs (2010) developed the comparison between birds and mammals in detail, indicating that mammals have a shorter lifespan. On the other hand reptiles have a senescence seemingly less acute than mammals and birds, in part possibly due to their having protective  40ème Leçon, Cours de Philosophie Positive.

20

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traits such as venom or shells (Hoekstra et al., 2020). Alper et al. (2015) show that two snake species (Thamnosphis elegans, antherophis guttatus) have dermal fibroblast cells more resistant than avian or mammalian fibroblasts when it comes to cytotoxic agents responsible for some macromolecular damages. Comparisons are crucial, not only regarding the respective merits of evolutionary vs metabolic or functional theories of death (speed of metabolism as Pearl thought, or in more modern terms, on the basis of oxydoreduction, free radicals, etc.) but also in assessing evolutionary theories in general. Comparisons between environments with various rates of extrinsic mortality are a way to assess theories like AP or MA, which tie death and senescence to the selective pressures exerted by predation, life hazards, and other external causes of death. Since “life-histories are astonishingly variable, even within a relatively homogeneous group of organisms such as eutherian mammals, where maximum life-span in captivity ranges from a low of a few months for a small insectivore to a high of 80 years or more for humans” (Charlesworth, 1994, 13), comparisons between those environments are a good test case for evolutionary theories of aging— given that comparison is indeed one of the major methods of assessing natural selection in the wild (Endler, 1986). But comparative analyses of aging have to be handled with caution when one goes into the details. The relevant variables to be compared are not obvious: is it lifespan? rate of aging? shape of senescence? The problem of the measure of aging already encountered is also problematic. In using such a measure in comparisons, Promislow argued for the rate of increase in age-specific mortality (Promislow, 1993) while others (Abrams, 1991) advocated including age-specific changes in fertility (see also 9.1.2). Comparisons especially may suggest correlations, but the direction of the causal arrow cannot be independently assessed. “Let us assume that across a variety of invertebrate taxa, we find a negative relationship between investment in spermatogenesis and lifespan. This correlation might suggest that selection for increased spermatogenic investment could have resulted in a corresponding increase in the rate of aging, but the causal arrows may point in the other direction. That is, short lifespan in males could select for increased investment in sperm production to maximize the probability that a male fertilizes a female before he dies. Work (Service & Fales, 1994) shows that the causal arrow can, indeed, be drawn in the other direction. They found that flies selected for delayed senescence had greater sperm competitive ability than control (rapid senescence) lines.” (Promislow & Tatar, 1994, 51)

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Granted, comparisons are useful to assess hypotheses and theories, but compared patterns are also tools to infer proper new hypotheses. As Promislow and Tatar (1994, 47) also explain, “if late-age mortality only decelerates in holometabolous insects (insects with complete metamorphosis), this might suggest a causative role for complex life histories with post-­mitotic adult somas. Or perhaps we may find that mortality does not decelerate in species with non-continuous population dynamics (as occurs in species with seasonally synchronized life cycles).” Philosophers of science used to distinguish between the context of justification, namely, the reasons that are produced in favor of a hypothesis or a model, and the context of discovery, namely, what led researchers to formulate this hypothesis in the first place. This difference is seriously discussed now but it’s often useful. While the next paragraph will consider in detail the logics of testing evolutionary hypotheses about death, it suffices here to indicate that comparisons are not only evidence backing up theories and hypotheses, within the context of justification, but also crucial pieces in the logics of discovery.  omparisons at the Genomic Level C Several studies have been comparing individuals within a population from the viewpoint of specific genes or whole genomes. Obviously, comparing long-living people to the rest of the population may provide information regarding the genes involved in aging. One found some relevant facts, even though their significance shouldn’t be overestimated. For instance, allele e4 of alipoprotein APOE, which is known to increase the risk of Alzheimer’s disease and cardiovascular disease, is found less often in nonagenarians and centenarians than in others. However, the exact function of APOE is unknown. These considerations call for being cautious in doing such comparisons, and for preferring intra- to inter-population comparisons. Genetics targets candidate genes and compares their alleles in distinct groups (here population vs centenarians), like APOE. But genomics—that is, the study of whole genomes, including molecules involved in gene expression21—carry out genome-wide analyses. Telomeres, the extremities of chromosomes, which shorten each time the cell divides, are supposed to be involved in aging, be they effects or causes (Blackburn, 2005; see below). Replicative DNA polymerase cannot 21  On what is usually called the “post-genomic turn,” see Dupré and Barnes (2012), Huneman (2019c).

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replicate the ends of DNA molecules. Actually, a specific enzyme called telomerase could do it, but it’s not expressed in most somatic cells. The question of aging implies understanding why telomerase is so absent in somatic cells. In centenarians, four SNPs22 have been identified, which lie on the telomerase reverse transcriptase gene (TERT), and are plausibly involved in the longer telomeres of these people. In the age of genomics, a key distinction has been made between coding genes, which code for proteins according to the rules of the genetic code (the correspondence table between triplets of nucleotides and amino acids), and noncoding genes, which may influence the expression of coding genes. Most DNA sequences associated with longevity—more present among centenarians than in the overall population—are intronic (namely, noncoding sequences) and are not linked to known coding SNPs, hence they are more involved in regulating gene expression than in building new proteins. For instance, besides APOE, the allele FOXOO3A has been found more frequently among centennials. In any case, the contributions of these genetic variations to the overall variance of longevity is not huge. Regarding longevity, heritability, that is, the part of the phenotypic variance which is due to genetic variance, is not very high. Finding out those genetic differences is therefore not likely to solve major questions about aging, especially if we plausibly assume that many genes with small effects are involved, something that is hard to detect with association studies that compare whole genomes in classes of individuals and detect nucleotides statistically associated with phenotypic differences (Genome Wide Association Studies, GWAS) in the sense that they would require larger and larger classes to detect any signal. More generally, there are several longitudinal studies that consider whole populations instead of focusing on the genomic differences between groups with regard to one specific gene. Longitudinal studies predate genomics: the oldest, the Baltimore Longitudinal Study of Ageing, started in 1958 and still has 1450 participants (from 18 to 97 years); metabolite levels measures or electrocardiograms were regularly used on the volunteers. The lnCHANTI study in Tuscany includes 1320 participants (20–102  years), and now is considering differences at the level of the genome. The cohorts “have been genotyped for approximately 550,000 SNPs” (Wheeler & Kim, 2011). Still, even though SNPs involved in 22  Namely, single nucleotide polymorphism: differences at the level of one nucleotide between alleles of the same gene.

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differences in aging rates have been found, no major explanatory role has yet been inferred. GWAS tests hundreds of thousands of SNPs at the same time, making it difficult to formulate hypotheses about the functional role of each gene detected: they are designed to detect association but cannot by themselves forge explanations. Currently, another approach called “genomic convergence” is intended to overcome this epistemic weakness of comparisons, by selecting candidate genes based on the results of GWAS, and using gene expression microarrays to detect levels of expression of these genes and their correlations with distinct age classes. Yet one initial finding, namely, the role of a gene involved in metalloproteins (ibid.), has not yet been replicated, indicating that this method is not fulfilling the promise of being a reliable approach to genetic determinants of aging and death. However, comparisons at the genomic level can focus on the level of genomic expression of given genes at various stages and in distinct environments, instead of the genes themselves. Many recent approaches use postgenomic concepts and theories in this sense. Charruau et al. (2016) is one of the first studies undertaking this program in natural populations (and not in the laboratory). They consider wolves (Canis lupus). Since gene expression levels vary according to many factors and the primary aim of this study is to discriminate between the effects of these factors—age, social status, sex, disease—the study is intended to disentangle them using “high-throughput RNA sequencing (RNA-Seq) of whole blood.” Interestingly for us, the researchers conclude that “age is broadly associated with gene expression levels, whereas other examined factors have minimal effects on gene expression patterns.” They compared these patterns to what happens in humans and saw “evolutionarily conserved signatures of senescence, such as immunosenescence and metabolic aging, between wolves and humans.” What is crucial and goes in favor of AP or MA is that “the more rapid expression differences observed in aging wolves is evolutionarily appropriate given the species’ high level of extrinsic mortality due to intraspecific aggression.” The method of tracking changes in gene expression has been extensively used, especially recently by the team of Eric Bapteste, who focused on bats and, instead of looking at gene expression, looked at the state of gene co-expression networks that trace the simultaneous expression of given genes. Assuming reasonably that if a trait is under strong selection the variation in structure of its gene co-expression network is quite constrained, they can question a key assumption of MA and AP, namely, the

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idea that the intensity of selection decreases with time. If this is the case, the investigation of the change of the topology of gene co-expression networks over time should reveal an increase in the diversity of these structures (since they would be less and less constrained, hence able to vary more and more…). The study (Bernard et al. 2021) shows that this is indeed the case, even though, unexpectedly, after a long period older individuals display the emergence of co-expression patterns, which may also manifest “targeted selection for very specific biological processes.” Thus, another kind of interage comparison allows one, when considering the genomic level, from a topological viewpoint to test the basic assumption of the general families of evolutionary theory. From another viewpoint comparison of gene expression across age between normal drosophila and flies without microbiome (i.e. germ free) shows that 70% of age-related changes in gene expression don’t occur in germ free flies, suggesting a role of microbiome in implementing aging patterns (Shukla et al. 2021).

References Allee, W.  C., Park, O., Emerson, A.  E., Park, T., & Schmidt, K.  P. (1949). Principles of animal ecology. W. B. Saunders Company. Alper, S. J., Bronikowski, A. M., & Harper, J. M. (2015). Comparative cellular biogerontology: Where do we stand? Experimental Gerontology, 71, 109–117. Ariew, A. (2007). Under the influence of Malthus’s law of population growth: Darwin eschews the statistical techniques of Aldolphe Quetelet. Studies in History and Philosophy of Biological and Biomedical Sciences, 38(1), 1–19. Austad, S., & Fischer, R. (1991). Mammalian aging, metabolism and ecology: Evidence from the bats and marsupials. Journal of Gerontology, 46, 47–53. Baudisch, A., & Vaupel, J. W. (2012). Evolution. Getting to the root of aging. Science, 338(6107), 618–619. Bernard, G., Teulière, J., Lopez, P., Corel, E., Lapointe, F. J., Bapteste, E. (2021). Aging at Evolutionary Crossroads: Longitudinal Gene Co-expression Network Analyses of Proximal and Ultimate Causes of Aging in Bats, Molecular Biology and Evolution, 39, 1,, msab302, https://doi.org/10.1093/molbev/msab302 Birch, J. (2017). Philosophy of social evolution. Oxford University Press. Blackburn, E. H. (2005). Telomeres and telomerase: Their mechanisms of action and the effects of altering their functions. FEBS Letters, 579, 859–862. Bonsall, M. B. (2006). Longevity and ageing: Appraising the evolutionary consequences of growing old. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 361(1465), 119–135.

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Olshansky, S. J. (2010). The law of mortality revisited: Interspecies comparisons of mortality. Journal of Comparative Pathology, 142(Suppl 1), S4–S9. Olshansky, S.  J., & Carnes, B.  A. (1997). Ever since Gompertz. Demography, 34(1), 1–15. Orzack, S. H., & Levitis, D. (2019). Human mortality from beginning to end: what does natural selection have to do with it?. In Human Evolutionary Demography. Edited by O. Burger, R. Lee and R. Sear. Open Book Publishing. Promislow, D., & Tatar, M. (1994). Comparative approaches to the study of senescence: Bridging genetics and phylogenetics. In M.  Rose & C.  Finch (Eds.), Genetics and evolution of aging (pp. 29–43). Springer. Reeve, H., & Sherman, P. (1993). Adaptation and the goals of evolutionary research. The Quarterly Review of Biology, 68(1), 1–32. Ricklefs, R. E. (1998). Evolutionary theories of aging: Confirmation of a fundamental prediction, with implications for the genetic basis and evolution of life span. The American Naturalist, 152(1), 24–44. Ricklefs, R. E. (2008). The evolution of senescence from a comparative perspective. Functional Ecology, 22, 379–392. Ricklefs, R. E. (2010). Insights from comparative analyses of aging in birds and mammals. Aging Cell, 2, 273–284. Ricklefs, R. E., & Scheuerlein, A. (2002). Biological implications of the Weibull and Gompertz models of aging. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 57(2), B69–B76. Roach, D.  A., & Smith, E.  F. (2020). Life-history trade-offs and senescence in plants. Functional Ecology, 34, 17–25. Rose, M.  R., Rauser, C.  L., Benford, G., Matos, M., Mueller, L.  D. (2007). Hamilton’s forces of natural selection after forty years. Evolution, 61(6), 1265–1276. Salguero-Gómez, R., Shefferson, R. P., & Hutchings, M. J. (2013). Plants do not count… or do they? New perspectives on the universality of senescence. Journal of Ecology, 101(3), 545–554. Service, P. M., & Fales, A. J. (1994). Evolution of aging: Testing the theory using Drosophila. In M.  Rose & C.  Finch (Eds.), Genetics and evolution of aging (pp. 130–144). Springer. Stearns, S. (1992). The evolution of life histories. Princeton University Press. Wheeler, H. E., & Kim, S. K. (2011). Genetics and genomics of human ageing. Philosophical Transactions Royal Society London B Biological Science, 366(1561), 43–50. Williams, G. (1957). Pleiotropy, natural-selection, and the evolution of senescence. Evolution, 11, 398–411.

CHAPTER 10

Epistemology of Death (2): Experiments, Tests and Mechanisms

As I indicated in the last chapter, a lot of the evidence regarding the phenomena of death and senescence is produced through experiments. Classically, these experiments have been of two sorts: laboratory manipulations, such as restraining food for a given lineage of model organisms, and applying selection to a target species in a monitored ecological community.1 More recently, genomics has come into the game, and now, much of our knowledge of senescence comes from a fine-grained experimental investigation of the role of several key genes. I will explore these two areas of experimentation in the first section. Then I will turn to the processes hypothesized by the major competing accounts regarding death and senescence, and will question how these hypotheses can be tested, in a relation with the evidence we can gather. This will cast a light on certain major epistemic difficulties regarding the theory of death, as well as suggesting a pluralistic sense that will be described at the end of this chapter.

1  Granted, some studies mostly monitor the natural effects of selection and compare groups: the boundary between applying and monitoring selection is not always easy to define, since monitoring efforts may often involve phases of artificial selection used to test some hypothesis.

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10.1   Producing Evidence About Death: Two Levels of Laboratory Experiments (Dietary Restrictions and Genomics) Besides comparisons, evidence to which theoreticians can point consists of various experiments. I have already extensively discussed Bichat’s experiments and the tradition of the physiology of death; however, in the context of evolutionary biology, there are several sets of experiments. 10.1.1  Diet I distinguish between laboratory experiments and ecological experiments. Among the latter I include all selection experiments, which may sometimes take place in a lab, and which I will discuss in the following section. They are mostly done by evolutionists or in the framework of evolutionary and ecological theories, unlike the former kind of experiments that mostly involve geneticists or developmental or molecular biologists. Among these ones, dietary restriction stems from a venerable tradition illustrated by Pearl’s experiments on rodents. One longstanding finding in many model organisms is that providing slightly less than the required caloric intake per day extends lifespan. Here is a useful summary of this tradition from two decades ago by Richardson and Pahlavani (1994): The dramatic effect of nutrition on the life span of rodents was shown initially by McCay’s laboratory in the 1930’s. They found that both the median and maximum survival of rats were increased significantly when the diet of weanling rats was restricted severely and growth retarded. This phenomenon became known as dietary or calorie restriction, and subsequent studies have demonstrated that the life span of rats could be extended significantly using less severe restriction regimens; e.g., a 30 to 50% restriction of calories generally results in a 20 to 50% increase in life span (mean and maximum survival). At the present time, it is generally accepted that dietary restriction extends the life span of laboratory rodents by retarding the aging process because dietary restriction increases the maximum survival of rodents and alters most physiological and pathological processes that change with increasing age. Therefore, dietary restriction offers gerontologists a unique system for studying the aging process.

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The rationale behind these experiments is that slowing up metabolism may increase lifespan, as if there were a finite expenditure of “energy” allowed to an organism, so that burning this energy more slowly would allow it to live longer (and by “burning,” one means metabolizing food2). An analogous experiment has been done by Michael Klass, who has shown that some ectotherm animals, such as nematodes, live longer at a low temperature than at a high temperature (Klass, 1977). Yet, the “biological mechanism whereby reduced calorie consumption increases the survival of rodents and retards aging is currently unknown,” wrote Richardson and Pahlavani in 1994. Nowadays, part of the explanation lies in the finding that mild stresses trigger protective mechanisms, which foster longevity, and dietary restriction brings about a series of such mild stresses, therefore inducing a pro-longevity pattern. But the discovery that some genes, which function in the regulation of insulin signaling, also impact longevity contributes to our understanding, as I will indicate in the next paragraphs. In her review, Partridge (2010) emphasizes the generality of the effect of dietary restriction (DR) across clades, but wonders whether this phenomenon has been evolutionarily conserved since the emergence of a remote lineage of multicellular organisms, or whether it has been invented several times by evolution.3 Dietary restriction experiments come with a caveat: they are experiments. In the wild, it is very plausible that such diets would decrease the various physical abilities of many animals and therefore impede their life expectancy, as compared to laboratory conditions. As has been often stressed, laboratory animals are special, they are correctly fed, they may evolve adaptations to the laboratory environment, and show more inbreeding than wild strains, all of which may hamper quantitative genetic

2  Most of these experiments intervene on the consumption level and keep the activity level fixed; one could imagine doing it the other way round, but I found no instance of that. 3  “DR extends lifespan not only in rodents but also in a wide range of distantly related organisms, including yeast C. elegans (Klass, 1977) and Drosophila. Indeed, recent work has demonstrated that DR increases lifespan in rhesus monkeys and short-term DR can produce improvements in function in humans. Because the details of the mechanisms by which DR extends lifespan are not fully elucidated for any organism, it is not clear whether this is a case of evolutionary conservation or whether instead there has been evolutionary convergence” (Mair & Dillin, 2008).

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analyses. And they may be fed in a way that is somehow too rich, so that decreasing their calorie intake would finally be beneficial and increase longevity, with no specific mechanism requested. Thus, the assertion that “dietary restriction overall lengthens life” is never warranted. 10.1.2   Experiments and Genomics I nsulin Pathway and daf-2 Another recent set of laboratory experiments focuses on genes. For three decades indeed biologists have been researching the role individual genes may play in aging, and the comparisons I cited above were mildly instructive. More recent molecular genetics experiments constitute another advance in our empirical knowledge of senescence and lifespan, since a genetic pathway regulating aging has been discovered. Here, experiments at the genetic level show that some genes, often considerably evolutionarily conserved, have a positive effect on aging. As Guarente and Kenyon (2000), summarizing a decade of research, wrote: “It is now widely accepted that the ageing process, like most biological processes, is subject to regulation and can be studied using classical genetics. When single genes are changed, animals that should be old stay young. In humans, these mutants would be analogous to a ninety-year-old who looks and feels forty-five.” For two decades, studies in functional genomics on animal models have revealed the significant impact exerted on aging by a gene network involved in the regulation of insulinergic signaling. Cynthia Kenyon, who was a major actor in this research at the University of California in the 1990s, writes about this research on signaling pathways: “At the heart of these pathways are stress and metabolic sensors such as insulin and IGF-1 hormones, TOR kinase and AMP kinase, whose up- or down-regulation can trigger a variety of cell-protective mechanisms that extend lifespan.” (Kenyon, 2011). Figure 10.1 presents a scheme of the activities in these pathways that regulate aging, and I will discuss some of the actors involved. Notice that mTOR, the “mammalian target of rapamycin pathway,” is a metabolic major hub and, besides its involvement in insulin regulation and signaling, hence in glucose assimilation and in nutrition, it is also involved in other major cellular metabolic functions such as cell autophagy, cell growth, and protein translation (not of our concern here).4 Of course, the 4

 In Chap. 7 I will consider extensively a theory in which mTOR plays a major role.

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Fig. 10.1  The intertwining of TOR and insulin pathway in the production of longevity (after Flatt & Partridge, 2018). See text: TOR is a major metabolic hub, and it connects to the insulin signaling pathway; both include genes whose mutant alleles may increase longevity in nematodes

fact that the insulinergic pathway—which is related to glucose regulation—connects to longevity holds a clue to the mystery of dietary restriction as the only known protocol that extends lifespan. This quest for genetic pathways stemmed from the connection of two ideas: genes are understood to be pieces in a vast network of up- and down-regulations which tune gene expression to environmental states; and aging is a “nearly ubiquitous phenomenon” and hence “something so universal seemed to be regulated.” From the viewpoint of the evolution of regulatory genes—a common theme in evolutionary developmental theory and itself a subdiscipline in evolutionary biology which started to flourish at this time (Gilbert, 1991; Bateson, 2017)—the diversity of aging patterns that came out in our findings “could arise rapidly if it were driven

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by changes in regulatory genes, which, like changes in the Hox genes (which, for example, can convert the antennae of flies to legs), could produce large transformations all at once” (Kenyon, 2011, 10). Epistemically, the experimental search for regulating genetic pathways of aging clashed with the common idea that aging could not be regulated because, as emphasized in AP and MA, selection doesn’t act after the reproductive period, and therefore no regulation could be fostered through evolution. Kenyon was a molecular geneticist, and this contrast between the generally received view and hers exposes the more general clash between the evolutionary viewpoint and a molecular geneticist’s one. In order to indicate the generality of these findings, namely, the significance of the insulin pathway and its regulatory genes regarding longevity, I cite a review by Linda Partridge: “an important recent discovery has been that the IIS pathway [insulin/IGF signaling pathway] has an evolutionarily conserved role in determining longevity; mechanisms of ageing therefore are, at least to some extent, “public” or shared. Remarkably, mutations in the single Drosophila insulin receptor and insulin receptor substrate proved to extend lifespan in the fly. Furthermore, mutations in the genes encoding both the insulin and Igf-1 receptor extended lifespan in the mouse. Subsequent work with all three organisms has amply confirmed the evolutionarily conserved role of this signaling pathway.” (Partridge, 2010)

Independently from the glowing prospects of life extension—which are actually very thin, for many reasons (Olshansky, 2010)—those findings are crucial for our understanding of senescence issues, because in addition to the theoretical models of selection or by product selection, which answer the question “why do we age?”, this molecular and genetic knowledge allows us to fine-tune our response to the question “how do we (and all plants and animals) age?” In this context, the object of Kenyon’s study was the nematode Caenorhabditis elegans, a classical model organism. As some species, nematodes are likely to undergo a specific phase of the life cycle occurring when the living conditions are harsh. It is its so-called “Dauer” phase (Fig. 10.2). “Dauer formation is essentially a checkpoint that arrests the growth of developing animals at a specific larval stage (an alternative L3

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Fig. 10.2  Schema of the Dauer phase (after Kenyon, 2011)

stage) if they encounter low food levels or crowding. Dauers are tiny, growth-arrested juveniles that have their own special morphology, do not feed or reproduce, and are quiescent and long-lived. Dauer formation essentially allows the juvenile to outlast harsh environmental conditions before reproducing” (Kenyon, 2011). Many genes condition dauer-­ formation. In some animals the dauer phase affects larva when the temperature is high and then, when low temperatures return, it rejoins the normal life cycle: this is the case for mutants for the daf-2 gene, which appears in the insulin signaling pathway, since it encodes the C. elegans homologue of the human insulin and IGF-1 receptors (Kimura et al., 1997). The experimental work has shown that altering daf genes extends the dauer phase; once back to low temperatures the mutants can reproduce as usual. Actually, these resulting daf-2 mutants appeared to live for a long time in general, even without going through the dauer phase. Hence the role played by the daf-2 gene in triggering the dauer phase allowed some daf-2 mutants to live longer. Further characterization of these long-living nematodes showed that in fact the combination of two genes daf-2 and daf-16 was the key to extending life: the protein DAF 16 expressed by daf-16 extends dauer formation, and standard daf-2 inhibits this, but

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mutant daf-2 alleles let DAF 16 to prolong life. The process can be summarized in the following way: When conditions are favourable during development, wild-type daf-2 inhibits the activity of daf-16, allowing growth to adulthood. Under harsh environmental conditions, daf-2 activity levels fall, allowing daf-16 activity to promote dauer formation. During adulthood, reducing daf-2 activity allows daf-16 to promote longevity. This genetic pathway was inferred from the mutant phenotypes of daf-2 and daf-16. Long-lived adults carrying relatively weak daf-2 mutations do not look like dauers, move actively and can be completely fertile. We now know that these genes act exclusively during adulthood to regulate adult lifespan, whereas they act during development to regulate dauer formation. (Kenyon, 2011)

In their seminal paper Kenyon’s team wrote: “Our findings raise the possibility that the longevity of the dauer is not simply a consequence of its arrested growth but instead results from a regulated lifespan extension mechanism that can be uncoupled from other aspects of dauer formation” (Kenyon et al., 1993). The groundbreaking character of this discovery is emphasized by Flatt and Partridge (2018): “aging in laboratory animals has—initially somewhat surprisingly—turned out to be highly malleable to simple genetic, environmental, and pharmacological interventions,” but the genetic intervention is indeed surprising, because one would expect genes inducing senescence and hence increasing the probability of death to be unable to be selected for. That is why Williams insisted that genes involving senescence are never directly selected. But in contrast with his view, “evolutionarily conserved high-level regulators of phenotypic plasticity have turned out to be able to produce a major rearrangement of physiology and to ameliorate the effects of aging” (ibid.). Kenyon and her lab checked whether this process was relying on taking resources away from reproduction, so that the reproductive output of daf-2 mutants was decreased, as predicted by an evolutionary perspective such as antagonistic pleiotropy (AP, or Disposable Soma Theory (DST), see below), but it wasn’t. However, this finding has been recently challenged: by measuring differently the fitness costs, Jenkins et  al. (2004) have shown that daf-2 mutants (with the daf-2 e1368 mutation), in competition with wild

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strains of daf-2, become extinct in four generations without a regime of constant food. Under nutritional stress—a condition that triggers the formation of the dauer form—there is also a net advantage for the wild strain, suggesting that even though fertility may be unaffected immediately by the mutation, there is a genuine fitness cost, which makes the finding compatible with the AP view. Similarly, with regard to another model organism, Austad and Hoffmann reported that in yeast, while suppressing some genes may similarly extend lifespan, 65% of the strains with extended lifespan lose competition against the wild type.5 “ Longevity Genes” as an Object of Study It would make no sense to synthesize here ongoing research, but I would like to point out that since Kenyon’s studies and classical dietary restriction mechanisms, the mitochondrial electron transport chain has also been shown to regulate aging and lifespan. Thus, “at least three independent mechanisms regulate ageing and lifespan; dietary restriction (DR), the mitochondrial electron transport chain and the insulin/IGF signaling pathway (IIS)” (Dillin & Cohen, 2011, 84) (See Box 10.1). However, some reservations have been raised: after all, the nematode has a dauer formation phase, but many of its ancestors and relatives do not. So homologs of the daf-2 or daf-16 genes may, in other species or clades, have very different causal roles in their genomic networks, and may extend longevity in a much less significant sense. Many longevity or aging genes have been identified and scrutinized through laboratory experiments, or more recently through supervised machine learning applied to extant studies and data banks. To date, about 2205 genes with effects on longevity have been found in the main model organisms, mouse, yeast, nematodes, and drosophila—among them, 1031

5  Another gene in the insulin/IGF pathway experimentally gave rise to a 65% extension in the longevity of the worm compared to the wild type; however, in this case too, when food is not regularly available it loses competition against the wild type. The fact that scarce food is rather the norm in nature, unlike in laboratory environments, indicates that the lifespan-expanding mutant has a lesser fitness than the wild type in natural conditions. This also warns us against direct inferences about biological significance from lab experiments.

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Box 10.1  IGF1 and Aging: Highlights from Research

The fact that IGF-1 (Insuline-Like Growth factor) regulates nutrition (because of insulin) indicates another explanatory approach to the mystery of dietary restriction as a lifespan enhancer. This led to carrying out additional experiments on mice in order to examine the role of the IGF-1 pathway in regulating aging, which yielded positive results.6 A key driver of lifespan appears to be the IGF-1 receptors involved in the insulin signaling pathway. Analogous discoveries of longevity genes multiplied in the 2000s (e.g. Selman & Withers, 2011). For instance, “‘little’ mice with a mutation of the receptor for GH-releasing hormone (GHRH), a hypothalamic peptide that stimulates GH release, also live longer than their normal siblings but the increase in their longevity apparently depends on the interaction of their genetic background with fat content in the diet,” writes Andretizj Bartke, a researcher whose work focuses on insulin regulation (Bartke, 2011). These studies explained Silberberg’s finding (Silberberg, 1972) that some Snell dwarf mice homologous for recessive mutations affecting pituitary development were long-lived. Actually, in mice, mutations to the GH pathways trigger more reliable life extension than actions onto IGF-1, because “GH is not essential for foetal or early postnatal development and therefore animals completely lacking GH or GH receptors are viable and available for the study” (ibid.). Since insulin is crucial in regulating glucose, and therefore in nutrition, the involvement of the insulin pathway in aging helps us to understand several facts about longevity—for instance, the crucial role played by diet in general and nutrition in longevity receives some explanation here (Finch & Tanzi, 1997). The insulin signaling pathway and its regulating lifespan property are still under investigation; a promising idea is that its induction might protect the organism from proteo-toxicity, because the reduction in the manifestation of the insulin/IGF signaling pathway (IIS) in worms points to aggregative, disease-linked proteins (Dillin & Cohen, 2011, 95). (continued) 6  “The physiological role of IGF-1 in the control of mammalian ageing is strongly supported by the recent demonstration of a significant extension of longevity in mice by deletion of pregnancy-associated plasma protein A (PAPP-A). PAPP-A is a protease that degrades IGF-1 binding proteins, in particular IGFBP4 (which is widely expressed), and as a result increases local levels of bioavailable (free, i.e. not complexed with IGF-BPs) IGF-1” (Bartke, 2011).

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Box 10.1  (continued)

But a major target of study, however, is the mTOR (Harrison et al., 2009). Overall, the three pathways here considered are known to be involved in basic developmental organismic regulations: “GH and IGF-1 promote proliferation and survival of cells and mTOR regulates translation, protein synthesis and cell size” (Bartke 2011). However, the mTOR-relevant finding is that the “pharmacological suppression of mTOR or genetic deletion of one of its targets extends longevity in mice” (ibid). mTOR is currently a privileged target of aging studies: the journal Frontiers just opened a call for papers on the topic “The Critical Role of mTOR in Longevity and Aging Regulation.”7 The editors, Daniela Bakula, Dudley Lamming, and Riekelt Houtkooper, present the issue by writing that “the critical involvement of mTOR in aging was first revealed in invertebrate organisms, where depletion of mTOR components was shown to extend lifespan. Subsequent research has shown that pharmacological inhibition of mTOR using the drug rapamycin consistently increases lifespan in diverse organisms, and also promotes healthspan in mice. mTOR signaling regulates critical cellular processes including autophagy, cell growth, and protein translation, and targeting these pathways also controls aging and health in model organisms. In flies, nematodes and yeast indeed rapamycin induces autophagy, which controls and eliminate more deleterious cells and extends lifespan, while in mice other mechanisms such as, possibly, inhibition of the ribosomal S6 protein kinase implicated in protein synthesis. Overall, mTOR signaling has emerged as a central node for longevity and aging regulation, and drugs to target mTOR as a means to treat age-related diseases are being actively explored by both industry and academia.” This last sentence of course emphasizes that longevity genes are not only of major theoretical interest, but also, very practically, are at the center of the more or less speculative research on life extension. (continued)

7  https://www.frontiersin.org/research-topics/17589/the-critical-role-of-mtor-inlongevity-and-aging-regulation. For a recent review of mTOR in metabolism see Simcox and Lamming (2022).

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Box 10.1  (continued)

What is now clear through those numerous studies is that the insulin pathway and its effect on lifespan are pervasive across many lineages, even though the genes may have different names in different families, so that daf-2 is the name in nematodes but not in mice, and more generally “in C. elegans, the insulin-like receptor (INR) is called DAF-2, PI3K is called AGE-1, and FOXO is called DAF-16; in humans, the FOXO homolog associated with longevity is called FOXO3A.” Yet all are homologs (i.e. genes are identical by descent), hence the difference in names will disappear. Thus a complex picture of the intertwining between those pathways eventually emerged: “In response to environmental inputs (e.g., nutrients) the IIS and/or TOR branches of the network become activated; reduced input (inhibition) of the signaling network leads to the activation of downstream transcription factors (such as the forkhead box O transcription factor FoxO) that regulate the expression of hundreds of target genes, many of which are involved in longevity assurance (but which also affect other life-history traits, including growth, size, and reproduction). Many of the genetically homologous components of this network have been experimentally shown to affect lifespan in C. elegans, Drosophila, and mouse; evidence from GWAS shows that genetic polymorphisms in some of these components are also associated with exceptional longevity in humans” (Flatt & Partridge, 2018; Fig.  10.1). Complexity here is the rule: insulin signaling reduction improves longevity, but, on the other hand, classically, it may produce diabetes (Cohen & Dillin, 2008), which complicates the prospects of fighting aging by intervening on insulin signaling. Writing the most recent review on the topic of IIS and aging, Regan et  al. (2020) emphasize that the relation between IIS and dietary restriction is still controversial, and hypothesize that “IIS and related pathways, such as mTOR, evolved to detect and integrate a wide range of environmental cues (not just diet) that are predictive of important selective pressures in the wild,” hence that it plays a major role in phenotypic plasticity, but requires mixed, ecological, evolutionary, and cell biology approaches to be understood.

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are anti-longevity genes like daf-2, whose silencing increases lifespan.8 Daf-2 silencing extends life up to 200%, which is almost the maximum: there is a 300% lifespan increase in yeast when abrogating via gene silencing the function Sch9, a protein kinase that regulates signal transduction activity and cell cycle. But most of the genes with a high effect on longevity were found in nematodes, a finding that presents many singular features.9 Yet, in the wild, studies of Drosophila have hardly found any active aging genes, which once again raises questions about the gap between lab studies and field studies regarding the evolution of aging and death. And beside this contrast between laboratory and natural populations, the search for aging genes is different in the research on animal models that I just considered and in medicine. Nonetheless, all these findings generated a huge appeal in the 1990s (e.g. review by Finch & Tanzi, 1997) and 2000s, in part because they understandably opened the door to possible life-extension interventions, which is a potential source of many fantasies, but also of obvious profits for biotech companies. As an example, Guarente and Kenyon (2000) ended their review paper by stating: “we begin to think of ageing as a disease that can be cured, or at least postponed. This paradigm shift is due largely to the analysis of single-gene mutations that influence ageing in model organisms. The field of ageing is beginning to explode, because so many are so excited about the prospect of searching for—and finding—the causes of ageing, and maybe even the fountain of youth itself.” (Not insignificantly, Cynthia Kenyon herself is today vice-president of the Google-­owned startup Calico, which avowedly develops anti-aging protocols…) The frequency of publications in major journals, however, decreased in the last decade, indicating that the enthusiasm had started to fade, possibly due to the many caveats that had accumulated. While many signaling and metabolic pathways have been ascribed a role in the aging process and many genes within them were targeted by this research, when the research assessed the robustness of the findings, it appeared that the homologs of the genes spotted in the first model organisms (nematode, drosophila) 8  A data base lists all the genes with an effect on longevity, together with the relevant literature (https://genomics.senescence.info) 9  For instance, C. elegans has a special sexuality, with higher rates of autofecondation than average, which strongly decreases the effective size of the population and therefore increases genetic drift (Philippe Jarne, personal communication).

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were not so effective on life extension. After all, conditions that surround daf-2 or daf-16 in nematodes include the existence of a dauer phase, which is already something rare, so one should not expect to see the impressive effects of those genes reoccurring in many other species. 10.1.3   Experiments on Stem Cells and the Role of Intestinal Epithelium Stem cells are totipotent and may engage in various possible cell fates, unlike differentiated cells whose fate has been determined in embryogenesis. Stem cells are operational through embryogenesis, and work to create cell types; then they exist in all tissues and ensure the rejuvenation and repair of tissues. Since the “homeostatic maintenance and regenerative potential of tissues wane with age” (Rossi et al., 2008), substantial research therefore started to find out what was correlative to longevity. Stem cells play a role in aging processes through various complex mechanisms that have been investigated for two decades now.10 They may also age and lose their rejuvenating ability, especially because of the accumulation of the deleterious effects of reactive oxygen species. Yet some of the changes, “especially those that are epigenomic or proteomic,” are reversible (Liu & Rando, 2011). For instance, caloric restriction has been shown to trigger autophagy—namely, a process by which defective cells are eliminated— and therefore revive the proliferation of stem cells, thus extending lifespan (Biteau et  al., 2010). This also contributes to explaining the positive effects of dietary restriction on longevity.11 Avenues of research opened up in the 2000s relied on findings, which had originated in the 1990s (e.g. Holt & Luk, 1990 on rats), that stem cells in the intestine were involved in possible life extension. Due to the frequent challenges by nutrient transport, the intestinal epithelium hosts a large amount of stem cells, which are critically required for its conservation. Hence, aging processes always often involve the degeneration of 10  “The degree to which aging is attributable to stem cell dysfunction or instead reflects a more systemic degeneration of tissues and organs will likely differ substantially between different tissues and their resident stem cells. Nonetheless, mounting evidence points to stem cells as an important contributing factor to at least some of the pathophysiological attributes of aging in a number of different tissues” (Rossi et al., 2008). 11  When mTOR is inhibited by rapamycin, it may also trigger such autophagy, which also sheds light on the link between calorie restriction (that inhibits mTOR), and longevity, via this reviving of stem cells.

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these stem cells, and sometimes even start with it. Research on mice and drosophila has shown that “changes in metabolic signaling during ageing are a major driver for the loss of stem cell plasticity and epithelial homeostasis, ultimately affecting the resilience of an organism and limiting its lifespan” (Funk et  al., 2020). These facts led researchers to investigate how such intestinal stem cells (ISC) could play a role in aging. Normally, repair is ensured by stem cells, so the deterioration of the aging function should be related to these cells; and decreasing repair efficiency is indeed a hallmark of senescence, as we know (and as the DST, addressed below, emphasized). Since then, many research papers have explored the aging process in ISC; thus intestinal epithelium in the last decade became the target of the community of researchers working on aging.12 To sum up, “gene expression profiling revealed aging-associated changes in mRNAs associated with cell cycle, oxidative stress and apoptosis specifically in ISC” (Moorefield et al., 2017).13 This research has multiplied since 2010 because obviously the prospects of preserving or extending lifespan by intervening in stem cells are both attractive and not unrealistic. Moreover, they easily connected with another, apparently unrelated research trend, namely, the research on the regulatory role played by intestinal microbiota in many physiological key functions—be they immunological, metabolic, or behavioral (through the so-called gut–brain axis, e.g. Morais et al., 2021). As a consequence, much research has been devoted to the relations between microbiota and aging, focusing on model organisms such as drosophila, mice and rats (Clark et al., 2015).14 For our concerns here, they also indicate something crucial

 For instance, Tran and Greenwood-Van Meerveld (2013).  A review paper considering Drosophila outlines the important role of ISC in aging: “In aging flies, the intestinal epithelium degenerates due to over-proliferation of intestinal stem cells (ISCs) and mis-differentiation of ISC daughter cells, resulting in intestinal dysplasia. (…) Conditions that impair tissue renewal lead to lifespan shortening, whereas genetic manipulations that improve proliferative homeostasis extend lifespan. These include reduced Insulin/IGF or Jun-N-terminal Kinase (JNK) signaling activities, as well as over-expression of stress-protective genes in somatic stem cell lineages. Interestingly, proliferative activity in aging intestinal epithelia correlates with longevity over a range of genotypes, with maximal lifespan when intestinal proliferation is reduced but not completely inhibited.” (Biteau et al., 2010). What is strongly expressed by this paper is the existence of an “optimizing proliferative homeostasis (i.e. limiting dysplasia, but allowing sufficient regeneration),” which allows lifespan extension. 14  See also review in Fana et al. (2018). 12 13

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from an evolutionary viewpoint. The first bilaterians were mainly an intestinal tract and an orifice, and any mechanism for cell regulation, reproduction, and growth in ISC that had been invented at this time has many chances to be evolutionarily conserved, as were other mechanisms and processes involved in cell metabolism; hence the findings about aging processes related to the intestinal tract may show something of the most universal and most original senescence mechanisms. Importantly in the present context, those experiments on nematodes, drosophila, and then mice adopt an inverse approach to that of Bichat’s experimental setting analyzed in the first part of the book: whereas the French experimental physiologist induced death experimentally in order to make visible the circular relationships of conditioning between organs and tissues, molecular geneticists intend to postpone death in order to identify the pathways responsible for senescence and therefore death. This inverse methodology calls for an evolutionary explanation showing why such pathways exist or—if they are evolutionarily conserved and act as constraints—why they originated in the first place. The open question is whether the major evolutionary theories, AP and mutation accumulation (MA), constitute such an explanation. I’ll turn to this issue after having reviewed the last sorts of experiments.

10.2  Selection Experiments on Model Organisms and in the Wild A major, additional advance in the field of the experimental knowledge of senescence and death comes from the diversification of model organisms. As it stands, mice, rodents in general, nematodes, and drosophila have been used as model organisms to answer our questions on aging in labs. Indeed, finding longevity genes in nematodes constituted a breakthrough because they have been proven to be homologous and orthologous (i.e. same function) to mammalian genes, which finally demonstrates a kind of universality in these genes. Yet expanding the range of model organisms increases the chances of capturing the facts of senescence or death that will be characteristic of a large part of the living clades, even though they are not present in one of our favorite model organisms. For instance, in 1994 Reznick highlighted that, since many of these models have a short life, “one possible limitation of the use of short-lived organisms is that they may not be subject to certain time-dependent mechanisms of aging. Some

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molecular/cellular aspects of aging, such as somatic cell DNA mutations, may take decades to develop and may play an important role in the aging process of longer-lived organisms, but may not be important in those with short life cycles” (Reznick, 1994, 99). In addition to model organisms, he studied guppies (poecilia reticulata) in the island of Trinidad for 15 years (in 1994), which constitute a good model organism (see below). But he also advocated crustaceans as an excellent novel model organism: they live in communities which aggregate several species, of various sizes, including the microcrustacea Bosmina longirostris (Cladocera) and Cyclops bicuspidatus (Copepoda). For a study of aging as a feature of life history theory, in a specific environment with particular patterns of risk and predators, those crustacean communities are a perfect model system. “These differences in the structure of microcrustacea communities are the combined consequence of the size preferences of the predators and competition among the different species of prey. In the absence of fish, the larger species are able to outgrow the size classes which are preyed upon by Chaoborus” (Reznick, 1994). Moreover, their size as well as their life histories, which vary across species, ensure they are a good model system to study aging. This approach of choosing model organisms as targets of selection experiments is key to a range of studies developed in the 2000s (including new studies on crustaceans). This leads us to the experiments mostly inspired by evolutionary hypotheses that have been done. As Reznick (1994, 96) writes, besides comparisons between different species in similar environments or similar species in different environments, “directly selecting for lineages that differ in the rate of aging is a powerful tool for developing new systems for studying the evolutionary biology of aging” and therefore for gathering new evidences in support of hypotheses and theories. Epistemologically, the experiments are inspired by the idea of finding the difference-makers at an ecological level: what are the difference-makers for senescence, whether in terms of lifespan or aging rate, in the assumption that the major way ecological differences impinge on senescence is through natural selection (antagonistic pleiotropy) or a lack thereof (mutation accumulation)? Lifespan is, directly or indirectly, explained by natural selection, according to the set of theories I have described. Gavrilov and Gavrilova (2002) noted that even though there are hundreds of competing theories of death and lifespan, all of them may be summarized into two groups, MA (mutation accumulation) and AP (antagonistic pleiotropy), which differ

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according to the way selection explains or causes death, lifespan, and senescence.15 Since natural selection operates in relation to environmental features, possibly by fitting organisms to these features,16 an obvious methodological way to go in order to understand the working of selection is to intervene on those features and check how lifespan and aging rate change. Many such experimental ecological actions have been taken since the formulation of the theoretical framework of the evolutionary biology of death. Those experiments are often of two varieties: (a) selection for longer lifespan—which allows one to see which other characters evolve, and (b) selection for a specific property, in order to see how it can affect lifespan and aging rate, which is then attested by measuring lifespan in evolved organisms. So within category (a) some experiments carry out artificial selection for longevity—that is, experimenters keep the longest-lived animals and have them reproduce, and so on, generation after generation. For example, Zwaan et al. (1995) have established that Drosophila selected for longevity show that a lifespan increase possibly comes from decreased allocation to reproduction at all ages. Another instance of the same kind of experiment is the following: the survival of females selected by age at reproduction has been compared when they are kept either virgin or mated (e.g. Luckinbill et  al., 1988; Partridge & Fowler, 1992). “The aim was to discover if the cost of mating seen in experimental manipulations played a part in producing the greater lifespan of ‘old’ line females. The reasoning was, if mating reduces lifespan, then a reduced mating rate would be expected as a correlated response to selection for increased lifespan, and enforced virginity would then be expected to remove at least some of the survival advantage for ‘old’ line females. All three studies found that virgins lived longer than mated females” (Partridge & Barton, 1994). An example of category (b) experiments occurs when researchers select for late reproducers, and consider what occurs: what about longevity, or early-life reproduction? Selection for late reproduction is actually a 15  The DST that they consider, and that I will present in the next section, may be seen as an instance of AP; this will be justified below. 16  The notion that in principle natural selection is maximizing the fit between organisms and environments is not exactly proven, even though since Fisher’s FTNS many biologists intended to do so (see Birch 2016 for a critique).

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standard way to test claims about reproduction and aging. “Rose and Charlesworth (1980, 1981) demonstrated that selection for increased late-life reproduction resulted in decreased early-life fertility and increased longevity in D. melanogaster (Rose, 1994). Yet even though some instances show negative correlations between early reproduction, late reproduction, and lifespan in some species, no general correlations can be drawn” (Charlesworth, 1993). Other selection experiments on D. melanogaster, however, have been unable to find evidence supporting the existence of a trade-off. Partridge and Fowler (1992), for instance, found “selection for late-life reproduction to result in increased longevity with no associated decrease in early-life fecundity” (ibid). Besides Drosophila, some species of beetles have been the object of experiments. “Bean weevils (Acanthoscelides obtectus) selected for late reproduction lived longer, developed longer and were heavier than beetles selected for early reproduction”. In this species, therefore, it seems that early reproduction is traded off against longevity and late reproduction. More generally, some of these experiments are aiming at uncovering correlations between traits in juveniles and adults in order to assess antagonistic pleiotropy. For instance, about plants, Roach, who ran several plant experiments on aging in the 1990s, declares: Most direct evidence for pleiotropic constraints between different stages of the life cycle is from an experiment with an annual plant Geranium carolinianum. This species is a weedy winter annual found in fields and waste places throughout the United States. In North Carolina; it germinates in October, persists as rosette close to the ground until April, then bolts to 25 cm tall, flowers, and dies. Three distinct life stages can be defined for this species: early juvenile with cotyledons and one leaf, late juvenile rosette, and adult bolted plant. Seeds from maternal half-sib families, from three populations, 15 km apart, were planted in a common garden. Plants were harvested at three times during the growing season, corresponding to the three life stages. At each harvest, the leaf area and dry weight of the plant parts was measured. There were positive phenotypic but negative genetic correlations between early juvenile and adult traits. (Roach, 1994)

Yet in all these experiments using selection, an important difference has to be drawn between populations in the wild and populations in labs and in general domestic settings, or now in genomics, which uses computational in silico analyses. A longstanding idea is that lifespan in the wild is shorter since animals are not protected against predators, and also are not

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regularly fed. As a result, aging would be mostly a process that’s visible in captivity—not to say anything about the fact that tracking aging animals in the wild is not always easy.17 Yet when senescence is eventually measured in the wild, it appears that it is more rapid than in labs, at least in insects (Zajitschek et al., 2020),18 which suggests that it’s even harder to study it in these natural conditions. The consensus indeed, now, is that even though predation kills many individuals in a given species while the populations living in captivity can live longer, senescence is a process that exists in the wild—at least in vertebrates, although insects also seem to display it (Nussey et al., 2013). Selection in labs is simply done by collecting individuals whose trait under focus is above a threshold value. In the wild, the selection would consist in intervening in selection pressures, for instance, by introducing predators. As a consequence, a possible way to conceive of what selection would do in the wild consists in considering populations of the same species living in two distinct environments possibly separated by an absence of gene flow. That is what Austad (1993) did with opossums on Sapelo island, in the key experiment I mentioned in the previous chapters. Insects are an interesting group in this respect. The recent paper by Zajitschek et  al. (2020) states that “accumulating evidence shows that senescence occurs and can impose fitness costs in wild insects such as antler flies, damselflies, dragonflies, butterflies, mosquitoes, and crickets. However, it remains unclear how important senescence is in wild insects, or how patterns of senescence vary among taxa or in response to environmental conditions in the wild. Indeed, some studies have failed to detect senescence in wild insects.” While “senescence is almost universally detected in laboratory studies,” they suggest that “costs could be strongly 17  “Aging manifests itself most clearly under benign environmental conditions in captivity, since in the wild individuals of many species are hard to track throughout life (…), and high rates of age-independent mortality (e.g., due to predators, pathogens, food shortage) can obscure the intrinsic tendency of adult survivorship and fecundity to decline with age” (Flatt & Partridge, 2018). 18  “Very few studies to date have attempted to compare life span and senescence in genetically similar populations under fully natural versus laboratory conditions, but the available evidence suggests that senescence can progress very differently in these contrasting environments. In some cases, senescence appears to progress more rapidly in the wild. For example, Tidière et al. compared life span and actuarial senescence rates in several mammal species in zoos versus natural populations and found that many species (especially those with a faster pace of life) exhibited shorter mean life spans and earlier age at the onset of senescence in the wild than in captivity.”

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environment-dependent or could vary markedly among species or between sexes.” Yet a methodological issue, which I have already stressed, concerns the comparison between lab animals and animals in the wild: while laboratory-­adapted populations are near evolutionary equilibrium, populations in the wild may be more sensitive to genotype–environment interactions, and therefore less phenotypically predictable. Reznick et al. (2006) studied populations of guppies that are either in high predation or in low predation environments; namely, they may have one predator, or several that eat, indifferently, guppies of all ages. The study compares populations but it also introduces predators in sample populations extracted from distinct environments, so it combines comparative and experimental methods. An important result of this paper is that, contrary to expectations from the classical theories we considered, guppies in high predation environments in general live longer. But the key idea in the study consists in considering not only lifespan, but lifespan divided in three periods, pre-reproductive, reproductive, and post-­ reproductive. It appears that what changes, with respect to the predators in environment, is the second period: guppies reproduce earlier and for a longer time, which makes sense because their extrinsic mortality is higher, and by so doing they increase their chances of leaving offspring alive. “High-predation guppy populations have longer total lifespans because they have significantly longer reproductive lifespans (…) The reason that guppies from high-predation localities live longer is solely because they have longer reproductive lifespans.” Figure 10.3 below shows that what indeed varies correlatively to high vs low predation environment is the reproductive period, which is longer in the second case—not the whole lifespan. Reznick et  al. (2006) therefore conclude that since the post-­ reproductive period is not under selection, it varies randomly. Hence differences in lifespan may not be wholly and directly explained by selection.19 They may, however, be correlated with a life-history-relevant property that will be under selection. Reznick, Holmes, and the authors of this study on guppies cite Hendry et  al. (2004), which studied wild salmon. Salmons present the clearest trade-off between survival and reproduction: once they arrive at the breeding period, they stop feeding and give birth, and survive while guarding

19  “The post-reproductive lifespan, which has no impact on fitness, is highly variable and there are no significant differences among treatment groups in this variable.”

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Fig. 10.3  Lifespan (bar) and reproductive (rectangles) periods for guppies in low vs high predation regimes. (After Reznick et al., 2006)

the offspring against arriving females that can reuse the site. “Their life history from that point on is like the flight of a ballistic missile, since all activities are fueled by the reserves that they obtained prior to the cessation of feeding” (Reznick et  al., 2006). However, selection is at work: there is selection for arriving earlier, hence getting the best breeding site in order to accumulate more resources there, and then, among the early arrivals, there will be selection for longer post-reproduction survival, since it maximizes the chances the offspring will develop safely. In this case, the post-reproductive period is also affected by natural selection. The lesson is that ecological factors play a huge role in determining whether the two periods, reproductive and post-reproductive, will be selected for, and what their ratio will be, even though such observational study, based on a small set of individuals, would require stronger corroboration. To sum up, we have a wealth of data gathered by these experiments, both ecological and genetic, as well as physiological. Each may support one or several theories about aging rate, senescence, lifespan, or death. As Gavrilov and Gavrilova (2002) highlighted, many theories exist and are

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still inconclusive, and besides their being subsumed under general families of theories, none has the credentials to explain all of the aging-related phenomena in all clades. The varieties of evidence and the diversity of patterns about senescence, as they begin to appear, may call for a specific pluralism regarding an evolutionary explanation of death. In the last part of this chapter, I will consider in more detail the mechanisms proposed to explain those patterns and facts, the tests we have to assess how plausible they are, and the major epistemic issues these assessments face, which will allow me to specify the kind of pluralism that may be required here.

10.3  Mechanisms, Evolutionary Processes, Causes: The Evidential Structure of Evolutionary Theories of Death and Senescence and Their Epistemic Issues Evolutionary theories of death address several distinct explananda; and they rely on several sources of data, which may either stimulate the forging of some hypotheses, or back up others. Population geneticist Brian Charlesworth in 1993 wrote: “the theory implies that senescence is an evolutionary response to the fact that the sensitivity of Darwinian fitness to changes in survival or fecundity declines with age, at a rate that is determined by the ecology of the population” (1993, 19). Notice the phrase “evolutionary response”: senescence and (intrinsic) death are explained as a response, namely, as a way biological systems produced this phenomenon in reaction to a set of conditions, through a specific feedback; this feedback is evolutionary, in that it took place along evolutionary time, through generations of populations of the same and then other species. We know since Darwin that evolution goes with natural selection but as Fisher reminded in the opening of his Genetical Theory of Natural Selection (1930), “Natural selection is not evolution.” The answer to the question of senescence and death is evolutionary, it is related to selection but it is not direct selection—namely, selection for aging and dying. Thus, here, neither senescence nor death is selected for, at least directly. The alternative between antagonistic pleiotropy (AP) and mutation accumulation (MA) accounts, explicated above, stands between a by-product of selection and an effect of an absence of selection; neither is direct selection.

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10.3.1   Death and Irrationality: A Parallel These distinctions are crucial because, as noted above, they indicate how evolutionary theorizing may explain features that prima facie seem detrimental to individuals and therefore opposed to natural selection, which works—as Darwin already stated—in favor of individuals. He famously wrote that “metaphorically (…) natural selection is daily and hourly scrutinizing, throughout the world, every variation, even the slightest; rejecting that which is bad, preserving and adding up all that is good; silently and insensibly working, whenever and wherever opportunity offers, at the improvement of each organic being in relation to its organic and inorganic conditions of life” (Darwin 1859, 84, my emphasis). But before addressing the question of the experiments deciding between these theories, and the structure of the evolutionary theory of death, I would like to draw a parallel with another biological feature and its explanations. Animals are decision makers, at least if one uses a notion of decision that’s not too wedded to cognitive dispositions. Faced with several distinct opportunities, animals indeed do one thing and not others: they choose to eat or not eat a banana they were offered, as in many experiences in animal psychology; they forage into this or that patch; they court or do not court another female, etc. A longstanding view in behavioral ecology states that decision making modules in animals have been designed by natural selection. Since natural selection proceeds by selecting alleles or trait values that maximize fitness, and for this reason are better than others at coping with environmental demands, natural selection seems to work as an optimizing process. As a result, when decision making modules evolve under natural selection, they should make the organism into a system that is itself oriented toward maximizing fitness—namely, choosing the option that has the highest fitness when faced with an alternative. Biologists and economists have noticed that this property makes natural selection akin to a rational process since rationality, at least according to economists or rational choice theorists, is a process that maximizes utility when choosing a basket of goods from within a set of baskets. Replacing fitness by utility or taking fitness as utility shows that natural selection behaves as rationality. Maynard Smith in his groundbreaking book Evolutionary Game Theory (1982) wrote that “in biology, Darwinian fitness provides a natural and genuinely one-dimensional scale [instead of utility as a maximized multi-dimensional magnitude in economics]. (…)

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In seeking the solution of a game, the concept of human rationality is replaced by that of evolutionary stability” (reached by natural selection). On this basis, organisms as decision makers are expected to behave somehow rationally (in this very narrow, economist’s sense of rationality20). Now, an economic agent being rational implies that she satisfies a few clauses, including the transitivity of preferences: if she prefers A to B and B to C, she should then prefer A to C. It’s easy to see that this clause is a necessary requirement for being able to predict the behavior of the agent, and its consistency between distinct choices—coherence and consistency being legitimately taken as hallmarks of rationality. However, in some cases, animals seem to choose in a way that violates the transitivity of preferences. For instance, “the wild rufous hummingbird … eats from flowers that have different kinds of variance in nectar. Hurly and Oseen examined whether it chooses flowers with no variance in nectar, medium variance, or high variance. When choosing between two flowers with different nectars, hummingbirds consistently prefer the flower with the lower level of variance. Yet, when choosing among three flowers with different nectars, hummingbirds prefer the flower with the intermediate level of variance” (Huneman & Martens, 2017), rather than the flower with the overall lower level of variance as the rationality hypothesis predicts. So, the question arises: is it possible that natural selection shapes irrational decision-makers? This question is quite symmetrical to the issue of senescence, or, as I noted in Chap. 8 (Part II), to the question of sexual reproduction: how could natural selection select for something that seems nonadaptive, or detrimental to the organism? It turns out that, as we demonstrated with Johannes Martens following several papers pursuing the same direction (Huneman & Martens, 2017), the cases advocated by those who think natural selection selects for irrationality can be, once redescribed, cases of by-products of selection. Hence there is no selection for irrationality—in the same way as there is no selection for senescence or death. But in the case of death, the additional question is whether by-product selection accounts for it, or whether the lack of selection (namely, selection for something else) should be the best explanation: in other words, it’s the alternative between MA and AP.

20  On the distinction between economic, biological and psychological rationality see Kacelnik, 2006.

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10.3.2   Diversity of Aging Mechanisms and the Rival Evolutionary Hypotheses Rose and Finch (1994) indicated that the physiological theory of aging, focusing more and more on molecular mechanisms such as the longevity genes involved in dauer phases of nematodes, is not exactly on a par with the evolutionary genetics of senescence. The question the physiological theoretician asks is: “is aging determined wholly or largely by a single mechanism, such as free-radical damage? Or are there some distinct physiological mechanisms that give rise to progressive deterioration in the older organism?” As I indicated above, evidence exists that a single mechanism, such as “wear and tear” as Ricklefs called it, is not enough to account for the varieties of senescence. Aging involves processes that are not only the pure negative effect of physiological working, such as the emission of free radicals deleterious to the proper functioning of healthy cells, or the accumulation of somatic mutations, but features that have evolved (“an evolutionary response,” as Charlesworth says), which are the focus of the evolutionary geneticist. These features may in turn give rise to distinct physiological mechanisms. In any case, as we have seen, aging is not absolutely universal across the living world: it assumes that at least some distinction between generations is realized, which is a condition larger than mere sexual reproduction, but narrower than the entirety of the class of living beings.21 Yet in the club of mortal creatures, the diversity of aging is now well documented, as has been presented above. However, for organisms that follow a given aging pattern (these are mostly in four groups, as we have seen (above Chap. 9), which are large groups), it is plausible that the evolved features are the same, and therefore define a common mechanism. As Rose and Finch wrote, there may be a “universal mechanism of aging, or perhaps one as wide as a phylum, which would delimit survival and reproduction in the chronology of adult life in essentially all species within the taxon” (1994, 10). The commonality of mechanisms involved in reproduction in a 21  “Generally, senescence should only evolve in those organisms that have a distinction between parents and offspring, even when reproduction occurs asexually; for example, if the parent reproduces by simple splitting or dividing symmetrically into identical offspring, then there is no clear delineation of parents versus offspring, selection cannot distinguish between them since there is no age structure, and aging is not expected to evolve” (Flatt & Partridge, 2018, 7). However, the matter is a bit more complicated, as I explain in Chap. 12 about unicellulars.

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phylum points towards such a hypothesis: senescence too should involve common mechanisms. It would be all the more plausible if AP turns out to be the best explanation of aging, because the antagonism stands between reproduction at an early age and late survival, and the genes involved in reproduction are much more common. Conversely, if MA is a better account of senescence-related facts, then the “genetics of aging are as phylogenetically diverse as most other features of life, if not more so”— since the deleterious mutations accumulated in a phylum are not necessarily related to what happened in other taxa. To conclude provisionally, it appears that the two families of theories, AP and MA, involve very different options regarding fundamental issues in aging and death. I will therefore now ask how they are tested, and what can be said about their relations. 10.3.3   Testing Competing Hypotheses: The Conundrum While there is no conclusive theory based on extant evidence, three decades of evolutionary theorizing about aging and death accompanied by model testing has resulted in more knowledge than was available to Medawar or Williams. However, in the present work, the point is less about the state of the art, and more about how the knowledge of death and aging is possible in principle and what are the norms of hypothesis testing and model-building in this domain. I will first consider how major theories are put to a test, based on the wealth of evidence we have (the studies I examined above), what are the issues faced by these tests, and how they respectively fare. I will then discuss another theory, one that remains close to the AP view, namely, the Disposable soma theory developed by Thomas Kirkwood in the 1970s and 1980s.22 To begin with, let us consider a current assessment of the two views, MA and AP. Flatt and Partridge (2018, 3) write: A large body of experiments, mainly in the fruit fly Drosophila melanogaster, but also other organisms, supports the AP and MA mechanisms (…). In particular, trade-offs between lifespan and fecundity (or other fitness components) consistent with AP have been found in artificial selection or 22  Although this is a crucial, somehow alternative theoretical option, I postponed its discussion for the sake of simplicity. Of course, my overall examination of the epistemology of theories of death will take it into account.

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“experimental evolution” experiments performed on outbred laboratory stocks, in analyses of mutants and transgenes, and in studies of naturally segregating polymorphisms. MA is also well supported, mainly by quantitative genetic studies (…). In humans, data from medical genetics and genome-wide association studies (GWAS) indicate that both mechanisms might play a role in explaining late-onset diseases and trade-offs between lifespan and fitness-related traits […]. MA is supported by a large number of dominant mutations with late age of onset, and by a recent quantitative genetic analysis of a human historical population.

As one can see, no overwhelming evidence points to either of the two conceptions as being the most accurate. Since researchers started to put these conceptions to the test, confronting them with the lines of evidence that I surveyed in the previous section, no obvious candidate for explaining the death-related explananda trumps all the other candidate explanations. And of course, it’s plausible that both processes, AP and MA, are playing a role at the same time, but perhaps not regarding the same explananda. Let us examine the differences between these two competing views. The MA account explains death and lifespan by appealing to selection, albeit indirectly and somehow negatively, namely, by considering that the strength of selection steeply decreases or vanishes after the reproductive period. By contrast, AP accounts appeal to selection in order to explain lifespan and the very fact of death. Thus, the alternative here stands between an (indirectly) adaptationist and a non-selectionist (or neutral) explanation of these explananda. From the basic viewpoint of hypothesistesting methodologies, the question therefore consists in finding what each of these accounts would predict regarding the available evidence. Signatures of neutral or selectionist processes are definable. If lifespan or senescence or rate of aging is selected, even indirectly, it should induce several patterns of genetic variance, which may differ from what is expected from a neutral dynamics. As we already saw, more variety in aging mechanisms should prima facie be expected under the MA account than under the AP account, because selection in the latter case will mold aging mechanisms into reproductive mechanisms, since the same genes are at stake in both cases—while under MA, no specific constraint limits the variety of genes involved in aging, as it is a mutational load (Rose & Finch, 1994). In theoretical models, Charlesworth and Hughes (CH) in the 1990s elaborated in detail what these differences in variance should be; differential

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inbreeding depression23 especially is expected in the case of MA, since alleles that have deleterious effects are expressed late in life, and therefore the negative effects of inbreeding are increasingly salient with the aging of the population. They paved the way for quantitative genetics analyses that in the last period would use theoretical tools made for a fine-grained scrutinizing of genetic variance, such as QTL analyses24 in order to test evolutionary accounts of death. “CH suggested that, under MA, additive variance, dominance variance, homozygote variance and inbreeding depression (ID) should all increase with age. By contrast, working with the assumption that AP loci are overdominant (i.e. that they contribute to segregating genetic variation by heterozygote advantage), CH argue that, under AP, only additive variance is expected to increase with age” (Moorad & Promislow, 2009). Thus, the signature of MA vs AP concerns the way the components of phenotypic variance increase with age. Robins and Connelly (2014) clearly explain it in this way: “an additional prediction of MA is an age-dependent increase in inbreeding depression and genetic variance of fitness traits. Since these measures are proportional to equilibrium allele frequencies, they are similarly expected to increase with age under MA due to a declining strength of selection.” So what about real life? Actually, some signatures of MA have been detected in experimental work on Drosophila, as summarized by Robins and Connelly (2014). These findings on Drosophila echo a study by Houle and colleagues (1992) who “constructed about 200 lines of Drosophila that had recessive mutations accumulating on the second chromosome. There was an overwhelming positive correlation among fitness components in this study, so that mutations that decreased early fecundity also tended to decrease late fecundity, and viability as well”(Clark, 1994). Escobar et al. (2008) have studied senescence in the snail Physica acuta, which was one of the first tests of evolutionary theories of senescence with animals taken from the wild and not raised in laboratories. They took advantage of the particular reproductive mode of snails—which can both self-fertilize and outcross—and compared self-crossed and outcrossed

23  Inbreeding depression is the reduced survival and fertility of offspring of related individuals. It is often caused by the fact that many deleterious recessive mutations are present in the population, and the inbreeding increases the deleterious phenotype being expressed. 24  Quantitative Trait Loci intends to single out on the genome loci that are related to variance in a quantitative trait; it’s a highly used method in quantitative genetics.

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populations in order to look at genetic variance. They monitored especially the change in inbreeding depression over time, because MA predicts a clear increase in inbreeding depression. (However, they note that in theory AP could, under some conditions, lead to the same increase in inbreeding depression, though this has not been empirically documented.) In addition, their quantitative genetics analysis does not show any negative correlation between early and late fitness traits, and positive correlation at close ages, which is what is expected from MA hypothesis, since no condition is put on the fitness value of the early expression of genes. Finally, the additional finding that interbreeding between populations can alleviate senescence is established in the study, and this is another predictable consequence of MA. On the other hand, the essence of AP involves a specific kind of correlation between early and late period of life in terms of mortality and fertility. “In effect, we can ask whether an increase in mortality over evolutionary time is associated with an increase in early reproductive effort or a decrease in late reproductive effort. Under antagonistic pleiotropy, we see reproductive senescence as constrained or even counteracted by changes in mortality. Under mutation accumulation, reproductive senescence should be concordant with but causally independent of changes in mortality rates” (Promislow & Tatar, 1994, 50). For this reason, much of the testing effort focused on early or late-period reproduction, and selection experiments that I mentioned attempted to intervene on these variables. These experiments are a clear way of testing these correlations expected under the AP hypothesis: “selection for late-life fitness is expected to result in decreased early-life fitness and vice versa” (Robins & Connelly, 2014). Rose and Charlesworth (1980) elaborated one of the first studies testing the evolutionary hypotheses, by intervening in the reproduction timing of a population of Drosophiles. The experience “was contrived so that the effects of selection for late reproduction could be detected at any age.” As a result, increases in late reproductive output were associated with decreases in early reproductive output, lowered overall reproduction, and increased longevity. They concluded that here is a “genetic variability in female life history components of Drosophila of the sort postulated by Williams’s pleiotropy theory of senescence” (Rose & Charlesworth, 1980, 142). This corroborates AP; yet the authors add the caveat that “it does not necessarily follow from this that senescence in all

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species is due to such pleiotropy.” And clearly, the several patterns of aging we have seen across various clades may call for other explanatory hypotheses; inversely among the several explananda related to aging and death—lifespan, patterns of aging, speed and shape of senescence—these tests merely show that some explanation is given by AP for some of these features in some clades. They leave room for other explanations regarding the other questions. Yet the most recent efforts on investigating senescence in the wild— especially in vertebrates, because it is methodologically less difficult—have documented the early-life/late-life trade-offs expected from the AP account. Surveying 26 studies on vertebrates, Lemaître et al. (2015) found that “more than three-quarters (21 out of 26 studies) of the studies provided support for the expected trade-off.” As an example “in both free-­ living jackdaws (Corvus monedula) and red deer (Cervus elaphus), individuals with the highest reproductive effort during early adulthood senesced the fastest in terms of actuarial and reproductive performance, respectively.” Actually, the wealth of selection experiments and comparisons conducted in the 1980s and 1990s tended to set the record in favor of antagonistic pleiotropy-oriented accounts. However, the weight of evidence is not so easy to establish, as we realized later on. Especially, as Ricklefs (1998) summarizes, “few plausible candidates for antagonistically pleiotropic genes have been recognized, and the physiological mechanisms connecting opposing early and late effects on fitness are not well characterized.” This puzzle raises general considerations about what evolutionary explanations should be. Philosophers and biologists alike attempted to characterizing what distinguishes mere speculation—or what Gould and Lewontin (1979) famously labelled as “just-so stories”—from genuine evolutionary explanations (Endler, 1986; Brandon, 1990, for instance). Showing that some phenotype is the most adaptive, or that the pattern of genetic variance represents a signature of some evolutionary force such as selection or drift, or realizes the pattern proper to a mutation-selection balance, is not enough to explain a phenomenon. Ecological, phylogenetic, and genetic knowledge should be provided, which will complement this demonstration and transform the plausibility of an explanation into a robust likelihood. In effect, before having shown that the environment is such that natural selection was actually supervening on a set of specific

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environmental demands that genuinely produce the adaptive value demonstrated in our models, and that there are indeed genes likely to account for the heritability of the evolutionary process we modeled, the purported explanation is still a “how-possibly explanation” (Brandon, 1990) and does not tell us how and why actually things happened. This is why, in the case of the evolution of senescence and death, tying the sophisticated selectionist models such as the various modes of the AP hypothesis to some knowledge of the genetic makeup of the process would constitute a good corroboration of the attempted explanation, and why, inversely, accumulating signatures of AP does not settle the debates. So, how to properly conceive of the articulation between evolutionary theories and the molecular genetics of senescence and death? I reviewed above some of the findings of the recent genomics of aging: many longevity genes have been documented, like genes involved in TOR pathway or IGF signaling, and even though it is a subject of debate in many cases they are indeed effects that have a cost in fertility. However, this is not singling out the AP genes required in Williams’s account and its refinements. In a reference publication in 1994—which was republishing a special issue of Genetica that had come out shortly before—Rose and Finch described the dual character of theorizing on aging: “On one face, the molecular genetics of aging often makes discoveries in which the biochemical effect is more apparent than the functional significance. On the other face, the population genetics of aging has difficulties with mechanistic content, such that its theories and their tests are often put forward in a manner that resists biological interpretation” (Rose & Finch, 1994, 5). Almost three decades later, this statement does not sound wholly outdated. The longevity genes are explored in laboratories—hundreds of them are investigated in yeats, drosophila, mice, and, above all, nematodes. While they might support AP hypotheses, they are present in conditions that are very distinct from natural populations. On the other hand, tests in natural populations require quantitative genetics, which looks for negative correlations between early life and late life. The two approaches do not match in practice. The testing of negative correlations surely contributes to corroborating AP, but it does not point to some of the supposed longevity genes, because the quantitative genetics models do not give us access to underlying genes. Inversely, because of their being tested in the very special conditions of laboratories, the putative longevity genes may not support, in nature, the negative correlations that indicate AP as a rationale for

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senescence.25 So even though evolutionary theories of aging and death involve genes, like any evolutionary theory since the Modern Synthesis, they are still not directly connected to molecular findings on aging. Thus, what appears striking regarding theories of aging and death is an epistemic gap between the overarching families of umbrella theories (AP, MA), under which given theories and models can be ranged, and the content of these theories themselves, which cannot be logically and straightforwardly derived from such umbrella theories. For example, a major umbrella theory, antagonistic pleiotropy, if corroborated, would require the existence of antagonistic pleiotropic genes, but on the other hand, many “longevity” genes such as daf 2 have been found, but often with no conclusive proof that they are indeed the antagonistic pleiotropic genes requested by AP as an umbrella theory. In the following I’ll consider in more detail the corroboration protocols of hypotheses and models in this context and their issues. 10.3.4  Undecidability? In effect, quantitative genetics (Charlesworth, 1993) is generally used to detect genetic correlations between a same trait at different ages: if AP is the true explanation, negative correlations are expected, while positive correlations could happen in the case of MA. But there is an a priori mathematical reason that makes these tests difficult to carry out: as explained by Charlesworth (1993), there should exist, in any population, such negative correlations between traits, because, thanks to Fisher’s theorem, the additive genetic variance in fitness in a population is nullified by selection when the population reaches the equilibrium, so that any positive fitness benefit on a trait related to a gene should be correlated by a negative effect on another trait. Since these negative correlations are expected in principle, finding negative correlations between life history traits early and later in life should not by itself be evidence for AP accounts. On the other hand, it is mathematically demonstrated that “some pairs of traits in a multivariate system must show non-negative genetic covariances in an equilibrium population” (Charlesworth, 1993); therefore, positive correlations 25  As Rose et al. (2007) indicated, they may not be the genes involved in AP: “The spectrum of ‘longevity mutants’ that have been created are not necessarily targeting the loci that have shaped the evolution of life-history characters among the species in which these mutants are obtained” (2007, 1271).

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between life history traits are to be expected. For this reason, even though negative correlation or positive ones are established in a population between life history traits at distinct moments, no easy conclusion can be derived. Even worse, considered in detail, the trade-offs that experiments can demonstrate may not be enough to prove antagonistic pleiotropy. In a nutshell, genes involved in the trade-off may be not pleiotropic, and, therefore, trade-offs would not be manifested by negative correlations between reproduction and early-life fitness. This has recently been experimentally tested by Khazaeli and Curtsinger, using recombinant inbred lines of D. melanogaster. Recombinant genomes were created from parental lines selected for longevity via late reproduction and unselected controls. Since pleiotropic effects are unaffected by recombination, this experimental method allowed the pleiotropic nature of the genes underlying the trade-off between longevity and reproduction to be tested. If AP genes significantly mediate the trade-­ off, a negative correlation between early- and late-life fitness traits is expected in both parental and recombinant lines. If, however, the trade-off is dominated by non-pleiotropic genes, recombination is expected to create new phenotypes that exhibit a positive correlation between the early- and late-life fitness traits that were negatively correlated in parental lines. Khazaeli and Curtsinger found flies in the recombinant inbred lines that demonstrated both long lifespan and high early-life fecundity. (Robins & Connelly, 2014)

This means that these newly inbred flies show positive, and not negative, correlations between early- and late-life fitness and therefore that AP is not the explanation for the trade-offs. The absence of a clear conclusion on the explanatory roles of MA and AP is reinforced by the fact that, even though they are opposed as neutral and indirectly adaptationist hypotheses and therefore should prima facie correspond to two mutually exclusive possible worlds, so that evidence cannot eventually be ambiguous, many of the predictions made by each of these accounts, if realized, would not definitively exclude the other account. For instance Robins and Connelly (2014) write: Quantitative genetic experiments measuring age-specific fecundity in populations of Drosophila melanogaster have found significant age-dependent increases in inbreeding depression, as well as additive and dominance genetic variances, as predicted under MA (Charlesworth & Hughes, 1996). These

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results, while initially thought to uniquely distinguish the role of MA, have also been suggested to be consistent with AP, confounding study conclusions (Moorad & Promislow, 2009).

More generally, while selection experiments and quantitative genetics analyses of genetic variance in natural populations have detected in many species or populations patterns that are proper to some of the hypothesized processes, advances in theoretical work have proven that many expected patterns from one account are in fact not incompatible with the other account. For instance, while AP involves specific patterns of genetic variation, as we have seen, it does not wholly preclude a pattern where there is a high degree of genetic variation on aging because there is a polymorphism on AP lifespan-related genes, which results in a large variance of deleterious alleles at a late age, a pattern similar to what MA would produce. In their challenging paper Moorad and Promislow (2009) indeed argued that a very natural method of partitioning age classes in order to identify patterns of genetic variance, which has been massively used to test AP, is indeed not likely to produce facts that would discriminate between AP and MA. And Rose et al. (2007) in their paper assessing the fruitfulness of the Hamilton (1966) framework are quite skeptical regarding experimental genetics in general as a test for AP for MA. From a very general viewpoint, differentially assessing AP about lifespan and death exemplifies the many issues raised by testing adaptationist hypotheses. Even without referring to the famous criticism of adaptationism by Gould and Lewontin (1979)26, AP and MA are distinct processes, for sure, among which only the former is a selectionist process; but this difference does not imply that all their consequences are distinct. What theoretical work on lifespan and senescence has shown in the last two decades is that the consequences of AP may not exclude the fact that, in addition to the AP longevity genes, some other genes have deleterious effects in late age and are maintained. Moreover, because they are different genes, negative correlations detected in genes involved in AP explanations will not concern these genes, and will not indicate anything about them. “In the case of the general trade-off between reproduction and longevity, results that are found to be consistent with AP/DST do not

26  See Huneman (2017) for my reconstruction and analysis of this critique in the current scientific context.

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simultaneously discredit the role of MA in the evolution of senescence and vice versa” (Robins & Connelly, 2014). A simple objection here would be the following: in the absence of massive evidence, why not use a parsimony criterium, and decide in favor of a non-selective process (MA) because it does not appeal to an additional process besides variation and heritability (since selection is less parsimonious because it also needs fitness differences, besides variation and heritability)? Yet, even if such reasoning often holds, it presupposes that everything else is equal between the two hypotheses, so that the genetic makeup occurring in the MA case is not much more complex than the one existing in the AP case—and this cannot be taken for granted. I do not want to suggest that the no selection account, in this case, is not parsimonious, but rather that in this case picking up the most parsimonious hypothesis is difficult because no definition of parsimony exists that would satisfy all conditions. 10.3.5   Epistemic Opacity of Death and Senescence  pistemic Opacity, Senescence, Causal Contributions, and the FTNS E Those two evolutionary accounts of death and lifespan are not in general incompatible; both explain a great deal. As we have seen, both connect mortality and lifespan to extrinsic mortality. If mammals, bats aside, on average have shorter lives than birds, a reason is that birds, because they fly, avoid predators more easily than mammals. Therefore, the highest mortality of mammals results from their higher exposure to predators and then extrinsic mortality, through one of the two processes hypothesized by evolutionists. Yet, while a key advance made by Medawar and Williams (and Hamilton formalizing them, see above) is this new tie between extrinsic and intrinsic mortality via selection, establishing this tie as a universal empirical fact is not as simple as it may seem. A basic difficulty, that I have not considered until now, consists in distinguishing between deaths causally due to senescence—which by definition increase with age—and deaths that are accidental but may not be independent from age. The evolutionary argument, in a nutshell, states: “Let’s assume that organisms do not intrinsically age, so that their chances of dying at any one instant do not increase with time; then natural selection acting on genetic variants would progressively generate organisms whose chances of intrinsic death increase over time.” But any complete

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empirical corroboration of the account assumes that one can distinguish between death by accident—which ex hypothesis has the same chance of occurring at any time—and “intrinsic” death (related to senescence, which is an evolutionary result). However, extrinsic mortality is not, statistically at least, independent of age, even if no physiological deterioration (as is entailed by senescence) occurs. Imagine a developing organism: by growing, it becomes more visible and therefore may attract more predators, and hence its chances of dying increase even if its physiological functioning doesn’t get altered. More concretely, as suggested by Abrams (1993), older organisms have more chances of getting caught by predators, since they run more slowly. Should their deaths be counted as extrinsic mortality (since they are due to predators, and so are somewhat accidental) or intrinsic mortality (since their senescence caused a physiological state which increased the chances of being eaten)? This complicates the possibility of testing how the increase in risk of mortality would act on natural selection for lifespan and senescence. It opens the way for a double counting problem, namely, counting predation risk as both the cause of aging and its effect. Predation is not the only thing affected by this double counting issue: obviously, senescence as an increase in chances of death includes chances of getting a fatal disease. This increased susceptibility to diseases is often seen as a sign of aging, because all the processes involved in maintenance become less reliable. However, once aging has evolved, it is clear that older people will get ill—whatever the gravity of the disease—more easily: this increased likelihood, in turn, is due to aging, hence aging somehow causes the disease. The question of disentangling diseases of aging from a putative “aging per se” actually divides researchers in gerontology,27 due to the causality issue I just raised. On the other hand, actually senescing organisms not only see their chances of death increasing because of their mutational load (in the case of MA) or their late deleterious genetic effects (if AP is correct), but they also have more chances of not dying accidentally, because they are more experienced, or just less fragile because of being larger. In this case, the effect of aging can go in two opposite directions, and it might be difficult to detect senescence by looking at the figures of death and survival. As Ricklefs (1998) pointed out, as long as this second, negative effect of

 I will expand on this in Chap. 12 .

27

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aging on extrinsic deaths is “not incorporated into mathematical models of aging, the value of m0 [a parameter estimating extrinsic death] is not strictly an estimate of extrinsic mortality.” This has a predictable consequence: since the latter, negative effect compensates for some time the effect of senescence as physiological deterioration, “adult mortality should exhibit a broad valley over which mortality rate is low and does not change rapidly with respect to age” (Ricklefs, 1998).28 This expectation matches reality, since senescence in most patterns of life history starts to be visible sometime after the peak of reproduction ability. Epistemologically speaking, one faces here a classical issue proper to explanations involving natural selection. In the 2000s, Denis Walsh, André Ariew, Mohan Matthen, and Tim Lewens elaborated an interpretation of natural selection that they called “statisticalist,” according to which natural selection is not a cause or a force acting on gene pools or populations, but rather a statistical effect of myriads of ecological interactions among which one allele, one genotype, or one trait exerts a differential mass effect that can be detected after aggregating the reproductive outputs of all organisms.29 Notwithstanding the heated debates that involved philosophers of biology in the following years, some of them defending the classical, “causalist” position—namely, selection is a cause and/or a force (e.g. Millstein, 2006; Bouchard & Rosenberg, 2004; Shapiro & Sober, 2007)— and others looking for reconciliation (e.g. Huneman, 2012; Huneman, 2013a; Desmond, 2018), one of the major arguments of the statisticalists consisted in pointing out that the force of selection cannot be computed as an addition of selective pressures, in the same way that Newtonian mechanics computes the abstract total force exerted on a body as a vectorial addition of different forces. In our present case, a similar situation arises. If there is an effect of aging on fitness—namely, survival and reproduction—it is made up of various effects: senescence itself, including physiological deterioration, but also the negative effect on chances of external death, and possibly at some point the increased effect of size, hence growth, hence aging, on the chances of being predated, etc. The conclusion is that, exactly as in the argument developed by the statisticalists about selective pressures in general, no general procedure of adding the 28  This prediction may not hold with some causal patterns of extrinsic mortality, for instance, when a specific class of the population is overwhelmingly affected. See below on these complications. 29  Walsh et al., 2017 for a primer; Walsh et al., 2002.

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fitness effects of aging can be applied to each individual in order to determine how aging affects them. Lewens (2010) concluded from this debate that there is a kind of undecidability about natural selection explanations: when one wants to consider the various selective pressures in the environment together, and the force of selection as an agent responsible for the changes of the gene frequencies in the gene pool, computing the latter renders the former indistinguishable, while knowing the selective forces does not unequivocally allow us to compute the force of selection. In our case things are similar: even though the effects of aging on the chances of an individual dying either from physiological deterioration or from mortality avoidance can be assessed and even measured in an age class, there is no proper way to infer a general strength of selection as a cause of lifespan in function of extrinsic mortality. More precisely, when one intends to check in the wild whether extrinsic mortality is a selective pressure that induces a specific lifespan, it is difficult to disentangle the senescence-enhancing effects of extrinsic mortality— namely, the fact that lifespan is negatively correlated to this extrinsic mortality—and the other effects, which turn selection in a direction opposite to decreasing lifespan. The reason once again is that the combination of these effects is not likely to obey an addition or combination rule as in a parallelogram of forces. They combine differently for each individual and at each age, and therefore, any general addition of such effects in the population risks being poorly informative, because there are not enough constraints on the methodology of this addition that would be capable of making all computations converging to the same result. Hence, a principled epistemic issue here arises when one wants to assess the very general claim made by evolutionary accounts regarding lifespan and senescence. While the argument ascribing senescence either to indirect selection or to the decreasing force of selection is sound, deriving the precise contribution of these selection effects to the value of lifespan is impossible. On this basis, detailed assessments of the two rival evolutionary views here mentioned, AP and MA, should be expected to lead to major indeterminacies. In the same vein, theoretical investigations of the models of aging and lifespan proposed by evolutionary theorists were conducted in the 1990s at a very high level of generality, and showed that the general evolutionary claim—“extrinsic mortality drives an evolution of decreased lifespan and fastens senescence”—should come with some caveats. Abrams (1993) proposed the clearest analysis of the model in this sense. In substance, Abrams

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argues that in some specific conditions, extrinsic mortality will enhance rather than prevent longer intrinsic lifespan and reproductive output, once either MA or AP is assumed. The models he elaborated took into account the fact that the relation between extrinsic mortality and senescence is not, as we saw, unidirectional (Box 10.2). This lack of unidirectionality, combined with the above-mentioned double counting problem, therefore hampers the prospects of having a general and mathematically univocal theory of aging and death. Box 10.2  Abrams’ Demonstration of the Many Predictions of Antagonistic Pleiotropy

Abrams (1993) started with the formulation given by Hamilton (1966) of the fitness cost of a change at a given age affecting continuous mortality or fertility, such as changes regarding senescence. This formulation expresses the partial derivative of the rate of increase r of the population over mortality or fertility.     r /  s  x      j  x  exp rj l  j m j     j exp rj l  j m j  ,   j  x 1  j 1 

In these formulations, l (j) expresses the survival from birth to age j, and m (j) is fertility at age j. In turn, l(j) can be expressed as a compound of the intrinsic mortality in age class (j, j+1) and an extrinsic mortality term, which takes into account all mortality that is independent of age and condition—a term compound of the probability of surviving extrinsic mortality at age j.30 It is therefore possible to (continued)

30  The formulation is so expressed by Abrams: “To determine the effect of altered extrinsic mortality on fitness costs, it is necessary that survivorship from birth to age x, l(x), be decomposed into ‘intrinsic’ and ‘extrinsic’ components. l(x) may be written as l(x) = lj(x)Px, where lj(x), the ‘intrinsic’ survival to age x, denotes the survival probability to age x in the absence of extrinsic mortality, and P is the annual (or period) probability of surviving extrinsic causes of mortality. The ‘intrinsic survival,’ lj(x), is affected by all of the variables that determine the rate of senescence, and may also be affected by population density. li(x) is the product of the intrinsic period survival probabilities, pi(j), from j = 0 to j = x−1, where pi(j) is the probability of surviving non-extrinsic mortality factors from age j to j + 1” (1993, 880).

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Box 10.2  (continued)

compute the effect of an increase in extrinsic mortality on the cost of a senescent change affecting mortality, or on its benefits to fertility or mortality. It turns out that in the case of density-dependent population growth, the effects of increasing extrinsic mortality theoretically point in two possible directions. Let us emphasize first that the effect of density-dependence is in an inverse relation between density and fertility: the less dense the population is, the more fertile its individuals can be. Three situations are then possible. “(1) Increased density decreases the period of survivorship of each age class by the same proportion. (2) Increased density reduces the survival of individuals during the pre-reproductive period or reduces the fertility of all age classes by the same proportion, or both. (3) Increased density differentially decreases the survival of the oldest individuals.” In the first one, “extrinsic mortality should have no effect on the rate of senescence, because any change in extrinsic survivorship will be exactly compensated for by an inverse change in the density-­ dependent component of survivorship.” So if extrinsic mortality increases, density decreases, which increases the period of survivorship, and eventually this compensates for the effect of increased extrinsic mortality: senescence thus does not change. But the two other cases of density-dependence are more challenging. In the second case indeed, the consequences of MA and of AP will be theoretically different. MA entails that a decrease in survival in the face of extrinsic mortality will involve higher costs of senescence, hence a more rapid senescence, as is classically understood. However, depending on whether the survival early in life happens before or after the reproductive period, once one increases extrinsic mortality, there is a benefit to fertility that can outweigh the cost of the changes, and therefore the model predicts a longer lifespan and a slower senescence contrary to what is classically taught. The demonstration is mathematical but Abrams provides a hypothetical example of such a case: “predators select the most senescent individuals, [hence] increased predator density will often select for decreased rates of (continued)

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Box 10.2  (continued)

senescence in the prey, at the same time that it causes increased prey mortality. Scenarios like this could result in a negative relationship between the mortality rate and the rate of senescence.”31 Another more recent model due to Shokhirev and Johnson using unbiased optimization strategy explored the evolution of short or long lifespans in the presence of extrinsic mortality. They “found that increased extrinsic mortality can lead to the evolution of longer lifespan if maturation costs are high and if energy is available in excess, while shorter lifespans evolve when mating costs are low and food is relatively scarce.” This result instantiates the theoretical result by Abrams, according to which extrinsic mortality in general may not drive shorter lifespan, if an additional condition is postulated in terms of the differential effects of density-dependence upon age classes. In line with Abrams, they identify maturation costs and available energy as the causes of the patterns of density dependence. In a word, as they summarize it, “the high extrinsic mortality can free up additional resources, which can lead to additional investment in repair by the remaining individuals in a population” (Johnson et al., 2019). Abrams summarizes his theoretical findings in these terms: 1. If survivorships at all ages are equally sensitive to density, changing extrinsic mortality will not affect the evolution of senescence. 2. If density affects fertilities of all ages approximately equally (or affects survival of prereproductives), increased extrinsic mortality will favor more rapid senescence. The effect on the rate of senescence is likely to be especially large under the pleiotropy theory when the benefit of senescence is higher fertility early in life.

 One should notice that a theoretical analysis by simulation has also shown that MA cannot be responsible for much of the evolution of senescence (Danko et al., 2012) The models therefore establish that much of the determination of optimal age at maturity has been due to adaptive processes. But once again the assumptions of a model may not be always empirically met. 31

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3. If density mainly affects survival or fertility late in life, increased extrinsic mortality will favor a decrease in the rate of senescence. 4. If density affects both fertility and juvenile survival and the survival of older individuals, increased extrinsic mortality may favor increases in the rate of senescence at some ages and decreases at other ages. AP connects highest extrinsic mortality to faster senescence or/and shorter lifespan, via natural selection. However, what this theoretical work has shown is the hidden premise in such reasoning: one always assumes that density-dependence equally affects all age classes. For instance, if (as I have just imagined) mature individuals are less affected by density-dependence effects because they are much better than individuals of other age classes at escaping predators, then we may face cases where the inverse relation between extrinsic mortality and lifespan eventually obtains, even though we had postulated antagonistic pleiotropy. But there is still a major concern here: the reason why density affects one age class more than another when it comes to extrinsic mortality may be a result of senescence itself. In this case, we face an issue of epistemic opacity, since the conditions for thinking aging as the effect of AP are the result of antagonistic pleiotropy. These models epistemologically achieve something parallel to the successive revisions of Fisher’s Fundamental Theorem of Natural Selection. As we saw, this “theorem” argues that the change in mean fitness of the population due to selection equals the additive genetic variance in the population, entailing the crucial fact that natural selection always brings out a positive change in fitness. However, even though this is the first strong mathematical attempt to relate natural selection with maximization, optimization, and therefore what biologists have steadily called “design” (Gardner, 2017), its validity is not as general as it seemed to Fisher. First, many population geneticists have pointed out that situations of frequency-dependent selection may show cases where natural selection leads populations to lower fitness (Moran, 1964). While some answered these critiques by making more precise the fact that the theorem does not state anything about actual change in populations but characterizes only the change due to natural selection, other critiques have pointed out that even such a restrained and abstract formulation does not capture all that theoretically may happen in hypothetical populations. It is always possible that what Fisher called “deterioration of the environment,” which also contributes to the overall intergenerational change in population fitness, overcomes the change in mean fitness due to selection, which is the object

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of the theorem. But Birch (2017) and Okasha (2018) recently concurred in showing that even in the absence of any constraints on variation—studied in the famous Gould and Lewontin (1979) spandrels paper—natural selection may be unable to maximize the fitness change it induces. Selection itself can contribute to the deterioration of the environment, as in the cases of frequency-dependence, blurring the distinction Fisher wanted to make between “deterioration of the environment” and “changes of fitness due to selection”. For this reason, Okasha (2018) argued that the validity of the theorem requires the possibility of decoupling changes in the environment directly due to natural selection (which, for example, distorts the genetic background of each allele) from changes indirectly due to natural selection. And because this requirement is not universally satisfied, the theorem cannot be taken as a general analytic result. What Abrams (1993) showed about evolutionary theories of death is that the claim that extrinsic mortality generates death and conditions lifespan is not completely universal but requires some conditions, at least regarding density-dependent growth of populations, even though empirically it is very often verified. Inversely, attesting such dependence between extrinsic mortality variation and lifespan can be used as a test for discerning the age structure of density-dependence in a population. Recent readings of the FTNS deflate its status as an analytic truth but show that it can be used as a tool to foster empirical inquiry; the same is therefore valid for the general claim of evolutionary approaches to death, namely, the theoretical claim to mathematical truth has been deflated but it remains a major guide for empirical research. In this vein, Annette Baudisch (2005, 2008) explored the conditions for the realization of the pleiotropy trade-off between early and late life as described by Williams. She has shown that “in systems where size or fecundity increase through adulthood, the onset of senescence can be substantially or perhaps even indefinitely delayed.” When it is infinitely delayed, one gets a pattern of “constancy” in mortality chances, which is one of the three general patterns of aging that, as we have seen, have been identified in research about senescence in nature. To this extent, Abrams (1993) provided a kind of generalization of AP: by conditioning upon distinct patterns of extrinsic mortality, one is able to account for the four different general patterns of senescence encountered, by pointing out the conditions for the realization of pleiotropy trade-offs (see Box 10.3).

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Box 10.3  Challenging Antagonistic Pleiotropy: The Current Debate

However, Abrams’ modeling investigation triggered an important theoretical discussion of antagonistic pleiotropy, which is still ongoing. The idea that researchers developed is that mortality affecting different classes of the population—age-classes in Abrams’ cases, or other kinds of classes, labelled “conditions” in the case of Chen and Maklakov (2012) or Williams and Day (2003)—changes the predictions regarding the effect of extrinsic mortality on selection differences between age classes, and then on senescence. Charlesworth (1993), after Hamilton (1966), already had focused on the ageclass structure of population while considering senescence in his 1980 book (and papers in the 1970s). But, in the wake of Abrams (1993), a strong case against Williams’s connection between mortality and lifespan is the latest 2019–2020 papers by Moorad and Promislow Moorad et al. (2020a, 2020b). Building on Williams and Day (2003) and Abrams (1993), they generalize the case against G.C. Williams’s hypothesis. According to them Williams failed to see that increasing extrinsic mortality (when this is age-­ independent mortality) also decreases population growth rate. But this increases selection at a late age, because the “expected fitness payoff” realized by those who reach a late age becomes higher. More selection at a late age means that the late-age fitness-hampering effects of antagonistic genes are then counterselected by natural selection (effect a). This effect goes exactly in the inverse direction of the classically postulated selection for pleiotropic antagonistic genes (effect b). In the end, it compensates for the selection for these genes (a compensates b), and the AP hypothesis cannot predict anything regarding senescence or lifespan. More information about the distribution of targets of extrinsic mortality should be given in order to predict which component of this compound force of selection—a or b—will overcome the other. Note that this reasoning parallels a crucial step in the elaboration of the theory of social evolution. As already noted, a pillar of this theory is the notion of kin selection: selection favors traits or alleles that increase the chances that these alleles, be they offspring of the focal individual or offspring of genetically related individuals, will be (continued)

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Box 10.3  (continued)

represented in the next generation. However, Taylor (1992) realized that this kin selection is theoretically compensated by another force, namely, kin competition. For instance, trees are supposed to evolve traits that, even if they are costly for themselves, increase the chances that related trees will pass on genes to the next generations. However, in this case, these traits will increase the competition between the focal individual and its kin, and this fuels a selective pressure against these traits: think of the size of the leaves which cast some shade around, while the offspring of a tree often develop from seeds that fell around its trunk. Hence, theoretically, we have two forces, kin selection and kin competition, that nullify each other. Determining what will evolve needs the details of the intensity of kin selection and kin competition. In the reasoning proposed by Moorad et  al., the fine-­ grained decomposition of extrinsic mortality plays the crucial role by determining in which direction the compound of selective pressures a/b will go. That is why they emphasize the “conceptual issue of what exactly defines extrinsic mortality,” because this, in turn decides whether such mortality is random or targets some classes rather than others (which, in turn, measures the magnitude of effect (a) of mortality upon growth rates). Analyses by Moorad et  al., like those of Abrams, prolongate Hamilton’s reformulation of Williams’s hypothesis. As we saw, Hamilton proposed a mathematical model of the intensity of selection over the course of life. The variable that defines fitness is the Malthusian parameter r used by Fisher, which derives from an equation linking the probability of survival at age x, and the birth rate of mothers of age x. Abrams, like Moorad et al. used this r to define the selection gradient over ages, and to confirm or reject Williams’s hypothesis that selection declines with age. In their perspective, one can show that an increase in age-independent mortality has no effect on the selection gradient. Thus, using Hamilton’s generalization falsifies the hypothesis that in general extrinsic mortality drives senescence—even though in some cases it’s predicted by the theory. But the expected generality initially desired by Williams is lacking. (In the same sense, see also Wensink et al., 2017.) (continued)

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Box 10.3  (continued)

However, this view is contested by other authors, such as Da Silva—who was targeted by Moorad et  al.—who claimed that “reports of the death of extrinsic mortality moulding senescence have been greatly exaggerated,” because AP, as he formulated it, does not predict that the rate of senescence is slowed by higher extrinsic mortality, except in those very rare cases where this increase of mortality affects specific condition-classes. Dańko et  al. (2012) argued that when density dependence does not act uniformly on age (which is true of the cases in which Abrams (1993) diagnosed the failure of Williams’s hypothesis), the proper measure of fitness is not r but the expected offspring lifetime production, measured at negligible densities. This measure relies on the notion of evolutionary stable strategy (Maynard Smith, 1982), a concept elaborated in behavioral ecology and intended to define which strategies will dominate the population when all strategies have consequences that depend upon what others are doing (which is labelled “strategic interactions”). This gets quite technical, because “evolutionary stable strategies” in turn are devised in the context of “replicator dynamics.” The take-home message here is that when one adopts such a measure of fitness, then Williams’ expectation about extrinsic mortality increasing the rate of senescence will be validated in most ecological contexts. Philosophically, a consequence is that the controversy between supporters and critics of AP has to refer to a very general contest between two approaches to evolution and modeling, namely, replicator dynamics vs Fisherian fitness/Malthusian parameter (hence classical quantitative dynamics). This chapter is not intended to settle this controversy. I simply wish to highlight the fact that deciding about the proper theoretical framework for addressing senescence and death finally engages the divide and the difference between the most general formulations of evolutionary theory. Yet even though Moorad et  al. are right about the flaws in Williams’ model, this does not contradict my point here, which is that epistemically, the question about death starts from extrinsic mortality—either because AP or (continued)

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Box 10.3  (continued)

MA is explanatory, or because in the most general versions (such as those designed by Abrams (1993) or Danko et al. (2012)), one has to check whether the conditions under which AP entails a positive relation between extrinsic mortality increase and rate of senescence are still holding. Another critique was recently issued by Mitteldorf (2019), who argues that pleiotropy cannot be taken as the original state of affairs. Some genes are pleiotropic and others are not when it comes to aging; and some longevity genes seem to present mutations that, as emphasized here, extend lifespan without harming the prospects of reproduction, thereby contradicting AP’s key prediction. Mitteldorf instead suggests that “antagonistic pleiotropy is not a precondition imposed on evolution, but an evolved adaptation in its own right.” Being committed to the idea that senescence evolved because of group selection, as an adaptation for the benefit of the group, AP has been selected as a defense against individual selection, which should favor mutants that live longer: it superimposes a cost in terms of offspring on these mutants and therefore preserves senescence, which is adaptive for the group. Mitteldorf coauthored the paper with Longo and Skulachev (Longo et al., 2005) on what they call “altruistic aging,” which is considered in Chap. 13. Its alternative view of AP therefore presupposes this account, which I see as a more sophisticated version of the group-benefit account of death, albeit an eventually inconclusive one.  rovisory Epistemological Conclusions P Evolutionary accounts of death are corroborated in many ways; however not only do none emerge as the explanation of senescence and death, but it appears that there is often no way to decide between them. Either parsimony should favor MA, but we need conditions for parsimony; or AP entails negative correlations that are often found, but most of these correlations can be derived a priori from any evolutionary situation; or, inversely, MA is likely to be at play at the same time. Moreover, theoretical reasons show that AP in general is not likely to hold for any evolutionary population, because not all pattern of extrinsic death can fuel the selection regime hypothesized by AP and favoring

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senescence. Therefore, any AP signature is likely to be ambiguous, because interpreting it assumes some clauses about the density-dependent effects of extrinsic mortality, and these are likely to result from senescence itself, as I emphasized above. Thus, even though the two major accounts of senescence and death appear irrefutable since they take into account the two facts that senescence has evolved and not because of direct selection, assessing these hypotheses in precise cases raises issues of epistemic opacity.

10.4   A Somewhat Alternative Theory: Disposable Soma Theory To sum up, while the evolutionary claim linking extrinsic mortality to death is often theoretically valid, it cannot be absolutely general because it requires several conditions on population growth and age structure, even though those conditions are apparently often met in the empirical world. Yet sometimes they are not, as in Abrams’ latest hypothetical example, among others. Considering work done on birds in the wild, Ricklefs (1998) noted that “the analyses reveal that populations with lower extrinsic mortality suffer a higher proportion of senescent deaths.” This, he emphases, “is inconsistent with genetic models of senescence based on MA and certain types of antagonistic pleiotropy, and it suggests instead that the pattern of senescence balances somatic wear and tear against maintenance and repair mechanisms whose efficacy is under genetic control.” The “somatic wear and tear” includes all mechanisms that have sometimes been seen as an exclusive answer to the question of death, namely, somatic mutations or the effect of free radicals. However, theoretical analyses of models, when they aim at the highest generality as Abrams’ analysis did, can account for the unexpected patterns found in empirical studies. These patterns are not very rare; we encountered an instance of them in Reznick’s paper on guppies (Reznick et al., 2006), which showed that increasing predator risk does not directly decrease lifespan, but targets the duration of the reproductive period, which in turn has varying effects on lifespan. Abrams (1993) had just theorized the framework in which these deviations from Williams’ or Medawar’s predictions are possible. But when Ricklefs mentions the balance between “somatic wear and tear”—namely, the deterioration of physiological systems at all levels due to their continued functioning—and the repair mechanisms, he means that sometimes the intrinsic mortality

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expected by MA theories can be counteracted by repair mechanisms, explaining the gap between evolutionary predictions and data. Yet he also alludes to another important account that I have not considered until now but that is important in the field of evolutionary accounts of death, namely, the Disposable Soma Theory (DST) put forth by Kirkwood in 1977. 10.4.1   Introducing DST The DST relies on the assumption of a trade-off between investment in reproduction and investment in prolongating life. It does not directly expect pleiotropic genes. The theory envisages trade-offs between survival and reproduction at any time, and considers in its widest generality the repair mechanisms that have evolved in cells and organisms. Those mechanisms exist at all levels, and track the defects and failures arising along the functioning of the physiological devices. For instance, there are DNA repair mechanisms, which fix the errors made by DNA polymerases during DNA replication32; there are mechanisms targeting bones, muscles, or the accumulation of wastes in cells. Repair can be an intra-cell process, which may involve actual signaling pathways in order to address somatic mutations, or processes at a multicellular scale, for example, programmed cell death, a topic which is addressed in the next chapter. Those mechanisms are here by necessity, because a living being, in order to be alive has to be robust, that is, capable of achieving its vital functions even if they are disturbed by environmental changes. Kirkwood, however, argued that if these mechanisms are so precise and effective that they indefinitely preserve the organisms against all inner and outer perturbations and attacks, they will appear as a waste of energy, because in a given environment, there is a threshold beyond which the chances that the organisms will still be there are almost zero (eaten by predators, poisoned by parasites, etc.). Hence natural selection is expected to optimize this investment in repair mechanisms, so that no energy is wasted on a task that will certainly prove nonuseful, while the organism could have instead used these resources to reproduce. Therefore, organisms will die as a result of this contrast between repair mechanisms and chances of dying from external mortality. “Genetic control of longevity is effected by setting the many different

32  Note that sex itself may be considered as such a mechanism; see, e.g. Michod and Levin (1988).

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maintenance and repair functions to provide a sufficient but not excessive period of longevity assured” (Kirkwood, 2011). From the viewpoint of evolution, too much investment in complex mechanisms ready to repair organisms at any time will negatively affect reproduction; otherwise, what is invested in maintenance, at an age when in any case it’s highly probable that the organism will have been wiped out by predators or parasites, will cost reproductive chances since a possible investment in offspring earlier would not have been made. Hence, natural selection by definition will favor those organisms that do not invest in predictive maintenance at this time of their existence.33 A strength of this hypothesis is that it covers many mechanisms; therefore, whatever the repair processes involved, the trade-off envisaged by Kirkwood may have evolved. Hence the hypothesis is compatible with the existence of a highly intraspecific variety of death mechanisms as well as a wide intraspecific diversity of such mechanisms. All of the mechanisms involved in aging obey the same scheme, namely, the trade-off between maintenance and reproductive investment. Another argument in favor of DST came from the fact that all tissues seemed to age at the same pace (But for a caveat, see 10.4.3.1.). This is what should be expected if natural selection controls the investment in repair mechanisms and trades them with reproductive investment. In effect, if one organ or one tissue is maintained much more than others, then the overall fitness of the organism decreases because this organ or tissue still can survive when all others are very likely to stop functioning, while the energy invested in its maintenance could better be invested in reproduction. Therefore, the fact that all tissues and organs age simultaneously is exactly what is predicted by DST. Indeed, the term “maintenance” used by the DST theory covers in principle several defenses against various processes that accompany normal physiological functioning. Kirkwood (1997) lists some of these: “oxidative damage, aberrant proteins, defective mitochondria and somatic mutations” 33  “Too low an investment in the prevention or repair of somatic damage is obviously a mistake because then the individual may disintegrate too soon. However, too high an investment in maintenance is also wasteful because there is no advantage in maintaining the soma better than is necessary to survive the expected lifetime in the wild environment in reasonably sound condition, and excess investment in maintenance will reduce the resources available for growth and reproduction. Fitness is therefore maximized at a level of investment in somatic maintenance which is less than would be required for indefinite survival” (1997, 1766).

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(my emphasis). These processes have been investigated separately, and various theories along the lines of Pearl’s idea that the use of cells and tissues generates senescence and death (see above Chap. 8) often see one or all of them as good candidates for being the key aging process. However, according to DST, their efficiency is controlled by repair mechanisms, which are in turn tuned by natural selection. Consider the last process mentioned in the quotation: “somatic mutations are known to be an important contributor to the age-associated development of many kinds of cancers” (ibid.), while “aberrant proteins can arise as the results of errors in synthesis and/or abnormalities of post-translational modification such as misfolding of the peptide chain or abnormal phosphorylation.” Yet it is known that the “selective proteolytic degradation of damaged, erroneous or misfolded molecules” protects from the latter process, and the investment in such a degradation process may be under the control of natural selection. Regarding the first of the mechanisms mentioned in the quotation, Kirkwood cites evidence that “long-lived species have better antioxidant defenses than short-lived species,” which supports his hypothesis. In addition, the mechanism known as programmed cell death34 targets somatic mutations and can get rid of badly mutated cells, while “active genetic controls on DNA synthesis and cell division play a part in the limited cell proliferation of fibroblast cultures that are commonly used as a model of cell ageing.” This suggests that a mechanism controlling these mutations can also be monitored by natural selection. An important epistemic consequence of DST is that it accommodates a fuzzy distinction between the aging process itself—which is invoked when one says that some person died of old age, or that few animals in the wild die of old age—and diseases that in general occur more frequently with aging, or even accidents of life, which the frailty of old organisms makes more probable. If the efficiency of repair mechanisms is controlled by natural selection in a way that fits the senescence curve (and molds it), then diseases occurring more likely after a certain age are not only caused by a pathogen, a parasite, or an immune process gone awry, but also by the lack of strong maintenance mechanisms, which is an evolved feature. As Kirkwood notes, “there is no reason conceptually to separate many of the conditions commonly labelled as age-related ‘diseases’ from the spectrum

 This is considered in Chaps. 12–13.

34

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of states that define ‘normal’ ageing, although in practice, the labelling of a condition as a ‘disease’ may properly reflect the fact that some clinical action is appropriate” (Kirkwood, 1997, 1768). We have seen how an evidence for DST would be the synchronicity of aging in tissues, which ultimately obeys the “unity of purpose” that is characteristic of organisms and that underscores the possibility of asserting an optimization explanation at the level of the organism, as Okasha (2018) recognized. Yet this is not the whole story. At another level, there is some stochasticity in cell fate. Each cell seems to age at a different rate, so that there is some unpredictability in examining one cell in isolation, even though a whole tissue has an aging rate that matches the aging rate of all tissues.35 Indeed, cells have a very different division potential, and the once-favored idea that the different length of telomeres explains this difference has since been refined. In effect, “the rate of telomere shortening is strongly affected by oxidative stress” (Kirkwood, 2011), and “an important source of damage-­inducing reactive oxygen species (also known as ‘free radicals’) is the intracellular population of mitochondria.” Hence, it seems that these two by-products of physiological functioning, oxidative stress and free radicals, which are targeted by known repair mechanisms, play a role in the diversity of cell aging rates in an organism. In the same way DST could account for the lack of telomerase in most somatic cells (i.e. the enzyme that reset telomeres), since maintaining all replicating cells would be an unnecessary expense in most circumstances of life. Consequently, Kirkwood and colleagues show that “the heterogeneity of cell senescence could be explained quite naturally by interactions of multiple mechanisms (oxidative damage, telomere shortening and the stochastic nature of mutation to mitochondrial and nuclear DNA)” (Passos et al., 2007). Hence both the synchronicity of senescence of tissues and the stochastic variety of individual cell fates are explained by the interactions between the major degradation mechanisms and the repair mechanisms controlled by natural selection.36 35  But the tissue presents an average value of aging rate, stemming from all the values of aging rate at individual cells; this last figure is an aggregation and therefore is governed by the central limit theorem, which states that the aggregate value follows a normal distribution. 36  DST has an important degree of corroboration; simulations by Le Cunff and Pakdaman (2014) have shown that by assuming only this theory and a simple model of biological regulatory network, differences in life history trade-offs and population heterogeneity produce distinct mortality curves corresponding to Drosophila, C. elegans, medflies, yeasts, and humans.

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10.4.2   DST: Trading Reproduction vs Repair vs Growth Noticeably, growth has often been overlooked, while it is often a confounding variable in explanations of death. In effect, people forget the effects of large size on survival and reproduction, and ascribe an increase in longevity to a lack of reproduction, when in fact it can be merely induced by large size (large animals live longer). For example, in 1994 Bell complained that “claims for the extreme longevity of some clones in plants which reproduce vegetatively, such as creosote bush and bracken, are commonplace, but beside the point: large organisms are usually long-lived, but the crucial information on the rate of mortality in relation to age is lacking.” (Bell, 1994) Hence, Cichon (1997) extended the DST models by introducing a new variable, growth, thereby modeling the whole life cycle of individuals with reference to three resource-demanding activities: growth, repair, and reproduction. The role of growth in senescence has often been emphasized; for instance, Williams (1957) already noticed the difference between rotifers or warm-blooded vertebrates that almost stop growing after reproductive maturity, while cold-blooded vertebrates keep growing afterwards, which makes them more likely to reproduce (old carps have many more eggs than young ones). He hypothesized that selection against senescence is stronger in the cold-blooded vertebrates because of their increased fertility and therefore they live longer. Growth is supposed to take part in those trade-offs constitutive of the AP account. It’s also the case in DST but here repair enters directly into the picture. When dealing with lifespan-enhancing genes, discovered in the wake of the experiments by Kenyon and colleagues on nematodes’ dauer phase (see Sect. 10.1.2), it appeared that yeast strains in which some alleles have extended lifespan were worse competitors than the shorter-lived wild type, for the reason that their growth was reduced. This suggests that a tradeoff holds here, which involves growth and repair (extending lifespan would strengthen repair at the expense of growth). In Cichon’s model, the optimal allocation between these three activities—repair, growth, and reproduction—given a particular level of extrinsic mortality, will vary with age. Investing in repair for an organism is high early in life and decreases later, which means that growth rate is always affected by the investment in repair. Slow growth and fast growth appear as two strategies that are optimal for distinct combinations of extrinsic mortality and repair efficiency.

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This extension of the DST model allows one to understand that the relation between extrinsic mortality and longevity is not always direct, as was exemplified by the above-cited study of Reznick’s team on guppies (Reznick et al., 2006). “Predicting the maximum lifespan from the extrinsic mortality rate, as the age to which survival is very unlikely, often yields estimations which are by orders of magnitude too large. This means that other factors must be involved” (Cichon, 1997, 1387). These other factors are understood when one realizes that repair mechanisms may be invested in growth as well as in longevity. This is exemplified by trade-offs found in spined stickelbacks, for instance: in the three-spine stickleback (Gasterosteus aculeatus) “fast-growing individuals have shorter longevity, which suggests that energy allocation to body development early in life leads to increased actuarial senescence” (Lemaitre et al., 2020). Of course, growth is not independent of reproduction: “individuals that allocate strongly to reproduction early in life have often grown faster” (ibid.) and therefore suffer higher cellular damage which accelerates senescence; but more generally if vertebrates are larger, this confers an advantage on them in sexual selection, hence in differential reproduction—so they will have a higher growth rate when they reproduce more or earlier. Thus, Cichon recalls that maximum longevity, here, is not a direct effect of selection, since ultimately selection targets the intensity of repair.37 This explains why the correlations within species or clades between maximum longevity and body size are not causal relations, but are the by-­products of a given degree of selection for repair. And selection for repair connects DST to the search for longevity genes examined above (Kenyon, 2010): the dauer alleles in Caenorhabditis elegans could be genes for the repair of somatic damage, and that is why they would play the role of aging genes. 10.4.3   DST and Other Evolutionary Accounts: An Attempt at Characterization  umping AP and DST (and Still the Epistemic Gap) L Since it may make sense of many known aging mechanisms, even the longevity genes, as well as provide other research avenues for testing its core idea, be they modeling resources (as in Cichon’s paper) or experimental 37  “It is important to remember that investment in repair, not the maximum life span, is the target for selection” (Cichon, 1997).

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designs, DST is among the most favored evolutionary hypotheses about death and senescence. I have not considered it until now, because, first, from an epistemic viewpoint it shares many traits with AP, especially the fact that they share some of the same evidence, and, second, it is an explanation that appeals to a selection-shaped trade-off, which instantiates the same logic as antagonistic pleiotropy, even if they don’t function at the same level. Like AP, DST predicts that decreasing the chances of dying from external mortality will increase lifespan by shifting the trade-off towards maintenance, and reciprocally. Hence many tests for AP will also corroborate DST. In particular, any observation or experiment that provides evidence for a positive effect of delayed reproduction on lifespan would support DST as well as constitute an evidence in favor of AP, since it indicates a trade-off that is hypothesized by both theories. But while AP hypothesizes pleiotropic genes involved both in senescence and early reproduction, and that those genes have proved hard to identify, the focus on repair mechanisms chosen by DST makes it more tractable to corroborate, to the extent that those mechanisms can be tracked more easily across clades, populations, or environmental differences. Yet the unpredicted fact of those species living longer in highly risky environments may contradict some AP views, but not all of them, said Ricklefs (1998): DST could accommodate such an unexpected fact. However, given that I mostly considered the nature of explanation here, the major relevant explanatory contrast separates a non-selectionist hypothesis (MA) and an adaptationist hypothesis, and from this viewpoint DST behaves like AP. In addition, and in support of the lumping of these two theories, Williams (1957) too predicted a similar feature about death processes: “senescence should always be a generalized deterioration, and never due largely to changes in a single system.” His reasoning here is that if the pleiotropic genes having deleterious late effects were such that they condition systems not deteriorating at the same pace, natural selection would favor mutants that would make fast-aging systems age more slowly, and slow-aging systems age faster, which in the end would produce some synchronicity. Hence, both trade-off theories—AP and DST—entail the same predictions regarding the synchronized rhythm of senescence. Yet, interesting issue arises precisely here: while DST, like AP as Williams already stated it (see Chap. 8), predicted that aging should happen synchronically in tissues, or in organs, empirical measures that we now develop are not showing such a synchronicity. A recent paper indicates that “the

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magnitude of senescence varies considerably depending upon tissue type, tissue section, and marker used to detect senescence” (Tuttle et al., 2019); this echoes analogous findings by a fine-grained analysis of cells and tissues in animals (e.g. Wang et al., 2009 in mice). This is a major instance of the epistemic gap I described above, between the umbrella theories, and the various theorizing about specific aging processes. Even though most articles would refer to one of these three theory families, so that the models and the finding can be integrated in an evolutionary context, the proper connection between the evolutionary predictions and, here, the various metrics of aging locally in tissues is not warranted.  ultiple Perspectives on the Status of DST M However, since DST is a powerful and attractive hypothesis, I will say more about its specificities. The next chapter will focus on trade-offs and I will also examine some particularities of DST there, but for now the very status of this account is interestingly problematic. DST is classified among the evolutionary explanations of death and lifespan, which seems obvious since it appeals to natural selection. Yet, some authors do not admit that it’s a third evolutionary hypothesis, besides AP and MA, as the standard view presents it (e.g. Gavrilov & Gavrilova, 2002). The two other possibilities are that it is just a version of AP and that it is not an evolutionary hypothesis sensu stricto. Regarding the former option, expressed among many others by Selman et al. (2012)—“Within this theoretical framework [AP], the disposable soma theory was proposed to help explain the evolution of aging” (570)—the argument would go this way: If AP is right, then selection for earlier reproduction will entail a lifespan y shorter than the initial lifespan x; this means that repairing mechanisms ensuring a lifespan x will be less efficient, hence the trade-offs between maintaining and reproducing hypothesized by DST will be realized. In turn, if DST is right, it’s highly probable that the genes underpinning early reproduction have a negative effect on maintenance, since there is an antagonistic trade-off between maintenance and reproduction, so from the genetic viewpoint AP supports senescence. This line of reasoning—especially the second argument—is not absolutely convincing. One can conceive of many mechanisms involved in maintenance, underpinned by many genes, while none of them is involved in the reproductive processes, so that pleiotropy is not realized. Inversely, it is possible that, once a trade-off is experimentally attested between

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early- and late-life fitness, some genes irrelevant to repair are involved and identified. This would corroborate AP rather than DST, in the sense that the principal explanans would be these genes. Thus, even if DST is very close to AP, and they often make the same predictions regarding selection experiments and observations,38 they are not logically equivalent. Neither are they obviously subordinated, even though AP seems at first sight more general than DST. But some authors do not see the subordination in the classical sense that DST would be a form of AP. Lemaître et  al. (2020) write: “The antagonistic pleiotropy can even be seen as a special case of the disposable soma theory, when some alleles code for a given resource allocation to reproduction during early life instead of a resource allocation to maintenance mechanisms later in life, although some alleles with antagonistic effects might involve pathways independent of somatic maintenance.” They consider that the indeterminacy of DST regarding which genes are involved makes this view more encompassing than AP, which requires unraveling some active genes in order to conclusively corroborate it. Whereas AP requires quantitative genetics as a proper corroborating framework, as Charlesworth and other evolutionists later acknowledged, DST is less demanding, since demonstrating trade-offs between early- and late-life fitness values, and more generally between maintenance and reproduction, counts as evidence in its favor. However, another way to conceive of their relations consists in seeing the two accounts as subordinated along the lines of the difference between ultimate and proximate causes set forth by Ernst Mayr in his famous 1961 paper, “Cause and effect in biology,” discussed above. Some indeed see AP as the ultimate explanation, since it’s about genetic evolution, and evolution ultimately is about changing genic frequencies, while DST is about the mechanisms that bring about the phenotypic effects scrutinized by natural selection. DST indeed at first appears as the “physiological corollary” (Lemaitre et al., 2020) of antagonistic pleiotropy, “a physiological explanation of AP” (Maklakov & Chapman, 2019) or, as Monaghan et al. (2008) in their introductory paper assert, “the disposable soma theory can be seen as a phenotypic version of antagonistic pleiotropy; its emphasis is on the agerelated consequences of resource allocation trade-­offs rather than the antagonistic consequences of the expression of a gene at different ages”. 38  “It is generally considered that both antagonistic pleiotropy and disposable soma theories of ageing lead to similar predictions in terms of life-history trade-offs between allocation to reproduction during early life and intensity of ageing in late life” (Lemaitre et al., 2020).

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According to this interpretation, DST would be more mechanistic or proximate, while AP would be more evolutionary.39 Identifying degradation processes that become increasingly powerful as time goes by, as processes whose control by repair or maintenance mechanisms decreases with age, would corroborate DST as a claim about the selective evolution of lifespan, but would also unravel the mechanisms of senescence, and therefore count among the “functional biology,” or biology of proximate mechanisms. Hence, DST has an equivocal status: initially formulated as an evolutionary theory of death and senescence, it has a place among the powerful frameworks for identifying aging mechanisms. This means that asking which of the two theories, DST or AP, is the most general or encompassing is not a sufficient way to settle the question. DST can be seen either as more general or as less general than AP. The problem here is that two epistemological distinctions are conflated and applying each of them produces distinct conclusions. • On the one hand, there is the proximate/ultimate distinction: evolutionary processes imply changing allele frequencies, therefore AP is an evolutionary, ultimate explanation; DST, while overlooking genes, is not so ultimate and instead, with regard to repair mechanisms, may count as a proximate explanation. In this sense, because many proximate mechanisms may produce the same evolutionary trajectory, DST can appear as less general than AP. • On the other hand, evolutionary biology has long seen a contrast between behavioral ecology and population or quantitative genetics. The former explains phenotypic traits as being the results of natural selection unraveling the proper selective pressure likely to have molded them, even though the genetic basis is wholly unknown (only some heritability is assumed); the former points out the processes, at the level of allele dynamics, that drive evolution. Because genes are often unknown for a given trait, the behavioral ecology approach may often assume that an evolutionary process at the level of genetics exists, but is unable to unravel it; Grafen (1984) termed “phenotypic gambit” the methodological attitude that assumes that whatever the behavioral 39  The most recent account given by Gems (2022) sees DST, along these lines, as an “ultimate—proximate theory” while AP is an ultimate theory; the former elucidates the proximate mechanisms hypothesized by the latter. “Disposable soma (DS) theory provides a clear and logical account of how trade-offs could arise between fitness traits at different points in the life history.”

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ecology model is, the (often) unknown allelic frequencies will ultimately support the predictions of the phenotypically expressed behavioral ecology model.40 According to this distinction, DST stands rather on the side of behavioral ecology—as a phenotypic theory—while AP is rather on the side of evolutionary genetics. This is why quantitative genetics is a major avenue of proving it, even though it’s not wholly conclusive (see also Rose et al., 2007). For this reason, DST will appear as more general—in the sense that it does not require genetic details.41

10.5  Conclusion. The Pluralistic Picture 10.5.1   Theory Families, Explanatory Pluralism, and Singular Developments Data, evidence, comparisons, experiments—genetic and ecological: all converge towards an explanatory picture of the evolution of death that I will summarize here. The key word, even if it may be disappointing for those who crave certainty, is pluralism. There are two, or three, major evolutionary theories: mutation accumulation, antagonistic pleiotropy, and, as possibly complementary to the latter, DST. It seems implausible that one of them fully explains death, the diversity of lifespans, and the phenomenon of senescence or its varieties (see Box 10.4 on mechanisms). On the one hand, these theories constitute a very powerful accounting framework for the phenomena of senescence and death; one or more of them explain many of the patterns and data examined in Chap. 9. More precisely, they constitute umbrella theories for more specific hypotheses: for instance, AP can be specified into hypotheses about specific genes that are pleiotropic and antagonistic—for instance, as genes for quickly reaching a developmental stage at the cost of being frailer later on. The same is the case with MA or even DST: the latter may, for example, be cashed out in terms of a hypothesis about repair mechanisms involved in controlling somatic mutations. 40  As to the justifications of the “phenotypic gambit,” which is a basic presupposition of any adaptationism, Grafen (2002, 2006), among others, attempted to provide it mathematically in the so-called “Formal Darwinism” project (see Huneman, 2014, 2019). Yet this proof is not as general as he wanted it to be (Birch, 2016; Okasha, 2018). 41  Levins (1966), in his famous tripartition of epistemic values of model-building, precision, realism, and generality, gives behavioral ecology and quantitative genetics as examples, respectively, of the more general vs the more realistic model of the same system.

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Box 10.4  DST, AP, Telomeres, and ROS: An Update About Mechanisms

Besides this, significant research has focused on the role of free radicals in aging molecules that have a single paired electron in their outer shell— including Reactive Oxygen Species (ROS, formed by the one-electron incomplete reduction of oxygen), which accumulate in cells. But these ROS are monitored by sensors, which are likely to signal damage and then activate repair mechanisms, which in turn are under selection, according to DST; as Monaghan et al. (2008) wrote: “production of ROS can be balanced to some extent by the maintenance of systems to prevent their damaging effects.”42 Thus an aspect of DST consists in investigating the role of ROS in aging and more generally in life history.43 Telomeres, the extremities of chromosomes, have been studied intensively for two decades, especially by Nobel prize winner Elizabeth Blackburn (e.g. Blackburn, 2005). They are “non-coding highly repetitive DNA that cap the ends of chromosomes, enabling cells to distinguish chromosome ends from chromosome breaks” (Monaghan et al., 2008). Various evolutionary explanations for telomeres shortening have been given; plausibly, many theories prove to be right at the same time. A common view holds that an adaptive advantage of telomeres consists in preventing the persistence of cells that have accumulated too many mutations: at each replication round, a cell integrates mutations, which are often deleterious, so that after many replications it might probably be dysfunctional. Since it cannot be copied when there are no more telomeres, the cells will not divide anymore and die, which is good for the organism’s fitness.44 On the other hand, shortness of telomeres weakens the genome when it occurs, making the cell unstable. Therefore, the mechanism that prevents the diffusion of bad mutations within replicated cells is also, in accordance with AP and DST, what fosters progressive physiological deterioration.

42  Among these systems are also various activities (catalase or superoxide dismutase) that keep the ROS in check and therefore protect instead of repairing afterwards. (I thank Alice Lebreton Mansuy for these precisions.) 43  See review in Selman et al. (2012). 44  Chapters 12 and 13 deal with aspects of cell death. Telomere length varies within a population—which suggests that some selection may act upon it—and at various stages of the individual life of an organism. Life-history-theory approaches of telomeres dynamics have been proposed, e.g. Olsson et al. (2018).

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Because each evolutionary stance about death and senescence can be formulated either in a very general way (e.g. Medawar’s MA hypothesis and the fragile glasses argument) or as a more specific plausible proposition regarding the proper mechanisms or genes involved in a species, a clade or a lineage, and accounting for its lifespan, rate of aging, or shape of aging, one could think that these three major ideas-AP, MA, and DST-are rather families of hypotheses, or even families of theories, than hypotheses. As families of theories, they are more or less backed up by evidence, and it is difficult to assess each of them. Thus, there are in fact many theories that are not tested or not fully corroborated, though not disproved, and many can be attached in one way or another to one or more of these three families. For instance, developing DST, Marcusz Cichon (1997) theoretically investigated the relation between growth, longevity, and repair-reproduction trade-offs. Others have designed hypotheses that can supplement extant theories and explain some differences that those main theories cannot account for. Thus, Finch (1990) hypothesized that modular organisms—whose parts are more independent from others than in other organisms—may experience less steep or rapid senescence than nonmodular ones in which any dysfunctioning or deterioration of a part affects the whole system. However, no unequivocal evidence has been found in favor of this plausible hypothesis (Bernard et al., 2020). Similarly, no crucial experiment or conclusive data have been developed in order to check whether sexual or asexual individuals senesce faster (by considering species that access the two options): in Daphnia, the asexual ones senesce more slowly, but not in 118 other plants (Salguero-Gómez, 2018). As to the MA theory, a version of it has been advanced by Maklakov et al. (2015), according to which instead of being expressed late in life, the deleterious effects of accumulated mutations are present throughout life, but increase in magnitude with age. It is a “positive pleiotropy” hypothesis, since the early-life and late-life fitness effects of genes covary positively (both are negatives) but the fitness cost of deleterious alleles increases with time because natural selection does not “see” those costs, which occur late, after the reproductive period. From an epistemological viewpoint this hypothesis stands between AP and MA, since the reason for senescence lies in the unselected deleterious effects of genes, but pleiotropy is still taken into account. Pure MA theory can then be seen as a limit-case of this view, where the negative effect at early life tends towards zero.45  This concurs with the reformulation by Hamilton (1966) of the theories, which sees both of them as cases of a general model about the time distribution of the “force of natural selection.” See also Baudisch (2005). 45

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10.5.2   Being Pluralist About Explanatory Pluralism More generally, many theories suggest that some trade-offs play a role in the explanation of senescence or lifespan and therefore they may be grouped under the umbrella of antagonistic pleiotropy.46 In specifying the DST, Kirkwood proposed the “network theory of aging” (Kirkwood & Kowald, 1997), which specifically focuses on cellular systems that have to cope with a suboptimal resource distribution and therefore face a selection-­ based balance between damages and repair mechanisms. The list could hardly be exhaustive but the point is that the umbrella theories can diversify into various partial theories that are more or less corroborated. Indeed, currently there are epistemic obstacles to gaining a reliable assessment of these various hypotheses. As Selman et al. (2012) note, it’s difficult to test the ROS role in aging beyond a laboratory, since “individual phenotypic heterogeneity due to variation in resource availability, early life conditions, or genetic background is considerable in wild animals.” They add that the “among-individual variation will bias estimates and lead to erroneous conclusions about the life-history costs and ageing, unless within and between individual processes can be dissected and explored separately with longitudinal data and appropriate statistical tools.” This statement holds for many other evolutionary theories of aging, and I have already mentioned the fact that the effects on aging of the many genes identified as involved in this process in the lab have not been corroborated in the wild. But besides the epistemic difficulties that may later on be progressively overcome, some facts indicate that explanatory pluralism is here to stay, and have proven that no empirical facts regarding senescence currently remain unexplained by at least one corroborated account. By “explanatory pluralism” here I mean two things. The first is that lifespan, senescence, and death are not likely to be explained by a single theory in all lineages. Some patterns of senescence in birds or in mammals seem to be well explained by antagonistic pleiotropy; in the same way, the classical study by Rose and Charlesworth supported AP as an explanation of lifespan in Drosophila. In snails, MA seemed to be a good explanation

 This will be addressed more closely in the next chapter.

46

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of senescence patterns (Escobar et al., 2008). DST has been accounting for many patterns of aging, including microbial species (Teulière et  al., 202047), a topic addressed more closely in the last three chapters of this book. Besides this—namely, the plausibility of each of the three families of theories and their varieties as accounts of aging and death in distinct clades and lineages—by “explanatory pluralism” I also mean that in a given case (a clade or a lineage), several theories could be equally explanatory.48 This in turn can be understood in two ways: • the weak, or epistemological, interpretation is that regarding a question A, two hypotheses can be equally assertable on the basis of available evidence, because both correctly predict the data, even though only one of the hypothesized processes is real; • the strong, ontological, interpretation is that each hypothesis appeals to processes that indeed exist and both contribute to answering A. In favor of the weak interpretation, let us recall that many of the predictions made by MA theory are also formulated by the AP view—especially, regarding the genetic variance, or regarding the effects of selection for late reproduction (see Sect. 10.3.5.2) And since DST can be seen as a variety of AP or as a mechanistic specification of AP (see Sect. 10.4.2), many of the data corroborating DST would in turn corroborate AP, so that one wouldn’t be able to distinguish AP and DST in relation to the data. For these epistemic reasons, it is often the case that at least two theories can be equally corroborated as explanations of the phenomena. However, this does not exclude the stronger interpretation, namely, that, if, for instance, AP and MA are equally backed up by evidence regarding a specific feature in a clade or lineage, then two processes take place at the same time, mutational accumulation and antagonistically pleiotropic

47  Notice that regarding the extension of the hypotheses about death, and trade-offs, De Paepe and Taddei (2006) have shown that phages do also feature trade-offs between survival and reproduction. There is a burgeoning field of research there that is left for further investigation. 48  We have already met pluralism in connection with dietary restrictions: several explanations of its lifespan-enhancing effect exist, and we saw two or three corroborated hypotheses.

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genes.49 In the absence of an experimental detection of some of these genes, one cannot say that one of these processes is absent, and even if, let’s say, antagonistic pleiotropic genes are discovered, this would not exclude that MA also takes place, although in an undetected way. The above-cited study on snails by Escobar et al. (2008) concludes that MA explains the senescence in the populations but suggests that AP genes “may contribute to the evolution of senescence without leaving any trace,” so that their findings do not “discount AP theory.” More recently, a study has demonstrated some single nucleotide polymorphisms in Drosophila that are associated with MA and with antagonistic pleiotropy; they react to some stressors (Everman & Morgan, 2018). However, besides these two interpretations of the equal explanatoriness of several theories or hypotheses families, “pluralism” has another meaning, which has been implicit all along in this chapter. As I said, the “evolution of death” includes many distinct phenomena, each represented by a set of data, be they curves, figures, or experimental results. These phenomena are the facts that all multicellular species die; that most but not all undergo senescence; that these patterns of senescence are unevenly distributed across the tree of life; that the patterns of senescence can be lumped into three very general patterns; that each species has a specific lifespan; that the values of this lifespan and their variance however obey patterns of variation—for example, with regard to size, or metabolism, or the environment they inhabit, birds being, on the average, more long-­ lived than mammals. All these phenomena indeed have been or can be accounted for by one or several of the hypotheses proposed, and generally by one or several umbrella theories, including of course the strong and weak interpretations of pluralism just mentioned. As a consequence, death could be an evolutionary convergence: it appeared several times, in distinct clades, through different processes.

49  For an example: “aging in some fitness traits is due primarily to MA, while aging in other traits is due primarily to AP. For example, the genetic variance in traits related to male reproductive fitness (in particular, sperm competitive ability) appears to be due primarily to dominance variance, while the genetic variation for mortality appears to be due primarily to additive variance (e.g., Hughes & Charlesworth, 1994).” (Snoke & Promislow, 2003, 555)

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But I also allude to another kind of pluralism here: there are many senescence-related facts, and each, whether in a given clade or lineage or in many of them, is explained by a specific hypothesis that originated in an umbrella theory. But none of the umbrella theories explains senescence as such, or death as such, or the varieties of lifespans. There are some overarching facts—for instance, the connection between external mortality and intrinsic mortality or lifespan, even though, as we have seen, this fact is not of the highest generality since some conditions may obtain under which AP would predict an increase in lifespan with an increase in extrinsic mortality (but those conditions seem quite marginal in our actual world). Yet besides those overarching but not absolutely universal facts, “death” and “senescence” have to be dismantled into a set of facts that are unlikely to be collectively explained by any one theory. This dismantling constitutes the last sense of “explanatory pluralism” regarding death and senescence, and may be of interest for philosophers. An analysis of this will conclude this chapter. It seems here that the phenomenon of death undergoes something that happens to many topics once they become the object of a scientific inquiry: they are decomposed into a plurality of facts, each being the object of an inquiry, with no guarantee that all these inquiries will lead to the same culprit. For instance, while “memory” in the lay conception is a faculty of the mind—as it was in medieval psychology or even in the eighteenth century when an empirical psychology started to be elaborated by authors such as Locke, Hume, or Condillac—in the early twentieth century, when memory entered scientific psychology and then cognitive science, it has been dismantled into several kinds of memory: memory of old facts, of language, recent past memories, memory of the meaning of signs, etc. All these memories can be investigated, through rigorous experimental processes, possibly linked to brain phenomena captured in neuroimaging or rooted in these various modules of which evolutionary psychologists are amateurs; and while they seem to be real processes or dispositions of the mind or the brain, “memory” itself appears rather as an abstraction. One could have many of these memory components but not all of them—as is exemplified by those pathologies in which one of these memories is lost

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but the others continue to function correctly50—and therefore memory cannot qualify as a scientific object. For memory, the cost of being worthy of being scientifically and empirically investigated consists in disappearing from the scientific view of the mind or the brain. Likewise, one could argue that there is a science of consciousness, and that this science emerged when “consciousness” as one compact thing— mostly studied by philosophers through introspection, from Descartes to William James or Husserl—was dismantled into phenomenal consciousness, access consciousness, etc. Here too, becoming an object of scientific study means that the compact, self-contained character and unicity of the thing at stake goes through a decomposition into distinct “consciousnesses” that may pertain to very different brain processes, different evolutionary histories, and a different distribution across the animal lineages. This is the second epistemic result of our journey into evolutionary theories of death: neither death nor senescence as such is something that calls for an explanation. These two terms have been turned into sets of phenomena, often comparative or relative phenomena, which at the same time are well characterized by numerous sets of data taking many forms, and each receives a putative explanation taken from the two or three51 major Darwinian explanatory families. The necessary explanatory pluralism of the evolution of death and senescence ultimately relies on the pluralization of death and senescence themselves. Nothing guarantees that one day we will have a unified explanation of death or senescence in the living world, or of their distinct patterns in the domains of animals and plants. This means that the current controversies as to whether there is one overarching cause of mortality that drives senescence, or whether there is a set of processes that are independent and irreducible,52 should first determine the degree of pluralism to which each side is committed. While I completed this book, the current landscape of aging research very recently negatively acknowledged this pluralism. A position paper recently published in the Aging research review and coauthored by tens of

50  Books by Antonio Damasio or Oliver Sacks popularized these splits of mind and memory, as did the impressive movie Memento by Christopher Nolan in the late 1990s (the main character loses his capability for immediate memory). 51  Depending on how one sees the relation between AP and DST; see above Sect. 10.4 on DST. 52  See below Chap. 6 on this, especially the debate on the presumed “hallmarks of aging.”

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researchers in the field (Cohen et al., 2020b) is entitled “Lack of consensus on an aging biology paradigm? A global survey reveals an agreement to disagree, and the need for an interdisciplinary framework.” This lack of consensus is manifest through a survey, which “shows little common ground on most questions in aging biology” but concludes on “a near-­ consensus that aging is heterogeneous and multifactorial.” I wanted to show how such conclusion is rather to be interpreted in terms of explanatory pluralism. This pluralism, parallel to what happened to consciousness or memory, consists in the fragmentation of “aging” into distinct processes and phenomena, involving distinct key concepts. In the same vein, Alan Cohen and two colleagues also published a paper sounding skeptical about the very idea of “aging.” They write: “we have a word for aging, and therefore we assume that science will accommodate us, providing a phenomenon to match our word. And in a colloquial sense this is certainly the case: no one can doubt that we see ourselves, our relatives, and our friends age. But is this colloquial usage scientifically justified? Is there really a ‘thing’ or a phenomenon we can call aging?” My own analyses here support this skepticism on the basis of this idea of a dismantling of “aging” occurring through its scientific appraisal. Such dismantling has been seen at the most basic level in the previous pages when I considered the multiplication of proper measures of age: not only chronological age has been supplemented by a biological age, but in some contexts it has been required to distinguish what Galipaud and Kokko (2020) called A-aging, which takes into account duration of life from the zygote stage on (and not birth).53 Evolutionary thinking has cast a precious light on death and longevity, and has shown that these phenomena can be accounted for in a perfectly naturalistic way, without assuming that death is necessarily entangled in the life of organisms along the lines of the formerly cited providentialist scheme. Nevertheless, the three families of hypotheses have been capable 53  Cohen et al. (2020c) on the absence of a reference for the term “aging” make a similar statement about multiple metrics: “DNA damage accumulation likely starts at parental gamete formation. Epigenetic changes are also likely to start before birth (Horvath, 2013). Meaningful impacts of cellular senescence, however, are primarily later in life. Some answers may be based on evolutionary expectations such as ‘essential lifespan’ (Rattan, 2006). Such discordant answers to the question are only problematic because we expect a single answer; by seeing the diverse processes and mechanisms as separate rather than as facets of aging, we can easily answer that each starts at a different point in the life course, as makes sense.”

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of producing testable accounts of death only because death was decomposed by science into sets of phenomena of various natures, each the target of a plurality of sound evolutionary explanations. Thus, what happened to death in evolutionary biology throughout the formulation of the first MA hypothesis, the elaboration of the major theories, the diversification of theoretical hypotheses and the multiplication of tests, echoes what Bichat did in his Recherches, when he concluded a much less general move that in his time occurred well beyond physiology (see Chap. 3, Part I), by distinguishing between a general sense of the death of the organism and a narrow sense of the death of various parts and tissues. Here too, the general meaning of death as process and state characterizing the living organism in general has been broken into distinct death-related explananda, each likely to receive its proper explanation. However, with Darwinian biologists the separation between death in general and actual death-related phenomena is much stricter because death in general receives a very broad theoretical explanation—the fact of a major connection between longevity-­ reproduction trade-offs and senescence, or, even more generally, the existence of a “selection shadow”—while the actual, testable explanations concern the many diffracted meanings of the death issue. The dismantling of the question about death is even wider than this, if we recall some of the analyses in the preceding sections about negative senescence, or rare conditions in which extrinsic mortality favors slow senescence. The exploration of the space of possible life-trajectories, including “negative” (Baudisch, 2005) and null senescence, induces a shift in the question of death. The most general theoretical articulation of the life-history trade-offs, stated by Abrams (1993), concurs with the systematic exploration of aging patterns in nature: most patterns match with the traditional, Gompertz-like, senescence curves, which call for accounts whereby the highest extrinsic mortality drives senescence; however, some of them do not match, and they instantiate the unusual and rare theoretical situations where higher extrinsic mortality prevents or hampers senescence. Hence the question of “death and senescence” covers many more cases than what appeared initially, and evolutionary explanations can now be seen as matrices for finding an answer to the two questions “Why do we age and die? And why do some neither die nor even age?” Summarizing this long exploration of the answers given to these questions, we can easily discern now a tripartition between approaches successively adopted. The first answers were on the modality of justification—they pertained to this metaphysical providentialism that is deeply rooted in the

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philosophical tradition. They pervaded not only philosophy, but also biology and the general considerations of life on Earth until early twentieth century. Darwin and Weissmann themselves, while they proposed a novel way to tackle the question, by introducing natural selection as a possible explanation and not only justification of death and aging, would still subscribe to this providentialism to the extent that the “good of the species” remained a key explanatory factor. The Modern Synthesis, through the theories of AP and MA, Williams and Medawar’s respective views, opened another era. Evolutionary explanations of death and aging can be given, but they are not any more formulated in terms of selection for the good of the group. In turn, the alternative is between by-products of selection or effects of the weakness of selection. This alternative will remain essential to explaining aging and death. However, regarding the status of death itself, in this new era, the contingency of extrinsic death replaces the providentialism that underpinned justifications of intrinsic death and aging. I believe that this term of contingency should be emphasized, because it clearly shows the breakup with early modes of addressing death and aging, until Darwin and Weissmann and beyond, modes that retained the justification providentialism proper to metaphysics. The complexities and conundrums of corroborating one of these alternatives, the multiplication of subtheories, as well as the diversification of the pathways and mechanisms likely to result from a given aging process— including various genetic elements—seem to lead to the current status of the overall theory of death and aging, namely, the explanatory pluralism. In the remaining chapters, I will leave aside the tests, the various assessments of diverse theories, and the overall structure of the evolutionary biology of death that were scrutinized in this chapter. I will first address the question of trade-offs, which have been extensively met in this chapter. Questioning what is traded in the trade-offs will advance our understanding of the evolutionary reasons of death. The last three chapters will question two major concepts that have been seen throughout the present inquiry: the possibility of a death or senescence program, and then the role of social structures in the explanations of death. To some extent, these chapters question the ontology of death, in the sense that trade-offs and their currency, potential programs, and communities will prove to be key elements of the ontology of death—namely, what does exist and is relevant for the question “why death?” Chap. 11, with its discussion of trading, exposes a sort of economics of death;

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Chap. 14 concludes with a sociology of death, because it will view senescence and death as something whose explanation concerns the community in which dying organisms exist. Chapters 12 and 13 specifically address the death of cells and unicellular organisms, hence revisiting in the context of evolutionary biology, the decoupling of the death of the part and the death of the whole, which was foundational for Bichat’s physiology. Since I started the second part of this book by contrasting the death of multicellular organisms and the ever-­ living single cells, a major assumption of pre-Darwinian views of life, and since the first section focused on the difference between the death of parts and the death of wholes, culminating in the figure of Bichat’s Recherches physiologiques sur la vie et la mort, it is somehow natural that this book should end with a reassessment of the difference between wholes and parts in relation to death, or between the life of the whole and the deaths of the parts.

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CHAPTER 11

Ontology (1): The Modern Economics of Death and Its Trade-Offs

With Gifts of Life How death’s Gifts may compare— We know not— For the Rates—lie Here— Emily Dickinson

There are many theories of why death and other mortality phenomena exist. They fall into three main categories, and are more or less corroborated. Across these theories, some key questions and themes appear again and again. They are part of what I’d call the ontology of death for biologists, namely, the entities and dispositions that are relevant to death in our best theories. Since the theme of trade-offs has emerged all along, from the times of Williams’s theories, I’d like to emphasize how much economics—as a science of optimal allocations and therefore rational trade-offs—shapes our knowledge of death. This does not come as a surprise. In the first chapter of this section, I have shown that metaphysics traditionally approaches death through the economic scheme of the cost of individuality—that is, what I called a providentialist lens. The evolutionary theories of death are wholly different, as I have shown in Chap. 8 of this section, since they invert the priorities of extrinsic and intrinsic death. They also differ because traditional © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_11

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metaphysicians don’t explain death scientifically, namely, by showing one or several causal pathways. Whereas philosophers apply an economic scheme to justify or interpret death, evolutionary biologists use an economic scheme to explain it, in the complex configurations we just explored in the preceding chapter. The notion of trade-off is the most obvious instance of such an economic line of thought. Others will appear. After all, the notion of “price” pervades Williams’ fundamental paper on senescence: “senescence results from genes that increase youthful vigor at the price of vigor later on” (1957, 410, my emphasis). In fact, the affinity between evolutionary thinking and economics arose with Darwin himself. He borrowed the notion of “the struggle for existence” from economist Thomas Malthus’s An Essay on the Principle of Population. Biology’s bond with economics became even tighter with the rise of behavioral ecology, the pervasive use of the concept of strategy, and the constitution of evolutionary game theory by Maynard Smith (1982) and a few others. To this extent, it could even be asserted that evolutionary biology is a science of the optimal allocation of scarce resources, in exactly the same way as economists theorize optimal allocation of goods. The difference is that in biology, natural selection governs the allocation, while in economics, rationality does it.1 This identity only covers a subset of all the evolutionary problems, but it indicates that once the question of death becomes an evolutionary issue, the solution will probably reside in some specific constrained optimal allocation. That’s where trade-offs come to the fore, since the only way to invest optimally in a broad range of demands often consists in finding the best trade-off, namely, the one that maximizes utility (for economics) or any other value of interest. The importance of trade-offs as a major focus of life history theory cannot be underestimated. As Cohen et al. (2017) write, “life history trade-­ offs—compromises in the allocation of limited resources toward fitness components such as survival or reproduction—lie at the foundations of ecological and evolutionary research.” I’ll therefore start by investigating the various instances of the trade-off concept in evolutionary theorizing about death—beyond the two trade-offs advocated by AP and by DST— and then question the pervasiveness of this idea of trade-off across the field.

1

 On this parallel between evolution and rationality, see Okasha (2018).

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11.1   Trade-Offs and Life History In a recent review on the ecology of senescence, Gaillard and Lemaître (2020) write: “Senescence nowadays is most generally interpreted in the conceptual framework of trade-offs (i.e., a trade-off between individual performance early in life and performance late in life) under both the antagonistic pleiotropy and the disposable soma theories of aging.” Baudisch (2009) concurs: “Based on the general trade-off between survival and reproduction, many life history models have been developed to understand how life histories are shaped by evolution, applying optimization models.” Dietary restriction, the only phenomenon acknowledged as leading to lifespan extension, is often analyzed in terms of reproduction-­ survival trade-offs along the lines of DST. For example: the evolutionary advantage of dietary restriction would arise because it allows an organism to maximize its reproductive effectiveness in response to changes in the food supply, not because of its ability to extend reproductive life span. Therefore, we believe that the extension of life span by dietary restriction is fortuitous and arises secondarily from an organism shifting its resources from reproduction to repair/maintenance in response to reduced calorie consumption. (Richardson & Pahlavani, 1994 in Rose and Finch)

Before analyzing the senses and underpinning ontologies carried by the notion of trade-off in this context, let’s explain more precisely exactly what a trade-off is. If A and B are two evolutionarily important operations, functions, or traits, an A-B trade-off is such that when one invests an additional amount x of something X in A, there is a cost of x′ units of X that could have been invested in B. The first problem of the trade-off consists therefore in determining the curve of the function x′ = f (x). The second question is to find the optimal trade-off, namely, the one that optimizes the relevant evolutionary magnitude. It is generally fitness, but there are several notions of fitness; many models focus on reproductive value, that is, the number of possible offspring alive, which may be a compound of the growth rate and the fecundity (which is itself the first term of the trade-off). It can also be the reproductive value per size unit. Moreover, the trade-off is sometimes considered at a moment of the life cycle, so the whole curve and its optimum are age dependent. After having described the varieties and issues of trade-offs in life history theory, and then in the evolutionary theories of death and senescence, I will consider the question of the precise specifications of these magnitudes.

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Life history theory since the 1970s has elaborated notions that capture this general trade-off. One of them is the idea of “reproductive effort.” It means a “measure of both the fraction of resources invested in reproduction and the costs of reproduction in somatic investments” so that, as the authors go on, “an increase in reproductive effort increases current reproductive output at the expense of survival due to reduced somatic investment” (Tuomi et al., 1983; they re-expose Williams, 1966). Life history theory asks how the reproductive effort is set by natural selection—or, in other words, optimized—at each age. Thus, “reproductive effort” designates a trade-off between investments in reproduction and then survival at a given age; and the realized value of this trade-off varies over time. The research question thus consists in determining the trade-off function that states how much survival will cost a particular amount of reproduction. More precisely, the question is: for a given female,2 what will be the cost to her survival if she adds one reproductive unit? The answer is a curve plotting survival at a given age against reproduction at this age, a curve that is itself a function of parameters of the environment and growth rate of the population (Fig.  11.1). The model has to make some assumptions—especially regarding the absence of parental care, which affects the survival of offspring in later generations and makes the equations much more complex. Reproductive effort favored by natural selection and likely to be expected in nature is the optimal value of this trade-off, namely, the one that maximizes overall fitness. “The principal evolutionary problem is to find the schedule of reproductive effort which maximizes fitness” (Taylor, 1991). Fitness, in turn, is represented by reproductive value vi, which is a compound of fecundity and survival until age i, namely, the addition over ages of the product bi * pi divided at each unit of time by growth rate of the population.3 Optimal reproductive effort, as it has been demonstrated first by Williams (1966), is given by the value of bi that makes vi optimal. Earlier on, Hirshfield and Tinkle (1975) attempted to model the value of reproductive effort depending on environmental variables such as extrinsic mortality. They concluded that “selection for high levels of 2  Life history theory is often formulated from the viewpoint of a given female. Because males emerge with the emergence of sexual reproduction, problems of reproductive investment and optimization are easier to formulate by considering only a female, as a first approximate. Things are already very complicated. 3  bi is the rate of birth given at time i; pi is the probability of having survived up to time i.

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ai

p

ri

bi

bi b

Fig. 11.1  Curve showing growth/survival trade-offs related to fertility. The reproductive effort at age i is given by the intersection of the curve with the line Ai–Bi, where Ai is that value of pi that would provide the same unit reproductive value vi entirely through survival/growth, i.e. with zero fecundity. Bi is that value of bi that would provide the same unit reproductive value entirely through fecundity, i.e. with zero survival/growth. (After Taylor, 1991)

reproductive effort should occur when extrinsic adult mortality is high, in environments with constant juvenile survivorship, and in good years for juvenile survivorship in a variable environment, provided that the quality of the year is predictable by adults.” These analyses rely on a complex equation that defines expected fitness in relation to parameters including Fisher’s Malthusian parameter, that is, the rate of growth of the subpopulation sharing the trait of interest. Their findings have been debated from the standpoint of modeling, as I will indicate, and on the empirical side. Subsequent investigations of reproductive effort as a trade-off-based concept central to life history theory endeavored to clarify the assumptions of Hirshfield and Tinkle. In a paper entitled “The relation of reproductive effort to age,” Charlesworth and Leon (1976) started to analyze

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the value of reproductive effort according to adult mortality, population increase, and sensitivity of growth to reproduction. They derived trade-off curves between reproduction and survival that define reproductive effort (see Box 11.1). They considered that it cannot be taken for granted that the curves themselves are dependent on age. Box 11.1  Analyzing the Notion of Reproductive Effort

Taylor (1991) complicated the situation. He allows the trade-off curve (between reproduction and survival) to vary with age and intends to capture these variations. He models reproductive value per unit of size (“unit RV”), and the fecundity/survival trade-offs at each age, which determines the optimal reproductive effort. The model shows how at each age the trade-off curve is defined, and then allows one to compute the reproductive effort as the one yielding the optimal value vi. But computing overall reproductive value, in order to find out overall reproductive effort, is an enormous task. “A major source of difficulty comes from the effect of changes in fecundity at one age on survival or fecundity at another age.” This nonindependence between ages makes it hard to compute the across-­ ages addition of fecundities. Taylor (1991) had followed Schaffer (1974) suggestion that to render the problem tractable one should merge growth and survival in the variable pi, since growth encompasses the potential effect on fecundity at late ages. As a consequence, two general laws of reproductive effort would appear: “unit RV will either decrease during the entire life of the organism, or increase at the beginning, reach a maximum, and decrease thereafter” (my emphasis). As we see, all these models are mathematically complex, and rely on unrealistic hypotheses. They are models that confront reality using comparisons and experiments. Especially, here, Taylor makes two assumptions (labelled stage I and II) that in fact already stem from the whole theory of senescence. As a result, they make these reproductive effort models somewhat useless in addressing the question of senescence. “It is assumed that there is an initial stage I during which the individual’s performance in the game of life (surviving, growing and/or reproducing) generally gets better, and a final stage (continued)

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Box 11.1  (continued)

II during which individual performance stays the same, or deteriorates.” Tuomi et  al. (1983) had envisioned the fact that the trade-offs underlying reproductive effort are not only survival and reproduction but are mitigated by other properties. They criticize a limitation of the standard concept of “reproductive effort,” which works only “when resources are invested in reproduction at the same rate that reproduction drains resources from somatic investment.” If these rates are different, the concept won’t hold. But these two rates of draining resources and investing resources depend upon the system of allocation, which is ultimately dependent upon the way the organism is designed. Thus, they contrast the usual life history theory, which they label “demographic,” with their organism-based view, called “organismic theory” (33). This implies a view of selection that is not targeting alleles but organisms. As they argue, “For simplicity, physiology and ontogeny are omitted (Stearns, 1982). However, it is useful to study how the reasoning of demographic theory changes if selection is assumed to operate on whole organisms, rather than on separate life-history traits.” Classical demographic theory holds that “separate life-history traits are free to coevolve under purely demographic forces. Selection operates on separate traits. Selection optimizes adaptive strategies,” whereas organismic theory, by contrast, claims that “selection operates on whole organisms.” As a consequence, it parts ways with optimization. “Selection eliminates unfit phenotypes but does not necessarily optimize adaptive strategies.” This entails the idea of “opportunity sets” that are constituted by the joint selective pressures, and in turn constrains future selection. “Selection probably operates not on separate life-history traits but on whole organisms through their entire life-history. The structural and physiological intercouplings between separate traits can result in phenotypic opportunity sets where selection can mould life-history traits only within the constraints of the opportunity sets.” Thinking in terms of opportunity sets allows one to explain the deviations from the predictions of standard life history theory that often contradicted the data, as noted by Hirshfield and Tinkle (1975). (continued)

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Box 11.1  (continued)

Once again, we see how the questions raised by life history entail a commitment to certain key evolutionary concepts. Most of the research I have commented on here relies on Fisher’s idea of reproductive value and Malthusian parameter. As observed by Okasha (2008), among others, Fisher is eventually sympathetic to a perspective that sees selection as targeting alleles. But Wright notoriously argued with Fisher on this question, because he held that selection targets integrated genotypes. What Tuomi et al. (1983) propose by opposing their “organismic theory” to the classical demographic life history sounds like a reintroduction of this Wrightian perspective into the research on reproductive effort. Before getting back to trade-off-based hypotheses on senescence, let me add a word about the status of the simplification hypotheses used to model the optimization of reproductive effort. Ideally, determining reproductive effort as an optimum (see Fig. 11.1, from Taylor (1991)) derived from differential equations is a powerful tool to explain differences in life histories. However, applying models to empirical data is difficult, and already Hirshfield and Tinkle (1975) were aware of that. They suggested that: The difficulties in understanding the evolution of reproductive effort stem from the fact that predictions from theory are, in many cases, results of assumptions in the models which require careful examination before the predictions may be considered relevant to organisms in nature. Difficulties also arise because it is not clear what data constitute adequate measures of reproductive effort.

Being abstract, allocation principles are quite different from many actual allocation systems (which is the major point made by Tuomi et al., 1983). Some claims about fecundity are also unrealistic. Especially, as Taylor (1991) indicated, parental care is not accounted for, in sharp contrast to real life. This last point is crucial, because while Taylor’s model computes reproductive value (RV) per unit size based on the age-class unit size reproductive value, overall RV is not computable unless parental care is excluded. The canonical models I just surveyed make a sort of Markovian

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assumption regarding age classes and reproductive or somatic investments, whereas reality is not so often Markovian. The situation of life history theory here presents an epistemological dilemma that is familiar to ecologists. In 1966, the evolutionary biologist and ecologist Richard Levins, who wrote seminal papers in the theory of allocation, foraging, and, in general, behavioral ecology, published a paper entitled “The strategy of model building in ecology” (referred to in 10.5.1). It deals with the distinct epistemic goals that a model should fulfill. It has been extensively cited and discussed, not only by his fellow ecologists, but also by philosophers and other scientists. Levins defends two claims with the essay. First, models can aim at three distinct epistemic goals: realism—namely, integrating most variables describing the system being modeled; generality—namely, models can apply to a wide range of possible systems; and precision—models can supply quantified predictions likely to be tested. He argues that no model is apt to reach all three goals. For instance, although Lotka–Volterra equations can expose the dynamics of predator–prey systems in general, they cannot also capture what goes on in a specific population of rabbits and foxes given their proper genetic makeup and ecological constraints and, at the same time, provide predictions for controlling the abundance of rabbit species. Hence, the researcher has to choose trade-offs between those epistemic goals. Thus, the more a proposition can be derived from many distinct models that make specific trade-offs, the more likely it is to say something about reality. That’s why Levins coined the aphorism “truth is at the intersection of independent lies.” In the case of behavioral ecology, the question of epistemic values and trade-offs is highly relevant. Behavioral ecology views the behavior of organisms in terms of strategies that are optimal, from a set of possible strategies. However, the strategies are themselves complex phenotypic traits whose genetic underpinning is hypothesized. On the other hand, a more realistic modeling of the evolution of traits should specify the genetic makeups on which the possible strategies are contingent. However, if this data is plugged in, the equation of the evolution of the system is much less mathematically tractable. Although the model gains in realism, it pays the cost of its general applicability. In the analysis of reproductive effort by Tuomi et  al. (1983), for instance, the various genetic makeups of different species might yield distinct allocation systems. Nonetheless, most studies choose the simplest definition of reproductive success, namely, the simplest allocation system.

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Behavioral ecology faces these epistemic issues in part because it has to assume that some measurable magnitude, for example, calorie intake or metabolism rate, is a proxy for fitness, understood as a complex magnitude related to the distribution of offspring number. Yet in many situations the claim that this is a good proxy is not valid. Most general models designed by behavioral ecologists aren’t realistic enough to explain a specific actual behavior in a given species. Moreover, these examples bring to the fore something Levins avoided in his discussion of modeling: namely, the importance of simplicity (yielding mathematical tractability), an epistemic value that could be added to the realism–generality–precision triplet. Models such as those by Taylor (1991) or Charlesworth and Leon (1976) are primarily simple, as well as being very general. Their pervasive applicability derives from this simplicity. Granted, Elliott Sober (2002) has tackled the problem, and he convincingly shows that choosing the simplest in a pair of equations is not unequivocal due to competing definitions of simplicity. My point here is that models may trade simplicity for realism, and this makes it difficult to connect them to the underlying actual gene-based evolutionary process. Models that assume Markovian dynamics for inter-age reproductive value, for instance, will hardly be applicable to many cases where the reproductive values or the fitness of alleles rely on intertemporal fitness effects such as parental care. In sum, the current models are not adequate to capture reproduction– survival trade-offs and, more generally, concepts such as reproductive effort that are based on these trade-offs. Since reproductive effort denotes an optimal value for a trade-off curve, the determination of its value relies on the establishment of such a curve, which may have sacrificed realism for simplicity. That is why no trade-off model of life history can generate as correct predictions most of the known facts.

11.2   The Diversity of the Trade-Offs Underpinning Senescence What kinds of trade-offs would senescence establish? Antagonistic pleiotropy (AP) theories claim that genes with a highly beneficial effect early in life, on reproduction, and a harmful effect on organisms late in life, should accumulate, and that would explain senescence. This account is frequently reinterpreted to state that reproduction is traded off against longevity. But

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since longer life means longer reproduction, the whole trade-off can then be understood as concerning moments of reproduction. According to Barton and Partridge (1993), “ageing is not an inevitable feature of life history optimization. For it to appear, there must be tradeoffs across different ages, such that an increase in early reproduction necessarily constrains late reproduction.” The distribution of those trade-offs across various clades and various environmental conditions allows one to talk of a “slow-fast continuum” in life histories: either live fast, reproduce once (be semelparous), and die; or live a long life, grow, reproduce later, be iteroparous (reproduce many times), and die later. Between those two poles there are many intermediary positions of the slow–fast indicator. Many extant species can indeed be distributed along this continuum, depending upon both their evolutionary past and their current environment. But the continuum does not cover all the questions about ageing trade-­ offs: what they are about, and just what is traded. In order to investigate these two questions, let us briefly go back to Williams’ ideas, and then consider Kirkwood’s disposable soma theory (DST). Then, after exploring the various shapes of the notion of “trade-offs” in evolutionary literature, we will formulate the major epistemological issues it raises. Then we shall identify what may be considered as undecidability issues, a major underlying reason for the pluralism regarding evolutionary explanations of aging and death. Finally, we shall focus on the deep entrenchment of the idea of trade-off within the logics of evolutionary thinking. 11.2.1   Trade-Offs, According to Williams In Williams’s seminal paper, the notion of a trade-off stems from his two-­ forces model of selection regarding senescence. “The rate of senescence shown by any species will reflect the balance between this direct, adverse selection of senescence as an unfavorable character, and the indirect, favorable selection through the age-related bias in selection of pleiotropic genes.” The key idea is thus twofold: the two sides of the trade-offs are two selective pressures, directed towards two different things, namely, deterioration effects of senescence and early-life positive effects. Also, there is an “age-related bias,” as we saw, namely, the effect that occurs earlier counts more regarding selection because it has a higher impact upon reproductive value. This latter fact is due to the structure of the reproductive value (or “p-value”) that Williams considers, which is the

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lifetime sum of chances of reproduction: traits having effect earlier have a higher effect on this reproductive value. In later formulations of the notion of trade-off, the reference to selection recedes into the background. Since trade-off, according to its notion, is a measure of selective value, it includes implicitly the concept of selection. And the contrast between the two opposite directions that can be taken by selection, emphasized by Williams’ account of senescence, becomes the contrast between positive and negative contributions to fitness. However, Williams had another formulation of the trade-off at stake in senescence. He writes, “all through development there must be compromises between the need for continuous fitness and the demands of morphogenesis.” Here, Williams contrasts fitness and continuous development of the individual, which indicates that the trade-off stands between early life growth and fitness understood either as mere reproduction or as reproduction in addition to late-life survival—this survival being relevant to fitness because it implies the possibility of reproducing for a longer time or fostering the survival of offspring. I quoted these two sentences to indicate that the nature of the trade-off is slightly equivocal, despite the agreement on its initial characterization; namely, fitness in early life as opposed to late life, and the role of age-­ related bias. Although the cause of the trade-off is the dual regime of selection, such original formulation underdetermines the definition of the trade-offs as fitness trade-offs. As I said, subsequent elaborations of the conception focus on fitness and push the two-forces model into the background. As a result, the ambiguities of the trade-off concept are exposed, and several different ways of reading the trade-offs emerge. The DST emphasizes different trade-offs, as we have seen, and Cichon (1997) introduces growth in addition to reproduction and survival in the trade-off. This makes the ambiguity of the fitness–morphogenesis trade-off mentioned by Williams explicit, since growth and survival can appear as two components of the term “morphogenesis.” 11.2.2   Trade-Offs in the Disposable Soma Theory As an alternative explanation of the same facts, the DST indeed favors a trade-off which is less explicitly centered on genes. Maintenance mechanisms are tuned in order to avoid being solicited at a time when the chances of encountering a fatal accident are high. As a consequence of this adjustment to environmental features of mortality, reproduction uses

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resources that are not invested in repair. At first, it appears to be a simple fitness trade-off, since possibilities of surviving and then having offspring later (thanks to repair) are traded for having more offspring early on. Repair is a very general term, and includes several phenomena, such as DNA repair. The existence of a cost of DNA repair has been shown by an experiment where Drosophila are exposed to radiation, which evolve repair mechanisms as a resistance to radiation after 56 generations; when radiation is removed, this resistance may be lost, thereby suggesting that it has a cost and is counterselected in environments where it yields no benefit (Nothel, 1987). The hypothesis of the DST trade-off mechanism is complex and includes two pathways. The experimental fact that limited reproduction is associated with dietary restriction and yields an extension of lifespan is indeed explained by the diversion of resources from reproduction to maintenance, but also by the reduction of damages due to reproduction that necessitated germline repair (Maklakov & Immler, 2016). But the whole thing is a bit more complicated, because of growth. As Cichon (1997) made clear, there can be a trade-off between late life survival and early growth, without changing the amount of offspring. The structure of the trade-off here is triadic: repair (hence survival), reproduction, and growth. Cichon (1997) adds to extrinsic mortality “repair efficiency” as a second variable that determines the trade-offs between repair, reproduction, and growth. This explains why a same extrinsic mortality value does not necessarily balance a same trade-off between repair and reproduction, and thus a same lifespan or maximum longevity. Considering such triadic trade-offs explains that body size is another variable determined by their value: instantaneous investment in growth, along with its duration, eventually determines body size. The multiplicity of parameters indicates why the relation between size, mortality, and longevity found in nature is not simple. “Low extrinsic mortality favors high investment in repair and in consequence low but long-lasting investment in growth. High investment in repair enhances longevity: thus growth can last longer and lead to large body size despite a slow growth rate. Against our intuition, the present model reveals a negative relationship between the growth rate and body size: fast growth leads to small body size and slow growth leads to large body size under the same trophic conditions” (Cichon, 1997, 1387). Hence DST not only introduces a novel modality of trade-offs, but also shows that these trade-offs have major consequences even beyond the

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determination of longevity. What changes here, compared to the original DST theory, is that the unknown resource allocation to repair is not supposed to be constant: the model therefore has to determine a function, and not a fixed value. The optimal allocation to repair changes with age, and this change determines growth rates through the reproduction– growth trade-off. This yields a general pattern of allocation optimized by selection: “if it is optimal to invest in repair at all, this allocation is highest early in life and decreases later, stopping completely before the end of life. Therefore, the growth rate is particularly affected by repair” (Cichon, 1997, 1388). The consequence is that the scope of by-product selection is broader than supposed, and includes morphological properties such as size. Following Cichon’s model, “the correlation between age or size at maturity and maximum lifespan is a by-product of optimal allocation strategies.” It is to be noted, however, that this is a complex trade-off, and large size does not predict, as such, anything. Perhaps large species on the average live longer, because of their metabolic rate; this has been admitted since the times of Pearl. Nevertheless, within species, sometimes large individuals have shorter lifespans. This is the case with dogs, as we know well, and Kraus et al. have shown that large dogs die first because, on the basis of those complex trade-offs involving growth and repair, they age quicker. Trade-offs relevant to senescence and death are not restrained to repair, reproduction, survival, and growth. Some trade-offs have been tested and attested in relation to immunity. They are reviewed by Austad and Hoffman (2018): “female common eider sea ducks that raise larger clutches have decreased immune function that may decrease future survival as well as reduce future reproduction of those who survive” (289). And in some insects, multiple matings have a detrimental effect on the immune system: multiple mated drosophila males are less able to face bacterial infections, and striped ground crickets have some immunity suppressed after mating. This can clearly count as a trade-off between reproduction and something related to survival, and of course later life is negatively affected by this decrease in the efficiency of the immune system. But it is not exactly what DST predicts. More precisely, it calls for expanding our understanding of repair mechanisms in a way that could encompass immunity, even though this could support AP since it involves a reproduction/late-life trade-off.

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In several papers, Alexei Maklakov criticized the focus on reproduction when biologists address trade-offs occurring throughout the evolution of senescence. An interesting fact is that when the germline is experimentally ablated in some sterile insects, lifespan increases, indicating that there is more to reproduction in the trade-offs that exist between longevity and fertility. Germline cells actually need maintenance; without it, they can degenerate too, even though, unlike somatic cells, they are not subject to deterioration through use (Maklakov & Immler, 2016). Germline cell maintenance differs from somatic cell maintenance because while the latter can be submitted to a trade-off against reproduction, according to DST, the former is required for reproduction and the potentiality of having functional offspring. Therefore, the two maintenance mechanisms cannot enter into the trade-offs hypothesized by DST in the same way. Germline immortality was emphasized by Weismann when he conceived of the separation between soma and germen, and then famously by Dawkins in his idea of “germline replicator.” However, it comes with a cost: the genome of the germline, and even its proteome, namely, “the set of proteins produced, folded and transported within individual cells,” has to be maintained. Such maintenance is a kind of repair, but it’s traded off against longevity and survival within evolution. Moreover, this trade-off involves not only organisms and their potential offspring, but also the next generation, since at the heart of the trade-off stands the possibility of having offspring that are themselves capable of reproducing. In this specific trade-off we see that fitness, as a measure of evolutionary success, extends over several generations. The fact has long been recognized by theoreticians, and its consequences are some difficulties in defining the notion of fitness itself (see also Box 11.2). Box 11.2  Insights from the Theory of Complex Systems

In the 1990s, some biologists had already been using the framework of the theory of complex systems to approach aging (e.g. Lipsitz & Goldberger, 1992, who argued that physiological aging goes with a loss of complexity and that the notion of fractals could help monitor senescence, or Goldberger et  al., 2002). These approaches have been revived over the past decade. Kriete et al. (2011) used computational complex systems to simulate the senescence of a cell or the (continued)

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Box 11.2  (continued)

assembly of the protein interaction network in the cell and its aging. As announced by de Magalhaes and Toussaint in a paper entitled “How bioinformatics can help reverse engineer human aging,” “computer methodologies will play a crucial role to reconstruct the genetic network of human aging and the associated regulatory mechanisms.” Another kind of trade-off has been set forth by Kriete (2013), who sees organisms through the lens of systems biology. Viewed from this perspective, organisms are complex systems that subsist on the basis of an intertwined and diverse set of nonlinear relations of elements involved in networks of interactions. Being shaped chiefly by natural selection, these machine-like systems are expected to be robust. But robustness is always defined in relation to a range of perturbations. Outside this range, perturbations can be deleterious for the system: “traits and control mechanisms tolerate the most common fluctuations and stressors, but remain fragile to unexpected perturbations.” Kriete’s “robustness trade-offs,” the result of natural selection, are the key notion. One may see this view as a variety of DST, since it concurs with DST in emphasizing that no perfect robustness—hence no perfect maintenance and repair—is to be expected. But here, by contrast, reproduction is not considered. The subsistence of the system itself, as robust against common disturbances, is the target of the trade-offs. Aging is introduced as a consequence of devices and dispositions that make the organism more robust. Kriete gives as an example the cells and asymmetric cell division, which prevents the daughter cell from inheriting the accumulated waste substances (released at each division). Here, cell aging in the sense of the accumulation of detrimental substances is the cost of the robustness of the daughter cells. Kriete generalizes this instance of the robustness trade-offs by summarizing his view in the following way: “aging evolved as fragility due to multifactorial robustness trade-offs in cellular performance and specialization, antagonistic control and limitation in resources.” In a similar vein, Gavrilov and Gavrilova (2001) propose a “reliability theory” that is a “general theory about systems failure.” The (continued)

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Box 11.2  (continued)

idea is that aging systems are such that a survival function S (x) of a part, which is the probability that the failure time X of a part is beyond x, is increasing. Survival functions of many parts add up and produce a Gompertz curve; the theory accounts for the difference with Weibull law, because it shows conditions under which systems will age in a Weibull rather than Gompertz fashion. It explains the late-life plateau that puzzled evolutionists. When a system has redundant parts, defects in one part are compatible with the system’s survival. The defects accumulate, until the organism ultimately dies: “aging is a direct consequence (a trade-off) of systems redundancy that ensures increased reliability and lifespan of organisms. As defects accumulate, the redundancy in the number of elements finally disappears. As a result of this redundancy exhaustion, the organism degenerates into a system with no redundancy; that is, a system with elements connected in series, with the result being that any new defect leads to death” (Gavrilov & Gavrilova, 2001, 532). Here, the trade-off occurs between redundancy, ensuring longer survival, and the cost of producing more redundant parts. This account is quite predictive in terms of senescence patterns; it assumes many things, especially about the initial defects of living systems. Boonekamp et  al. (2014) performed lifelong brood-size manipulation in free-­ living jackdaws. The lifelong intervention, by contrast with usual experimental interventions that occur in a single year, yielded findings in accordance with this reliability theory. However, such an account may not seem evolutionary, at first glance. The various redundancies could be thought of as needing an evolutionary explanation, while the whole trade-off hypothesized here pertains to a rather functional, proximate explanation, and therefore complements the evolutionary explanations.

11.3   Multiplying and Combining the Types of Trade-Offs The complexity of the concept of trade-off when it comes to life history and senescence is still more complex. First, most of the trade-offs we’ve seen until now, especially in the DST framework, are allocation trade-offs.

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However, before organisms can allocate resources, they must acquire them. Therefore, there may also be acquisition trade-offs, though they are much less explored.4 The trade-off hypotheses about death and senescence often assume other trade-offs, such as those related to acquisition, for example, which remain in the background, playing no significant role in determining aging rate and lifespan. In this paragraph I’ll unfold the complexity of the notion of trade-off. Beyond the many trade-offs that are intertwined in producing senescence-­ related trade-offs, as I just indicated, I will show that there is a difference between two types of trade-offs, and question their relation. The following paragraph will target the heart of the question, namely, the nature of what is traded in distinct types of trade-offs and in all of them. There are indeed trade-offs that are not focused on either repair, reproduction, growth, or longevity. They do indirectly affect these trade-offs, however, and are affected by them. Baudisch indicates some of them. Foraging, for example, has been a key topic for behavioral ecologists since seminal papers by McArthur, Levins, Pianka, or Charnov.5 Foraging time, in effect, may itself be determined by an exploitation/exploration tradeoff—exploitation, in turn, being characterized by a law of diminishing returns whose parameters contribute to settling this trade-off. But how long and with which resources one forages has a direct effect on resource acquisition. That may impact the acquisition/allocation trade-off that is simply assumed by hypotheses about allocation trade-offs designed by AP or DST theorists. One could consider this as irrelevant for the major, reproduction/repair (DST) or early-life/late-life (AP) trade-offs. But it has direct effects on the way these trade-offs shape senescence.6  See, for example, Van Noordwijk and De Jong (1986).  McArthur and Pianka 1966, McArthur and Levins, Charnov (1976). 6  Baudisch (2009) sketches these intertwinings between damage, foraging, fertility, and growth, mediated by various costs, in the following way: 4 5

the trade-off between mortality and fertility is not direct, but is instead mediated via physiological variables—size and damage. They describe the state of an organism at every age. Mortality is inversely related to size and proportional to the level of damage. The change in size and damage over time is regulated by the amount of foraging activity which is to be optimized. Mortality from predation increases with increasing foraging activity. The trade-­offs in this model thus include energy acquisition costs. More activity leads to higher energy intake that increases the total amount of energy available for growth and the repair of damage, but more activity also increases the risk of predation and the level of metabolism. Metabolism causes damage and requires energy. Growth increases size. A larger size lowers the risk of death and raises the ability to take in energy intake, but being big requires more energy for repair and higher levels of metabolism.

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In this sense, the work by Vaupel and Baudisch on trade-offs and senescence (Vaupel et al., 2004; Baudisch, 2009) contributes to explaining how the final shape of the trade-off between reproduction and maintenance emerges, in the spirit of DST, but including all these complexities surrounding actual trade-offs. They show that the form of the trade-off curve—illustrating how reproduction units are traded against maintenance units—determines whether senescence will be shaped as a Gompertz-style curve or as something very different, matching the nonstandard patterns of senescence seen in tortoises or some trees (see Chap. 8).7 This shows how crucial the trade-off concept and functions are, since they determine what type of senescence will occur or, in vernacular terms, whether senescence will occur (given that only “positive senescence,” in this typology, corresponds to what we usually call senescence, namely, the deterioration of physiological functions and fertility and an increase in chances of mortality, over time). Because of the theoretical impact of this notion, some theoreticians have questioned whether the trade-offs supporting senescence should be limited to reproduction, survival and repair, or, on the contrary, be extended to other aspects of life. Cichon already extended them to growth, although many life-history models combine growth with survival (see Chap. 10 above, §4.2). Taylor (1991) cited tractability as a reason for combining the two, a move which, following Levins, constitutes a methodological trade-off between simplicity and realism. Maklakov and Chapman (2019) investigate the homogeneity of the trade-offs considered by the evolutionary theory of aging. Many of the trade-offs involve an exchange of resources or energy. A trade-off is sometimes said to exist between investing energy in task A, rather than in task B: for example, A is survival, repair, or growth, and B is reproduction (1). But these authors notice that sometimes trade-offs means that a same task X, continuously done over the ages, has different consequences (2). This is hardly a new idea. They cite one of Williams’ first examples when he talks about AP: a gene that increases calcium formation enhances fitness during reproduction, but in late life has deleterious effects. Such a 7  “Whether or not senescence is the optimal strategy, they wrote, crucially depends on the shape of the trade-off between reproduction and maintenance. In our vitality model, concave trade-offs lead to inverse senescence, linear trade-offs lead to sustenance and convex trade-­ offs lead to senescence.” These three possibilities are the three kinds of shapes of senescence analyzed in our Chap. 9, even though senescence is by far the most common pattern.

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trade-­off appears to belong to type (2) above rather than to the most commonly studied type (1) Yet many of the trade-offs actually involved in senescence should be classified as type (2). Maklakov and Chapman (2019) cite a recent RNAi screening of genes involved in nematode development. Of a total of 2700 genes, 64 are “detrimental when deactivated during development, but (…) extend longevity when deactivated in adulthood.” If an energy trade-­ off was occurring, deactivating these genes in adulthood would not change lifespan, since energy allocated to early life reproduction has already been spent. What happens is that the genes are still doing something, which impedes longevity. The best explanation therefore consists in saying that these genes are doing what they were already doing, independently of what had happened earlier on, exactly as in Williams’ calcium example, where the only change is not in what the gene does, but in its consequences in what he calls the “somatic environment” in early life and in late life. Historically, it’s plausible that AP has been inclined towards a sense of “pleiotropy,” namely, energy trade-offs in sense (1), which was not the one favored by Williams. But the fact is that several examples of these type (2) trade-offs affect death and senescence. Maklakov and Chapman (2019) mention the effect of IIS signaling in nematodes. It converts gut biomass into yolk. Early on, therefore, it contributes to reproduction. However, in late life, unneeded yolk accumulates and hastens senescence. The point here is that no unrepaired damage occurs, as DST would hypothesize; on the contrary, senescent deterioration is caused by the functional effect of signaling mechanisms. Epistemologically, this kind of trade-off, called “function trade-off,” by the authors, and the usual energy trade-offs, yield different hypotheses: DST and functional trade-offs make different predictions. The role of the somatic environment is decisive in function trade-offs whereas it is not in energy trade-offs. However, someone could object that this type (2) trade-off is not a complete explanation. In the example of the nematode yolk, what makes the yolk production detrimental is that the nematode does not reproduce more in late life, or at least reproduces less. Thus, the life history of the nematode is what explains the change of somatic environment, in which the same signaling pathway can give rise first to usable yolk, good for fitness because it fosters reproduction, and later to unused yolk, detrimental to life. But this life history could itself be explained in terms of trade-offs, since it could instantiate a trade-off between early-life and late-life

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reproduction, and, in this case, an energy trade-off supports the life-history pattern: investing in reproduction earlier rather than later is a typical figure of many life histories, and directly derives from the “age-related bias” on fitness pointed out by Williams: namely, even in the absence of any senescence, chances are higher that the organism will be alive after n units of time than after a*n (a>1) units of time; therefore selection favors reproduction at n rather than at a*n, everything else being equal. As a consequence, while we found out that there are several types of trade-offs (beyond the many trade-offs adjusting reproduction and survival), these might not be symmetrical, because the function trade-off possibly calls for an explanation that would involve an energy trade-off and not reciprocally. Such great complexity demands radical questioning about trade-offs. Exactly what is being traded? The paragraph above tends to suggest that trade-offs are ultimately about energy.8 But epistemically speaking, energy itself is not directly a causal variable in selective processes. What plays a causal or explanatory role9 is actually fitness instead. Yet there is no consensus about how to define fitness, even though measuring fitness is much less controversial than defining it, and published estimations of fitness in a specific case ordinarily obtain approval from peers. In this case, a possible account could consist in adopting a more skeptical position, and embracing the idea that there are various trade-offs between allocation, acquisition, energy, and function, etc. (even though these may finally resolve into energy trade-offs)—but no single item x that is always traded between early and late life. Such trade-off skepticism or pluralism may not be incoherent or unexpected, given the attractiveness of pluralism showing up in this book. But such precise skepticism is problematic because several multiple trade-offs among those I mentioned in this chapter ultimately combine into a general explanation of a senescence pattern, and, by definition, combination assumes a sort of compatibility, hence possibly a common stuff to be traded.

8  Obviously energy here is not what physicists call energy, even though some biologists could say that eventually everything can be weighted in terms of calorie intake and investment. 9  We saw when I mentioned controversies over “statisticalism” that this alternative is disputed.

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Thus we face the following apparent antinomy: –– Many trade-offs exist, and a plausible interpretation of their heterogeneity is that what is traded is not always the same thing; –– but explaining senescence means showing that the possibly multiple trade-offs between early life and late life (and between several functions, or processes, as I extensively reported) can combine and yield a single life history distribution and senescence pattern, in the face of an environment in equilibrium.10 Yet, pluralism about trade-offs is not skepticism, since there might in theory be several kinds of items traded through each trade-off relevant to senescence, still leaving the possibility open for an ultimate homogeneity of these trade-offs. Let us now explore this possibility.

11.4   What Is Traded? Currencies, Stochasticity, and Limits of Trade-Offs 11.4.1   Multiple Currencies, Multiple Weights: Introducing Stochasticity and Constraints Recent theorists have questioned what exactly is traded in these trade-offs that underpin senescence, at least following Williams’ views. Maklakov aimed at distinguishing trade-offs of function from more ordinary energy trade-offs by pinpointing the consequences of incompatibility between them. Cohen et al. (2017) model the way energy trade-offs can compare with other kinds of trade-offs and affect the evolution of senescence. What is traded off is called the “currency.” Metabolism trade-offs, in which energy is traded between late life and early life, are not the only ones; others can use other currencies. For instance, “the potential limiting role of multiple nutrients has long been recognized in plant ecology”; and in animals, “the amino acid cysteine, α-linoleic acids, and carotenoids” may mediate trade-offs, an example of which is a “carotenoid-dependent sexually-­ selected displays versus immunity” trade-off (Isaksson et al., 2011).

10  A requisite that contributes to the difficulty of setting experimental corroborations of hypotheses on trade-offs and thereby contributes to the epistemic opacity analyzed in the previous chapter.

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In Cohen et al.’s model, fitness is affected by a trade-off between reproduction and survival, but this trade-off itself relies on several currencies: energy, as it’s classically assumed, but also nutrients or time. The question is therefore how the form of the trade-off is affected by its relying on several currencies instead of one. Especially, they compare trade-offs with one, two, and three currencies, examining how the increase in the number of currencies changes fitness. It is true that several traits often affect fitness, and these traits trade off survival and reproduction with various currencies—energy, but also nutrients or time (Fig. 11.2). The authors use the concept of weight, namely, a measure of “how much reproduction could be gained for a unit loss in survival, or vice-versa”: the weights can be different for different traits about which distinct currencies are traded. These differences are the key explanans for their findings, to which we shall now turn. The authors designed several simulations, which yielded significant results. First, having two currencies instead of one provides a longer lifetime reproductive value, hence, a higher lifetime reproductive success. Second, “multiple trade-offs rendered evolution of the underlying

Fig. 11.2  Example of the trade-offs between reproduction and survival that determine fitness of an organism. Several traits trade off these two functions, and those trade-offs involve distinct currencies. (After Cohen et al., 2017)

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physiological traits more stochastic, with a much greater range of trait values possible across different runs.” What happens and underpins the dynamics presented in the simulation is that when two traits compound fitness, the optimal trade-off between survival and reproduction can be reached through a set of combinations of trade-offs realized in the two currencies belonging to the two traits. Hence, some trade-off values for one compound trait move into the range of optimal trade-offs, whereas they were not there when only this trait was the sole target of a trade-off (occurring in its currency). And if the weights of the several currencies are different, this increases the range of possible combinations of trade-offs even more, allowing more room to increase lifetime reproductive value. But the other consequence is that, while one currency defines one optimal trade-off, several currencies, especially when the respective traits have different weights, define a large set of possible optima, in which stochastic processes alone determine the actual set of values of the traits. This is why multiple currencies—the situation closer to most real cases—reinforce the role of stochasticity in determining trait values. Cohen et al. (2020) use the language of fitness landscapes in population genetics: the single-­ currency case gives rise to a fitness peak; the multiple currencies/multiple weights case gives rise to an “optimality ridge.” The position of an actual system on this ridge is therefore left to chance, hence the key role of stochastic evolution in this situation. Such a model has the virtue of accounting for many of the problematic gaps we see between reproduction and survival. As we know, the trade-­ offs induced by AP entail increased longevity that goes with decreased reproduction, and vice versa. However, some cases have been observed where reproduction and survival seemed to be independent from each other, especially when the so-called longevity genes were investigated. The stochastic processes whose effects are amplified by multiple currencies trade-offs may explain these numerous failures of our expectations regarding trade-offs. When trade-offs are addressed in the highest sense of generality adopted by this paper, they “may in fact be much less constraining and straightforward than previously thought.” But a major consequence follows from this: “trade-offs are perhaps less important than once thought, while constraints are more important.” Why constraints? Because model by Cohen and colleagues hypothesized independent currencies and weights. However, in fact they may often be dependent, and this dependence constitutes physiological constraints. Thus, what explains an actual value of a

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trade-off—given that in the multiple currencies/multiple weights cases this value is underdetermined by selection—can be, in addition to stochasticity, the correlations that already exist between currencies, hence what evolutionists call “constraints,” a concept that is crucial in disputes over adaptationism. And in a single-authored paper, Alan Cohen (2016) explores what these constraints would be. He conceives of them in the framework of research on complex systems, seeing the set of metabolic and genomic pathways that support an organism’s life as a complex system. This categorizes his research as “systems biology.” He contrasts this perspective to that of DST precisely because of the explanatory role of constraints here and there, since “evolutionary mechanisms referred to in the disposable soma theory imply that complex systems dynamics are not central to aging: if they were, aging would likely evolve based on regulatory constraints in complex networks, rather than based on a large number of small trade-offs of things like energy allocation” (Cohen, 2016, 206). The interesting alternative imagined here stands between a multiplicity of trade-offs—for example, DST—and major emergences yielded by the network itself and finally shaping aging. Constraints are posited by the structure of the complex network that defines the system. Aging is a dysregulation of the system which is designed to withstand some perturbations, and the dysregulation can be seen when mapping the gene regulatory networks: the more variable these networks are, the more the organisms age. Because the robustness of a complex system plays a key role in this approach, Cohen connects his views to those of Kriete (2013), which focuses on trade-­offs likely to foster robustness (see Box in 11.2.1.). In the same sense, Ricklefs and Wikelski (2002) had already indicated that the endocrine system imposes a constraint upon trade-offs by restricting available variation. “Behavioral control mechanisms that are part of the neuroendocrine system constrain the potential range of variation in life histories tightly at all levels. These control mechanisms might lack genetic variation that would otherwise allow adaptive modification. The corticosterone stress response and steroid hormone control of risk sensitivity appear to produce a single dominant axis of behavior modification and life-history traits” (my emphasis). A recent paper by Cohen et al. (2020) pursues this critique of the paramount explanatory power of trade-offs, which has been driving senescence research since Williams’ seminal paper. They concur in restraining the explanatory role of trade-offs and inflating the explanatory interest of constraints. However, since a trade-off limits

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the value of a trait, and a constraint is a limit upon the value of a trait, these two concepts may not be so easy to distinguish. In a classical manner, the authors define “trade-off” as follows: “an increase in fitness or a specific aspect of functioning via one component mechanism/trait inevitably results in a decrement to the fitness/functioning through another component mechanism/trait, producing a limit on the total fitness/function achievable.” These trade-offs “may be modulated via organismal or evolutionary processes to adjust the balance between the mechanisms/traits in question” and they are opposed to constraints, “which are limits on fitness or functioning that are not subject to important modulation.”11 This is a rough distinction. For instance, “while the level of DNA damage might be adjustable via resource allocation, some minimal level is probably unavoidable and might be considered a constraint” (161). Cohen and colleagues focused on cost of reproductions (CoR), which is often supposed to be constant to define the trade-offs relevant to senescence (Cohen et  al., 2020). However, substantial papers have shown that CoR is very often condition dependent; namely, some individuals in a population undergo higher CoR than others according to their age and condition—and this fact determines the shape of the reproduction–survival trade-offs. But this implies that, once again, stochastic processes (governing conditions) impinge substantially on the cost of reproduction and therefore upon the trade-offs (not to mention their impact upon empirical estimations, of fitness, etc.).12 The research presented here shows that a multiplicity of pathways makes the notion of trade-off complex and unwieldy as a means of determining patterns of senescence. Especially, often there might be distinct causes of death, such as ROS or mitochondrial damage. Conventional theory considers all causes as a sum, coming under the category of “repair-­ mechanism failures” (in DST) or “negative correlations with reproduction” (in AP). However, this overlooks the fact that some causes of death don’t significantly affect physiological deterioration. Especially “selection pressure on an allele increasing susceptibility to a specific cause of death depends on the age-specific amount of other deaths in the population” 11  On the definitions of trade-off and constraints, see our entry “Trade-Offs” in André et al. (2022), 12  “Trade-offs are subject to strong stochastic influences caused by multiple driving forces, transforming detectability of survival CoR into a statistical challenge” (Cohen et  al., 2020, 157).

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(Cohen et al., 2020). This contributes to explaining that the cost of reproduction, caused by the effect on reproduction on these causes of death, can depend upon the age-class distribution of the population and then be age dependent. That complexity stands out when one considers that such a multiplicity of causes of death constrains possible trade-offs. For example, suppose that an allocation of resources to repair can reduce cellular senescence by fostering cell proliferation. This would, on the other hand, increase cancer risk, and therefore mortality risk per age-class, and senescence rate. Within causes of death, a trade-off therefore exists, even though all causes of death are traded against reproduction (Cohen et al., 2020, 161). A conclusion of the above-cited paper is that “trade-offs as key drivers of ageing are also likely a special but important case,” because some aging mechanisms “emerge from constraints related to the particular physiology and environment of the species; others reflect trade-offs that are modulable via mechanisms such as resource allocation. The various mechanisms can then interact with each other via feedback effects. The importance of tradeoffs in determining the aging rate of a given species thus depends on the particular combination of mechanisms and their susceptibility to trade-­ offs.” And those mechanisms are conditioned by constraints that are often phylogenetically inherited. Such constraints may be of various natures. One of the first papers to address constraints directly was Gould and Lewontin’s “spandrels” paper. They distinguished developmental, mechanical, and historical (phylogenetic) constraints, though these categories obviously overlap. In many clades, senescence can easily be understood as the result of developmental constraints, and I’ll consider this option in the next chapters. Similarly, phylogenetic constraints may explain commonalities of senescence patterns in different species in the same clade with environmental differences. What emerges through the research I just presented is a general issue regarding the components of the trade-off under focus in AP/DST theories, and more generally its consistency. The question is about weighting different currencies; namely, how do you match a unit of energy in a metabolic trade-off and a unit of nutrients in, for example, the abovementioned carotenoid trade-offs? And how do you match the various effects of causes of death at given ages on cost of reproduction, assuming a given age distribution in the population? Is the weighting measurement always local (i.e. proper to a clade, or a set of environments, or both), or does it behave like a general currency, serving as a commensurate equivalent?

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The response to these questions seems to be negative, thereby hindering the generality of the trade-off theories, even though the trade-off scheme remains powerful for making sense of the necessity of senescence and death. What happens to the theory next is interesting. On the one hand, trade-offs cannot be the core of a simple theory that explains the senescence-related explananda. On the other hand, however, kinds of trade-offs multiply within the explanations of death-related explananda. They diversify and expand beyond the initial late-life/early-life trade-offs that constituted the major insight of the AP hypothesis. Trade-offs of various natures occur variously in populations, and within the life cycle of an individual, and all these trade-offs combine into an explanans of senescence and death. As Baudisch and Vaupel (2012) recognized, “by widening horizons to consider not only early- versus late-life compromises but all the difficult choices an organism must make in allocating limited resources to competing needs over its life span, it is possible to gain insights into the diverse demographic patterns observed in nature.” This double trend—observing explanatory limits along with diversification of trade-offs that account for senescence and death—summarizes the theoretical fate of trade-offs in recent evolutionary accounts of death and senescence. 11.4.2   The Commensurability Issue: Fitness Trade-Offs and an Incursion into Community Ecology Remember how Williams introduced trade-offs as a conflict between two forces of selection, one that favors reproduction and therefore entails lifespan reduction as a by-product, and one that counters senescence. The open question here is how the two forces can be measured and compared. How are they commensurable? Assuming that a general theory of trade-­ offs is possible implies that some general measure exists and is context-­ independent. This is exactly what was challenged in the examination of senescence-related trade-offs I just undertook. But because it’s ultimately about natural selection, one could argue that in principle there is indeed some general measurement that makes the two selective forces, and ultimately the various compounds of trade-offs, commensurable. It is called fitness. After all, selection is the “survival of the fittest”—to recall the Darwinian (and initially Spencerian) phrase that gave rise to the term “fitness.” I’ll therefore end this examination of senescence

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trade-offs with a question reaching for the highest generality: is it correct to infer that fitness is what makes the selective forces commensurable? But before addressing this philosophical question, I want to make explicit an interesting consequence of the theories of trade-off and aging concerning ecology. As I said, the evolutionary accounts of death, by shifting priority from internal to external death, introduce ecology within the landscape of theories of senescence and death. However, the development of theoretical examination of trade-offs opens in turn a space for an ecological understanding of species diversity. A major question addressed by community ecology since the late nineteenth century is indeed the explanation of biodiversity patterns. Why do such and such species coexist in a given environment, and what accounts for the way various species populations are distributed? Without entering this question, I shall suggest that the theories of senescence, death, and the relevant trade-offs do play a role in explanations of species coexistence. Obviously, explaining lifespan and patterns of senescence could impact our conception of population regulation, since it has major consequences upon the abundance of a species during a given unit of time. Thus, it also impacts abundances of other species, since all species in a community are connected through relations of predation, competition, or mutualism/ parasitism. As Bonsall (2006) indicated, senescence has two faces: one evolutionary, about which I spoke extensively, and which is massively studied—and one ecological. He distinguishes between them as follows: “from an ecological perspective, we are interested in how life-history traits effect changes in population size through time. From an evolutionary perspective, we are interested in how and why traits under selection evolve” (Bonsall, 2006). Understanding trade-offs that regulate lifespan therefore becomes explanatory with respect to the account of biodiversity patterns. The question of species coexistence in ecology can be tackled according to the “competitive exclusion principle.” It states that when two species face the same predators and need the same resources, they cannot coexist. Only one can remain, while the other must go extinct. This is simply due to natural selection. As a consequence, coexistence is possible between species whose set of resources and predators—that is, their “fundamental niches”—overlap, at the very most. If their fundamental niches are identical, one must disappear. But this principle, which was first formulated by Lotka and by Gause in the early 1920s, does not govern the whole world of species assemblages. As famously indicated by Hutchinson, who coined the modern concept of

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niche (Hutchinson 1957; see Pocheville 2015), in the ocean, thousands of species of plankton coexist, despite the narrow range of environmental parameters yielding a small niche, which would lead one to expect few coexisting species. This “paradox of the plankton,” as he calls it (Hutchinson, 1961), is an ecological puzzle, and has been addressed in many ways. Especially, ecologists have understood that other ecological interactions may exist and counteract competition, leading to the coexistence of species that seem identical in terms of niche. Dispersion, that is, the ability to send seeds, or one’s descendants, far away, can in this sense counterbalance competition, so that at the equilibrium a community can be understood as shaped by a trade-off between competition and dispersion. While most trade-offs I have contemplated until now revolve around survival vs reproduction and take place in time, this trade-off concerns space rather than time; and actually, in this inquiry, I mainly considered nonspatialized models (spatially explicit models are used mostly in ecology, but are much less frequent than nonspatialized models). In a nutshell, when several species are supposed to be in the same territory, the best competitor is surely there, but lesser competitors can turn towards dispersion and still be there regionally (this argument has been recently made in defense of skepticism by Calcagno et al. (2006)). And in the same vein, colonization is a virtue that may overcome a lesser competitive ability (Mouquet & Loreau 2003). Here, the concept of trade-off, in ecology rather than in evolution, plays a major explanatory role once again. And among these trade-offs that may explain diversity, a suggestion made by Levins and Culver (1971) touches our present concern. Competitive ability might be traded off against longevity, which in turn affects not only the abundances of species, but more generally, species coexistence and ultimately species diversification. Hence, death is directly involved in a hypothesis intended to address a major problem in ecology. In a 2004 paper, Bonsall and Mangel focus on rockfishes (Sebastes) in the North Pacific. There are about 100 species within the order Scorpaeniformes (including the scorpionfishes and lion-fishes). Sixty-five species cooccur in the Northeast Pacific, and 56 species coexist in southern Californian waters; they feature a wide variability in their life-history traits, with highly variable lifespans, from 12  years (the calico rockfish, Sebastes dalli) to about 200 years (the rough-eye rockfish, Sebastes aleutianus). This diversity cannot be explained merely by competitive exclusion in environments with narrow ranges of characteristic parameters.

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Therefore, the variability of lifespans suggests that a longevity–competition trade-off could play a role. Differences in longevity may mitigate interspecific competition. This competition governs the death rates of the weaker competitor, but if that species outlives the best competitor, its death rates decrease over a longer period, which may allow for coexistence. For instance, when an individual in the species of the lesser competitor lives longer, it can still predate upon a prey species, while the better competitor can’t, assuming that there is a period in which this best competitor is still developing and therefore is not yet able to succeed in catching prey. The variety of lifespans among rockfish species corresponds to a situation where differences in longevity are traded off against competitive abilities. Longer species lifespan in turn fuels coexistence and then diversification patterns. Interestingly, the connection between evolution in a species and community ecology—namely, biodiversity patterns—is partially explained by an entrenchment of trade-offs: evolutionary trade-offs that yield longevity in a species, and then ecological trade-offs between species, which drive diversification in the community. This explanatory pattern is also circular, since the initial evolutionary trade-offs, between survival and reproduction or late-life and early-life effects, are indexed on extrinsic mortality, which is in turn determined by the ecological environment, hence by the assemblage of species in the community. This assemblage, in turn, is in part explained by a trade-off involving precisely the longevity of distinct species. This is an excellent example of what some people call “eco-evolutionary feedback”: interactions between evolutionary and ecological dynamics in which each explains and is explained by the other (e.g., Govaert et  al., 2019). But, for our purposes, it will suffice to note the relevance of the topic of trade-offs, and the explanatory power of these trade-offs regarding not only evolution but also community ecology (see Box 11.3). Box 11.3  A Hypothesis About Ecology and Evolution of Aging

In a recent paper Eric Bapteste, Charles Bernard, and Jerome Teulière introduce a radical idea, with the concept of “age-distorter.” Through an extensive review of literature on viruses, symbionts, and plasmids, they have shown that some of these act as modifiers of the aging rate of the host. For instance, they may accelerate the aging (continued)

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Box 11.3  (continued)

rate, an effect measured by comparing wild type with infected type of a species (Teulière et  al., 2021). Those age-distorters—a name reminding the “segregation distorters,” which are selfish genetic elements intensively studied (e.g. Burt & Trivers, 2006), hijack aging pathways in a way that increases reproduction, to the expense of the lifespan of the host—a modification that is obviously in the interest of the virus or plasmids. Often, prokaryotes are less resistant to this distortion than eukaryotes or metazoa. This view has a major potential for theories of death as well as the idea of the interplay between ecology and evolution. Teulière et al. (2021) indeed indicate that these age-distorters can be seen as either another form of repair vs reproduction trade-off, in accordance with DST, or as a novel source of antagonistic–pleiotropic element. In both cases, they challenge the idea that a biological individual has to be understood on the basis of its genome. Here, foreign elements—a virus or a plasmid—plays the exact same role as genes regarding the aging behavior of the individual. It means that aging is the stage of an ecological relation between two species—host and the virus or some other entity. Epistemologically, understanding aging would require a look at the interplay between species, and not only at the evolutionary trajectory of the focal species. On an even more general level, this view would push for the move some researchers are making when they consider that an ecological concept of individuality—namely, an individual as an ecosystem, constituted of many species in competitive and mutualistic relationship, for instance, a plant or metazoan host and many bacteria species—should be introduced in evolutionary theorizing (Van Baalen & Huneman, 2014; Huneman, 2020).

11.5  Fitness as a General Equivalent? The Roots of Trade-Offs and Some Epistemic Undecidabilities 11.5.1   Trade-Offs, Fitness, and Time You may recall that our discussion of the trade-offs involved in the evolutionary theory of senescence and my examination of the ontologies of trade-offs led to an open question. Can everything be converted into

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fitness, understood as a general equivalent, exactly the way money, in economics, is seen as the universal equivalent of all utilities?13 In many perspectives, death and senescence result from trade-offs that engage reproduction, together with other features such as survival or growth. By definition, senescence is “the decline in fitness with age” (Lemaitre et al., 2015). Hence it directly engages the concept of fitness, and it is plausible to think that what is traded off in each of these trade-offs that have multiple currencies can ultimately be translated into fitness. Fitness is defined as a mixture of survival and reproduction, and in actual environmental settings fitness value is often a specific combination of survival and offspring number. By definition, all that is invested in reproduction will not be used for survival. Thus, each species in a given ecological setting needs a specific definition of “fitness” as a measure of evolutionary success, and this measure is a properly weighted combination of survival and reproduction. The possibility that survival is traded off against reproduction in a given ecological setting—namely, the basis of DST and more generally AP—is therefore a logical consequence of the concept of fitness itself. In order to decide whether these considerations allow fitness to be considered as what is generally engaged in trade-offs that underpin senescence, I’ll focus a moment on this relation between survival and reproduction intrinsic to fitness. Reproduction and survival are prima facie not symmetrical terms. In the end, fitness is the probability distribution on the number of offspring, or some statistical moments (properties) of this distribution (e.g., Orr, 2009; Abrams, 2007). Hence some theoreticians might say fitness is mainly about reproduction. Notice that this different weighting of survival and reproduction mirrors what George Williams said about the two forces of selection, forces against senescence or in favor of fertility to the detriment of survival: there is an “age-related bias.” Such a bias is precisely the dissymmetry between reproduction and survival within the concept of fitness and its measures. But survival can be weighted against reproduction in many different ways. For instance, surviving longer and helping offspring may result, later on, in a higher number of offspring than a shorter lifespan and more offspring, since many will not survive when the parent is gone. If evolutionary success as the number of descendants (or alleles, or genes) left behind is assessed over the long term, the fitness of the longer survivor is actually greater. Thus, even though offspring may be the ultimate bookkeeper of  This paragraph mostly concerns individual fitness. The last chapters will introduce inclusive fitness. 13

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fitness, integrating survival in a complete notion of fitness is not superfluous, since a count of offspring may not be a sufficient evaluation of evolutionary success. As recalled in the beginning, quaking aspens have few descendants, but they have persisted for 80,000 years, which is hardly an evolutionary failure. Nevertheless, there is still a way to redefine fitness mostly in terms of reproduction. In this perspective, survival counts only as a promise of future offspring. To this extent, one could compare organism A that lives for a period of 2 T and has n offspring during each period T, with an organism B, which lives only one T and has 2n offspring during T. A and B have the same fitness, namely, 2n offspring, if one considers the mean offspring number, the roughest evaluation of fitness. A finer-grained view of fitness, here, would still argue that survival and reproduction are not combined in the same way in both cases, since A lives twice as long. But here, the same difference can be expressed without reference to survival: organism A reproduced 2 n times in a period 2 T, while organism B traded-off having n more offspring at T against having n offspring in the next period. The whole fitness function can now be expressed with no reference to survival, because it is a specific trade-off between reproduction at various stages. Actually, this simple model could make sense: in B, the organism’s strategy might be optimal because having many offspring at the same time may divert the predators. This is the strategy used by North American cicadas, which flourish once every 17 years, all at the same time, and minimize the amount of predator species encounters since 17 is prime. Inversely, in A, the strategy would consist in having few offspring in the first period, because too many would lead to a shortage of resources, a shortage alleviated by reproducing a second time, a third, a fourth, etc. Along these lines, fitness indeed seems to boil down to the quantity of offspring, hence reproduction distributed across time. Thus, all the various trade-offs that underpin senescence, if they are ultimately about fitness traded, concern the quantity of offspring, which provides the ultimate benchmark for these trade-offs. Ultimately, such trade-offs are about past and present vs future offspring, or actual vs potential offspring. No general formula for such temporal trade-off exists, but one can a priori say that past offspring are less risky since they are already there; present ones are fragile; and future ones may not exist, depending upon the conditions, but don’t compete with present ones, and hence increase the chances of a common survival. (Of course, there should be cues to assess the probability of these future offspring being viable.) That would answer our quest for a general currency and formulation of senescence trade-offs.

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But the internal character of a trade-off that pertains to fitness is not enough to solve this question of a common currency involved in senescence trade-offs. First, considering parental care and the so-called “quality” of offspring (i.e., their ability to have fertile offspring themselves) makes the measurement of fitness profoundly context dependent. Following a metaphor used by Fisher in his Genetical Theory of Natural Selection, an offspring is an investment that is paid off with its own offspring. But the question is, how can the value of these grand-offspring be assessed and compared to first-degree offspring, if all of them have to be weighted in the same units, namely, as a certain quantity of potential offspring? The answer is not straightforward—because all of this depends upon a kind of rate of interest. How so? Computing the “value” of a grand-grand offspring means being able to say how much a future offspring is worth, compared to a present offspring (all evaluated in terms of their potential offspring). And this is exactly a question of rate of interest, or, more theoretically said, it’s about the function used to discount time. Namely, there should be a mathematical function according to which the worth of one offspring at time t is estimated in function of one offspring at time 0, and this function is often called by economists the discounting function or discounting rate. Since future offspring of a parent now are traded off against present or immediately next ones, present survival is overrated, and what governs this trade-off is the discounting rate, namely, how much an offspring born in n units of time later is worth compared to a present additional offspring born now? An additional difficulty here, as Williams already saw it, is that in the population there are other offspring, stemming from my own offspring—hence, in a few species like humans, the role of parental care provided by grand-­ parents and especially post-menopausal mothers, whose existence is possibly evolutionarily selected because they increase the chances that cared-for grand-offspring will survive (the so-called “grand-mother hypothesis”). Yet no uncontroversial discounting function exists in biology; this is not because discounting functions would vary greatly depending on individual lives (as is the case among humans), but because a single universal discounting rate would be generally suboptimal and therefore dismantled by selection.14 Why? In cases where the future is highly uncertain, a more  All too briefly stated, in many contexts selection favors what is optimal, hence rational when “fitness” is taken as the utility in the evaluation of rationality of choices. (See Okasha (2018) on this equivalence between selection and rationality and its limits, and, in a more limited way, Huneman and Martens (2017)). 14

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distant future offspring would obviously be worth less than offspring in a closer future, which would be more likely to reproduce. Suppose indeed that there are several mutant individuals in the population whose discounting rate differs from the unique discounting rate f°, and assuming that discounting rate is slightly heritable. Ultimately, after several generations, some of them will have more offspring’s offspring than others, because their discounting function f did match better what goes on in nature, in the sense that they would tentatively exchange one offspring now against the equivalent of n offspring in time t, and then could have these n offspring in time t. Therefore, the final discounting rate in the population will instantiate the new function f. But how much would these selected individuals be more likely to reproduce? That depends upon the rate of degradation of the environment. Hence the reliability of future environments and their rate of self-similarity is crucial for determining the discounting rate. Since there is no common framework for such discounting function, the “offspring” taken as a sort of general equivalent to organize comparability and transferability of the investments traded is not unconditionally conceivable. Once again, even if all the basic trade-offs explored by biologists can be said to involve fitness in the end—which is the closest thing we could find to a “universal theory of trade-offs”—a general model of these trade-offs likely to be applied in any context and lineage seems out of reach. This question of how to weight the potential future offspring, and of the sense of the discounting rate, is deeply entrenched within the fitness concept itself. When assessing the fitness of traits or alleles, biologists are often facing modeling choices about the future offspring and their integration within fitness values. For example, in situations that some people call “niche construction,” which includes cases like beavers’ dams, the fitness of traits considered, such as being a dam-builder, extends towards several future generations (Lehmann, 2007). Hence, in order to apply a fitness concept, one has to settle for a discounting rate that sets the correspondence between the offspring now and the offspring at time or generation n (thus, not necessarily the offspring of a focal individual). But there might not be any context-independent answer to this problem. Therefore, the question often raised by theoreticians about what the genuine concept of fitness generaliter should be may not be decidable. There are several ways of interpreting the absence of a general discounting rate. One may think that indeed this is a question of concepts (a), or that it is a question of application (b). In the former case (a), in principle the conversion between past and present offspring has no value in general, independently of contexts of evolution. In the latter account (b), there is

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an abstract formula that would set the correspondence between offspring now and offspring at time n, but it has to be supplemented with empirical clauses to be applied. Therefore, its epistemic use needs criteria to be possible, and the criteria are not always self-evident. In other words, it would appear that in some cases, some epistemic community would prefer one criterion, whether another uses another criterion. I can think of behavioral ecologists and population geneticists as two distinct communities here, but there are many other instances of these communities. Thus, in the latter case (b) the issue with discounting rate is the pluralism of criteria for applying the general abstract formula, whereas in the former case (a), there is no general theory with such formula. I’m not deciding this question here, and in practice the difference between the two options is tiny, but I would tend to think that fitness trade-offs in the case of aging and death are rather presenting us with the former, no-theory case (as is proposed just below). 11.5.2   Senescence and Fitness: Contemplating the Plurality of Discounting Rates This plurality of discounting rates has major consequences for the understanding of senescence and death in terms of trade-offs. There is a deepset connection between the concept of fitness, its difficulties, and the evolutionary accounts of death proposed by trade-off theories. In order to be operational, however, each account should specify a discounting rate. A priori, this rate cannot be assessed on a general basis; therefore, it is bound to be diverse. For multicellular individuals, at least, death is thereby still evolutionarily necessary, because it is rooted in the concept of fitness, the overarching concept in evolutionary biology. More precisely, accounting for death necessarily involves trade-offs, because fitness itself is instantiated, each time, as a specific trade-off between reproduction at earlier and later stages. Thus, once again, against traditional metaphysics, death is not an intrinsic disposition inherent to living things to the extent that they are live individuals. Instead, death is somehow inherent to the conceptual framework of evolutionary biology. Hence, death is indeed something essential and intrinsic, as traditional metaphysicians had it, but not intrinsic to life itself: rather, it is intrinsic to fitness, or, more precisely, to the nature of evolutionary entities (see Box 11.4).

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Box 11.4  FTNS, Population Genetics, and Theories of Death

In a paper about Fisher, Medawar, Williams, and senescence, Brian Charlesworth wrote: These ideas [Fisher on reproductive value] greatly influenced Medawar (1952) when he was formulating the first explicit model of the evolution of aging. Medawar took it for granted that Fisher’s reproductive value measures the relative effectiveness of selection at age x. Given this premise, a hypothetical mutant gene that increases survival over a small time interval at an age when reproductive value is high would thus have a higher net effect on fitness than a gene acting at an age when reproductive value is low. Since reproductive value declines over much of adult life, this leads to the expectation that selection will be more effective in improving performance early in adult life than late in life. (Charlesworth, 2001).

The connection Charlesworth makes here articulates the major evolutionary claim of the decrease of the force of selection, at the heart of Medawar’s and then Williams’ alternative conceptions, to the notion of reproductive value and the correlative idea of differential contributions to reproductive value by age classes, fundamentally developed by Hamilton (1966). Charlesworth himself had mathematically developed Hamilton’s views in his book about evolution in age-structured populations in 1980.15This historical remark, by a leading population geneticist investigating the question of senescence, indicates that the theory of death traces back historically to one of the most theoretical and fundamental insights about evolutionary biology, namely Fisher’s Fundamental Theorem of Natural Selection (FTNS). Senescence appears here as a key issue in revealing (continued)  From a purely historical viewpoint, what allowed these advances in evolutionary genetics of senescence beyond Hamilton (1966) is not only behavioral ecology and life history theory (as argued above), but also the development of quantitative genetics based on the “breeder’s equation,” which connects a population’s response to selection to narrow heritability (additive genetic variance) and the selection coefficient. Lande and Arnold (1983) crucially developed it by substituting a multidimensional variance–covariance matrix to the mere narrow heritability coefficient, opening new dimensions for evolutionary genetics, also worked out by Deborah and Brian Charlesworth at the same time (Philippe Jarne, personal communication). 15

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Box 11.4  (continued)

something about the structure of evolutionary theorizing and modeling; and this reference to Fisher’s population genetics signals that Medawar’s approach at least is rooted in population genetics. As I indicated above, following Depew (2011), the Modern Synthesis had two branches, the American one, more concerned by diversity and organisms, and the British one, more concerned by adaptation and genes. Fisher was the overwhelming figure in the latter, while Williams was an American biologist somehow acclimating the British brand of the MS in the USA. Regarding the evolutionary views of death, ultimately, AP is theoretically supported by Fisher’s FTNS, which states that natural selection, by itself, maximizes mean population fitness.16 As Charlesworth (1993, 18) writes, “Under rather general conditions, selection theory thus predicts that life history traits in equilibrium populations exhibiting additive genetic variance which is maintained by selection will be expected to show negative genetic covariances and correlations with some other additively variable traits. (…) It is a consequence of the fact that selection exhausts additive genetic variance for net fitness (Fisher, 1930) [i.e., the FTNS], so that any remaining additive genetic variation in fitness-­related traits must reflect the properties of genes whose beneficial effects on some traits are counter-balanced by deleterious effects on other characters (antagonistic pleiotropy).” Additive genetic variance being exhausted, equilibrium means that positive effects in fitness for some traits should be compensated by negative effects in other traits, in other organisms of different age. The fact of aging and death is therefore connected to the most general and deepest theoretical facts of population genetics—at least, according to some (Fisherian) evolutionary biologists. Thus, both Medawar’s mutation accumulation view and Williams’ AP view can be rooted within the major theoretical ideas advanced by Fisher, and could be seen as two developments of its central tenets—respectively, the notion of reproductive value and its decrease, and the consequences of nullifying additive genetic variance through selection according to the FTNS.

16  See Birch (2016) and Okasha (2018) for reservations regarding such an optimization claim.

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Getting back to the plurality of trade-offs and currencies that structure the explanation of death and aging, here are some lessons we can draw. Everything hinges on two correlated things: the context-dependence of all discounting rates of fitness, and the omnipresence of discounting in all trade-offs that underpin senescence. The reasoning is the following: there is such a thing as a set of trade-­ offs that yield patterns of senescence in various species. Those trade-offs are based on several distinct currencies, and one can see them as compatible if the common currency assumed to make two distinct currency-based trade-offs comparable is fitness. In this sense, each trade-off could be translated into another trade-off. However, each trade-off may involve a distinct discounting rate, since those are context dependent and under selection. In this case, explanatory assumptions are needed to define the discounting rate specific to a given trade-off. Yet several explanatory assumptions—regarding, for instance, at which future generation an offspring is negligible because its probability of being born is very low, or to what extent resources can be considered to be constant or renewable, and under which rule—can be equally legitimate, but they could change, given the explanandum at stake. Thus, there is no fixity of the discounting rates that should prevail for each trade-off. Several are possible and legitimately hypothesizable at the same time. Hence, there is no general formulation that can be applied to two distinct trade-offs originally made with two distinct currencies, to make them comparable. Any modeling assumption may not hold for another trade-off or another species. Suppose indeed that there are several trade-offs, in distinct currencies, explaining lifespan L in species E. As we did, we assume that each currency C translates into fitness, so that its trade-off can be stated in terms of a trade-off between i offspring now and j offspring at time n, involving a discounting rate Rc. The question is how to compare Rc with Rcʹ and Rcʺ, the discounting rates proper to C′ and C″. My point is that all these rates Rc, Rcʹ, and Rcʺ cannot be articulated as a single rate, in the sense that a single function f would convert Rc into Rcʹ and Rcʹ into Rcʺ. Why is it the case? Because unraveling such functions assumes hypotheses regarding environment stability, species niche, etc., that are different for each currency. That is the reason why in this case, between the two interpretations of discounting rate undecidability (a and b) exposed above about fitness, I favor the strong one, (a) in which the problem is about the general

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concept. Because, in the end, thinking that there exists indeed a concept unique, and merely an issue regarding criteria of applicability (which are multiple and explanatory-­dependent), means that one already assumes such a function f whose existence I find problematic. In order to better figure this out, think of a hyperdimensional space, where each dimension is a trait that enters into a trade-off. In this representation, inhabiting the same space (for each dimension) means that there is a common currency for all trade-offs (in our case, fitness) (Fig. 11.3). The fact of a trade-off between x and y, two trait values on two dimensions, is represented by the curve that makes a unit of x correspond to a unit of y—namely, if x changes by t (respectively, dt), y should change by t’ (respectively, dx/dt). There is a discounting rate Rc holding between x and y; but here is the crucial theoretical question: Is there a general discounting rate that makes it possible to convert all dimensions? Not necessarily, because the assumptions needed to assume a trade-off between x and y may not hold for the discounting rate Rcʹ connecting y and z, which requires other assumptions. And changing all explanatory assumptions

Fig. 11.3  Hyperdimensional space representing currencies that support trade-­ offs between traits and the problem of a conversion rate R? between rates of convertibility expressed in distinct currencies

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would yield other values of these rates (for converting between other dimensions), which may be relevant for another explanatory purpose. In this case, an overall compatibility between trade-offs exists, but no precise definition of convertibility (i.e. a conversion rate applicable when one switches a unit of one axis towards another one of another axis) can be found. The distinct trade-offs underpinning senescence, even if they are all amenable to reformulation in terms of fitness as a single currency, can’t give rise to a single trade-off model, because the pairwise comparisons of traits can’t rely on the same and context-free rate of conversion. Thus, the attempt to produce a general convertibility between trait values, and therefore a general formula that explains the pattern of senescence, falls apart. This is not a mere concern for rationalist philosophers who would fetichize formalisms or the unity of science, as many philosophers of science have been ironically portrayed. It has consequences in real science. Think of what I termed the “epistemic gap” in theories of aging and senescence (in Chap. 10). By this term I meant the gap between the overarching theories of death and aging (AP, MA, DST) and the specific models explaining one issue (e.g. lifespan differences) or the characteristics of one clade with respect to aging. I claimed that we witness a lack of straightforward connection between the latter and the former—as is exemplified by the fact that the research on so-called longevity genes hardly corroborates AP by providing universally acknowledged antagonistically pleiotropic genes. Now we come to a reason for this gap. If a general evolutionary account of aging should involve trade-offs models, and if there is no straightforward way to derive all specific trade-offs models from a general theory, then there should be an epistemic gap between these models and the purported general theory. Which is what my analyses tend to show. Therefore the present chapter supports the idea that the structure of evolutionary accounts of aging should be characterized by an epistemic gap—which in turn constitutes a reason for doubting that the explanatory pluralism I extensively documented in Chap. 10 could be overcome one day.

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11.5.3   The Logics of Trade-Offs: The Limits of an Economics of Death Investigating the logics of trade-offs involved in senescence and death leads us to some general conclusions. (a) First, the generality of trade-offs as an explanans of all death-related explananda has been questioned, both theoretically and empirically. Even though one accepts that trade-offs in general explain why death in multicellular organisms, and differences in lifespan or in the shape of senescence, therefore agreeing with Da Silva (2020) or Gaillard and Lemaître (2017) that the core view of Hamilton (1966) and Williams (1957) is mostly correct, some limitations on trade-offs as a general explanation appear. No general theory of early/late-life fitness trade-offs and death or senescence holds, because the many specificities of trade-offs are playing key explanatory roles in these explanations. So only local trade-off theories (in various clades) can cast a light on these phenomena. In other words, there can be a general trade-off theory but it would leave unspecified what is in fact traded in trade-offs, the currency, or the rates of translation between units that are traded. Whether this counts as a genuine general or global theory of trade-offs and senescence is a matter merely of semantics. I anticipated above that it should pertain to a pluralistic but not skeptical theory of trade-offs. (b) The second limitation is that recent research concurs in showing that trade-offs alone are not likely to explain senescence phenomena of interest and rehabilitate the roles of constraints. This calls for three comments: –– I sketched the parallel between sex and death as two features of life that are prima facie difficult to explain by natural selection. Williams investigated both. As to sex, his view stated that among higher taxa such as birds, mammals, or beetles, sex was entrenched and acted like a constraint. Thus his theory had two parts, a selectionist account of the proximate advantage of sex, and a constraint-­based account of its inevitability among many clades. Recent research on senescence and death in the program initiated by Williams reevaluates the role of constraints and tends towards a two-­terms account. –– Trade-offs are modulable, whereas constraints are not; at least, on a specific, not too long timescale (Maynard Smith et  al., 1985).

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Hence, while the AP or DST accounts left room for the project of intervening on some genes and finally dealing with human longevity, the fact of constraints seems less sympathetic with such a research program. –– As indicated, the critiques of adaptationism use “constraint” as their mantra. Even though the meaning of the concept has changed since Gould and Lewontin (1979) (see Maynard Smith et al., 1985; Brakefield, 2006), it is still a keyword for evolutionary theory of development (Evo-Devo) and its research plans. The acknowledgment of the role of constraints in shaping senescence implies that Evo-Devo should have a role to play in this investigation. After all, Williams (1957) once again spoke of “morphogenesis” (namely, a key component of the “Devo” part of Evo-Devo) as one of the terms of the senescence trade-off. Indeed, developmental theory is now expected to have a role to play in understanding senescence and death. More generally, the acknowledgement of the limitations of trade-offs in explaining senescence and death parallels the critique of adaptationism, to the extent that adaptationist methods have always been focused on tradeoffs. Adaptationism in principle is what I called a “trade-off adaptationism” (Huneman, 2017); that is, each trait is assumed to be an optimal trade-off rather than some random value. Developmentalists have long argued that this can’t be the whole explanation of traits and adaptations, because many constraints are not merely the effect of the fitness cost of some trait upon the focal trait. Here, something similar occurs: optimal trade-offs are not the whole story. While trade-offs face limits as a predominant explanatory tool of senescence and death, and leave room to constraints of various orders, a major shift may be happening. Since the “trade-off” goes with the notions of optimizing and maximizing utility, it is indeed an economic concept, and since the beginning of this part of the book I have been using this conceptual view to explain death, senescence, and their relata. If these notions are not the alpha and omega of explanations in this domain, it means that there may be some limits to economic rationality.17 As I said, Darwinian

17  One may object here that not all economics instantiate these schemes, and that I am only considering so-called “orthodox” economics here. The point may be valid, but this is not the place to have this discussion. Instead, some readers may just want to insert “orthodox” each time I write “economics.”

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biology may be understood as a science of the optimal allocation of scarce resources, and this science is explained using the schemes of economic rationality. If trade-offs are not all-encompassing and explanatory, perhaps, when it comes to explaining death, the general economic scheme pervading evolutionary biology can fail. (c) Third, the economic model of life history and more generally evolutionary biology, whose tradition is at stake here, resonates with the economic providentialist scheme used by metaphysics to address the enigma of death, as I examined it in the first chapter of this second part. For many classical philosophers, death is the price paid by individual organisms for not being equal or identical to their (ideal) species, or to the universal, as Hegel made it explicit. A same scheme underpins the question that puzzled biologists examining death before Medawar and Williams; that is, why do multicellular organisms age and die, whereas unicellular ones do not (as it seemed to them)? It appears that death is the price paid for not being unicellular. Neo-Darwinian views of death brought up by Medawar and Williams and extensively investigated here seem to have overcome this scheme, since death is not a cost paid by multicellular individuality. The primacy of extrinsic mortality, which becomes the key for explaining death and aging, debunks Aristotle’s old adage that a living being dies because it’s alive, which had made death a necessary consequence of living, more essential than the contingencies possibly leading to accidental death. However, even though the kind of cost and trade is wholly different, something remains from this scheme in our current evolutionary understanding of death, namely, the economic idea of cost, investments, and allocation. To some extent, it seems therefore that we are not really distanced from this long-lasting and deep understanding of death; yet the terms of the deal have changed. Whereas the metaphysics of death would trade the life of the individual against the universal (the species), so that death of individuals is justified as the price paid for not being the universal, neo-Darwinians start with those trade-offs between surviving and reproducing, which could arguably be shown to retain some affinity with the conceptual pair individual/species. Survival is of the individual, reproduction produces the species (at least, on a definite, not too long, timescale)— even though, for orthodox Darwinians, nothing is there for the good of the species. And this economic scheme is rooted in the very essence of fitness, as a key Darwinian variable. Thus, the last difficulties faced by the trade-off approach are conceptually important, because they finally indicate the limits of the economic

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scheme of price and trade in general—as a conceptual grid capable of explaining the necessity of aging and death among most plants and animals (including us). This limit of the usual economic-inspired schema of fitness allocation as an explanans for senescence and death invites us to revisit a major question discussed by biogerontologists as well as evolutionary biologists, namely, the issue of a senescence program. In a nutshell: if there is a program for death, driving organisms to display the deterioration and fertility decrease proper to senescence, then this program should be counter-selected, because variants that don’t respect the program would have a major advantage in reproduction. By definition, trade-offs can be modulated, and that could be a major argument here. Such modulations would be able to shift the death program towards unpredicted aims. Thus, the consensus among evolutionary biologists is that there is no death program. But constraints are not modulable, by definition. Therefore, if they play a role in aging, the existence of a program could be reintroduced as a possibly explanatory idea within the theory of senescence and death. This is all the more plausible insofar as the existence of longevity genes has been demonstrated. In some cases, these longevity genes, when activated, do not obviously display a loss in fertility typical of the trade-offs that DST or AP refer to when explaining death. Hence, the next chapter will consider this question of a death program in the light of our current examinations.

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Gaillard, J. M., & Lemaître, J. F. (2017). The Williams’ legacy: A critical reappraisal of his nine predictions about the evolution of senescence. Evolution, 71(12), 2768–2785. Gaillard, J.-M., & Lemaître, J.-F. (2020). An integrative view of senescence in nature. Functional Ecology, 34, 4–16. Gavrilov, L.  A., & Gavrilova, N.  S. (2001). The reliability theory of aging and longevity. Journal of Theoretical Biology, 213(4), 527–545. Glücksmann, A. (1951). Cell deaths in normal vertebrate ontogeny. Biol. Rev. Camb. Phil. Soc. 26, 59–86. Goldberger, A. L., Peng, C. K., & Lipsitz, L. A. (2002). What is physiologic complexity and how does it change with aging and disease? Neurobiology of Aging, 23(1), 23–26. Gould, S. J, & Lewontin, R. C. (1979). The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proceedings of the Royal Society of London. Series B, Biological Sciences 21, 205(1161), 581–598. Govaert, L., Fronhofer, E.  A., Lion, S., et  al. (2019). Eco-evolutionary feedbacks—Theoretical models and perspectives. Functional Ecology, 33, 13–30. Hamilton, W. D. (1966). The moulding of senescence by natural selection. Journal of Theoretical Biology, 12(1), 12–45. Hirshfield, M. F., & Tinkle, D. W. (1975). Natural selection and the evolution of reproductive effort. PNAS, 72(6), 2227–2231. Huneman, P. (2017). Kant’s concept of organism revisited: A framework for a possible synthesis between Developmentalism and Adaptationism? The Monist, 100(3), 373–390. Huneman, P. (2020). Essay review: Exploring the conceptual foundations of post-­ hamiltonian evolutionary biology—Rationality and Evolution of Social Agents. Acta Biotheoretica, 68, 453–467. Huneman, P., & Martens, J. (2017). The behavioural ecology of irrational behaviour. History and Philosophy of life Sciences, 3(23)17;39(3):23. Hutchinson, G. E. (1957). Concluding remarks. Cold spring harbor symposium. Quantitative Biology, 22, 415–427. Hutchinson, G. E. (1961). The Paradox of the Plankton. The American Naturalist, 95, 137–145. Isaksson, C., Sheldon, B. C., & Uller, T. (2011). The challenges of integrating oxidative stress into life-history biology. Bioscience, 61(3), 194–202. Kriete, A. (2013). Robustness and aging—A systems-level perspective. Biosystems, 112(1), 37–48. Kriete, A., Lechner, M., Clearfield, D., & Bohmann, D. (2011). Computational systems biology of aging. Wiley Interdisciplinary Reviews. Systems Biology and Medicine, 3(4), 414–428. Lande, R., & Arnold, S. J. (1983). The measurement of selection on correlated characters. Evolution, 37(6), 1210–1226.

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Lehmann, L. (2007). The evolution of trans-generational altruism: Kin selection meets niche construction. Journal of Evolutionary Biology, 20(1), 181–189. Lemaître, J.-F., Berger, V., Bonenfant, C., Douhard, M., Gamelon, M., Plard, F., et al. (2015). Early-late life trade-offs and the evolution of ageing in the wild. Proceedings of the Royal Society B, 282(1806), 20150209. Levins, R., & Culver, D. (1971, Jun). Regional coexistence of species and competition between rare species. Proceedings of the National Academy of Sciences of the United States of America, 68(6), 1246–1248. Lipsitz, L.  A., & Goldberger, A.  L. (1992). Loss of ‘complexity’ and aging. Potential applications of fractals and chaos theory to senescence. Journal of the American Medical Association, 267(13), 1806–1809. Maklakov, A. A., & Chapman, T. (2019). Evolution of ageing as a tangle of trade-­ offs: Energy versus function. Proceedings of the Biology Science, 286(1911), 20191604. Maklakov, A. A., & Immler, S. (2016). The expensive germline and the evolution of ageing. Current Biology, 26(13), R577–R586. Maynard Smith, J. (1982). Evolution and the theory of games. Cambridge University Press. Maynard Smith, J., Burian, R., Kauffman, S., Alberch, P., Campbell, J., Goodwin, B., Lande, R., Raup, D., & Wolpert, L. (1985). Developmental constraints and evolution. QUARTERLY REVIEW OF BIOLOGY, 60, 265–287. McArthur, R. H., & Pianka, E. R. (1966). On optimal use of a patchy environment. American Naturalist, 100, 603–609. McArthur, R. H., & Levins, R. (1967). The limiting similarity, convergence, and divergence of coexisting species. American Naturalist, 101, 377–385. Medawar, P. B. (1952). An unsolved problem of biology. H. K. Lewis. Mouquet, N., & Loreau, M. (2003). Community patterns in source-sink metacommunities. The American Naturalist, 162(5), 544–557. Nothel, H. (1987). Adaptation of Drosophila melanogaster populations to high mutation pressure—Evolutionary adjustment of mutation rates. PNAS, 84, 1045–1049. Nowak, M. A., Tarnita, C. E., & Wilson, E. O. (2010). The evolution of eusociality. Nature, 26; 466(7310), 1057–1062. Okasha, S. (2008). Fisher’s fundamental theorem of natural selection—A philosophical analysis. British Journal for the Philosophy of Science, 59(3), 319–351. Okasha, S. (2018). Goals and agents in evolution. Oxford University Press. Orr, H. A. (2009). Fitness and its role in evolutionary genetics. Nature Reviews Genetics, 10, 531–539. Partridge, L., & Barton, N. H. (1993). Optimality, mutation and the evolution of ageing. Nature, 362(6418), 305–311. Pocheville, A. (2015). The ecological niche: History and recent controversies. In T. Heams, P. Huneman, G. Lecointre, & M. Silberstein (Eds.), Handbook of evolutionary thinking in the sciences. Springer.

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CHAPTER 12

Ontology (2) Death Programs and Their Discontents

The last chapter addressed in detail the theme of “trade-offs.” It is the key concept underpinning two major evolutionary accounts of aging and death, disposable soma theory (DST) and antagonistic pleiotropy (AP). It turned out that this concept of trade-offs is multifaceted, and that while its explanatory power is broad, certain aspects of longevity, aging, and death are better explained by constraints. This fact appears as a limit to the economic scheme of thought that ultimately governs our scientific (evolutionary) conception of death. The reference to “constraints” re-opened a highly disputed question: namely, whether there is a program governing death and senescence, instead of just “wear and tear” on organs. Its scope would be prescribed (by AP or DST), through some trade-offs that in turn are modulable according to the environment. In this chapter, and the following I will consider the debate over death programs, and then in the last chapter turn toward something implicit in this debate: the role of social and group structure within the evolution of senescence and death.

12.1   The Disputed Question: Is There a Death Program? A death program embodies a very old intuition, namely that senescence and death are a kind of destiny and, as such, are seemingly written somewhere. In the Jewish tradition, during the week between the Jewish New Year and Yom Kippur, God writes the names of those who will survive the © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_12

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coming year. In a wholly different culture, Death Note is a Japanese manga telling the story of a young man who possesses a notebook in which he writes the names of the people he wants to see dead, and immediately these persons pass away. Thus, the notion of death program has a strong appeal in many imaginary representations. But does current biology endow it with some plausibility? As we saw in Chap. 10, research has unraveled several longevity genes in a range of model organisms. These genes are such that, when neutralized, the organism would live longer than expected. The notion of “program” in biology appeared around 1950, in the context of genetics, as I noted. Hence, the fact that some genes have an effect on longevity could be interpreted in terms of a program in which these genes would operate, a program that sets longevity. After all, the fact that more than a thousand genes are involved in the determination of lifespan may indicate that a significant part of the genome determines the lifespan of a species and even the way this lifespan is produced, namely, senescence. Perhaps these genes are therefore elements of a hidden program. A death program would make sense of the striking feature of salmon and similar species that die once they have mated. Instead of being random, death and senescence would be programmed to occur: “hatch / mate / die.” But the bulk of evolutionary theories, as we have extensively seen, rely on trade-offs between survival and reproduction. If, once neutralized, a gene extends lifespan, all things being equal, it does not contradict any evolutionary account; AP theory predicts merely that this life extension goes with a restriction in fecundity. And it’s the same with DST accounts. Granted, daf-1, the first nematode gene identified as a longevity gene, seemed to have no consequences upon reproduction. However, the in-­vitro conditions in which the experiment was carried out are extremely different from what happens in vivo. It has often been noted that nature does not always corroborate experimental data. Second, there is evidence (cited in the previous chapter) that silencing a longevity gene like daf-2 has effects on reproductive output (Jenkins et  al., 2004). This would conform to the predictions of AP and DST, and therefore wouldn’t indicate anything new. It would just be a modulation of the survival-reproduction trade-off, and possibly reachable only in very specific and rare conditions such as laboratory environments. Those genes can’t be said to be part of a senescence or death program since they appear as a clear manifestation of AP or DST, and these theories don’t predict any such program. However, given the large amount of such genes—about 1205, as surveyed in the above-mentioned website—the

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question is not yet settled. Many genes have not been studied, and it’s possible that in the end, when silenced, they will not display any negative effect on fertility. Thus, they could be part of some death program. The jury therefore seems to be out. One of the most interesting methods used for recent explorations is network analysis. It focuses on one of the model organisms often studied in the biology of aging, namely Saccharomyces cerevisiae, or yeast. Yeast is unicellular, and since it is a classic model organism, much of its gene and protein-protein interaction network is already known. It is assumed that, because certain mechanisms are fundamental for the maintenance of the cell itself, many of them would have been passed on to lineages that evolved later and are conserved, so that the identification of genes impacting lifespan in yeast may help explaining what takes place in metazoa or plants. Studies on yeast and on nematodes in the last 15 years have unraveled important aspects of senescence that could be interpreted in favor of the existence of a death program, although that is not the dominant interpretation. Among them, what is now known as the “hallmarks of aging” is important. Modeled on the syntax of the seminal notion of “hallmarks of cancer” (Hanahan and Weinberg 2000), this concept provides a way to lump together the many biochemical or cellular pathways that support senescence. They include phenomena related to the IIF Insulin/Insulin Growth factor/Foxo signaling pathway, and more generally, nutrient sensing, in which the aging genes were first detected, as well as telomere attrition. In some species, only some of them exist, and their relative importance depends upon the clades and is not yet well understood.1 As Schmeer et al. (2019) argued, the generality of these hallmarks, their evolutionary conservation, and their reliance on many genetic networks can be understood in terms of a program theory of aging but not exclusively. As enunciated in the seminal paper by the team of Linda Partridge in 2013, the complete list of these hallmarks now known includes the following: • Epigenetic changes. • Impaired protein homeostasis (mostly concerning the decline of chaperone proteins that guide proper protein folding). • Deregulated nutrient sensing (including the IIF Insulin/IGF/Foxo and IGF1 Insulin Growth Factor signaling pathways, or mTOR etc.). • Telomere attrition. 1  A current “major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging” (López-Otín et al., 2013, 1194).

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• Mitochondrial dysfunction, which includes an increase of ROS (reactive oxygen species) production and therefore supports the longstanding free radical theory of aging mentioned above. • Cellular senescence.2 • Altered intercellular communication—at the endocrine, neuroendocrine, or neuronal level (manifested first inflammation, possibly due to accumulation of proinflammatory tissue damage, proinflammatory cytokines released by senescent cells, and failure of the system to clear dysfunctional host cells and pathogens). • Genomic instability—including DNA replication errors in nuclear DNA or mitochondrial DNA, or alterations of the nuclear architecture. DST theory has focused extensively on these phenomena, since they are all likely to be addressed by repair mechanisms. • Stem cell exhaustion. (After López-Otín et al., 2013) The theory of hallmarks of aging is not a mechanistic or evolutionary theory of senescence but a descriptive framework for thinking about deathrelated facts at all levels of the organism. Mitochondrial alterations, genomic instability, and protein homeostasis are such basic phenomena that they are the most general, and may be the most evolutionarily conserved. A noteworthy phenomenon is that some of these hallmarks may have ambiguous effects: they promote aging, but when their activity reaches a threshold they may resist it; or, inversely, they rely on a process or pathway that prevents alteration, but after some degree of use or intensity, become itself deleterious. We saw that decreased Insulin/IGF 1 signalling (IIS) may increase longevity by decreasing the cell metabolism rate; however, excessively low levels of IIS can harm life itself. Inhibition of target of rapamycin (TOR) in mice has side effects such as insulin resistance or testicular degeneration. Cell senescence, as exposed below, may allow the organism to get rid of dysfunctioning cells, therefore survive; however, past a threshold too many senescent cells promote aging. Deficiency in stem cells is a hallmark of aging but excessive proliferation of stem cells exhausts stem cell niches and finally casts aging: premature aging has been demonstrated by Rera et al. (2013) in the case of intestinal cells (see above on intestine stem cells). Often, ambivalence is a hallmark of the hallmarks of aging (see also Box 12.1 on complex systems).3  In the next chapter I’ll come back to this phenomenon.  Among prolific literatures on the hallmarks of aging—some being devoted to the critique I just mentioned—Lemoine (2021) proposed a sketch of the evolution of these hallmarks across clades. 2 3

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Two kinds of aging are distinguished at the level of a unicellular organism: replicative aging, which is the number of divisions a cell can undergo, and chronological aging, namely the time a cell can subsist after division. Some longevity research intends to use mathematical modeling and experiments to reconstruct the network of so-called longevity genes that underpin replicative aging or chronological aging of the cell, even though most of these genes are barely identified. In their 2008 paper Managbanag and colleagues claim that “Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity.” They first consider 40 already known longevity genes (concerning replicative aging), and build a network defined by the least numbers of interactions linking those genes with genes and proteins, where the term “interactions” “included physical binding, genetic relationships, and transcriptional regulation.” Then this “shortest path longevity network (SPLR)” is used to infer a protein-protein interaction network. The resulting “Binding SPLR” would include 138 putative longevity genes; and this prediction is then tested on these genes: deleting some of such alleles indeed produces long-lived strains, and while some of these alleles are already known, four of them are new. This method allows an exploration of the large set of genes involved in aging, in addition to the ones that have been experimentally detected. It’s to be noted that mechanisms entailing replicative life extension are poorly known—even though, “abundance of the ribosomal large subunit has recently emerged as a key longevity determinant in yeast and it seems likely that deletion of RPL37B is increasing life span via a similar mechanism.” Hence, this network analysis provides insight into the variety of genes involved in aging processes without studying all the processes in detail. It will also show that these living genes may be even more numerous than currently believed. But an awful lot of tests will be necessary to show that each of them could trigger fertility decrease when it’s deleted. As a consequence, the notion of a genetic program, already present in yeast and then conserved in subsequent clades, is still conceivable.

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Gems and de Magalhães (2021) recently argued against the confusion of understanding this way of describing some processes as a causal account of aging. Tenants of the “hallmarks” view confer to cellular damage a key causal role in aging, while this centrality of molecular damage as a cause started to be discussed around 2005; the major critique against such a view is that the reference to the uncontroversial “hallmarks of cancer” paradigm is a way to “save” this key assumption of the centrality of molecular damage. From an epistemological viewpoint this is an interesting critique: while they elsewhere support another paradigm (see below on “quasi-­programs,” Chap. 8), Gems and De Magalhaes point out that the hierarchy of causes, centered on molecular damage, is asserted and not proven, and that the “hallmarks” framework, taken causally, blurs the complex relation between aging and diseases of aging,4 therefore it forgets the problem of causal circularity and double counting that affects any theoretical account of health, as we have seen.

12.2   What Is at Stake? The question of the existence of a genetic program for death or senescence carries major consequences not only for fundamental research, but also for medicine and public health. For that reason, research into the matter is surrounded by intensive activity from pharmaceutical labs and the field of biotechnology. There is massive investment of researchers and funds in all of the topics connected to the question. Why is this the case? Bluntly speaking, the existence of a death program touches upon the possibility (or impossibility) of extending the human lifetime by modifying the program. In the craziest transhumanist dreams, death might be abolished. I won’t go into the transhumanist argument and its general consequences for medicine, nor will I describe the social organization of the community of biogerontology who considers the possibility of a death program. I will merely indicate the arguments that support this connection between projects of enhanced health and life extension on the one hand, and the fundamental question of a death program on the other.

4  “Neglect of diseases of aging and the belief in damage as the main cause of aging are mutually supportive, since it is evident that factors other than damage are major determinants of many diseases of aging”(Gems & de Magalhães, 2021, 8).

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In his 2007 paper entitled “Biological Aging Is No Longer an Unsolved Problem,” published by the Annals of the New York Academy of Science, Leonard Hayflick, whom we met when considering the Hayflick limit, was making reference to the title of Medawar’s seminal paper on aging, “An Unsolved Problem of Biology,” published 50 years earlier. Hayflick provocatively wrote: For the first 25 years after Medawar’s lecture most studies on aging were descriptive. But, in the subsequent 25 years the enormous advances that have been made in our understanding of fundamental biological mechanisms has been exploited by biogerontologists to provide us with new insights into the immediate cause of age changes.

Hayflick was confident that these mechanisms were, for the most part, understood. His paper distinguished aging as a process from diseases occurring mostly in old age because the aging process makes organisms more disease-prone. Hence, he calls for focusing on aging itself, instead of confusing the process with the diseases of old age. In humankind, he notes, strikingly, the life expectancy has increased by 27 years since 1900. This increase is equivalent to the number of years gained in the previous 2000  years. It is mostly due to the fight against infectious diseases. However, most of the gain occurred in the first 70 years; after 1970, life expectancy increased by only 6 years. Even more striking, if all causes of death “currently written on death certificates” were wiped out, life expectancy would only be increased by 15 years. Hayflick argues here that aging is a process per se, and that even in the absence of the diseases to which aging makes us more prone, people would still die, albeit slightly later than the current life expectancy. Hence, finding and combatting causes of aging is different from understanding and fighting diseases. First, note that the perspective of the “immediate causes” of aging that Hayflick takes is quite different from the evolutionist’s view. The latter, as I explained, mostly considers that increasingly frequent illnesses should be considered part of the aging process. Regardless of theory, evolution indeed made organisms more disease-prone with age, because of the genes that may be involved in these diseases. Whereas from the viewpoint of the proximate causes, it may be important to distinguish between

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physiological aging itself and the increased susceptibility to diseases it causes, from a Darwinian perspective, the evolutionary reasons for physiological aging and for susceptibility to disease are the same (namely, either trade-offs or mutation accumulation). Second, Hayflick argues that aging itself and not diseases should be studied, either because such research could provide the basis for action to prevent aging, or just because it’s something we want to know, even if we can’t act on it. Hayflick himself favors the second stance.5 By so doing, he seems to contradict much research that has been conducted since the 2000s with the aim on slowing human aging. This research was boosted by the discovery of longevity genes, as well as progress made in our understanding of pathologies such as cancer and Alzheimer’s disease. Hayflick thinks scientists who seek to fight pathologies associated with aging are misguided, precisely because all they can do is act on diseases, instead of addressing aging itself. The major causes of aging are already known, however, so once the distinction between aging and aging-related issues has been made, research programs can be structured and undertaken. By major causes, Hayflick means a fundamental division between two main theories of aging, which pertains to the topic I address in this chapter: “Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events.” And his view is that “aging, which commonly appears after reproductive maturation, is driven by random events not governed by a genetic program.” One of his arguments is the lack of evidence of any such program—but the absence of evidence is not evidence of absence, as we know. The other is that “there is a huge body of knowledge indicating that age changes are characterized by the loss of

 “Why then is it useful to pursue research on aging if the goal is not to intervene in the process? It is useful for the same reason that research in other areas of biological inquiry is useful and where there is an implicit and easily understood appreciation that intervention is not a goal. Research conducted on embryogenesis or fetal, childhood, or adult development is not conducted with the goal of understanding how to stop, slow, or reverse the development of embryos, fetuses, or the maturation of children. It is conducted to satisfy the human need to understand the processes and to learn how the pathologies associated with young cells and their role in developmental processes might be prevented.” 5

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molecular fidelity.” He applies this latter term to many processes we surveyed when considering loss of repair processes according to DST (somatic mutations, ROS, etc.) But the parallel he makes with the study of development—that it is not applied to changing development, but only to understanding it—is striking. If the parallel genuinely holds, it points to the existence of an aging program. Otherwise, many biologists could object that unless Hayflick considers the existence of a genetic program for aging and death, the parallel with development is meaningless. Therefore, unlike developmental theory, the science of the determinants of aging may be useful for controlling and possibly reducing aging. For this reason, Hayflick’s position, which is the dominant one—namely, “there is no death program”—coheres with a surge in aging research directed toward the major causes of senescence and the possibility of neutralizing them. In a recent paper we read, “frailty is caused by the accumulation of molecular damage that is also responsible for ageing. In this view, frailty can develop independently from any disease” (Chmielewski, 2020). The author calls this the standard biological model. And if such frailty is caused by ongoing loss of molecular fidelity, instantiated by various processes, and independent of diseases, reinstating this fidelity seems a legitimate endeavor: this model, says Chmielewski, “is associated with health-oriented approaches and pro-longevity interventions” (My emphasis). Thus, while the focus on this “accumulation of molecular damages” mentioned by Chmielewski has been recently increasing, within the proximate explanations of aging, against “earlier accounts that tended to be more broadly multifactorial” (Gems, 2022), the feasibility of life-extensions became stronger, since it’s easier to act upon one process than on many. It is therefore understandable that the question of the existence of a program underpins the possibility of potential interventions toward which biogerontological research would be oriented. Moreover, theoretical arguments against the program can be turned into justifications for longevity-­enhancing research. In the absence of a program, there is nothing necessary in the fact of aging; if aging is mostly random, then we might easily act on it, and ultimately, overcome the necessity, if not to die, at least to die this way. All the hype about transhumanism and life extensions is nourished by these arguments, because once the sources of

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molecular frailty have been identified, they can be acted upon. And if, for some reason, certain genes are part of the source, they too can be targeted. To this extent, the longevity genes I presented can be seen as objectives for this research. Likewise, intestinal stem cells, which were recently the focus of worldwide interest, are another important target for anti-­ senescence interventions. These assumptions can even be interpreted within the evolutionary framework of DST. All interventions that make frailty less intense diminish the need for repair; hence—assuming a constant cost for repair, and the fact that post-reproductive period is now less risky than it used to be— allowing more opportunities for repair later in life. Granted, Williams predicted that according to the AP account, any increase in survival should go with a decrease in fertility. However, as I have noted, DST is widely accepted when it comes to theorizing about senescence, and this hypothesis is based on DST. To sum up, the more the current research supports the non-­programmed view of aging and isolates systemic reasons for molecular fragility, the greater the potential for pro-longevity interventions, and the more a general transhumanist program, such as the one advocated by the iconic Aubrey De Grey, looks attractive. But transhumanists are simply an extremely radical version of what already exists in biogerontology and shapes its research efforts, namely, a commitment to promoting “healthy aging” that slightly shifts into a quest for “decelerating aging” (Gems, 2011). Given that for many gerontologists aging is “a disease process,” the two objectives, healthy and decelerated aging, tend to merge. And according to its proponents, the healing/enhancing process is unavoidable and promising; it “has an element of tragic inevitability: its benefits to health compel us to pursue it, despite the transformation of human society, and even human nature, that this could entail” (Ibid). In this context, some of the researchers involved in the search for the determinants of aging also develop start-ups based on their findings, which promote products supposedly having anti-aging virtues. Some of them (Longo, LopezOtin, Horvath…), who authored several of the papers cited in the present book, have had to retract or correct a few papers, especially about rejuvenation. The sociology of the research field of the determinants of aging is a topic of major interest because of what is economically and socially at stake but it will be the object of another study.

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Leaving biogerontological prospects aside, Cevenini et  al. (2010) emphasize that the aging process “does not occur only at the organism level,” but—revivifying Bichat’s intuition—“also acts differently in each organ system, organ, tissue and even each single cell in the body, determining a different aging rate for each of them.” This means that after exposure to stress, the “mechanisms of maintenance” can be remodeled together—a phenomenon called hormesis, which yields resistance to stress. Mild stress or even exposure to toxins trigger responses that can produce “an improvement in cellular fitness” (López-Otín et al., 2013). Cevenini et  al. (2010) therefore suggest that promoting this hormetic response could improve aging and longevity.6 The antiaging method hype exploded in the 2000s. Naturally, entrepreneurs are eager to sell products based on the latest fashionable discovery that promises to slow aging. The market had already expanded so widely by 2002 that many prominent researchers in biogerontology such as Hayflick or Olshansky felt obliged to write a “position paper” stating that science does not back up many of these products (Olshansky et al., 2002).7 Clearly, the non-programmed view of aging supports many attempts to combat the process and extend longevity. Those ambitions in turn attract funding for studies of the mechanisms of aging and lifespan genetics. The circle that emerges might be expected to lead to the discovery of increasingly precise knowledge of the facts of longevity and aging. Of course, within this circle, the question of whether the aging process is programmed or not may never be settled, since, as Hayflick made clear, the non-­ programmed view assumes that stochastic deterioration and not program is the major explanans.

12.3   The No-Program Consensus Denying the possibility of programmed death is not just the bedrock of intensely funded research on anti-aging treatments and pro-longevity interventions, targeting not only the diseases correlated with aging but aging itself, it is also a position solidly backed up by theoretical research.  Concerning the intestinal epithelium as a target of longevity, the paper by Biteau et al. (2010) cited above was entitled “Lifespan Extension by Preserving Proliferative Homeostasis in Drosophila.” It shows that “promoting proliferative homeostasis in aging metazoans is a viable strategy to extend lifespan.” 7   For a more recent warning, from younger aging researchers, see de Magalhães et al. (2017). 6

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The reason, in a word, is that programmed death would not make evolutionary sense. As Flatt and Partridge in their 2018 review paper recall, the notion of an aging program is at odds with the evolutionary view: “Everything we know about the evolution of aging tells us that it is not a programmed process.”8 Explaining aging is therefore divided between ultimate explanations, in terms of mutation accumulation (MA), AP, or DST (the relations between these three frameworks having been explored in Chap. 5), and proximate explanations, in which stochastic degradations is the general account. In one of the first papers documenting AP by unicellulars (E. Coli) based on microfluidic, Yang et al. (2019) clearly express this divide thus: “The ultimate cause views aging as a component of the optimized life-history strategy. In bacteria, aging and mortality processes are indeed stochastic but still could be characterized quantitatively by the Gompertz law of mortality in terms of lifespan distributions.” In turn, the stochastic processes are of several kinds, and often the increasing molecular and cellular damages are supposed to underlie all of them. I’ll summarize versions of this objection before turning to the various alternative theoretical takes that seriously consider the notion of programmed death. First—as evolutionists argue—if there were a program for senescence and death, it would quickly have been counter-selected and eliminated by natural selection, since variants whose aging is not programmed would fare better in terms of survival and then reproduction. Second, since the strength of selection decays with time, genes expressing a senescence program in aging can’t in principle be selected for. Zimniak recapitulates: In general, however, unless a controversial formulation of group selection (Nowak et al., 2010) is invoked, traits that would become manifest only in old age cannot evolve. This precludes the evolutionary emergence of aging programs, which have been sometimes postulated to exist (Goldsmith, 2012; Mitteldorf, 2012) in analogy to developmental and other biological programs. (By the same token, selective pressure that diminishes with age would also prevent extreme longevity from evolving, if “extreme” denotes a potential life span much longer than that imposed by extrinsic mortality in a given environment.) (Zimniak, 2012, my emphasis) 8  Interestingly, they notice that the non-existence of a program seems to make senescence “intractable to experimental analysis or medical intervention.” But they add that “evolutionarily conserved high-level regulators of phenotypic plasticity have turned out to be able to produce a major rearrangement of physiology and to ameliorate the effects of aging” (Flatt & Partridge, 2018). Thus, there are also arguments for pro-longevity interventions that would derive from the existence of a program. However, most anti-aging research adheres to Hayflick’s consensual view that there is no program, just as our knowledge of evolution tells us.

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Others concur, such as Rando (2006), for whom “aging” cannot be a phenotype targeted by selection: Evolutionary theorists have entertained the possibility that ageing is genetically programmed, based on the notion that elimination of individuals who are past their reproductive prime would be beneficial for the species, as this would theoretically preserve resources for the most reproductively fit individuals and for future generations. However, this view has not withstood rigorous analysis, primarily because the ‘aged phenotype’ is rare in nature. The majority of animals in the wild succumb to starvation, predation, exposure, disease or accident long before the appearance of characteristics that are recognized as ageing in humans and in domesticated and laboratory animals. (Rando, 2006, 1081)

Steven Austad, a long-time researcher of senescence and death, summarizes his arguments in a short paper entitled “Is aging programmed?” He says that “aging is not design, it is decay. Decay and design are fundamentally different unless the nature and rate of decay are part of the design, which is very rarely the case.” Fruit is not genetically programmed to ripen and then rot; it does so for other reasons. The main justification for this claim is that programs produce an orderly sequence of events, whereas decay happens differently every time. Note that this is not the counterfactual reasoning evolutionary theory would have; it is merely an argument that nothing in the data we have on aging yields evidence of a death program. Austad compares “organisms which seemingly have been programed for decay, for example Pacific salmon of the genus Oncorhynchus” to the aging of other organisms, such as mice, in the laboratory. Granted, salmons display a sequence of possibly ordered events: “(1) an extreme increase in circulating levels of the stress hormone cortisol, leading to (2) degeneration of a number of glands and organs, including the stomach, liver, spleen, thymus, thyroid, gonads, pituitary, kidneys and cardiovascular system, which (3) causes death by multiple organ failure” (McQuillan et al., 2003). But Austad remarks that the cortisol increase may by itself lead to this series of events. In contrast, mice that are genetically identical and raised in identical circumstances “exhibit a wide variety of phenotypes as they age. For instance, in a cohort of C57BL/6 mice raised on a standard diet under specific pathogen-free conditions, about 10% of the population developed ulcerative dermatitis, the other 90% did not. In addition, about 40% of males developed cardiomyopathy by 1000 days of age, leaving 60% that did not” (Turturro et al., 2002). Similarly, some mice will develop

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cognitive deficits or tumors, others will not, and so on. And Austad emphasizes that “the key issue is not variation in length of life—even salmon vary in the age at which they spawn—but variation in the aging phenotype. The point is that there is no aging phenotype as standard as the developmental phenotype which leads to a young adult.” The contrast between development and aging consists in the typicality of the phenotypes for developmental stages, compared to a lack of typical aging phenotypes in most species. We therefore have no reason to believe that aging is programmed in the same way development is. Austad also notes that if we really want to call the aging process “programmed,” then anything could be a program, and the term becomes meaningless. Interestingly, contrary to Austad’s view, salmons have been cited by supporters of the idea of senescence programs such as Prinzinger (2005): A wide range of plant species, for example, die shortly after flowering, and there are thousands of animal species, among them insects, worms and fish, in which death occurs immediately after reproduction or even soon after successful copulation. One of the most dramatic examples is the male Argiope spider, which dies shortly after copulation by a programmed stop of the heartbeat and is then eaten by the female.

Austad objects that these facts are not convincing enough. He argues that no strong reason supports the claim that there are programs; it contrasts with the a priori argument stating that for evolutionary reasons, programs could not exist. The latter theory is often formulated by evolutionary biologists. Kirkwood, for example, discusses the “possibility that ageing is in some way programmed” (Kirkwood & Holliday, 1979). Although this theory is popular among gerontologists, they say, we are not aware of any serious attempt to explain how a programme could evolve. Nevertheless, once ageing has evolved as a result of reduced accuracy of macromolecular synthesis in somatic cells, then developmental changes could be superimposed on this as a secondary effect on the basic process of ageing.

Thus, in the section entitled “Development programmes and aging,” addressing a parallelism that we met earlier, the authors deny the possibility that a program could explain senescence, but leave open the possibility that the development program itself might impact on senescence.9 9  As I will indicate later, this paves the way for an influential theory on aging called “quasiprogram” (see below, Chap. 8).

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Are “the teeth of the horse, which wear down with time” a case of programmed aging? they ask. The DST-style trade-off between repair and reproduction explains such a fact. “In general the disposable soma theory, as well as that of Medawar and Williams, predicts that senescence will be associated with more or less synchronized changes in many tissues. Some of these may be due to error accumulation or the failure to renew cells; others may be due to developmental processes.” But “apart from age-­ related developmental changes, there are scattered examples of ageing that is specifically programmed.” They also consider the case of salmon semelparity, together with “the death of the female octopus a few weeks after her eggs have hatched.” DST answers those who make it into a case for programmed aging. The female puts so many of her resources into producing offspring that she is in any case unlikely to survive to produce a second brood. (…) If the likelihood of survival past the first act of reproduction is very low, then there will be little selection against developmental changes that result in death after reproduction. This is fairly convincing in the salmon, since to achieve a second reproductive cycle, the hazards associated with migration have to be circumvented. (Kirkwood & Holliday, 1979)

As we already saw, no obvious argument can support the idea that natural selection would evolve an aging program. Aging is obviously detrimental to organisms and, as Darwin made it clear, selection scrutinizes all tiny variations in order to foster the good of the individual. Thus, evolutionary biology concurred in showing that if senescence had evolved, it can’t have been directly selected. Haldane, in New Paths in Genetics, coined the phrase “selection shadow” for the period when the pressure of selection declines and the decline itself explains the age distribution of traits. After him, the major evolutionary theories concurred in explaining death-­ related phenomena by appealing to natural selection, but indirectly; selection shadow is either the progressive absence of selection (mutation accumulation) or the by-product of selection (antagonistic pleiotropy) (Chaps. 8 and 9). Thus, the only reason why an aging program would evolve directly by natural selection in organisms seems to be for the good of the species: to leave resources for conspecifics. But this is group selection and, as I’ve said, it has not been admitted by orthodox evolutionary theory since Williams (1966), at least in this simple form.10 That’s why there is a strong consensus among evolutionary biologists against the existence of aging

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programs. Nobody would like to reintroduce group selection explicitly, as Zimniak (2012) indicates. Later, I’ll reconsider something I’ll call “group-­ selection shadow,” to make sense of heterodox claims about programs. But for the moment, aging programs are a non  sequitur for most Darwinians. However, being rather general, this reasoning does not wholly conclude the debates. Certain facts, both novel and re-examined, are triggering new discussions.

12.4  Aging Programs, Reloaded (1): Unraveling Apoptosis For a few researchers, longevity genes—thousands of them—may challenge this consensus. The quick death of salmons and other similar organisms after reproduction is also given as an argument for aging programs, as we saw. Granted, standard evolutionary views have answers. But the few supporters of the aging program often point out events occurring at the cellular level as a good reason for leaving the program hypothesis open. The Hayflick limit is an interesting fact, in this respect. As Prinzinger recalls (Prinzinger, 2005), cells have a “maximal mitotic capability,” so that “the older the individual, the fewer cell divisions can be achieved before cellular senescence and death.” This defines a clock within the cell, often related to telomeres, the small DNA segments at the tips of chromosomes that lose one unit at each cell division, and gives rise to the idea of some lifespan program. Yet this is obviously not enough to explain all of our phenomena at all levels in terms of programs. Moreover, mitosis waste products are not equally distributed between the mother and the daughter cell. The mother cell is affected by division, while the daughter cell seems on the contrary to rejuvenate. These phenomena call into question the traditional formulation of the question of death in a Darwinian context, used by Weismann and then again by Williams, namely the contrast between immortal single cells, and mortal multicellular organisms. As a matter of fact, single cells die too, be they prokaryote or unicellular eukaryotes. But they don’t die in the same way, and it seems that the unicellular/multicellular contrast is another difference within patterns and

 In the last section of this chapter, I’ll consider contemporary forms of group selection.

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shapes of senescence that has to be added to the range of such profiles identified by researchers along the three last decades. Philosophers will be prone to notice that an erroneous idea, namely, the contrast between immortal single cells and mortal organisms, actually led to interesting research questions, and fruitful and robust accounts of the phenomenon at stake—aging and death. Yet, the phenomenon of rejuvenation between mother and daughter cells also raises another evolutionary issue about senescence: why doesn’t rejuvenation operate within all clades, in all cells? In general, an appeal to DST would answer this question. But another important cell-level phenomenon interests the supporters of the idea of a senescence program, namely programmed cell death. In 1972, in a paper entitled “Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics,” biologists J.F.  Kerr, A.H.  Wyllie, and A.R.  Currie coined the term “apoptosis” to signify a process whereby a cell, upon receiving a specific signal, enters a regular sequence of events that leads to its destruction and the release of the matter enclosed in the cytoplasm. This paper is an excellent example of the importance of naming phenomena, as long as the new name prevails, as it did here. As early as the 1950s, certain embryologists had understood that cell death could indeed play a role in ontogenesis, especially in limb formation. German embryologist Alfred Glücksmann, who had fled the Nazis, was studying chick development at Cambridge when he noticed that dead cells were often found in the lumen, cavities within tubes that form during development. In effect, embryogenesis systematically proceeds by generating tubes, which will finally form the lungs, kidneys, or digestive tract. The basic generative process is the folding of an epithelial tissue, creating a “lumen.” The correlations of dead cells with such lumens indicated that cell death should play some role, and Glücksmann (1951) wrote of morphogenetic cell death. In the 1960s, James Saunders, also an embryologist, was using the technique of staining embryonic tissues with Nile blue dye when he observed many disaggregated cells near the wing in formation. He understood that these spots were not traces of pigment, but shrinking and degenerating cells. His group thus compared stained chick embryos at various stages, in order to track the distributions of cell death during embryogenesis, using “the Hamburger-Hamilton schema of the forty six chronological stages of normal chick embryo development” (Jiang, 2012).

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In 1962, in “Cellular death in morphogenesis of the avian wing,” written with Mary Gasseling and Lilyan Saunders, Saunders had clearly hypothesized that a specific cell death plays a role in the morphogenesis process. He proved that cell death occurred in later stages, in a region condensed around the wing-body junction, as well as between the digits of chick embryos.11 Nowadays, the shaping of limbs is known to be a spectacular effect of programmed cell death. More generally, organogenesis proceeds by massive programmed cell death, but the central nervous system as well as the immune system are now known to be overproducing cells in order to systematically destroy many of them during development (reviewed in Zakeri et al., 2015). A major advance here was the fact that he characterized this cell death as a “programmed” process (Saunders, 1966). He and his colleagues pointed out a “death clock” that starts ticking at stage 17 of the development but is reversible until stage 21. Kerr and colleagues followed up on the idea, and their 1972 paper focused on this programmed cell death. Actually, “programmed” here meant that the sequence of fatal events does not come from the outside. Environmentally caused cell death is called necrosis. It has long been a well-known process. But what all these people, back to Saunders, had observed was not necrosis. Naming it “apoptosis” clearly set this newly observed process apart from necrosis. The latter comes from the outside and the former instantiates from the inside, a sequence of events that seems universal. Kerr, an Australian biologist who had been observing cell death for a decade, joined Wyllie and Currie in Aberdeen, and they started to think of what was specific to the cell death they studied. Necrosis initiates the rupture of the cell membrane, because the failure of the cell’s ionic pump accumulates lactase, leading to the entry of water by osmosis, then acidification and lysis. But Kerr had observed what he called “shrinkage necrosis,” which differs from rupture. Until the 1972 paper, he had been trying to understand why the cell would shrink and then die, going through chromatin coalescence and cell and nucleus fragmentation. The significance of Kerr et al. (1972) is that it gives the first general description of programmed cell death, directly addressed as PCD, and not only through a study of chick embryo, in order to sustain the assertion of its paramount biological importance. Hence the need for a new name.

 On this story see the dissertation by Jiang (2012).

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Why this paper, the culmination of a decade of ongoing research on cell death, crucially matters for us is described by Lockshin and Zakeri (2001) thus: “death was recognized as an interesting and biological event.” Kerr and his colleagues forged a new name for the phenomenon because they had recognized its pervasiveness, the commonality of its phases, and its relevance in contexts that are both normal—such as embryological— and pathological—such as tumoral. In a series of preceding publications, Kerr had led teams studying the adrenal cortex in rats, embryonic mesenchyme in animal and human neoplasms, and in the adrenal cortex following the withdrawal of adrenocorticotrophic hormone. Thus, the 1972 paper followed two decades of works by several groups (including Kerr’s), and by tying together old knowledge and novel advances, it isolated a new research object, namely “a distinct mode of cellular death with ultrastructural features that are consistent with an inherently active controlled phenomenon” (by contrast with the externally controlled, passive death that is necrosis). This phenomenon was detected in neoplasms, in many of the tissues of healthy animals and especially “at specific times during normal ontogenesis,” indicating its implication in development. In a paper illustrated with dozens of plates from electronic microscopic photography, Kerr and colleagues minutely characterize the morphological changes occurring in this process that “characteristically affects single cells.” Histologically, these are “the formation of small, roughly spherical or ovoid cytoplasmic fragments, some of which contain pyknotic remnants of nuclei.” They describe two stages in this process: the formation of the apoptotic bodies detected by their electronic microscope studies, and then their phagocytosis and degradation by other cells. While the nature of the initiating events is not clear, the paper describes these two stages and argues for their generality. In modern terms, the morphological aspects of the first step of apoptosis are “particular morphology in which the chromatin condenses or coalesces to heterochromatin in one or more masses in the nucleus. It usually settles along the still-intact nuclear membrane. The cells also shrink and become denser as determined by staining or flow cytometry, and often fragment into several pieces” (Lockshin & Zakeri, 2001). These pieces are eliminated by phagocytosis. The generality of this process as well as its specificity with regard to other known types of cell death grants a new name, thus Kerr and colleagues chose apoptosis. This is a Greek term “used to describe the dropping off or ‘falling off’ of petals from flowers or leaves from trees” (Kerr et  al., 1972). In addition to these descriptions of a process that had

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previously been captured in various contexts and from various viewpoints, but never identified as a single biological reality, Kerr et al. (1972) pinpointed two major features: the process is “completed fairly rapidly,” in about 24 hours, because few apoptotic bodies found in tissues means that an “extensive cell ‘drop-out’ is taking place”; and the process does not lead to any inflammation, unlike necrosis. They highlight this feature, stressing the efficiency of the process: “the process is economical in terms of ­re-­utilization of cell components.” Thus, the major message of the paper consists in emphasizing the key role apoptosis should have in many biological functions, and therefore, the further research it deserves, which should “determine the extent and frequency of apoptosis in the organs and tissues of healthy adult animals” and identify “the factors that determine which cells will be affected” (ibid). The search for these factors has been continuous ever since. For instance, in the 1990s, research on the role played by PCD in morphogenesis and especially lumen formation established that PCD is triggered by a “death signal” from an endodermal cell type. Apoptosis may be the “only mode of controlled cell death” and therefore Kerr et al. (1972) hypothesized that it has a crucial role in “the regulation of normal cell populations,” in addition to the much better-known process of cell production, namely mitosis. Embryogeny and teratogeny— processes that basically supervene on a certain regulation of cell proliferation—are therefore understandably seen as a field where apoptosis plays a major role. While its involvement in embryology has been long observed, “ultrastructural features” of the process were detected only in the early 1970s through the electron microscope. Kerr et al. connected these observations to other instances of controlled cell death in this paper, which proposes a broad interpretation of the “implications of this process in tissue kinetics” in general. In this framework, apoptosis is actively engaged in embryogenesis but also in tissue homeostasis in general, as well as tissue degeneration in neoplastic phenomena. From this moment on, apoptosis appears as the accomplishment of a program specific to the cell, intrinsic to any kind of animal tissue, and likely to fulfill several functions as well as bring about pathological processes. Granted, the notion of programmed cell death was already around in the 1960s. In Carroll Williams’ Harvard lab, cell death in the pupae of metamorphosing insects was considered; there, in his dissertation defended in 1963 and then in Lockshin and Williams (1964), Lockshin introduced the expression “programmed cell death,” meaning that “cells followed a

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sequence of controlled (and thereby implicitly genetic) steps towards their own destruction” (Lockshin & Zakeri, 2001). Although still uncertain of the exact triggers of the process, Kerr et al. (1972) write: “it seems clear, however, that in certain circumstances apoptosis is an inherently programmed event, by intrinsic ‘clocks’ specific for the cell type involved.” Such a clock, here, implicates genes. Saunders already used the expression, saying that “the death clock is ticking” in his 1966 paper “Death in embryonic systems.” The general idea of programmed death or apoptosis, seen now as a regular biological process, as universal and basic as mitosis, is expressed by Kerr and colleagues: “if indeed apoptosis is part of the genome, which is normally repressed in viable cells, the initiation of changes by a wide variety of stimuli would be understandable.” The early observations in embryology and molecular biology were thereby linked. Kerr and colleagues extended the significance of apoptosis from mammals and birds, where it had previously been studied, to “animal cell populations,” and so animals in general. Later research indeed focused on genes involved in the death program for a cell, discovered later in the 1970s by Sydney Brenner, Horvitz, and Sulston, working on Caenorhabditis elegans.12 “In 1976, Caenorhabditis elegans was developed as an organism useful for genetics, and John Sulston and H.  Robert Horvitz demonstrated that ~13% of somatic cells in the embryo die predictably, shortly after appearing” (Lockshin & Zakeri, 2001). This provided a simple model to study the genetic basis of cell death. The research bore fruit in the 1990s and 2000s—Lockshin and Zakeri (2001) found about 80,000 publications, with a rise in importance starting in the 1990s. In comparison to the seminal 1972 paper, later researchers realized that “apoptosis” is actually only one way of achieving programmed cell death; it “refers to a particular morphology in which the chromatin condenses or coalesces to heterochromatin in one or more masses in the nucleus.” Other ways of bringing about PCD in eukaryotes, namely necroptosis, pyroptosis, and ferroptosis (the latter two are forms of regulated necrosis), are less represented among PCD events. Apoptosis engages a so-called mitochondrial pathway, whereas the other forms don’t; the process starts with developmental cues or stress altering the expression of the Bcl-2 gene family, which is involved in the integrity of the outer mitochondrial 12  In 2002, they received the Nobel Prize for these findings. See Metzstein et al. (1998) for a review of all of their work on C. elegans.

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membrane, and therefore triggers the permeabilization of this membrane.13 A cascade of events ensues. It has gradually been reconstituted (see Box 1  in Green 2019 for a description of the four types of PCD). Green (2019) distinguishes cell “suicide” strictly speaking from cell “sabotage”: in the former, death is the result of a specific process that has evolved to produce cell death upon the reception of certain signals, while in the latter, a process changes something within the cell, so that its normal functioning leads to death. Ferroptosis is a kind of sabotage, unlike the other three forms of PCD. As it often happens in science, the constitution of a new object of investigation, apoptosis, initiated a process whereby distinctions were found and subvarieties of the object became relevant. Most recently, biologists have conceived of a kind of “assisted suicide,” in between suicide and sabotage (Green, 2019), “through which a cell actively ‘burrows’ via actin-mediated locomotion into a neighboring cell. The now engulfed cell dies due to nutrient deprivation and/or is killed upon fusion of lysosomes with the engulfed compartment” (Fais & Overholtzer, 2018). Programmed cell death brings out the realization that death—in the form of cell death—is involved in the normal activity of life and in its generation. In addition to participating in development, as Glücksmann (1951) had begun to observe, PCD is also a major tool in fighting infection. Rather than delving into immunology,14 I shall simply quote the short paper by Green (2019): “That regulated cell suicide can be essential for combatting infection seems to be especially clear in the case of pyroptosis. Mice lacking caspase-1 and caspase-11, and thus lacking all pyroptotic inflammasomes, are sensitive to a variety of bacterial and viral infections, as are animals lacking specific pyroptosis-inducing sensors such as NLRs or AIM2.”

13  Because researchers uncovered many processes, relying on distinct mechanisms, that accomplish cell death, a Committee on Cell-Death Nomenclature was constituted, in order to avoid unnecessary neologisms and foster convergence in labeling (Galluzzi et al., 2018). It published its recommendations in 2018. Although the details of this nomenclature are not crucial here, since cell death is not directly the center of our study, it is interesting to note that whereas the nomenclature committee numbered 40 members in 2012, in 2018 it had expanded to about 200 researchers. 14  Considering immunology in the context of the study of cell death, and resistance to death in general, is an immense task. I suggest the reader consult The Philosophy of Immunology by Thomas Pradeu (Cambridge: Cambridge University Press, 2018).

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That organismal life and cell death are strongly interwoven will come as no surprise to readers aware of Claude Bernard’s aphorism la vie c’est la mort (“life is death”). We shall later turn to the intertwining of cell death and death in general. However, let us look now at the idea that cell death programs seem to challenge the consensus that death programs do not exist. After all, if organisms host death programs within their cells, why would they not be themselves inhabited by a death program? The evolution of PCD in multicellular organisms is quite conceivable. Because this process plays a role in homeostasis and development, it clearly appears to enhance fitness. A cell that dies within an organism is a clone (or almost a clone, given somatic mutations) of other cells. Its evolutionary interests are equal to the interests of other cells and of the organism itself. It’s even plausible that PCD was part of the evolutionary origins of multicellularity, and was among the conditions that made it possible, given its role in both immunity and development (Koonin & Aravind, 2002). But for the same reason, the major objection to the existence of death or aging programs in organisms, namely, the difficulty of seeing why they would be selected, does not apply here, so objecting to the impossibility of death programs on the basis of the facts of PCD is still inconsistent. And clearly, while programmed cell death has been investigated since the 1960s, around the time when the major evolutionary theories of death were conceived, no strong argument in favor of an aging program has been raised on its sole ground.

12.5  Aging Programs, Reloaded (2). Yeast, Bacteria, and Their Suicides Nevertheless, later research on cell death discovered the occurrence of an even stranger phenomenon. Certain species of unicellular organisms, such as green algae, some bacteria, or yeast, are also subject to programmed cell death. These findings belong to a set of major scientific breakthroughs, in the last three decades, that have provided us with a much better understanding of aging and death among unicellular creatures. While it’s still believed that many unicellulars can live far longer than multicellular organisms, the basic dichotomy between mortal multicellular organisms and immortal unicellulars is no longer the norm. As we know, unicellular organisms replicate by mitosis, but a cell can’t replicate infinitely: the number of telomeres around the DNA shortens at each replication. The

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cell stops replicating when there are no more telomeres. The exact role of the telomeres, whether they are a cause or a symptom of the replicative limit, is still under discussion. Yeast is a eukaryote, possibly evolved from a lineage of multicellular organisms that lost multicellularity, and Escherichia coli is a bacterium, a prokaryote. Those has been shown to age, and the fact that they also “suicide” themselves has been later abundantly demonstrated through studying yeast or Saccharomyces cerevisiae, and then bacteria.15I will consider these two facts successively. 12.5.1   Aging Bacteria First, as I noted earlier, it is necessary to make a distinction between replicative aging, which is the number of replications undergone by a cell, and chronological aging, which is the amount of time a cell remains alive after all replications have been done. Both are a measure of something that corresponds to aging in multicellular organisms, since these parameters are related to the increasing probability of death. Of course, aging seems equivocal here, because yeasts face two kinds of aging, chronological and replicative. Both display interesting features. However, no immediate connection can be made between the findings on these model organisms and a general theory of aging. Second, if a cell that has been replicated many times replicates once more the daughter cell should be similar to the mother. Interestingly, the daughter cell of the penultimate replication should then have only one replication left. But this is not the case, meaning that there is an asymmetry between mother cell and daughter cell. Apparently, a sort of rejuvenation process takes place, so that the daughter cell is the same as the mother cell was prior to its many replications. It is true that the waste material secreted during mitosis is stored in the mother cell, making it less prone to replicate, whereas the daughter cell is rejuvenated and can start anew a set of replications, free of waste materials. Daughter-mother asymmetry and rejuvenation are among the key principles in aging research focusing on the cell. They have replaced the earlier dogma of unicellular immortality. This was a landmark finding, even though the consequences were not 15  The model organisms generally used by biologists are nematodes, mice, drosophila, and sometimes zebra fish, among animals; Arabidopsis thaliana among plants; and Escherichia coli and yeast among unicellulars.

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immediately captured after Mortimer and Johnston first published a study of yeast replication demonstrating this asymmetry (1959). Remember that Williams (1957) contrasted potentially immortal unicellulars with senescent multicellular organisms, and biologists discussing Williams clung to the same idea in the following years. But even in Finch’s book on aging (1991), prokaryotes were thought to be potentially immortal. In fact, the last eukaryote to be thought potentially immortal was a species of yeast, Schizosaccharomyces pombe, but Barker and Walmsley (1999) established that it featured subtle asymmetries. In the early 2000s, researchers using acute electronic microscopy flow chambers by which they test bacteria that produce stalks and free-floating daughter cells identified asymmetries in prokaryote cell division. They established that when bacteria divide, there are two poles in the division, and the pole that remains in the mother cell ages. After a certain number of divisions, it is ultimately unable to produce progeny. Ackermann et al. (2003) studied Caulobacter crescentus, a prokaryote that produces stalks in some conditions. They conclude that “even bacteria that are generally thought to be symmetrical often localize subcellular structures to their poles. As a consequence, division gives rise to two cells that differ with respect to the age of their poles.” This asymmetry indicates that senescence also happens in bacteria. In 2005, in the Tamara lab in Paris (which had established the existence of the SOS system in bacteria), a team led by François Taddei used automated time-lapse microscopy to study species of E. coli previously considered to be symmetrical. They showed that “two supposedly identical cells produced during cell division are functionally asymmetric; the old pole cell should be considered an aging parent repeatedly producing rejuvenated offspring” (Stewart et al., 2005). They conclude rather metaphysically that “no life strategy is immune to the effects of aging, and therefore immortality may be either too costly or mechanistically impossible in natural organisms.” Indeed, metaphysically speaking, this means that generations of older and younger bacteria can be identified. Williams (1957) used to think that where no generations can be distinguished—for instance, when there is no germline sequestration—there is no possibility for aging.16 But because here, 16  Also: “Generally, senescence should only evolve in those organisms that have a distinction between parents and offspring, even when reproduction occurs asexually; for example, if the parent reproduces by simple splitting or dividing symmetrically into identical offspring, then there is no clear delineation of parents versus offspring, selection cannot distinguish between them since there is no age structure, and aging is not expected to evolve” (Flatt & Partridge, 2018, 7).

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asymmetry makes it possible to distinguish generations, senescence can also evolve in bacteria, as has been also argued for by Turke (2008). In Yang et al. (2019), authors from the Taddei and Lindner team used the recent microfluidic methods, aiming at targeting cells one by one, to study the effects of stress on growth in E. Coli and test the optimal trade-­ offs theories of aging that are often corroborated in metazoa. In bacteria, the general stress response system (GSR) is controlled by the master transcription regulator rpoS. Their experiment considered two mutants on this factor, one that increases and one that decreases the level of GSR, and looked at the effect on growth, aging rate, and lifespan, in two conditions, a constant environment one, and a condition where excess and lack of resources (“feat” or “famine”) alternate. When the alternance between famine and feast privileges famine, then the overexpressed GSR mutants seem selected, meaning that the bacteria favor maintenance; inversely, when environments are more constant, mutations underexpressing GSR are less frequent, thereby indicating that selection favors reproduction over maintenance. The same trade-offs as in many animals and plants hold in bacteria. By monitoring a fluorescently tagged chaperone (IbpA) involved in aggregate processing, Lindner and colleagues in the same lab used time-­ lapse microscopy to find an explanation of the division asymmetry that attests senescence in cells: protein aggregation at the time of division accumulates at the older pole. This “accretion is associated with >30% of the loss of reproductive ability (aging) in these cells relative to the new-pole progeny.” What happens here parallels the reproduction of metazoans, where the zygote is purified of almost all epigenetic markers, and starts anew, while the cells of the parent continue aging. The unicellulars’ asymmetries in cell division are theoretically analogous to the bottleneck stage that characterizes the reproduction of many multicellular organisms. In both cases, what happens is a rejuvenation corollary to establishing a distinction between the old and the new. Lindner and colleagues speculated that this asymmetry in accumulating aggregated proteins as residuals is evolved to “segregate damage at the expense of aging individuals, resulting in the perpetuation of the population” (Lindner et al., 2008). This is clearly a group selection hypothesis, since it appeals to the “good” of the population. It therefore faces the critiques Williams addressed long ago to any conception of this kind. I will get back to this hypothesis in Chaps. 13 and 14 below.

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These findings also cast a light on Hayflick limit, the term for replicative aging, and it occurs in part because of the asymmetric division that grants daughter cells the possibility to live. The senescence occurring in single cells, which determines their replicative lifespan, has been extensively studied and reviewed, for instance in Henderson and Gottschling (2008). Protein aggregation, ROS, and decrease in protein homeostasis are all contributing factors in the limited replicative lifespan. The authors also hypothesize that any molecular asymmetry between mother and daughter cells could potentially contribute to age-asymmetry. For instance, like the diffusion barrier to the outer- membrane proteins of the nuclear envelope, budding yeast also have distinct plasma membrane compartments created by this septin-­ mediated diffusion barrier at the mother-bud neck. The diffusion barrier prevents translocation of transmembrane proteins in the plasma membrane from the mother cell past the bud neck and also affects the cortical endoplastic reticulum. Thus, age-asymmetry could be established by the requirement for daughter cells to synthesize new plasma membrane and cortical endoplastic reticulum proteins.

In such a way the very mechanism of cell division would contribute to the senescence of the dividing cell. Interestingly, it has also been shown by microfluidics based-method focused on single cells than in bacteria this aging process is decoupled from growth, so that “in E. coli cultures, all cells will be in the same steady state of growth and will be indistinguishable from one another regardless of their replicative age” (Wang et al., 2010). 12.5.2   Suicide Bacteria But this explanation of replicative lifespan is not the whole story. As Henderson and Gottschling further indicate, “this ‘age-asymmetry’ between mother and daughter deteriorates later in life. The closer a mother cell is to the end of her life, the shorter the life span of the daughter cells she produces. At the extreme, daughter cells produced by very old mother cells have life spans only 25% the length of the mother cell’s life span.” So while DST would predict the mother-daughter asymmetry because it appears as a trade-off between the fitness (in terms of amount of cells produced) and survival (of the mother cell), it is harder to account for such

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phenomena as the deterioration of the quality of the daughter cell in the classical DST scheme. There might be more to senescence than evolved effects of cell division in mitosis. Yet finding that yeast ages replicatively, and that the replicative quality also deteriorates, does not tell us anything about purported programs. However, since 1996, research has accumulated showing significant signs of apoptosis in prokaryotes such as E. coli as well as in yeast. Discussions are still open about why these bizarre features are to be found, but at least they exist, just as they do in multicellular organisms. An advantage of PCD in yeast is that it can be studied more easily than PCD within other organisms (see Box 12.2 on PCD in prokaryotes). Since the discovery of yeast apoptosis in 1997, “multiple yeast orthologs of crucial mammalian apoptotic proteins have been identified; conserved proteasomal, mitochondrial, and epigenetically regulated cell death pathways have been outlined; and physiological death scenarios have been described” (Carmona-Gutierrez et al., 2010, 763). Box 12.2  More Details About PCD in Prokaryotes

In prokaryotes, PCD processes are involved in the anti-antibiotic resistance of cell colonies, and in other phenomena such as the growth of bacterial colonies. In yeast, damaged or defective cells are the object of PCD.17 In bacteria such as E. coli, cell damage is sensed by a protein and may lead to the lysis of the cell. Genes involved in this cell death pathway have been identified. Cell death occurring after a triggering, due either to an internal factor or to an external factor, has often been described. Lee and Lee (2019) recently described three types of PCD in eukaryotes. In addition to the main one, apoptosis (Fig. 12.1), thymine deprivation, and toxin-antitoxin systems were the most important. Thymine is the nucleotide that exists in DNA but not in RNA (where it’s replaced by uracil). Although RNA still functions in the cell, thymine might be bypassed, and therefore the DNA can’t replicate and the cell breaks apart. Cells also have a toxin-antitoxin system through which potential toxins (continued) 17  “DNA damage and replication failure can stimulate the activation of yeast cell death programs; oxygen metabolism and ROS generation are thereby major causes of DNA damages” (Carmona-Gutierrez et al., 2010, 767).

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Box 12.2  (continued)

Fig. 12.1  The schema of apoptosis (Lee & Lee, 2019)

can be neutralized by antitoxins that bind to them. PCD may happen by the activation of one of the toxin-antitoxin modules. “Toxin-­ antitoxin (TA) systems, which consist of a bicistronic operon, are widely distributed in the prokaryotic kingdom, often in multiple number” (Lee & Lee, 2019, 1018).18 Simply said, in such systems, one finds “a pair of genes that specify two components: a stable toxin and an unstable antitoxin that interferes with the lethal action of the toxin” (Engelberg-Kulka et  al., 200619). As Van Melderen and Saavedra De Bast (2009) indicate, there are two types of TA systems one in which the antitoxin is a small RNA, complementary to the toxin mRNA so that it “regulates toxin expression by inhibiting the toxin’s translation”; in the other type, “the antitoxin is a small, unstable protein that sequesters the toxin through proteic complex formation.” TA systems are proteiforms and mobile: they are “capable of moving from one genome to another through horizontal gene transfer, as well as maintaining themselves in bacterial populations (continued)

 The functioning of the TA-induced PCD is described there in detail.  There exists a variety of toxin-antitoxins systems distributed in bacteria and elsewhere, which realizes PCD. Engelberg-Kulka et al. (2006) study in detail the mazEF system, present in E. Coli and in many bacteria. 18 19

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Box 12.2  (continued)

even at the expense of their host cell, at least when they are encoded in plasmids.” Hence it’s hard to single out their evolution, their common function, or their general structure. The complexities of PCD mechanisms among prokaryotes have just begun to be unraveled. Types of PCD that may not match those in eukaryotes go through very distinct and complex pathways. But these phenomena are so complex that another of the genes involved in similar processes, HipA, “has the potential to act both as an inhibitor of cell death and as a killing factor” (Lewis, 2000, 506). Experiments on penicillin resistance shed light on this ambivalence. Some hip E. coli mutants show resistance to antibiotics. However, in natural populations, they are rarely found. It is as if most E. coli cells choose to die in the presence of antibiotics. The explanation suggested by Lewis (2000) is that “improved survival to lethal factors is a deleterious trait” because the clonal populations ultimately would be composed of defective cells; while the “ability to eliminate defective cells (through programmed death) provides a clonal population with a significant competitive advantage.” Namely, the population will be quickly restored after the penicillin event (ibid). This explanation obviously seems to call for some group selection and would then be problematic. However, since the population is clonal, certain systems are similar to those at work in multicellular organisms, where PCD may protect the whole organism against damage caused by defective cells. More generally, PCD in bacteria would play the same role in the development of the colony as PCD in the embryology of multicellular organisms, a function that has been extensively studied since Glücksmann (1951). Of course, let us not forget that bacteria live not by themselves, but often aggregate in communities, mostly under the form of what is called biofilms. The formation of the biofilm is the analogue of “development” for multicellular organisms. Fibrobacter succinogenes bacteria lyse in culture—thus are destroyed not by apoptosis properly speaking but by another channel—but when sugar is added to the colony, they secrete a protease digesting the autolysins (produced formerly by the lysing

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bacteria). The interpretation is that, since the bacteria can convert sugar into proteins, there is no need to autolyse many cells in order to receive their content as nutrients. The experiments show that, very possibly, cells lyse in order to benefit daughter cells for the growth of the colony. Myxococcus bacteria behave similarly to the slime mold of Dictyostelium: namely, it forms a fruiting body which sporulates, and the spores found new colonies. In order to grow the fruiting body, the colony generates “autocides” that induce autolysis in dense culture, so that the growth of the fruiting body can be triggered by the nutrients released by dying cells. Authors like Carmona-Gutierrez, Büttner, Madeo and colleagues, working on unicellular eukaryote PCD, acknowledge the same parallel with PCD in multicellular organisms: “conceiving why yeast apoptosis follows the same physiological purpose known for multicellular organisms, namely eliminating superfluous cells, demands a conceptual change. Yeast populations should not be interpreted just as a group of partitioned unicellular organisms that do not communicate among each other, but rather as a multicellular community of interacting individuals. Under certain circumstances, the death of a single cell might be beneficial for the whole population, thus promoting the survival of the clone” (Carmona-­Gutierrez et  al., 2010, 764). Or, as Büttner et  al. (2006) put it: “similar to yeast colonies, cells in a metazoan multicellular organism undergo cell death to ensure normal development and survival of the whole organism.” PCD in S. cervisiae displays the same pattern of “suicide,” releasing nutrients for other cells as do the abovementioned bacteria, a release which couples with the interest of killing defective cells. This may occur with cells that are less fit. For example, a mother cell, said to be replicatively aged after many cell divisions, “eventually undergoes cell death that is accompanied by typical apoptotic markers such as ROS overproduction, phosphatidylserine externalization, and DNA fragmentation, thus eliminating damaged cellular material from the population” (Carmona-Gutierrez et al., 2010, 768). In bacteria, a process similar to the PCD of cells in multicellular organism occurs as a defense against cells that have turned cancerous (or that have the potential to do so). Lewis (2000) considers the case of clonal populations of E. coli bacteria that reach a stationary state after a phase of unceasing exponential growth. PCD phenomena in those populations at the onset of stationary stage explain it in part; GASP (for “growth advantage in stationary phase”) mutants are such potentially multiplying cells and therefore they are

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analogous to cancer cells—they outcompete the wild type but are likely to ultimately die out without leaving progeny. It is quite possible that the main danger that unicellular organisms face is not competitors, pathogens, or lack of nutrients, but their own kin turning into ‘unhopeful monsters’ [sic] and causing the death of the population. Any population surviving to stationary state faces the danger, and it is reasonable to expect that bacteria evolved countermeasures to limit its impact. (Lewis, 2000, 504, my emphasis)

Among those “countermeasures,” the PCD directed toward damaged DNA plays a major role, since mutant cells are under the scope of this program. Therefore, PCD in bacteria favors a low mutation rate, which is an appropriate strategy against over-dividing mutants that might take over the whole population and overexpand it, until it reaches its own extinction. Another strategy, documented in Lewis (2000) about S. pneumoniae, consists in a mechanism that produces lysis of a significant part of the bacterial population at the stationary state (such lysis kills cells regardless of whether they are wild or mutants). Besides the mutation control strategy offered by apoptosis, unicellular organisms have invented a “preventive suicide”: “once the population density becomes dangerously high and likely to produce takeover mutants, a quorum-sensing mechanism triggers lysis. This strategy is essentially preventive suicide” (Lewis, 2000, 509).20 To sum up, through parallel research programs bacteria and yeast have been shown to harbor varieties of death programs, fulfilling functions evocative of what PCD does in multicellular organisms regulating developmental growth, preventing rogue mutants, and eliminating defective cells. But before turning to the general considerations likely to be inferred about death programs, let us go into a few epistemological considerations.

12.6  Epistemological Considerations Regarding PCD, what exactly can be observed in unicellular organisms? The answer is first a morphological pattern. PCD is made up of a characteristic sequence of events occurring within the cell: apoptosis, for example.

20  The phrase “unhopeful monsters” refers to a famous concept forged by geneticist Goldschmidt in his 1941 The material bases of evolution. He thought that populations may host extreme variants, poorly adapted (monsters) but likely to be very fit after an imminent environmental change (hopeful). Evolution would massively rely on these “hopeful monsters”: this view has been severely fought by the architects of the Modern Synthesis, especially Ernst Mayr.

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What the teams of Frohlich—who authored the first paper on PCD in yeast in 1997—or Kim Lewis first saw was a replica of the standard PCD in metazoans. In their seminal paper, Frohlich’s team claimed to have found “Diagnostic Markers of Early and Late Apoptosis” in yeast. The signs of apoptosis are: “membrane staining with annexing V, indicating an exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane; intense staining, using the terminal deoxynucleotidyl transferase– mediated dUTP nick end labeling method, indicating DNA fragmentation; and chromatin condensation and fragmentation” (Madeo et al., 1997).21 This process involves substances that trigger apoptosis. They can be compared to known trigger substances, like certain proapoptotic proteins. The role of caspases in PCD in multicellular model organisms has received special emphasis over the last two decades as inducing apoptosis, and in yeast, orthologs of caspases play a similar role.22 Caspases are divided into “inflammatory and apoptotic caspases, with the latter further organised into initiator and executioner caspases” (Klemenčič & Funk, 2018). Homologs of caspases are metacaspases and metacaspase-like proteases, to be found in plants and in prokaryotes. And among external inducers of PCD, ROS (reactive oxygen species) are also important for triggering apoptosis in multicellular organism. Meanwhile, their role in inducing PCD in yeast is now attested: “interestingly, impaired ERAD due to deletion of ERV29  in yeast causes ER stress and induction of the unfolded protein response (UPR), which results in ROS production by mitochondria and ER, and subsequent apoptosis” (Carmona-Gutierrez et al., 2010, 769, my emphasis).

21  Actually, as Durand makes it clear in his recent book, identifying PCD is not trivial at all because it resembles strongly to other deaths (e.g. necrosis), so that subtle morphological features of the process should be detected, which requires transmission electronic microscopy—the only “gold standard” of PCD, together with the known genes involved in the process (Durand 2021, 87). 22  “Yeast bears at least one ortholog of mammalian caspases: the metacaspase Yca1p. Numerous cell death scenarios have been shown to depend on Yca1p. This applies to oxygen stress, where disruption of YCA1 results in reduced cell death and decreased formation of apoptotic markers.” (Carmona-Gutierrez et al., 2010, 708). See also Madeo et al., 2002. The caspases are involved in PCD but also in other processes, so that, as Durand (2021, 97) writes, “detecting caspase activity via their substrates and caspase inhibitors, therefore, is a sensitive marker of PCD (it will detect PCD if caspase-dependent PCD is occurring) but is not specific for PCD (detecting caspase activity does not prove PCD).” In his words, caspases are “soft signs” of PCD (103), and not “hard signs” or even less “gold standard.”

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Morphology aside, it therefore appears that in yeast and bacteria, orthologs of genes involved in multicellular PCD have been identified (e.g. Wissing et al., 2004), even though, as indicated by Klemenčič and Funk (2018) studying homologs of caspases in plants and bacteria, these enzymes are not only essential to inducing apoptosis, but also play roles crucial to survival.23 Epistemically, this completely warrants the claim that the phenomena in both multi- and unicellular organisms—including both prokaryotes and unicellular eukaryotes such as yeast organisms—are similar. Aging and programmed cell death are two different things but it emerges that: –– they are highly conserved across lineages, and identifiable through homologous and orthologous genes and proteins; –– they are instantiating complex and persistence-enhancing relationships between on the one hand a cell, and, on the other hand, respectively a cell colony or an organism. PCD at each evolutionary level plays a role—the question being: “which one?” As Carmona-Gutierrez et al. (2010) summarize it, this functional conservation reaches back to worms such as Caenorhabditis elegans (emerged 700 million years ago), the plant kingdom (1 billion years), unicellular eukaryotes (1–2 billion years), and even bacteria (4 billion years). Thus, evolution seems to persistently select cellular self-destruction mechanisms, which over time have been harnessed and refined with the growing complexity of organisms. (Carmona-Gutierrez et al., 2010, 764)

These findings are crucial for the debates around an aging program. Not only do unicellular organisms age,24 but they have evolved processes to replicate and rejuvenate the daughter cells through asymmetric division. They also display well-studied features of PCD, whereby colonies

23  “Increasing evidence suggests that plant metacaspases are involved not only in deathrelated events, but also are important for survival of the plant cell. In ageing plants, the type I metacaspase AtMC1 seems to participate in the removal of age-related cell aggregates (Coll et al. 2014). The dual role of AtMC1 on one side inducing cell death and on the other side acting as survival factor again indicates the delicate fine tuning of cellular processes orchestrating actions from various external and internal stimuli.” 24  Through mechanisms that are intensely studied: Burtner et  al. (2009) concludes that accumulation of acetic acid is the primary cause of death in yeast cells.

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proliferate better than they would without them. This also revivifies the idea that living things could be not only aging, but instantiating a program for their aging. In the next chapter I’ll turn again to the notion of death and aging programs, from the viewpoint of PCD.

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CHAPTER 13

Ontology (3): The Case for Programs: Altruistic Suicide, Quasi-Programs and Smurfs

The theoretic significance of the instincts of self-preservation, power, and self-assertion shrinks to nothing (…); they are part-instincts designed to secure the path to death peculiar to the organism and to ward off possibilities of return to the inorganic other than the immanent ones, but the enigmatic struggle of the organism to maintain itself in spite of all the world, a struggle that cannot be brought into connection with anything else, disappears. It remains to be added that the organism is resolved to die only in its own way; even these watchmen of life were originally the myrmidons of death. Hence the paradox comes about that the living organism resists with all its energy influences (dangers) which could help it to reach its life-goal by a short way (a short circuit, so to speak). Sigmund Freud. Beyond the pleasure principle (1922)

The fact that even single-cell organisms are capable of developing a death process when triggered called for intensive research. Researchers spoke of cell suicide. Their findings affected the alternative between stochasticity and programs that govern the understanding of senescence and death, even in multicellular organisms. Some philosophers may be confused by the word “suicide,” applied to entities that don’t deliberate or think. But this is not my point here; the extension of the common term “suicide” to prokaryotes and cells is similar to using “recognition” or “memory” to © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_13

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describe molecular processes in DNA replication and expression. A novel meaning, precisely defined in the locutors’ context, is ascribed to these words; they keep only one dimension of their usual meaning. In the case of “memory,” that is “conservation of a trace of past events”; in that of “suicide,” it is “process leading to death, initiated by the agent itself.” It could be required that the processes described by those anthropocentric terms are caused by natural selection, as adaptations, in order to distinguish them from similar processes that occur somehow by chance. This strategy has been used to fix the meaning of “communication” in behavioral ecology, because otherwise any interaction between organisms could count as communication. In our case, all depends upon the relation of cell suicide to natural selection, a question that will be raised in the next chapter. In this chapter, I will study the way a case for a program has been made several times in the current literature, based on strong arguments that demonstrate the conservation of suicide programs in the phylogenetic tree.

13.1   Investigating Programmed Cell Death (PCD) in Unicellulars: Talk of Cell Senescence and Suicide As we have seen, genomics offered ways of identifying longevity factors at the genetic level, triggering a new set of approaches to aging. However, the so-called post-genomics turn (Griffiths & Stotz, 2015) also means a focus on expression factors that are not DNA itself, but all other factors (miRNA, epigenetics, etc.) that condition DNA expression. In a cell, the aging process involves many epigenetic factors that have been unraveled over the past two decades. This knowledge of cell senescence completes our understanding of cell death, derived from the discovery of PCD in prokaryotes and yeast, as well as the replicative lifespan induced by division asymmetry in mitosis, that I considered in the previous section.1 Epigenetics can be defined as the phenomena related to the expression of the genome, such as the dynamics of molecules that bind to DNA, namely histones and chromatin, along with the methylation process silencing the DNA sequence targeted. A set of epigenetic changes is considered as one hallmark of aging (López-Otín et al., 2013). In their

1  About the post-genomic turn in aging research, and especially the prospects of investigating regulatory networks of genes involved in longevity via computational tools, see de Magalhaes (2009), Kaeberlein (2004).

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review paper, Kane and Sinclair (2019) examine many of these epigenetic phenomena, for instance the “decline of protein synthesis of histones with age,” or phenomena specific to methylation processes (see Box 13.1). Box 13.1  Aging Clocks and Epigenetic Regulation of PCD

Most of the methylation sites are on cytosines which precede a guanine. They are written CpG, in which p stands for phosphate. These “CpG islands” are DNA sequences of at least 200 nucleotides, with a higher proportion of CpG than in the rest of the genome. When cells age, there is a decrease in overall methylation in repetitive regions of the sequence; in addition, there is also regions of hypermethylation, “especially at CpG islands near gene-rich regions.” As a consequence, “age-related methylation” can be used as an epigenetic clock (Horvath, 2013), applicable to many animals, including humans. It can also “predict accelerated or delayed aging caused by lifestyle changes such as diet and exercise” (Quach et al., 2017). It therefore provides a notion of “biological aging” slightly decoupled from chronological aging, measured by watches. Epistemologically, let’s note that these findings are descriptive, but by themselves, they do not distinguish between causes and effects. For instance, Kane and Sinclair (2019) also notice that “increased transcription of transposons” comes with age, but this “may be either a consequence of epigenetic changes with aging or contribute to these changes.” Thus, while some of the facts described have been seen as aging factors because they demonstrably imply effects that are among the phenotypic profile of aging cells, many of them are causally indefinite. A clock itself, while obviously related to aging, may be just a consequence of fundamental processes, as is any normal clock, whose time-displaying effects supervene on basic mechanisms occurring in time but don’t cause them. This is the case not only of epigenetic clock, but of other clocks that have been hypothesized on the basis of our knowledge of some basic process involved in aging, for instance processes at the level of the microbiota (the set of bacteria included in the living organism at each boundary with the environment, such as gut, hands, mouth in humans. In very recent literature one would also cite the notion of “inflammatory clock,” based on the inflammatory theory of aging (or “inflammaging”) seen above, which allows to “track multimorbidity, immunosenescence, frailty and cardiovascular aging,” and is (continued)

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Box 13.1  (continued)

“based on deep learning,” (Sayed et al., 2021). Or, more recently, the “human gut microbiota clock” (Chen et al., 2022). Such plurality of clocks reflects the fragmentation of aging diagnosed in Chap. 10 above. Clocks being indifferently the cause or consequence of the aging process is the reason why finding clocks inside cells doesn’t per se imply the existence of a program that is a causal factor of senescence. However, the epigenetic perspective of Kane and Sinclair acknowledges the possibility of “reprogramming” cells, which implies that aging can rely on an opposite program. They cite the demonstration of the reprogramming of cultured cells by Takahashi and Yamanaka (2006), who showed that “the expression of the transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) in mouse fibroblasts induces them to become pluripotent stem cells that can be differentiated into almost any other cell type.” This reprogramming causes an “epigenetic remodeling” of the aging fate of a cell. That is why finding clocks inside cells doesn’t per se imply the existence of a program that is a causal factor of senescence. However, the epigenetic perspective of Kane and Sinclair acknowledges the possibility of “reprogramming” cells, which implies that aging can rely on an opposite program. They cite the demonstration of the reprogramming of cultured cells by Takahashi and Yamanaka (2006), who showed that “the expression of the transcription factors Oct3/4, Sox2, Klf4, and c-Myc (OSKM) in mouse fibroblasts induces them to become pluripotent stem cells that can be differentiated into almost any other cell type.”2 This reprogramming causes an “epigenetic remodeling” of the aging fate of a cell. Reprogramming studies were done initially in vitro on cultured cells. In the last seven years, though, they have been tried in vivo on mice and other model animals. Interestingly, while reprogramming often works, the naked mole-rat seems the most resistant. Given that this animal is known for its very low susceptibility to cancer, one might hypothesize a link between the efficiency of programmed cell death as an immunity-inducer in these organisms, and their (continued)

 This finding granted them a Nobel prize.  For a review of epigenetic reprogramming in cells see Rand and Chang (2016). They call the field opened by their studies the “biology of rejuvenation.” 2 3

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Box 13.1  (continued)

reluctance to being reprogrammed. Since in vivo epigenetic reprogramming is much less costly and hazardous than genetic reprogramming, these views open new horizons regarding age-­control and life extensions. To sum up this survey of postgenomic investigation in aging cells, molecular clocks and the possibility of epigenetic reprogramming characterize aging in cells, be they single cells or cells from multicellular organisms in vitro (cultured) or in vivo.3 This knowledge complements the acknowledgment of PCD in unicellular organisms, because here, its interpretation may involve, but does not necessarily point to, a program. As a matter of fact, Kane and Sinclair (2019) conclude their review paper by alluding to “DNA damage? Environmental influences, or simply information loss in the form of epigenetic noise stemming from the chaos of life at the molecular scale?” instead of a programmed course of senescence, even though the causes of this senescence are still only partially unraveled. Turning back to unicellular PCD, the fact that apoptotic yeast cells release nutrients into the colony, in a manner analogous to dying bacteria in biofilms, may suggest an evolutionary explanation of the process. Durand et al. (2011) among others showed that in the unicellular eukaryote Chlamydomonas, a cell that died of PCD provided nutrients that were not released when death occurred by other, external means. They infer from these facts the plausibility of an “adaptive explanation for the origin and maintenance of PCD.” Fabrizio and Longo (2008) examined apoptosis and the so-called chronological aging in yeast (by this name one means aging after the end of replication cycles). They found that chronological aging involves an apoptosis program because such aging relies on a cellular pathway whose activation “reduces cell protection and maintenance.” Hence, it raises superoxide production, which leads to DNA damage and triggers apoptosis. They argue thereby that, this seems to work in favor of the survival of the group, for the following reason: in “50% of the wild type culture” after the death of the majority of the population, “cellular ‘regrowth’ is observed.” Such “adaptive regrowth,” as it is sometimes called, requires nutrients released by the dead cells, which would constitute evidence for “cellular suicide”—and DNA mutations accumulated during aging—as an “adaptive strategy for the group.” It would seem that the multiplication of cells that are aging at the same time triggers an apoptosis program that shrinks the population size and fosters such regrowth.

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Analogously, regarding PCD in bacteria (prokaryotes), a curious feature is the induction of “persistor cells”—namely, cells that remain after a mass PCD event, and can therefore perpetuate the existence of the population in the midst of a deleterious event such as antibiotic emission. As Lewis (2000) explains, after exposure to antibiotics, many bacteria activate a death program, which leads to the existence of a few cells that can persist. “Persistor” variants are cells in which PCD has been disabled and which are responsible for the survival of the population under these conditions. It appears that persistors are especially important for the extraordinary survival properties of biofilms. (...) The existence of persistors suggests that a bacterial cell potentially has the choice of whether to live or die, and the real puzzle is not how the rare cells survive, but why the majority of cells choose to be killed by antibiotics. (Lewis, 2000, 504)

The phrase “altruistic suicide” is favored by several authors when they consider these phenomena. For instance, “unfit cells undergo apoptosis in order to avoid wasting nutrients and by their death to release nutrients for the benefit of younger and fitter cells. Thus, survival of the population is promoted, and under certain circumstances regrowth of fitter mutants is enabled” (Carmona-Gutierrez et al., 2010, 768).4 The “altruistic aging program” studied by another paper (Fabrizio et al., 2004) applies a similar term. Authors indeed show that when oxidative stress is imposed on a yeast population, “after 90–99% of the population dies, a small mutant subpopulation uses the nutrients released by dead cells to grow. This adaptive regrowth is inversely correlated with protection against superoxide toxicity and lifespan and is associated with elevated age-dependent release of nutrients and increased mutation frequency.” Alluding to the high degree of conservation of genes and pathways involved in apoptosis, they conclude: “these results suggest that under conditions that model natural environments, yeast organisms undergo an altruistic and premature aging and death program, mediated in part by superoxide. The role of similar pathways in the regulation of longevity in organisms ranging from yeast to mice raises the possibility that mammals may also undergo programmed aging” (My emphasis). Notice, however, that the sentence makes no mention of bacteria. Indeed, genomic analysis revealed that the genes involved in PCD in eukaryotes are 4  Or: “possible reasons for apoptosis in protozoans would be the same as for yeasts and bacteria—ridding a population of defective cells, obtaining nutrients from neighbors committing altruistic suicide, stemming an infection by pathogens, decreasing the mutation rate, and lowering the probability that take-over mutants will arise” (Lewis, 2000, 512. Note that when Lewis talks about “preventive suicide,” as quoted above, he obviously refers to an external beneficiary).

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not at all the ones involved in the same process in prokaryotes (Koonin & Aravind, 2002). Eukaryotes originated through the endosymbiosis event between an archaebacteria and a prokaryote that engulfed mitochondria in the cell. The mitochondrion is the source of the metacaspases involved in PCD. Multiple horizontal gene transfers seem to be responsible for other proteins and genes involved in PCD, one event being close to the origin of eukaryotes and one much later. As Koonin and Aravind write, “at least two important lines of evidence support HGT [horizontal gene transfer] from bacteria to eukaryotes as the principal route of evolution of these proteins.” Hence, in terms of evolution, the PCD systems in prokaryotes and eukaryotes are two distinct phenomena, whose origins involve a mosaic of distinct transfer events—even though they might have been cumulatively selected for through a similar selective process (Fig. 13.1). The processes investigated in yeast led researchers to talk about “molecular clocks,” to the extent that programmed death involves senescence

Fig. 13.1  Simplified scheme of the origin and evolution of the eukaryotic PCD system (after Koonin & Aravind, 2002). Thick arrows: vertical evolution; red arrows: horizontal gene transfer; red connectors: recruitment of eukaryotic-specific protein domains

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factors that are recursively expressed in a cell (Sinclair et al., 1998). That would allow the colony to get rid of aged cells, which accumulate mutations. Yet others, like Lewis (2000), object that such a clock would have no effect, since mitochondrial mutations are generally more frequent, so that it is much more likely that the senescent cell due to the former (often deleterious) mutations would already be dead before the putative program could come into play (see also box above about various “clocks” of aging). But this discussion opens avenues of research for rehabilitating the notion of an aging program.

13.2  Altruistic Programs Versus Quasi Programs In a 2005 paper in Nature Genetics, Valter Longo, Joshua Mitteldorf, and Vladimir Skulachev elaborated a theory of “programmed and altruistic aging” that draws radical conclusions from the facts of PCD, the conservation of aging molecular pathways across many clades, and the known facts of regularities in aging in many species (including death in salmons). Skulachev has consistently endorsed this theory since the 2000s and Longo has extensively studied cell senescence, especially in yeast, often together with Paolo Fabrizio. As a matter of fact, on these subjects, small groups of scholars have been debating with each other for two decades, so the same names (Dilman, Blagosklonny, Sinclair, Longo, Frohlich, Fabrizio, Madeo, Mitteldorf, Skulachev, etc.) keep showing up, and we will be surveying their dissensions in this section. Acknowledging that there is discussion about whether free radicals, protein aggregation, mitochondrial deterioration, and other facts of physiological aging are related to senescence, the authors of the 2005 paper wonder whether they are the “primary cause” of aging, or whether, against the claim of disposable soma theory that a “putative program that regulates protection repair or replacement systems become less effective,” one could hypothesize another explanation called the “programmed and altruistic aging theory” (869). They concur with another paper co-written by Longo (Fabrizio & Longo, 2008—cited above) that analyzes mechanisms of cell death in yeast and sees “adaptive regrowth” after a mass suicide as a “form of kin selection.” Among the evidence for such an altruistic program, which generalizes to life overall what some researchers said about PCD in unicellulars, one finds the existence of the thousands of longevity genes that I considered in Chaps. 9 and 10; “the similarities between normal ageing and mammalian

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apoptosis,” be they morphological or genetic, as I mentioned in the end of the last chapter; but also “evidence for the benefit that is provided by the ageing programme (for example, a correlation between lifespan and the ability of a population to adapt to changing environments)” and “the identification of a sequence of molecular processes that are required to cause normal ageing and death” (such as the molecular pathways leading to apoptosis in yeast, analyzed by Fabrizio & Longo, 2008); and “the demonstration that the programme occurs both under conditions that mimic those encountered in natural environments and in organisms that are isolated from natural environments.” The reasoning makes great use of the parallelism between yeast aging and apoptosis, as demonstrated in Fabrizio and Longo (2008). “The evidence for apoptotic-like death in yeast leads to the question of whether components of the apoptotic process might be involved in an ageing program. Many of the features of apoptosis—including chromatin condensation, phosphatidylserine externalization, increased oxidant generation, and caspase activation—are observed in ageing yeast populations before death” (Longo et al., 2005). Another argument for the idea of altruistic programmed aging is the competition between wild-type cells and mutant cells of yeast (Fabrizio et  al., 2004). Mutants are long-lived, because they lack the caspase-like protease Yca1, involved in oxygen-stress-dependent apoptosis. In all experiments, the wild type, likely to express apoptosis but shorter-lived, outcompetes mutant types, especially because the regrowth of the population after mass death ultimately makes this population larger. As the authors write, “it would be surprising if the association between increased superoxide levels, markers of apoptosis, a shorter lifespan and the frequency of regrowth was not part of an adaptive mechanism. It would also be surprising if the role of Yca1  in adaptation was not linked to programmed death.” Thus, programmed cell death is altruistic and adaptive for the group, and aging itself is the expression of such adaptation. Observations concur, since populations that overexpress superoxide dismutase and catalase genes, and therefore have a longer lifespan, have “reduced frequency of adaptive regrowth.” And besides experiments, observations, and simulations consistently show that wild-type yeast, expressing apoptosis, decreases but starts anew, thus in the end approaching its initial population level, while the long-lived mutant types ultimately decrease in fitness (Fig. 13.2). The simulations can reproduce the experiments cited consistently.

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Fig. 13.2  Simulation results: Cell population growth dynamics (a). Wild type: Programmed aging (suicide); (b) Mutant: Stochastic aging (no program, caspases neutralized). Red cells are new cells (from Fabrizio et al., 2004)

Here, aging is programmed as an adaptation to group life; Longo et al. (2005) recognize that their view should appeal to group selection, which is a very controversial idea, as we saw, but they also envisage that it could

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be explained by kin selection.5 And besides yeast and unicellular, facts of semelparity—the octopus, the mite Adactylidium, salmon, or even bamboo which live 15–20 years but die after the seed ripens—exemplify the same pattern of programmed aging. There are other views defending the idea of an aging program. For instance, Prinzinger (2005) considers that there is a finite amount of energy produced by mitochondria in organisms, and that actually, once calculated for the mass of the organism, expressed in units of energy metabolism per gram, “physiological lifetime is almost identical within an animal taxon” so that we “reach a fixed physiological age as the organism works its way through a roughly constant quantity of energy until the internal clock initiates death.” However, Skulachev’s 2005 paper elaborated the most consistent and detailed program-view of aging and death. In 1997, Skulachev coined the term “phenoptosis” to cast the aging phenotype, in a way comparable to “apoptosis,” as a program. It signifies “all cases of programmed death of organisms” (Skulachev, 2011). In this perspective, semelparous species show cases of acute phenoptosis, while many other species are affected by slow phenoptosis—namely they display “slow and concerted decline of many physiological functions.” The theory of “programmed altruistic aging” claims that phenoptosis is a generalized phenotype in life overall, the known genes and pathways involved in phenoptosis being highly conserved. For Skulachev, the series of neologisms includes “mitoptosis,” the process of getting rid of deleterious mitochondria. Actually, mitoptosis, apoptosis, and phenoptosis are all the same process, only they occur at different levels of biological organization. All three evolved for the same reasons; hence, phenoptosis is programmed death, and operates to purify the population of dysfunctional organisms.6 In their 2004 paper about altruistic aging programs, Longo, Fabrizio et al. concur in writing that “the role of similar pathways in the regulation of longevity in organisms ranging from yeast to mice raises the possibility that mammals may also undergo programmed aging.” The evolution of some plants provides an argument in favor of this claim of generalized phenoptosis. In the plant Arabidopsis thaliana, a classic  This question is addressed in the next paragraph.  “Mitoptosis purifies a cell from damaged and hence unwanted mitochondria; apoptosis purifies a tissue from unwanted cells; and phenoptosis purifies a community from unwanted individuals. Defense against reactive oxygen species (ROS) is probably one of the primary evolutionary functions of programmed death mechanisms” (Skulachev, 2002a, 2002b, 214). 5 6

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model organism, individuals that have mutations of SOC 1 and FUL genes turn from sexual to vegetative reproduction and don’t show “seed-­induced senescence”; in fact, they live indefinitely because they reproduce with rhizomes like perennial trees or bushes (Melzer et al., 2008). But if deleting two genes provides a form of immortality, it indicates that death should be part of a genetic program. Skulachev cites the speculation, by these authors, that Arabidopsis thaliana (the most well-known plant used as model organism) originally reproduced vegetatively as a perennial shrub, but became the grass-type A. thaliana known today, which is short-­lived and “killed by its own seeds.” The new form does better in the struggle for existence since it does not compete for the niche with other species. But the genes for the immortal form are still conserved in its genome. This attractive idea shows that the phenoptosis hypothesis of programmed altruistic aging appeals to something above selection at the level of individuals: group or kin selection, or, as we saw here, selection for evolvability. A species is said to be more evolvable if it features traits that make persistence more likely for this species than for another; for instance, if these traits allow the species to be a better competitor than another species, even to the detriment of the individuals. And genuine evolvability is not easily conceived without thinking of selection at the level of species, which is another kind of selection above the level of organisms or genes (see Box 13.2). Box 13.2  Explaining Lifespan Through Selection for Evolvability: An Example

The evolvability hypothesis has been revived in a model by Martins (2011), elaborated and developed in a paper co-written with Mitteldorf (Mitteldorf & Martins, 2014) who co-championed with Skulachev the notion of altruistic programs. The key idea is that if dying is programmed “on a fixed schedule” then the population can “have a higher rate of population turnover” and then can “incorporate adaptive changes more quickly.” Hence programmed lifespan (but not patterns of senescence) can improve evolvability. How? In the agent-based model there is a fixed maximum population, which limits reproduction, new offspring have to find a niche, and then individuals can replace less fit ones with a probability 30  days) we observed a fraction of animals that displayed a strikingly different phenotype. In these animals, the blue dye was clearly visible throughout the body post-feeding; subsequently, these flies were referred to as ‘Smurf flies’” (Rera et al., 2013). Smurf flies are blue because “the leakage of dye into the hemolymph and consequently all tissues, reflect a defect(s) in intestinal integrity.” Subsequent work (Rera et al., 2013; Rera, 2015) focused on the smurf phenotype. Smurf flies “show an altered control of intestinal permeability a few days prior to death regardless of chronological age.” Once the flies display this smurf phenotype, they enter a regular process with typical features, “a set of co-segregating phenotypes” (Rera & Tricloire, 2015) which culminates with death. It indeed came out that “these same [smurf] individuals also showed a striking increase in the expression of inflammatory markers (antimicrobial peptides, AMPs) as well as systemic metabolic defects, including impaired insulin/insulin-like growth factor signaling (IIS)” (Rera, 2015), increased expression of FoxO (transcription factor “fork-head box O”) targets, “decreased energy stores (glycogen and triglycerides-TG), decreased spontaneous motor activity,” all hallmarks of aging associated with an increased probability of death. More importantly, it seems that these traits are concentrated in the proportion of the population that exhibits the smurf phenotype: “chronologically age-matched individuals from the same population, without altered intestinal permeability, do not show major changes in these parameters with age” (ibid). Non-smurf flies have a negligible chance of showing these features; and, strikingly, “the proportion of individuals characterized by this phenotype increases quasi linearly as the population ages” (Rera & Tricloire, 2015).10 A major conclusion of these studies is that aging seems to occur probabilistically on each individual as the launch of a specific set of events triggered by the onset of the smurf phenotype, namely, the alteration of the intestinal epithelium. It contradicts the idea that, in each individual, aging is the random accumulation of alterations and mutations that continuously aggregate and finally end in the event of death. Here, aging appears as a rather discontinuous process: at a given moment that can be early or later, individuals enter into a new phase which appears regular (it harbors “cosegregated phenotypes,” as indicated above) and lasts about ten days to 10  For recent criticisms of the claim, see Bitner et al. (2020). This chapter is avowedly relying on science in the making, and the corroboration of the findings that I expose here may decrease in the future. This risk is part of the fate of doing philosophy of science.

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ultimately bring about death. The fact that smurf phenotypes occur in other model organisms, like nematodes or zebra fish (Danio rerio), as established by a later paper from the team (Dambroise et  al., 2016), as well as the knowledge that many of the genes involved in smurf flies have homologs in mammals and other animals, suggest that there is something universal in this scheme of a two-step process. A new model of aging was called for. Tricoire and Rera (2015) elaborated a “Two Phases of Aging Mathematical Model” that takes into account the existence of these two steps, and the fact that the latter step occurs randomly, with a given probability, on each age-class of the population at first step. In the first phase, individuals do not die, but do have a given age-related probability of entering phase 2; in phase 2, there is a constant probability of death per unit of time. From these two assumptions, the dynamics of the population can be described. They are governed by only three parameters: the rate at which the Smurfs die; the rate at which Smurfs appear in the population; and the first day of Smurfs appeared in the population. This modeling allows the authors to generate curves of the population dynamics that are more accurate than the extant Gomperz law or Weibull model (see above Chap. 9). Above all, they are more useful for a biologist, because each parameter can receive a straightforward biological interpretation. This description of aging puts forth the idea that “highly stereotyped transition between these 2 phases and more importantly the phase 2 itself are programmed” (ibid). It opposes the current consensus that senescence is a random process, continuous from the first day of life. On the contrary, it is a discontinuous process, and the second phase is programmed. There is a strong appeal in this view, because the attempt to model life histories based on three variables makes for a very simple and generic model of life courses. The various patterns of senescence are abstractly derivable from the values of the three parameters. This theorizing toward genericity was pursued by a later paper, which relies on the admittance of a discontinuous model of aging, and explores the possibility that all life histories can be described by such simple models with few parameters. Méléard et al. (2019) construct what they call the “birth–death model” which is “a simple life-history trait model where each asexual and haploid individual is described by its fertility period xb and survival period xd..” The model shows that xb and xd will tend to converge, which means that ultimately individuals live up to a value xb, reproduce, and then die. The coupling between b and d appears to be a program. Evolution promotes

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senescence programs that push for individual reproduction and at some point, when reproduction is over, death is entailed. This abstract model of life history based on the new two-variable function attempts to explain the capability of the aging process “to be selected through evolution.” Very abstractly, the model presented pertains to “adaptive dynamics” (Metz et  al., 1992), an approach to evolution that merges ecology and population genetics, and uses complex mathematical tools to describe what they call “invasion fitness” of traits, namely, an estimation of the potentiality of the population subclass defined by trait x to be invaded by a mutant. Such a model by definition allows one to explore natural selection, by concentrating on the population changes induced by invasion fitness differences. Here, the individuals are described by simple two-­ valued variables (xb, xd). There are variations on each individual, as in evolution. Individuals reproduce at rate one/timestep when younger than xb, and cannot die when younger than xd.. This is a very simple model of evolution, but it shows by simulation that the individuals (xb, xd) tend toward xb = xd. This defines a coupling between d and b, which can be interpreted as a coupling between death and reproduction period, quite similar in essence to what senescence is. After this, the values tend to increase, but at a pace that slows. Ideally, this equality corresponds to semelparity, to salmon dying after reproduction. Varying the initial conditions allows one to see how other forms of senescence, especially menopause or negligible senescence, can occur. The simulations indeed show that (xb, xd) tend to concentrate around the diagonal xb = xd in a two-axis (xb, xd) plot, and then slowly increase. Analytical derivations confirm this result, even if they are too complex to be described here. But the main point is that a key driver of this phenomenon is something called the Lansing effect. First noticed by Lansing (1947), this effect denotes the fact that offspring of older parents tend to live shorter lives than their parents. This effect has been attested in many species, including humans. Once implemented in the model as a constraint on the values of b and d, the Lansing effect supports the dynamics leading to the coupling xb = xd because individuals who reproduce later in life are prevented from invading the population with their offspring, which can’t live long enough. Thus the dynamics tend to shorten too-­ long xd values, while increasing xb values means increasing the amount of offspring, hence fitness. The upshot of the combination of this simple model and the experimental work just outlined is a revival of the notion of the aging program

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as a pervasive trait, supported by natural selection, across all clades. Smurf phenotypes behave as if they were run by a program, with all of the cosegregated traits that are the hallmarks of aging occurring after a given step that occurs randomly for any individual. Natural selection can be modeled as a major explanans for the many couplings between reproduction period and death that characterize aging programs. Therefore, the pending question raised by this groundbreaking work is: why? As we’ve seen, there are, despite Skulachev and others, very strong evolutionary objections to the idea that aging is programmed. However, all accounts share the notion that aging is continuous. Thus, the discontinuous model opens the way for an account in which an aging program is not continuously at work—unlike the extant versions, and also unlike the traditional alternatives, namely the hyperfunction theory (since programs start at development) and the stochastic damage accumulation theories (such as Hayflick’s, cited above). At some point, an aging program that leads to death in a regular and inexorable manner begins, with a starting date that is mostly stochastic. But why would such a program exist in the first place? And why would it be so universal?

13.4   Inquiring About the Possibility of Aging Programs: Altruistic Suicide, Kin Selection, Population Structures Here, we may remember Williams’ account of the evolution of sex—whose relations with the evolution of aging and death have been exposed above (Chap. 8). While looking for a selection-based account of sexual reproduction by rotifers or aphids, and more generally by many ancient lineages, Williams hypothesized that sexual reproduction in large metazoans such as mammals was not something to be explained because it’s a constraint—in the sense of some evolved feature that is conserved and on which many other features have been built, so that no way back is open for natural selection, even though in abstracto getting rid of such feature would sound advantageous in terms of fitness. Assuming that the pervasiveness of the n-days death program instantiated by the smurf phenotype establishes the existence of an aging program, it sounds plausible to consider that in many clades, especially chordates, such program exists as a constraint. There, finding a selection explanation in terms of either direct selection, or a by-product of selection,

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doesn’t make sense. Thus, the question would be, why does it exist at all, in the species where it was not yet a constraint? Since PCD exists in prokaryotes and unicellular eukaryotes, this gives us a hint toward a possible explanation of an aging program, given that PCD parallels the features of the smurf phenotype: once triggered, it continues until it ends with the death of its carrier, in a relatively constant amount of time, and through a set of typical stages.11 PCD being involved in the development of multicellular organisms, and possibly a determining feature of all multicellular organisms (Koonin & Aravind, 2002), the claim that death programs are so entrenched in many multicellular organisms— such as metazoans, and many plant genera—that they exist as constraints gains some plausibility. So, why have these death programs in the first place? By-product selection through trade-offs in an AP-style scenario is not available as an explanation of unicellular PCD, since the cell endowed with this program differs from the salmon, for instance, which lives and dies in a way that maximizes its number of offspring. By definition, living beyond PCD would allow more divisions, hence greater fitness, so it’s hard to see it as a trade-off favoring early direct reproduction. Because prokaryotes live often in biofilms, and yeast in colonies, an explanation of the aging program underpinning the two-step model of aging could be traced back to selection in social environments. As I emphasized, PCD benefits other cells because the dying cell releases nutrients—but this characterizes programmed death by opposition to accidental death (e.g. by necrosis or lysis). Durand et al. (2011) examined PCD in Chlamydomonas reinhardtii, a eukaryotic green algae species, comparing PCD to abrupt lysis by sonicating. PCD had a beneficial effect on other cells in the culture, while lysis had detrimental effects. This indicates that when death occurs through PCD, the substances released are beneficial nutrients, whereas death by other means releases substances that harm growth prospects for other cells. These findings are all the more important in that phylogenetically, this species belongs to the groups Volvox, in which multicellularity has evolved. Thus, the presence of PCD and its possible emergence via kin selection due to these benefits may in 11  But remember that the evolutionary origin of PCD in eukaryotes is not PCD in prokaryotes (Koonin & Aravind, 2002). As Durand (2021, 93) emphasizes, “in contrast to PCD in prokaryotes, the mechanistic basis for programmed forms of death in unicellular eukaryotes is extraordinarily complex.”

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turn have played a role in the origin of multicellularity. Perhaps the availability of PCD mechanisms was a precondition for the emergence of multicellularity. In support of this hypothesis, recall that, in the Méléard et al. (2019) model, the Lansing effect was a plausible cause of the existence of the second-step senescence, which in turn behaved as a death program. But the Lansing effect has to be understood somehow in relation to social interactions. One explanation for the shorter life of offspring from older parents is it minimizes competition between offspring and grand-offspring. There is no uncontroversial model that would explain the Lansing effect (see Priest et al., 2002; Monaghan et al., 2020), but it’s very plausible that such an explanation in terms of group or kin selection is available. This would in turn mean that a sort of group selection or kin selection process yields the evolving process that leads to programmed death. Here, I would favor a twofold explanation of death programs: first, they being evolved by group or kin selection; and second, they being entrenched especially in major features of multicellularity, which makes them pure constraints. But as I said, there is a strong sense, within the community of evolutionary biologists, that group selection is either non-existent—as Williams advocated—or contradictory. The requirement that all properties that ultimately constitute fitness be ascribed only to groups would be either impossible or too strong. However, where early biologists invoked group selection and the good of the species, post-Hamiltonian evolutionists came up with an alternative option, kin selection (explained above). All the phenomena that seemed to require group-selectionist explanations turned out to be explainable through kin selection; i.e. a selection that accounts for the positive effects on the others of the focal trait, but mitigates these effects by the coefficient of genetic relatedness. Thus, if aging programs exist, seemingly pervasive and locked into many species, possibly inherited from PCD programs, the latter programs could have evolved through kin selection. Such an evolutionary explanation of PCD is neither (a) obvious nor (b) unformulated. Here are a few hints. (a) The fact that this explanation cannot be taken for granted emerges from a set of papers written by Pierre Durand (University of Johannesburg), Rick Michod (University of Arizona) and colleagues, who extensively studied cell suicide in unicellular organisms such as cyanobacteria. This event, when it occurs simultaneously and intensely, leads to spectacular algal bloom, as happened off the western coast of South Africa. Durand

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et  al. (2011) acknowledged that kin selection might be a possible hypothesis for PCD in these organisms. However, it’s also plausible that it emerged as a by-product of other selective processes. They emphasize that the fact that some process, such as PCD, benefits the kin of the dying cell, does not necessarily mean that PCD was selected because it has this benefit. Although the nutrients released after death clearly benefit the kin, that is not proof that PCD was retained through kin selection. In the absence of a “specific mechanism” that directs these benefits to kin, it is even less proof of this hypothesis. In many cases, the nutrients released also benefit non-kin. Durand and Michod suggest conducting experiments that disconnect the non-random association between cells and their kin, in order to check where, in such conditions, PCD still persists. If it does, that would be evidence against the kin selection of PCD. Another explanation would be that some genes involved in PCD have pleiotropic effects that account for their evolution, in a scenario close to antagonistic pleiotropy. Alternatively, PCD could have originated as a strategy used by selfish genetic elements to kill certain competitors; later, the altruistic benefits PCD provides would have maintained this trait. Or, without any kin selection involved, it may have resulted from a persistent inability of the cells to get rid of this “killing machinery.” The possibility that PCD originated from the effect of selfish genetic elements destroying their competitors gives rise to various hypotheses about its further evolution, as Durand et al. (2011) theorize: either PCD was a maladaptive feature that was maintained by selection due to the prosurvival effects of some of the genes involved, or it was maintained because its benefits to kin in the group allowed its selection. Thus, in the latter case, PCD would require some initial group structure, while in the former case, it could have been involved in the road to a more social life. But the major point about PCD in general made by the authors is that no available evidence, at least in 2011, allows one to decide whether it was the product of kin selection, because evidence is “equally compatible with components of the PCD machinery being pleiotropically linked to prosurvival traits” (Durand et al., 2011, 16). Theoretically speaking, however, Durand and Ramsey (2019) argued that when one focuses on evolutionary characterizations of PCD, rather than solely on the mechanisms, it’s possible to make a distinction between PCD as adaptations, and PCD that are evolved through other processes. Only the former is true PCD, according to the philosophical strategy mentioned in the beginning of this chapter relative to the word “communication” (which requires an interactive behavior to

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have been selected for the benefits it provided the agent). The latter is “ersatz PCD.” For example, autophagy in harsh conditions happens because cells “recycle their intracellular components to sustain themselves until conditions improve” and eventually may end up digesting “vital energy stores and organellar structures” so that they “lose vital functions” and die (Durand, 2021, 116). This phenomenon is mechanistically like a cell suicide, but it did not evolve for this reason: “Programmed death of the autophagy kind is a side effect of the program that has evolved as a survival mechanism” (ib., 117). (b) However, the direct selectionist view about PCD has been formulated in various ways in terms of kin or group selection in two other contexts, indicated below. The first is the account of “adaptive suicide” in host-parasite relations. Deborah Smith Trail (1980) was the first to notice this. The host may harbor a behavioral defense against the parasite, in addition to physiological or immunological ones: a host may use its own death to increase in inclusive fitness. (…) The host may be unable to affect its individual reproductive fitness but it can affect its inclusive fitness. The host can change the time and nature of its death; it can ‘commit suicide’, or behave aberrantly and increase the probability of death by predation, thus preventing the maturation of its parasite and lowering the risk of parasitic infection for other members of the host species. If the mature parasite would have been more likely to infect the host kin than non kin, the host’s suicidal behaviour will increase its inclusive fitness and then have a positive selective value.

This theoretical view triggered much discussions. In 1987, McAllister and Roitberg published the first experimental evidence of “adaptive suicide.” In theory, if the imminent infection by a parasitoid drastically decreases the individual’s reproductive chances, the possibility exists that its kin may benefit from its “suicide,” since its death will entail the parasites’ death and protect the kin. In real life, indeed, the pea aphid (Acyrthosiphon pisum) dies in the presence of the braconid wasp Aphidius ervi. The aphids release an alarm pheromone that attracts a coccinellid, the ladybug (McAllister & Roitberg, 1987). Their later research shows that the stage at which the aphid is approached plays a role in the “decision” to commit suicide. In one case, the aphid produces no offspring before mummification. In the second, however, it can still expect seven offspring, and only the

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latter kills itself, which leads McAllister et al. (1990) to state that adaptive suicide is “cost sensitive.” As to the behavioral strategy itself, studying the aphid parasitized by Macrolophus pygmaeus, a hemipteran, Duran Prieto et  al. (2018) showed that some aphids tend to run toward parasites, thereby luring parasites away from their own kin. The evolution of adaptive suicide is constantly being studied. It’s relevant for my inquiry, since the possibility of suicide relies on the same mechanisms that are involved in PCD.  Its evolution tells us something about suicide, cell suicide in unicellular organisms, and finally aging and death programs. More recently, adaptive suicide was reviewed by Humphreys and Ruxton (2019). They noted that in cases of eusocial insects such as bees and ants, which have been investigated for adaptive suicide after works on aggregating insects such as aphids, testing the hypothesis of adaptive suicide raises an epistemological issue. The death of the host may turn out to be a manipulative strategy originating with the parasite. Any beneficial consequences that occur for kin would just be a by-product. Humphreys and Ruxton judge that the most convincing evidence we have of adaptive suicide is therefore in bacteria, by what they call the abortive infection system: a bacteria infested by a phage aborts and therefore kills itself and the phage. This strategy is “likely to be selected for where a bacterium’s neighbouring cells are kins emerging from clonal expansion,” which suggests kin selection. Strategies like this may involve quorum-sensing. Moreover, as established by work by Koonin and colleagues, in the case of virus infections, the same system functions in a way that involves “sensor molecules (that) indicate an attack is not manageable” (otherwise, the cell mobilizes an immune system against the virus) (Koonin & Zhang, 2017). This research does not provide any universal explanation, for unicellular organisms, of PCD or aging programs such as those attested in the Smurf experiments and hypothesized in the two-step model of senescence. But they suggest that kin selection could be a proper explanation of such phenomena, to the extent that it represents a robust explanation for certain cases of adaptive suicide in bacteria. Nevertheless, a few experiments (even added with simulations) (see Box 13.5) don’t constitute a knockdown argument in favor of the origin of PCD (and even less that of an aging program) through kin selection. But reconsidering the case of suicidal strategy by bacteria, the most plausible evidence for “altruistic suicide,” provides new resources, emphasizing the role of spatial structure. Berngruber et al. (2013) modeled the evolution of

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Box 13.5  Kin Selection and PCD in Unicellular Organisms: Findings from Simulations

With a team of fellow biologists versed in IT, Charles Ofria devised the AVIDA software (Ofria et  al., 2009), an agent-based model designed to explore artificial life. In 2019, Heather Goldsby and Anya Vostinar used the model to investigate whether “programmed cell death can evolve in unicellular organisms due solely to kin selection” (Vostinar et al., 2019). “Artificial life” means mimicking the dynamics of life as an evolving system by tracking events in a system of individuals that reproduce with heritable variations. It provides candidate explanation for existing phenomena, even though the actual explanation would need data about initial conditions that may be unavailable. That’s exactly the situation of the Darwinian biology of programmed cell death, since it originated billions of years ago. The AVIDA evolution system is a useful tool to explore the possible evolution of unicellular organisms by staging digital organisms. These digital organisms replicate and mutate like Darwinian individuals, and here, the death of a related unicell allows a unicell to increase its metabolic rate, which potentially allows it to reproduce faster. In this simulation, the death of an individual may either increase the metabolic rate of kin or decrease the metabolic rates of non-kin. These strategies correspond to extant behavioral patterns. The individual may either secrete a bacteriophage (which protects kin) or secrete a toxin (which kills non-kin). In the simulation, the distance that separates kin from non-kin is objectivated by weighing the amount of nucleotide changes between their genomes. Beyond three changes, the second unicellular organism is considered non-kin in relation to the focal individual. The simulations show that 12.52% of the single-celled organisms commit suicide in the presence of a pathogen when the strategy is of “direct benefit to kin,” whereas only 7% of the population commits suicide when the suicide is harmful to non-kin. This means two things. First, unicellular suicide can evolve through natural selection. Secondly, this selection would favor the direct benefit over indirect benefit of kin (within the context of the ecological behavior of suicidal strategies). The weight of kin selection as a reason for altruistic (continued)

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Box 13.5  (continued)

suicide is higher with the former colony, where suicide positively affects kin. But the AVIDA simulation also shows that the evolution of the suicidal strategy is less likely if “kin” is considered too broadly; i.e. if kin are more distantly related. Interestingly, experiments made on the unicellular chlorophyte Chlamydomonas reinhardtii by Durand et al. (2014) show that these two strategies exist and are not exclusive. Heat-induced PCD in this species is unsurprisingly associated with positive effects on neighbors, hence on kin (given that they live in biofilms). However, this study also observed the effects on other species of bacteria: “the fitness effects of PCD materials released by one strain (C. reinhardtii strain CC125) on another strain C. reinhardtii UTEX89 and two other species (C. moewusii UTEX9 and C. debaryana UTEX1344),” with the following results: Growth dynamics were atypical due to the relatively nutrient-depleted media (PCD supernatant obtained after 1–2 days). The effect of PCD on growth of the same species was positive. Unexpectedly, PCD supernatant from C. reinhardtii CC125 inhibited the growth of two other species [of Chlamydomonas], C. moewusii and C. debaryana. After a brief initial overlap for 3–4  days, the curves separated and remained so for the duration of the experiments.

altruistic suicide as a defense against hosts in a structured environment. The model contrasts two defense strategies: the resistance against the pathogen and the altruistic suicide, and then describes their frequencies based on two differential equations. The host defense is determined by the balance between costs and benefits of each strategy. Resistance increases in frequency if the infection is so strong that the benefit of resistance compensates for its cost. But altruistic suicide cannot increase in frequency when the population is well mixed, since all bacteria, whatever their strategy, have the same probability of benefitting from the suicide. However, if the benefit of the altruistic suicide is “transferred preferentially” to similar bacteria, then altruism may increase in frequency, and hence be selected against resistance. This idea is the basics of the evolution of altruism: altruistic traits, defined as traits that benefit others but cost to the focal individual, evolve if and only if there is something that ensures

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that the receiver of the altruistic act has more-than-average chances to be an altruist itself. In the case of bacteria altruistically committing suicide, this coupling between an altruistic suicide and an altruistic receiver can be achieved by spatial structure, when the population is not well mixed so that altruists turn out to be clustered. In the absence of resistance strategies, in theory, altruistic suicide is favored if altruistic bacteria have less chances than others to be exposed to lytic viruses, another outcome related to spatial structure. The researchers intended to confirm these results by designing an experiment on Escherichia coli endowed with the gene Lit, which reduces viral production by altruistic suicide. They found that the bacteria expressing Lit could increase in frequency in spatially structured environments, but not in liquid environments, which by definition are well mixed. However, some mixing should occur, because otherwise the virus can’t spread, which prevents the selection of defense strategies. This paper followed another one, by Fukuyo et al. (2012), linking the evolution of “altruistic suicide” to “structured habitat.” They too combined mathematical simulations and an experimental setting. The experimental procedure contrasts a soft agar environment in which Escherichia coli may preferentially interact with similar types of bacteria, and a wellmixed liquid, where interactions should be homogeneous (see Fig. 13.6). Simulations show that altruistic suicide evolves only in the former population. Noteworthily, the benefit increased by the altruistic strategy is (a)

(i) no suicidal defense S P

(ii) suicidal defense P

(c)

A A (altruistic)

host pathogen (bacteria) (phage)

S (non-altruistic) within soft agar

+ liquid shaking

spatial structure present

spatial structure absent

Fig. 13.6  Cell suicide in E. coli as a function of spatial structure (mixing vs. structure). (After Fukuyo et al., 2012)

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contingent on the ratio of resistant strategies to altruistic ones. If the ratio is too high, the benefit will be lower. The upshot of these studies is that population structure is crucial in the evolution of suicidal programs. More generally, if we suppose that the bacteria are not kin, in the sense that they don’t have a common ancestor closer than the ancestors they share with non-altruistic cells, the same models would still predict the evolution of altruistic suicide. Here, we touch upon a major element of the theory of the evolution of social interaction traits. Common descent is the best and most robust way to produce two individuals that are more strongly related to each other than to others, at least regarding a specific genetic locus, and thus, the best proxy to assess relatedness. Nevertheless, any process that produces such relatedness will also be instrumental in fostering the evolution of altruistic suicide. For this reason, if we adopt the hypothesis that aging programs evolved by selection, kin selection in the sense of a process that relies on genetic relatedness by ancestry may not be necessary. Population structure, to the extent that it ensures a better relatedness between carriers of a program and individuals interacting with them, can explain aging programs. This suggestion fits the recent detailed analysis of the Hamiltonian biology of social interactions elaborated by Jonathan Birch. Birch (2017) resists the common view that group selection is, in fact, always kin selection. He considers that kin selection and group selection are two legitimate possibilities for evolving social traits, and that they differ in terms of population structures. The most general class in which these processes enter is the evolution based on indirect fitness benefits—where “direct” and “indirect” refer to Hamilton’s partition of inclusive fitness between payoffs conferred to the focal actor of the trait under study, and payoff conferred to others mitigated by the degree of relatedness. Kin selection occurs when interacting individuals have a high relatedness ensured by common genealogy, while group selection occurs when a specific stable spatial structure ensures that indirect fitness benefits will be produced and overcome the direct fitness costs, regardless of any possible genealogical connection. “Group” (G) and “Kin” (K) are therefore less properties of two distinct processes than features of population types; actual populations can be rather “K” or rather “G,” while pure “K-populations” or pure “G-populations” are rather rare. K and G can be imagined as the axes of a two-dimensional space, and we can think of kin selection and group selection as large, overlapping regions of

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that space. Paradigm cases of kin selection occur in high-K populations: they are cases in which we find selection on indirect fitness differences in a population with a fairly high degree of relatedness between social partners, and with kinship-dependent mechanisms serving as the main source of this relatedness. Paradigm instances of group selection occur in high-G populations: they are cases in which we find selection on indirect fitness differences in a population in which social interaction is structured by stable, well-integrated, and sharply bounded groups. The distinction here is not sharp, but nor is it merely arbitrary or conventional. (Birch, 2017, 101)

The view I consider here is therefore that programmed death emerged through G-selection in the sense of Birch (2017), in prokaryotes and simple eukaryotes, and then was locked in later as a constraint in higher metazoa, endowing them with the possibility of being programmed to age in a discontinuous way. Moreover, the explanation of the asymmetry in cell division in bacteria—itself a key feature of aging in cells and then in organisms—advanced by the Taddei group (Lindner et  al., 2008—see Chap. 11 above) in terms of “good of the population” could be expressed by this brand of “group selection,” since the bacterial colony in which the phenomenon occurs, being formed by the aggregation of descendants of a first cell, presents the properties of sharp bounds and stable, strong integration conducive to G-selection.12 I started the consideration of death programs by a reflection on the limits of senescence-explaining trade-offs and the possibility that constraints could play a major role in explaining senescence and death. The view I just developed accepts the idea that constraints and not trade-­ offs explain death. But in prokaryotes, death is mostly due to trade-offs that compare a focal individual and other individuals (born after her) in 12  In his book Durand (2021) invokes Refardt et al. (2013) demonstration that “altruism can evolve when relatedness is low”(130), which in my context is an argument in favor of selection for prokaryote PCD. The book (pp. 137–146) proposes a fascinating account of the emergence of PCD in unicellulars in eight steps (gene level selection of autonomous replicons, protection against unregulated cell death, protection against viral parasites, resource sharing and signaling, multicellular-like behavior in prokaryotes, the eukaryote cell, cooperative groups of unicellular eukaryotes, and multicellular behavior in unicellular eukaryotes). Step 5 would represent often a case of G-selection, as he himself indicates: “depending on the cost-benefit ratio and the degree of relatedness between individuals as well as population structures, kin or group selection or both are the explanatory framework”—even though Durand’s concern here is less about solving this question than presenting a plausible scenario of the evolution of PCD across prokaryotes and eukaryotes.

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the same group. Thus the explanatory limits of trade-offs emerge when we want to extend our understanding of death to all living beings. The question “do trade-offs or constraints explain death?” would be ill-­formulated since the answer varies according to which branches of the Tree of Life (or the Great Network of Life) are considered. In this framework, the last studies I considered about altruistic suicide, PCD in unicellular organisms, and more generally, aging programs as they may have been detected by Rera and colleagues, which feature characteristics of apoptosis—all that could be understood in terms of G-selection, a selection based on stable features of population structure. This leads me to the last aspect of this inquiry, namely, the prevalence of properties of populations and population structure, and in general social properties, in the experimental and theoretical approaches to the evolutionary causes of aging and death.

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Refardt, D., Bergmiller, T., & Kümmerli, R. (2013). Altruism can evolve when relatedness is low: Evidence from bacteria committing suicide upon phage infection. Proceedings of the Royal Society of London B, 280(1759), 20123035. Rera, M., Clark, R.  I., & Walker, D.  W. (2013). Why do old flies die? Aging, 5(8), 586–587. Sayed, N., Huang, Y., Nguyen, K., Krejciova-Rajaniemi, Z., Grawe, A. P., Gao, T., Tibshirani, R., Hastie, T., Alpert, A., Cui, L., Kuznetsova, T., Rosenberg-­ Hasson, Y., Ostan, R., Monti, D., Lehallier, B., Shen-Orr, S.  S., Maecker, H.  T., Dekker, C.  L., Wyss-Coray, T., Franceschi, C., Jojic, V., Haddad, F., Montoya, J.  G., Wu, J.  C., Davis, M.  M., & Furman, D. (2021). An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging. Nature Aging, 1, 598–615. Sinclair, D. A., Mills, K., & Guarente, L. (1998). Molecular mechanisms of yeast aging. Trends in Biochemical Sciences, 23, 131–134. Skulachev, V. (2002a). Programmed death in yeast as adaptation? FEBS Letters, 528(1–3), 23–26. Skulachev, V.  P. (2002b). Programmed death phenomena: From organelle to organism. Annals of the New York Academy of Sciences, 959, 214–237. Smith Trail, D.  R. (1980). Behavioral interactions between parasites and hosts: Host suicide and the evolution of complex life cycles. The American Naturalist, 116(1), 77–91. Somel, M., Guo, S., Fu, N., et al. (2010). MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Research, 20(9), 1207–1218. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126, 663–676. Tricoire, H., & Rera, M. (2015). A new, discontinuous 2 phases of aging model: Lessons from Drosophila melanogaster. PLoS One, 10(11), e0141920. Vostinar, A. E., Goldsby, H. J., & Ofria, C. (2019). Suicidal selection: Programmed cell death can evolve in unicellular organisms due solely to kin selection. Ecology and Evolution, 9(16), 9129–9136. Zimniak, P. (2012). What is the proximal cause of aging? Frontiers in Genetics, 3, 189.

CHAPTER 14

Death Is a Social Issue

I’ll be considering here that a putative death program evolved from a kind of group selection—what one could call “group selection shadow,” in order to emphasize that we are not dealing here with “group selection” in the sense of Weismann or any earlier biologists who explained death or aging via some “good of the species.” It may be that, in eukaryotes, all elements involved in an aging program evolved separately first because many genes are here because of Lateral Gene Transfer, second because some steps in aging may have relied on by-product selection as hypothesized by Durand et al. (2014), but the whole thing would have been maintained by selection. But once one pays attention to the role population structure plays in evolutionary analyses of aging and death, it turns out that this is all over the place. Social distance really makes a difference upon plausible aging programs and their fulfilling. Population structure has been recognized early on as a key driver of the evolution of aging and death. Abrams (1993) already explained that density of a population had important effects on such evolution since it may contradict Williams’ prediction about the effects of changes in the probability of extrinsic death, when such death “acts primarily on the survival or fertility of later ages.” In a review paper about Reactive Oxydative Species (ROS) and oxidative damage in life history, Selman et al. (2012) more recently noticed that “social status” impacts on oxidative damage and then on aging: in the birds Acrocephalus sechellensis, “subordinate non-helping females had © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 P. Huneman, Death, https://doi.org/10.1007/978-3-031-14417-2_14

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poorer body condition and elevated plasma reactive oxygen metabolites relative to subordinate female helpers and dominant females. Low-quality territories are also associated with elevated plasma ROMs (reactive oxygen metabolites: hydroperoxides generated primarily by lipid peroxidation) in this species.” I’ll indicate how aging and death evolves in relation with, first, social structure, then social interactions. Then I’ll draw some consequences from these facts, which cast a new light upon the fitness trade-off structure that conditions death, and the possibility that group selection favors original death programs later entrenched.

14.1   Social Structures Reflecting in 2004 on the ongoing investigation of longevity genes (see Chap. 10 above), Justin Travis designed an agent-based model that explores the evolution of death programs on the basis of changes in population structures. In the model, individuals have an inherited lifespan that may mutate (adding or subtracting one time step); their fecundity decrease with age; they can also suffer stochastic mortality. They may disperse locally or globally. The dramatic result is that, on the one hand, “in a freely mixing population with global dispersal, evolution selects for individuals with ever-increasing lifespan,” but on the other hand, when added local dispersal, then a lower longevity evolves. The explanation is that with local dispersal, “the population develops a spatial structure in which individuals are likely to be located close to their kin.” To this extent and given the patch structure of space, “the patch vacated when an individual dies is likely to be reoccupied by a relative.” Hence, if an individual dies earlier than the common longevity (because of its mutation), it opens a patch for others, who will be likely to be its relatives (because of limited dispersal); those younger relatives are, by definition, likely to produce more offspring; therefore, from the viewpoint of the kin class, the strategy of dying earlier is better. It has a higher inclusive fitness. The major cause of this evolution of programmed death is the limitation of dispersal. In contrast, “when dispersal is global, an individual can never increase its inclusive fitness through dying, as kins are no more likely to benefit from the newly available patch than non-kin.” And the model shows that by restricting the range of dispersal—which continuously varies from “disperse to closest neighbor” to “disperse globally”—the lifespan decreases even more (Fig. 14.1).

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Fig. 14.1  Effect of local dispersal on the evolution of lifespan (After Travis, 2004). (a) Global dispersal. Programed age of death increases with time (b) Local dispersal. Programmed age at death decreases; selection “favors individuals with an intermediate age of death d.” Trajectories are shown for five starting values of d: 10, 20, 50, 75, and 100

Travis (2004) considers that this is a kin selection explanation. And he sees it, not as an alternative to the major evolutionary theories—antagonistic pleiotropy (AP) and mutation accumulation (MA)—but as an “expansion” of them. Noticeably, this process does not create senescence, which is supposed to already exist—agents don’t live forever; additionally, they don’t have an equal probability of dying, which is presumably the result of an orthodox evolutionary process: but Travis’ mechanism induces shorter lifespans. However, what shows this theoretical model is that a

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mechanism inducing heterogeneous patches that are more similar within themselves than with other patches creates conditions for the evolution of programmed death at a younger age, because such phenotype provides indirect fitness benefits. But this means that it constitutes a population in “which social interaction is structured by stable, well-integrated, and sharply bounded groups”—exactly what Birch (2017) considered as a G-population, giving rise to what he calls “group selection.” The upshot of those simulations is therefore that population structure can have a causal effect on the evolution of programmed death, which is an argument in favor of the view I put forth earlier. And from the empirical side, there exists some literature establishing this relevance of population structure to longevity. Graves and Mueller (1994) survey experiments that document the effects on varying density in Drosophila Melanogaster upon longevity. It also considers effects of food restriction, and attempts to select for longevity by changing the density conditions under which larvae are cultivated (“juvenile crowding”). As expected, high densities often decrease longevity. However, it appears in some cases that high density, because of food scarcity, involves a kind of dietary restriction which can result in an increased longevity. And other species feature specific properties that may make high densities a facilitator of longevity: “juvenile survivorship of the coral reef fish, Dascyllus aruanus, [is] increased with increasing adult density. For this species adults may serve to provide juveniles with predator warning and thus reduce one source of mortality.” More recently, Lucas and Keller (2020) considered population structure more directly, and beyond the mere facts of density. Their conclusion is that the forms of sociality impinge on longevity in various ways. First, group living may increase longevity by decreasing the rate of external death—thanks to some protection provided by the life in a multitude— and therefore, through either MA or AP, increasing lifespan. But on the other hand group living “incurs costs through competition among group members and exposure to infectious diseases by social contact.” As a consequence, there is some ambiguity in the relation between death and social life: the relation between sociality and longevity is not uniquely a facilitating or a preventing one. Two other major facts emerge from their examination of the relations between group living, population structure, and longevity in numerous species, including many social insects. First, the relation is bidirectional: sociality influences longevity, but reciprocally longevity impinges on sociality, for instance “longevity therefore

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Fig. 14.2  Various effects of extrinsic mortality on longevity, depending on social parameters. (After Lucas & Keller, 2020)

creates more opportunities for cooperative interactions between kin,” and it can also impinge on density, which itself affects longevity. For this reason, “analyses of the influence of sociality on longevity, requir(e) to either disentangle the direction of causality or critically evaluate the most likely interpretation where a significant correlation is found” (Lucas & Keller, 2020). The authors therefore propose a diagram of the various causal relations between sociality, longevity, and extrinsic mortality (Fig. 14.2). Second, assuming that the population is divided into casts or classes, sociality has differential effects upon longevity, dependent upon the groups to which the organisms belong. For instance, from the viewpoint of disposable soma theory (DST), a species made of breeders and helpers such as many species of bees displays two distinct profiles when extrinsic mortality increases: in accordance with DST, helpers die younger; however, breeders like the queen can die later, since “the energetic allocation needed for reproduction is reduced because of the work provided by helpers.” As a consequence, “greatest extensions to longevity should be seen in breeders of species with high levels of cooperative brood care and reproductive division of labour (‘eusocial’species), while workers in these species, which bear the burden of work and colony defence, may have substantially

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shorter lives” (Lucas & Keller, 2020). But this pattern extends beyond eusocial insects: in mammals too, “it may not be sociality itself that is important in promoting longevity, but rather the position at the top of the social hierarchy, because reproductively dominant individuals receive care from others and are protected from many causes of extrinsic mortality” (ibid). Eusocial mole rats, in which a sharp divide exists between reproductive and non-reproductive classes, exhibit thereby large differences in longevity. Thus, while the feedback on extrinsic population mortality by natural selection is a key driver of lifespan and aging, as it has been established both by MA and AP or DST models, population structure in species which this structure is rigid and codified impinges upon the results such driver can yield. Emphasis on these facts enriches initial analyses that I previously considered without envisaging population structure. However, I should remind that such a structure exists along several dimensions: casts, spatial structure, as explored in the model and experiments I just mentioned—but also ageclass structure. And the fundamental intuition of evolutionary theories of death by Medawar and Williams was that death has to be analyzed in relation to the differential force of selection upon diverse age classes: Hamilton’s more general model, and, above all, Charlesworth’s mathematical treatment of Hamilton’s ideas, constituted the formal core of these theories. This has been recently developed in theoretical work by Cotto and Ronce (2014), based on Hamilton’s formalization of the molding of senescence, as well as on studies of extinction of population in changing environments initiated in the 1990s by Russell Lande. They show that the environmental changes would impinge on the rate of senescence through a complex process impinging differently different age classes: on the one hand rate of senescence increases because of environmental change that involves higher mortality because of lack of adaptedness of the previously best phenotypes, and on the other hand increase of genetic variance in late age classes because of senescence increases the potential for a response to selection. But the model shows that the former effect is higher, which means that when environment changes gradually, or abruptly, or through habitat change, one predicts that late age classes will be less likely to respond to selection, and therefore, lifespan will be negatively affected. As a general consequence, we see that the present analysis of social structure in the evolution of death mainly generalizes an accent on population structure (as causally implied within the evolution of death and aging) that was originally in the theory. To sum up this section, while most

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theories of aging and death focuses on the species itself with no social differentiation, considering social structure allows understanding that “longevity is associated with various measures of sociality”; group size, but also “the number of group members with which individuals interact” (Keller & Lucas, 2020, my emphasis) play a significant causal role.

14.2   Social Interactions Hence, besides social structure, a more fine-grained account of senescence and lifespan investigates the effects of social interactions—meaning by “social interaction” any interaction between individuals such that the fitness of each of them is impacted by it, as is the common use in evolutionary theory of social behavior. Granted, there is something artificial in distinguishing, as I do, social structure from social interactions, in the sense that structures always mean a specific pattern of interactions— however, what I considered previously, namely cast structures, are such that subclasses of individuals are engaged in proper cast-specific interactions, whereas in the general case of social interactions, there may be no casts or classes, and each individual is likely to interact with any other in some ways. Cohen et al. (2020), relying on extant literature, conclude that social and sexual interactions have an effect on the “cost–benefit balances of somatic maintenance and reproduction,” which in turn shapes the trade-­ offs responsible of senescence. They reconstitute a complex causal scenario which starts with intergenerational interaction and is deployed as follows: “cooperation by food transferral from adults to their descendants can promote the evolution of longer life span in populations of overlapping generations” (Gurven et  al., 2012; Lee, 2003; Pavard & Branger, 2012); then “long life and post-reproductive life span can in turn promote the evolution of cooperation (Ross et  al., 2015) and suppress conflict (Port & Cant, 2013),” which triggers a “positive feed- back” that reduces the costs of maintenance and therefore allows increasing lifespan. Yet, as in the case of social structures, the effects of social interactions on lifespan and aging, via effects on extrinsic mortality, may have distinct and opposite direction. Here is an illustration given by these authors: Berger et  al. (2018) showed recently that in cooperative breeding Alpine marmots, the presence of helpers (subordinate males) on the one hand improves the survival of male pups via thermoregulation during hiberna-

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tion, but on the other hand can impose strong intrasexual competition pressure on these pups. The opposing influences from social and sexual interactions produced a nonlinear effect of the presence of helpers on the life span of male dominants.

Besides experiments and observations reviewed by these authors, from the viewpoint of theoretical modeling, Ronald Lee (2003) proposed a theory that adds to the classical factors, mostly mathematized by Hamilton, what he calls the “cost of transfer” between parents and offspring, namely, transfers of energy and materials through parental care. I assume this relation may be extended toward any caring relation to any genetically related individual, which makes the model even more general but less tractable. This overly frequent interaction (parent and offspring) maybe more or less substantial, depending upon the time-lapse offspring rely on their parents. In some species it can be almost nothing whereas in others it can be several years, hence a substantial amount of resources; and this transfer is often oddly distributed between males and females. Lee’s reasoning emphasizes that these transfers have effects on fitness, in terms of both amount of offspring and capacity of offspring to produce new offspring; such transfers are therefore under selection, and this selection on transfers combines with the declining force of selection on traits after the peak of the reproductive period to entail longevity and patterns of senescence. For instance, selection on transfers acts in this way: “if an organism evolves greater transfers to juveniles, permitting greater growth and development before they must begin production themselves, this investment should return higher net production at later ages.” This theory predicts better than the classical antagonistic pleiotropy Hamiltonian theory the data regarding mortality among the Ache tribe of hunter-­ gatherers (Fig. 14.3), which confers a high likelihood to it. Classical theories, extensively examined in the previous chapters, focus on the relation between the individual and its offspring, but only in terms of reproduction. The parent-offspring (or kin) interactions are at the heart of Lee’s model, and it has interesting consequences. The idea that after a reproductive period, some individuals could stop reproduce and remain healthy for a long time—namely, menopause, which happens in humans, and some cetaceans—can be derived from this view: selection would favor transfers over reproduction, to the extent that these transfers produce better grand-offspring. Lee’s model formalizes the intuition expressed by Williams about this fact (Chap. 8). Another interesting consequence is the

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Fig. 14.3  Predictions from the Hamiltonian model, where mortality is related to fertility, which defines the force of selection (F(a)); and from Lee’s “transfer theory,” where transfers from parent to offspring are taken into account as underpinning the dynamics (T(a)). (After Lee, 2003)

drastic decrease in mortality after birth; in effect, given that the more offspring grow up, the more transfer of resources is invested in them, selection should be more and more drastic when individuals initially grow up, and therefore, mortality severely drops until a time before reproductive period. This rivals the theory of ontogenescence—surveyed in Chap. 9— but may not be ultimately incompatible, given that the two formalisms could plausibly be reconciled. However, the novelty is that the account focuses less on the individual than on the group, or at least the family. The fact is that all these experiments, data, and models exposed in this chapter concur in showing that death-related explananda, namely lifespan and senescence, require an explanation that takes groups into account. And this was the only thing needed to confer some credibility to the idea that G-selection in the sense of Birch (2017) can account for death programs, even though these programs could have been locked later on during evolution toward “higher” metazoans. As an addition to this line of thought, consider again prokaryotes programmed cell death. The team led by Pierre Durand (Johannesburg), which has been investigating microbial cell death for a decade, focused on “the impact of programmed cell death (PCD) on a population’s growth as well as its role in the exchange of carbon between two naturally co-occurring halophilic organisms” (Orellana et al., 2013). Dunaliella salina, an algae, is shown to produce through PCD some organic algal photosynthate that are used by others as nutrients, fostering its growth. This fact would by itself

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support the kin selection account of prokaryotic PCD. However, the paper investigates what’s called the microbial loop, a model “fundamental to our understanding of biogeochemical cycling of nutrients and minerals in aquatic eco- systems”; it interrogates the role of D. salina’s PCD in such a loop. Such PCD “causes the release of organic nutrients such as glycerol, which can be used by others in the population as well as a co-occurring halophilic archaeon,” the Halobacterium salinarum (ibid). The latter “exploits the process in a density dependent manner” and therefore indirectly promotes algal growth. Measures of primary productivity of the population show that the interaction with H. salinarum “increases the overall fitness of D. salina,” because productivity increase yields increased growth rates which, added to “the death of 57% +/-17% of its members,” promotes a “young and healthy” population of D. salina (ibid). The microbial loop, here, is made up by the PCD likely D. salina cells, and the H. salinarum (itself supported by D. salina PCD and its released photosynthetates), which in turn increases the carrying capacity of the environment for D. salina. The microbial loop, here, explains how the many interactions between species make possible and maintain the PCD in D. salina. Interestingly, kin selection would not be enough to account for this phenomena, since individuals of another species (hence, non-kins) are among the bearers of indirect fitness that support the trait; in turn, what happens is a population structure that promotes between-species interactions likely to make PCD-­ prone cells in relation with cells that could, either directly (by eating nutrients) or indirectly (by benefiting from effects of H. salinarum, which, in turn, is promoted by PCD in D. salina), benefit from the death of these cells. In other words, in an ecological setting we see how group structure may promote interactions that in turn would entertain the evolution of programmed cell death. This contributes to the topic raised earlier on when I emphasized that death and aging connect evolutionary biology with community ecology (Chap. 9). Here, programmed death plays a role not only in the evolution of individuality and colonial structures, but also in the stability of the ecological community. I would speak here of a horizontal circularity between PCD in some bacteria, and each of the microbes in the loop: PCD may evolve to foster the stability of the community, and reciprocally, the structure of the community is shaped by the material post-suicide costs and benefits provided by bacterial PCD. Additionally, there is what I call the

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vertical circularity—here, there is a link between bacterial PCD and overall the population of cells of such species. As hypothesized, the programmed death of a cell evolves because of benefits conferred to the population itself, as if it were a cell in a multicellular organism undergoing PCD. It allows the population to subsist in environments where all kinds of entities threaten its survival, by getting rid of weaker cells. Inversely, the individual cell benefits from all the other cells in the group, for anti-predation and nutrition reasons. Vertical circularity corresponds to the dual relation between the cell of an organism, possibly undergoing PCD for the sake of the organism, and the organism itself—but it exists in an ecological context independently of, and prior to, plants and metazoan emerge. Horizontal circularity, in turn, designates a contribution of PCD to community ecology. Therefore, programmed cell death allows us to sketch the reasons why death matters in ecology, regarding the interplay between ecological interactions and evolutionary processes. PCD, like death and aging, connects evolutionary and ecological dynamics in microbial communities. This connection has various facets, if one includes now microbial PCD and aging: first, the distribution of age and PCD-capacities within a population of a focal species entails that some fitness trade-offs between various individuals of various species are possible. It would be too long a description, but the fact is that trade-offs on life-history traits between individuals of many species contribute to the processes underpinning biodiversity patterns.1 Second, because of these effects of death upon the distribution of age classes of various organisms, the probability distribution of predators in the community, according to their age and harmfulness, is impacted by the various processes of death (see also Box 14.1). In turn, the evolution of aging and death, as we saw, is molded by such a distribution. That is a major form of causal circularity that was not considered until now. It is highly complex, and modeling such an interplay between aging, PCD of unicellulars, predation risk, and evolution of senescence seems mathematically intractable. All we can do is choose some simplifications suited for our explanatory purposes, and model an aspect of this complex and causally circular dynamics. 1  We addressed these trade-offs possibly underlying what is called “neutral community ecology” in Munoz and Huneman (2016)—see also references therein regarding “ecological equivalence” and “stabilization mechanisms.”

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Box 14.1  The Case of the Black Queen Hypothesis

One piece of this dynamics however, regarding PCD, could be this account recently suggested by Pierre Durand, Grant Ramsey, and Andrew Ndhlovu (Ndhlovu et  al., 2021) called the Black Queen Hypothesis about PCD. The Black Queen, an idea named in direct relation to the infamous Red Queen advocated by Leigh Van Valen to make sense of evolutionary changes species have to make in order to keep their rank in the overall competition, means that a species or a class bears the trait producing the costly common good from which others benefit, so that the others that might have had the trait can lose it through evolution. PCD in microbes that do that, in the microbial loop, could therefore represent typically a Black Queen. While the characteristics of a Black Queen are the following according to the designers of the concept (Morais et al., 2021): “(a) leaky enough for the resulting public goods to be used by other species; (b) costly (energetically or nutritionally expensive or bearing some other fitness cost); (c) vital to the community, not just the producer; and (d) performed by only a fraction of the community.” Ndhlovu et al. (2021) show that PCD in microbes features all of them. This means that PCD in some microbes in a community may lead to loss of the traits in many species. This prediction is attested. However, while many species can lose the PCD trait, it might be that at the point at which all species have lost it, extinction is lurking. As they write: “avoiding the BQ, as a general strategy, is beneficial only if other local species are stuck with the BQ.  During the course of evolution, there may be times when no species bearing the BQ are to be found. Thus, while avoiding the BQ may be good in the short term, it may make the species more likely to go extinct.” This remark shows once again how death in general and PCD in particular convokes issues of levels of selection: in effect, saying that extinction threatens communities losing all their PCD-able species appeals apparently to some kind of selection at the level of the ecological community, which is even more speculative than the G-selection I advocated.

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Finally, PCD and aging in general, by contributing to the articulation of ecological dynamics and evolution, introduce again the idea that death plays a regulatory role in ecosystems, and, when taken to the limit, in the overall Earth dynamics. We already met this idea as a form of providentialist metaphysics in Chap. 7. Here, it pops up again, but in the context of an investigation of various trade-offs between species that ultimately promote biodiversity and ecosystem stability.

14.3   Discounting Rates: Temporal and Social As a conclusion, all these models and empirical investigations don’t force us to give up the classical accounts of death and senescence in metazoans—namely AP, MA, DST. They don’t promote a return to Weismannian views of the good of the group. They rather rely on a Hamiltonian logic extended in such a way that G-selection appears as an expansion of Hamilton’s kin selection, because both of them rely on the idea of “indirect fitness benefits” and their role in evolution. Trade-offs between now and later, present self and offspring or future selves, as constitutive of fitness, and, subsequently, of senescence—as explained in the previous chapters (Chaps. 9, 10, 11)—were not enough to explain all features of aging and death, as we saw in this chapter. What was missing was the impact of population structure and individual interactions upon these trade-offs. Examples taken from the “microbial loop” indicate that, beyond populations, communities and their ecological interactions may be constitutive of these trade-offs, and therefore a complete account of senescence and lifespan should integrate ecological dimensions—while, in turn, as alluded to by Lucas and Keller (2020), the direction of causality is twofold. Senescence and aging in a focal species emerge from trade-offs and constraints, not only through relations between present time and future consumption and investments—but also through interactions between individuals within and between species. But in turn, lifespan and senescence induce behaviors and trade-offs between life-history-traits that will have major ecological consequences. Any theoretical model can only but circumscribe one aspect of these causal relations. Here, more than ever, truth can only stand at the crossroads of distinct models and modeling choices. However, putting together the latest developments and the examination of trade-offs in Chap. 11 above, a general picture emerges, which is the following.

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What appeared crucial in the epistemological analysis of the AP account and more generally the trade-offs explaining death and senescence patterns was the balance between now and then, or in other terms, current and future offspring (Chap. 11). Therefore, the discounting rate was essential to understanding the senescence-yielding trade-offs; and ecological, genetic, and phylogenetic constraints were concurring in determining such a rate. The “discounting rate question” means: “How much is an offspring occurring in n units of time worth as compared to a present offspring?” In other words the question bears on weighting current against future offspring, and also the past again present ones: past offspring are less risky since they are already there; present ones are fragile; future ones may not exist, depending upon the conditions (and of course there should be cues to detect the probability of these future offspring being viable). The discounting rate itself should be under selection, and depend upon environmental conditions. In a word, future offspring are traded-offs against current offspring, and the discounting rate is what tells you how much is a future offspring worth in terms of current offspring, in function of elapsed time (leaving aside the possibility of major environmental changes). Both can produce grand-offspring, and this is what makes the computation possible—because there is a common currency used to compare them. What emerges now, in the present chapter, is an issue with organisms that are related between themselves, an issue that classically involves considering kin selection. The basics of inclusive fitness is that sometimes it’s better in terms of final evolutionary success to favor kins rather than oneself, because it pays off ultimately in terms of the total amount of offspring sharing genes of the focal individual. In other words, and to parallel the case about temporal trade-offs and death, others’ offspring can be compared to one’s offspring, and sometimes it is worth favoring others’ offspring because the overall fitness gain (measured as the total copy number of a focal gene in later generations) is higher. This comparison should therefore involve a metrics, hence a rate of convertibility between one’s offspring and the others’ offspring. Relatedness holds the key for this rate of conversion, since any measure X of relatedness means that a fitness benefit (negative or positive) w for an individual A′ related at degree x to A represents a benefit xw for A, therefore relatedness X allows conversion of benefit to A into benefit to A′ related to A. Thus, in the social contexts I’m considering, relatedness plays the same role as discounting rate does regarding the temporal trade-offs in which senescence is rooted. Two

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discounting rates, then—two kinds of inter-units trading and assessments: one is about time, the other one is about population. Temporal discounting rate and relatedness are these two rates. Yet, they don’t behave exactly equally. The discounting rate can’t be set independently of any genetic and ecological context, it means nothing in the absolute (i.e. comparing individuals A and A′ with no context), as I argued in Chap. 11. It might be very high or very low depending upon ecology and genetics; and it can evolve. On the other hand, the inter-­ individual discounting rate seems yet to be fixed and objective: relatedness is determined by comparing genomes—it’s a statistical association between alleles at a given locus (compared to the average correlation over all loci). Theoretically speaking it seems therefore that in a real setting life-­ history in general is constituted across two spaces of comparability and trading: the social landscape and the temporal landscape. The temporal landscape and its trade-offs are at the heart of what “death” and “senescence” mean in evolutionary terms, and that’s why they are something so essential to evolutionary logic. But our recent investigation of PCD in prokaryotes confronts us with another dimension of senescence, which is precisely this social landscape as a whole. How so? First, consider the kin selection explanation of PCD that I have exposed previously. It consists in pointing out the interchangeability rate between offspring of related individuals, and realizing that in some cases fitness is finally higher by dying and favoring individuals that are properly close, in the sense that the death of the focal individual and the life of offspring of these other individuals can be traded-off one against the other in function of the degree of relatedness, in exactly the same way as the temporal trade-offs do between a current and a future offspring. Now, advocating a more general G-selection account—namely, an account in which population structure itself ensures that indirect fitness benefits can be computed and overcome direct fitness benefits—extends this reasoning beyond cases where the kinship relations constitute the convertibility rate. There, we are indeed generalizing towards a convertibility defined by a relatedness that includes a term representing social distance, which is characterized both in terms of population structure and in the pattern of social interactions. If one considers for example cases of what is called helping in behavioral ecology—individuals contribute to raising offspring of other individuals, even though they are no more related with them than with other individuals—one sees that kinship is not the only source of proximity and distance in the social space. Besides, individuals

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that disperse more locally, for instance, in a population, are such that, when they do something from which their close neighbors benefit, they entail that some related individuals will benefit from that (since these individuals can’t be too far). Here the social structure—through dispersal— ensures indirect fitness benefits, while without this structure, indirect benefits should rely on some mechanisms such as kin recognition. In this case, spatial structure of the population would ensure that in some occurrences dying provides higher indirect fitness benefits than surviving, as we extensively saw it with prokaryotes in unicellulars or “altruistic suicides.” The last theoretical problem about death and aging consists therefore in combining these two kinds of convertibility rates, social and temporal, since the evolution of lifespan and possibly other death-related explananda involves trade-offs, which, as we have seen, take place on these two dimensions. Thus, in simple terms: how could we measure the fitness ratio of one’s offspring in future n units of time to the offspring of one’s related individual (where relatedness is taken as a measure of social discounting rate)? Yet it appears that sketching such metrics should involve taking into account the relation between social structure and environmental change, in such a way that the metrics cannot be stated with no reference to environment-specific and clade-specific parameters. (The reasoning here builds upon the arguments in Chap. 6 about the lack of general temporal convertibility rates, and takes them to a higher level of complexity, bringing on board social structures.) In the absence of a single convertibility rule between these two rates I don’t see how a general theoretical account could emerge that would reconcile the AP or DST accounts based on temporal trade-offs, and the G-selection account of programmed death here sketched. Remember that temporal trade-offs were not straightforwardly allowing for a single convertibility rate between all of them. But now, the problem is worse since we need a convertibility rate between the set of discounting rates involved by these temporal trade-offs, and relatedness or any other kind of social discounting rate. I therefore think that here we are doomed to a radical pluralism, consisting in a series of convertibility rates, each fit for a given theoretical problem, but unlikely to be unified under a single formula. The simplicity of traditional evolutionary accounts of death and senescence now breaks up. Granted, there were the three major families of accounts. But considering how social space and social discounting rate contribute to explain PCD and in general patterns of senescence indicates

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that the theoretical landscape of senescence is not wholly determined by these three major families, which complexifies the epistemic gap I witnessed in Chap. 9 and explained in Chap. 10. The next issue is the explanandum-­dependent integration, at the theoretical level, of those perspectives focused on social convertibility and social discounting rates, and the question is whether some among the three classical accounts fare better in this task.

14.4  Coda: The Parts and the Whole: Darwinian Style 14.4.1   Parts and Wholes: Kant and Darwin and Cell Death Organisms are systems in which the parts can’t be explained or understood without their relation to the whole—and they cause themselves one another in accordance to this idea of the whole. However, such an idea of the whole is not the principle of the production of the system, since in this case we would be witnessing a work of art—but a “principle of cognition” for the biologist. This characterization of an organism was famously put to the fore by Kant in his Critique of Judgment (§65), in a patient reflection upon the changes in life sciences that were occurring at his time, especially in embryology and in comparative anatomy (Huneman, 2006, 2008a, b). While the three major breakthroughs that shook biology since then, namely Darwin’s evolutionary theory, the cell theory, and DNA-based molecular biology, proposed new accounts of the relations between wholes and parts, the idea that there is something proper to the part-whole relations that characterizes organisms is not much outdated. The contrast stated by Kant between these organisms, taken with the “teleological judgement” that addresses them (teleological in the sense that it relies on the presupposition of such an “idea of the whole,” before even considering the parts) and systems amenable to what he calls a “mechanical explanation,” namely an explanation that starts from the parts to explain the whole, is not erased by these major paradigms.2 For orthodox Darwinians, organisms are “bundles of adaptations,” which are themselves results of natural selection (Huxley, 1942, used this phrase). For molecular biology the whole exists 2  On Kant’s view of organisms and this difference see Huneman, 2008a, b, 2017a, b, forth.).

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initially as encoded in each part, in a sort of preformationist way, in the form of DNA (Müller & Olsson, 2003). In cell theory, the whole is just built up by the parts, and embryologists in the late nineteenth century, after Schwann and Virchow, struggled to understand why development— which is this building-up by the parts, characterized as cells—tends to always reach the species-typical adult form. In each of these cases the fact that the whole has a specific relationship to the parts—not just a derivation—and that it has some (at least) epistemological priority over the parts, proves to be crucial.3 Within the evolutionary framework, the question of the organism has been provocatively raised by Dawkins (1976): “why, he asks, should every living thing come under the form of an organism?” Answering this question means answering why multicellularity evolved on the basis of cells—the pervasive fact of organisms, after all, means that life is not only made up of free-floating cells—why the sequestration of the germ line occurred, and possibly why sexual reproduction occurred. Those are deep issues, which are handled by huge research projects that I won’t touch here. Among them, the “major evolutionary transitions” program, initiated by Maynard Smith and Szathmary (1995) and Michod (1999) after Buss (1987), who focused on the sequestration of the germ line, intends to understand how collectives of individuals who live and reproduce apart eventually make up a compound individual that reproduces as one entity. Natural selection is the major process at stake, generally under the form of selection at multiple levels: one selective process occurs at the level of the individuals, and favors the best competitors; the other occurs at the level of sets of individuals, and favors traits that are beneficial to this set, which does not yet exist autonomously.4 Concurring with the analysis of organismality and programmed death provided here, Durand (2021) in his book thinks transitions in terms of “coevolution of life and death,” and investigates them at several levels, within prokaryotes and their environment, at the emergence of the eukaryote cell—where PCD fosters an alignment of interests between all organellar genomes (158)—and at the emergence of multicellularity 3  This is not the place to argue in detail for this claim since it is not central to our point. I have proposed arguments for the persistence of the idea of a singular part-wholes relationship as definitional of biology, in Huneman (2017a) (for developmental biology) and in Huneman (2015, 2017b, 2019) (for evolutionary biology). 4  For an in-depth exploration of multilevel selection see Okasha (2006).

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(159). What is important for us here is that PCD has been a major adaptation rendering possible the emergence of multicellular individuals. As we saw, PCD is essentially involved in morphogenesis, and multicellular organisms require a complex development, including morphogenesis. Hence, PCD is a key contributor to the very existence of multicellular organisms.5 Thus, death of cells is a major condition of possibility of multicellular life. The specific relationship between the “idea of the whole” and the parts, understood as the condition of possibility of any teleological judgment in biology, should nowadays integrate the notion that the parts “die” for the whole of the organism, and not only create themselves in accordance to an “idea of the whole” of the organism, as says the standard Kantian view. Thus, PCD constitutes at least one specific modality of this subordination of the parts to the whole, characteristic of what “organism” means. And, as we saw, in this case (unlike in prokaryotes) its emergence is easily understood in terms of natural selection in a clonal population. Thus, multicellularity would have recruited PCD as a major condition of possibility for organismic development. Recently Teulière et al. (2020) on the basis of a phylogenetic analysis of genes involved in various forms of regulated cell death (including apoptosis, but also autophagic cell death) have proposed that indeed “transiently multicellular taxa appear enriched in apoptotic and autophagy markers compared to free-livings, supporting the hypothesis of a selection for Regular Cell Death [a concept including PCD] as a developmental mechanism linked to multicellularity.” This hypothesis of PCD as essentially recruited for organismic development of multicellulars interestingly parallels another one regarding another matter, namely, epigenetic inheritance.

5  There are several scenarios proposing a role for PCD in the evolution of multicellularity; some involve immunity, which I don’t consider here. But I cite one here, which emphasizes the connection between multicellularity, PCD, and immunity. A paper from the team of Jan Koonin, Iranzo et al. (2014) argued that PCD emerged as an adaptation to defend organisms against viruses. In the simulation model they built, where pathogens like viruses can be more or less present, they see that lack of pathogens promotes “faster reproduction of single cells,” and hence unicellular mode, while the presence of pathogens—especially viruses—means that if PCD is possible “clusters of cells” will benefit from it and therefore acquire some immunity. “Joint evolution of multicellularity and PCD appears to be beneficial in microbial populations that are regularly exposed to pathogens as a way to overcome the limited efficacy of immunity mechanisms.” The authors indicate that, since PCD is often initiated by a Toxin-Antitoxin system in arches and bacteria, there should be a “suggestive of coupling between the 2 types of defense” (PCD and immunity).

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Epigenetic markers, which affect genomic sequences in a way that is generally adaptive, can be transmitted through mitosis to daughter cells. As we know, there is an ongoing debate about epigenetic inheritance in transgenerational inheritance, namely through meiosis. The received view is that meiosis deletes all epigenetic marks, but evidence has been found of epigenetic marks subsisting after three or four generations or more (e.g. Jablonka & Raz, 2009; Pocheville & Danchin, 2014). Clearly, epigenetic inheritance at mitosis plays a major role in cellular differentiation in multicellular organisms, since it allows the stability of cellular types—“type” meaning here a specific profile of genetic expression. But epigenetic inheritance seems to occur also in unicellular organisms. We recently proposed a hypothesis about epigenetic inheritance that was intended to reconcile those who think it’s crucial in evolution, and those who argue that it’s negligible because its effects exist on a tiny timescale as compared to genes. In Danchin et  al. (2018), Etienne Danchin, Arnaud Pocheville, and I suggested that epigenetic inheritance is an adaptation to quickly changing features of environments. In a nutshell, while organisms rely on inherited genes in order to be adapted to the features of environments that are very much long lasting, epigenetic inheritance provides them resources to be adapted to the very recent features of the environment, properties to which their parents and grandparents adapted, perhaps through phenotypic plasticity. As an example, air is a stable long-lasting feature of our environments, hence the genes coding for Krebs cycle and the metabolism pathways involved in respiration in our cells are very old, and inherited; but we may inherit through epigenetic inheritance some genetic expressions that adapt us to much recent features of the world we’ll have to deal with. A consequence of this hypothesis is that in multicellular organisms, epigenetic inheritance has been recruited to foster development through its contribution to cell differentiation, which is another function, in addition to its initial role as an alternative inheritance system. (Gould and Vrba (1982) famously used the word “exaptation” to name such recruiting.) Considering PCD in unicellular eukaryotes, what happened would be something similar to this recruiting: when multicellularity arose, PCD, which was plausibly here because of G-selection, has now been recruited for an additional function, which pertains to development too, but is not cellular differentiation (as did epigenetic inheritance); rather, it was for pattern formation (morphogenesis), as exemplified by investigations led since Glücksmann (1951) on the formation of digits and limbs.

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Kant insisted that cells “cause themselves” in accordance to the idea of the whole—in contrast with technical items, whose pieces are produced by an external designer who contemplates a blueprint. This notion of “production” has been immensely enriched since the times of Kant, especially with the advent of cell theory. What the researches on PCD teach us is that such production of a whole by the cells involves targeted destruction of cells, based on a mechanism—apoptosis mostly—which has been inherited and exapted. The very notion of an organism, philosophically characterized by Kant independently of the subsequent debates on the meaning of the “idea of the whole” and the “self-production” of cells, therefore, acquired a more concrete meaning from all the theoretical advances that explain how parts produce themselves and something else: cell theory, genomics and epigenomics, and finally evolutionary theory and its understanding of inheritance. Death of parts, under the form of PCD, is now a major contribution to this wide theoretical account of what “producing,” and therefore “organism,” means. Additionally, cell senescence, which is the other way for cells to die, and which has been explored in the last three decades, also allows organisms to get rid of deleterious cells, that have replicated too much. Because of telomere attrition, it favors the destruction of cells after rounds of replication; asymmetric cell division, accumulating garbage materials in the mother cells, and allowing rejuvenation of the daughter cells would indeed make over-replicating cells into deleterious cells, likely to harm their cell neighborhood and the overall organismic functioning. Yet, even if asymmetric cell division is a by-product of molecular mechanisms, telomere attrition can be understood as selectively controlled repair, since telomerase could indeed avoid it by reproducing telomeres at each replication, but is not expressed in most of the somatic cells. Not re-synthesizing telomeres through telomerase allows getting rid of cells that are altered by accumulation of aggregated proteins, and clearly favors survival of the organism as a whole. Yet, too much cell senescence accumulates in multicellular organisms and eventually leads to organism deterioration, the reason which it is also considered a hallmark of aging (López-Otín et al., 2013). Yet, from the evolutionary standpoint, parts and wholes in an organism, considering that they are cells, evolved from the free-floating life of ancestor cells: “today’s organisms are the evolutionary result of societies of entities that lived separately in ancestral times” (Wilson & Wilson, 2007).

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Thus, this specific relation between parts of an organism thoughtfully understood in our theoretical framework that makes sense of Kant’s notion of “production” presents us with the final evolution of a group of initially independent cells, one billion years before us. Among other features, programmed cell death allows this group to exist as one whole. Besides morphogenesis, it has other functions, as we saw: above all, the protection against cancerous developments, which should have been more frequent given the strong incentive for particular cells to multiply quickly and faster than others.6 This brief concluding examination leads us to a general ontological conclusion: metaphysically speaking, death of the parts, in the form of PCD, underpins the identity of the organism. As a preliminary, notice that “identity” as distinction from everything else, and identity as persistence of the whole into existence are two faces of a same metaphysical concept of identity. Then, first we have understood PCD as a sculptor (Ameisen, 1996) of forms in morphogenesis, which confers the organisms its form and shape, characteristic of its identity—second, we saw its contribution to maintaining this global identity against subversion from individual parts (cancer). Hence, we see that the two facets of the identity of an organism are indeed clearly instantiated in a way that involves the death of the parts of the organism. Death is a social phenomenon—it is, above all, a phenomenon pertaining to a society of cells within an organism or without it (i.e. prokaryotes, unicellular eukaryotes). Hence, in the former case the explanation of the death of parts (the cells) has to be referred to the life and state of the whole. That’s exactly what happens with PCD in multicellular organisms—therefore, PCD stands as a straight realization of the first Kantian criterion of organismality, namely the determination of the parts by the whole. There was, as we saw, a social origin of PCD in prokaryotes and 6  This book didn’t consider cancer much, nor did it give immunology the role it has in these matters. It’s already long enough. It suffices to say here that the larger individuals are, the more the chances that they develop cancer, since they are made up of more cells, and each one has a chance to become cancerous. Hence, protection against cancer has been a major evolutionary force in evolution: elephants don’t have immensely much more cancers than mice, which is an evidence of the existence of such selection pressure. Recently, Risques and Promislow (2018) have shown that the length of telomeres, which are very various and often not much longer in large mammals, evolved as a result of, first, selection against replicative senescence (which tends to extend telomeres) and second, inversely, selection against disposition to cancers (which tends to shorten telomeres so that cells can’t replicate too much).

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unicellular eukaryotes such as Chlamydomonas or Dunialella salina; it is pursued in multicellular eukaryotes since they embed within themselves a society of cells. Because these organisms are social, in the sense of “societies of cells,”7 such sociality involves that they are explained by and through the group. The explanation of parts from the whole, which, according to the Kantian criteria of natural purposiveness, characterizes organisms, is instantiated in this case by the explanatory role played by social life vis-àvis cell death. One may in turn ask why PCD has an important place in this book, since it’s not the only reason for aging, and is not even a hallmark of aging. The point is that it proves crucial to understand complex multicellular individuality, while all of philosophical theorizing about death had been (Chap. 7) centered on the contrast between individuality and universality (or “the species”). Moreover, until the 1970s or after, the contrast between immortal cells and mortal organisms shaped the formulation of the accounts of death; however, when cells have been shown to senesce and die naturally, this contrast couldn’t be a theoretical assumption any more. But cell suicide now provides a way to question the relation between single cells and multicellular individuals in a novel manner—thus, allowing us to reframe the major theoretical framework in which the evolutionarily question of death had been raised. This intricating of cell death, and the life of a society of cells, is indeed what is recently alluded to by Durand (2021) when he talks about “coevolution of life and death.” 14.4.2   Back to Black To sum up the second part of this book, this long investigation into evolutionary biology enriched our understanding and concept of natural death. We successively considered two major oppositions that structure the debates over the explanation of senescence and death: –– selection vs. no selection (i.e. neutrality), a divide clearly visible when considering the theoretical difference between AP and MA; –– program vs. stochasticity, a divide explored in the two penultimate chapters. 7  Birch (2017) offers an important attempt to revive this notion in the context of Hamilton’s concept of social evolution.

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By so doing, we met a third distinction that was already expressed in the discussion of Bichat and physiology in Sect. 14.1, namely, the distinction between parts and wholes, because the fact of PCD requires one to posit a distinction between the death of the parts and the death of the whole, and view it in an evolutionary perspective. But this brings us back, in fact, to an issue raised by Bichat and Claude Bernard and considered in Part I of this book with regard to the Recherches physiologiques sur la vie et la mort, which enquired about death of the parts provoking the death of the whole, and to Bernard’s saying about la vie c’est la mort, referring to these celllevel chemical destructions that underpin an organism’s life. Recognizing the key role of PCD in multicellular organisms, both at the evolutionary level (since it was involved in the selection for high fitness multicellular combinations, making them relatively immune to cancer) and at the developmental (because of morphogenesis) and physiological (because of immunological control of defective cells) levels, entails that organismic life relies on the death of the parts, under many definitions of the term “rely.” This actually provides us with two or three interpretations of the Bernardian aphorism, la vie c’est la mort. Interestingly, some of the key questions faced by the physiology of death at Bichat’s time here resurface: “is death the result of a continuous or a discontinuous process?” I have shown how a condition for Bichat’s investigation of death was a breakup with the prevailing view of a continuous process of death by use and “wear and tear.” Similarly, in this Part II of the present book, the concept of a “smurf phenotype” broke up with the view of death as a continuous process, either in the form of the “wear and tear” hypothesis that sees senescence as an accumulation of stochastic failures—or under the form of the “hyperfunction theory” of death, which sees it as the continuous effect of a developmental program. On the other hand, recognizing that the death of the parts fuels the existence of the whole, as I’m extensively explaining it here, contrasts with Bichat’s view of the deaths of the parts combining in a specific (and to-be-­ unraveled) order to eventually produce death. Yet, there is no contradiction of course, because we are not looking at the same “parts”: the physiologists considered organs, while la vie c’est la mort concerns the level of cells, which was already Bernard’s concern. The question “why death?” therefore does not lead to a univocal answer. Programs are not to be excluded theoretically. The question “why these programs?” involves considerations about time discounting and sociality. Such considerations are also at stake in any account of the

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interplay between life and death of the parts and of the whole. No complete biological picture is available for long, but what brought us seven decades of questioning of cellular death, in physiological, molecular, ecological, and evolutionary terms, is a rich view of the intertwining between life and deaths at all levels: cellular and organismic, physiological and ecological, at least. As a consequence, death is both explanans and explained: it’s an explanandum in evolutionary theory after Medawar—but at the same time, as cell death, it is an integral part of the explanation. This reversibility is manifest in relation to the cellular level, where, in the case of cancer, the death of the organism may be explained by a deficiency in cell suicide. Hence the death of a part simultaneously promotes the life of the whole, and, by contrast, its not dying may favor the death of the whole; however, if the cell-suicide signals go awry, by an extension of the suicide signal in specific cases (in particular: hepatitis, alcoholism, or brain asphyxiation), the individual may slow down and also die. Life and death are intertwined, at all levels—but even though this sounds a bit trivial, evolutionary biology shows us how and why it’s the case. Some philosophers name such an intertwining “dialectics.” It means that even though death and life are antinomic, they relate to each other in a way that makes each of them possible; as Hegel expressed it throughout his whole philosophy, it’s not sure that the meanings of these two terms— as of any term involved in a dialectical process—could be fixed and remain stable while we employ them in our theorizing activity. The preceding considerations were a set of snapshots of this complex dialectics, which is far more complex than any scientist contemporary of Hegel could have imagined. It’s left to the reader to determine to what extent these snapshots add up in a coherent way.

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CHAPTER 15

Conclusion

It’s time to close this long journey through death in biology. In this book I tried to knot together several threads, and most generally, the epistemic issue about the role death plays in the structure of biological knowledge with the ontological issue about what death is, according to our best science. This combination echoes the most general articulation of this book, namely the functional biology of death—“how does death occur (and what does it allow us to know about life)?”—and the evolutionary issue— “why death?” Because the second question was about death as a necessary process, and senescence is defined by the increased probability of death across life—at least, among a large part of plant and animal clades—the philosophical question regarding the evolutionary biology of death was about aging; in contrast, the first question centered on death as it can happen at any time contingently and pathologically, by disease or violently. Thus, the physiological-functional question about death focused since the beginning on the event of death, and, as we saw, turned it into a regular process of short duration—inversely, the evolutionary understanding of death questions the processes that more or less ineluctably lead to death on a longer timescale. So doing—and this was the metaphysical shift I extensively dealt with—these natural processes are explained via a reference to the stochastic event of accidental death, since, through the major accounts, mutation accumulation (MA), antagonistic pleiotropy (AP), and

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disposable soma theory (DST), the various probabilities of this lethal event in the population hold the key of the question “why death?” Because the literatures examined in the two parts of this book are so distinct, and because they deal with immensely different problems, the common lesson to be drawn from these two enquiries seems at first stake very thin. However, a general message about death in biology emerges from these two investigations, and I’ll quickly describe it here. (1) Philosophers debate whether death is crucial for human beings, or whether it’s something that is nothing, by definition, so that, after Epicure, one should not rationally worry about it. Regarding the way one should behave and think, I have no idea about the role the idea of death should play. But at the term of this long inquiry about death in biology, it clearly appears that death stands at the heart of our scientific understanding of life. The two very different examinations undertaken here, about physiology and about evolution, concur in establishing and detailing this simple idea: understanding death touches the very possibility of explaining life. As the conclusion of a recent paper about death processes in yeast claims: “it is as important to learn how to live as to know how to die” (Carmona-­ Guttierez et al., 2010). In effect, my inquiry into the constitution of experimental physiology shows precisely that unraveling the sub-sequences of events leading from organ failure to death deploys the chains of conditioning relations between organs or processes proper to each organ, that ultimately support life. As I argued in the first section, physiology arguably became a scientific discipline, distinct from anatomy, natural history, and medicine, through the constitution of experimental physiology, which required among other steps such knowledge structure elaborated by Bichat’s investigations of death, as I claimed in the first part of this book. The epistemic centrality of death in biology was also a lesson to be learned from the long examination of evolutionary accounts of death after Medawar: all these theories appear to be rooted in something essential, namely fitness, and more precisely the trade-offs between survival and reproduction that are in principle compellingly included in the fitness concept. Thus, death, to be explained, requires touching upon something fundamental in the very concept of Darwinian evolution—that is, the structure of fitness. Another thread is commonly shared by the two perspectives investigated here, evolutionary biology and physiology of death: the emphasis on sequences. As explained in detail, physiology is partly grounded on the sequences of partial lethal events that experiments are intended to unravel:

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this was Bichat’s proper breakthrough, and it carries effects all along experimental physiology, as I tried to show. For instance, toxiocologic reasoning by Claude Bernard clearly inherited the features of this novel epistemic focus. On the other hand, a major thing to be explained through evolutionary accounts is the sequences of events that, within life, constitute patterns of senescence: this focus is best represented by the major controversy, analyzed in the last chapters, over aging and death programs. Natural death is not a sudden event occurring while nothing happened before; it generally comes after some changes definitive of what is physiological senescence, and many issues revolve around the patterns of these changes: whether they are robust, whether they are continuous or discontinuous, how they differ across species and clades, etc.—these questions culminating in the discussion, examined here in Chaps. 12 and 13 about whether a program should be inferred from these patterns. (2) These commonalities emerging from a retrospective look at the two aspects of the present inquiry are not the whole story. Of course, the “deaths” that are investigated in physiology and in the evolutionary biology of death are not the same. Bichat focuses on the process of pathological death, be it from disease or violence: not instantaneous, but brief.1 Evolutionists are interested in mortality, in natural death and what’s related to it: across species differences in lifespan, patterns of senescence, etc. However, even though the focus differs, at the most general level questioning death in both cases implies two things: (a) Detecting, reconstituting, and explaining sequences, as I said—and these sequences express something fundamental for life: inter-­ organic relationships of dependences, in Bichat and then experimental physiology; constraints and trade-offs constitutive of fitness, in the case of Darwinian accounts. (b) Making sense of specific relations between parts and wholes—a kind of relation that, as I reminded in the coda of the last chapter defines epistemologically what organisms and “knowing organisms” should mean. More precisely, this latter concern is instantiated by the question about the relation between dying parts and a dying whole, investigated by 1  Aristotle would say: violent death here, natural death there—relying on the key difference between “violence” and “nature” that structures his philosophy of nature.

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physiologists through the devices Bichat described in his Recherches sur la mort. Generally speaking, the questions about “how death?” and “why death?” raise fundamental issues about the relationship between life and death of an organism and what happens to its parts. Experimental physiology of pathological death determines the way dying parts produce the death of the organisms; the notion of programmed cell death (PCD) underlines, inversely, the way the life of the whole is underpinned by deaths of the parts. And those latter deaths are possible because of a specific feature, programmed death, whose evolutionary explanation is still controversial; it may contribute to the explanation of death itself, as we have seen in the last section when it came to arguing in favor of death programs, originated through G-selection and locked as constraints in later evolution. Evolution and physiology are definitely distinct takes on this relation between parts and wholes, which is proper to what an “organism” is. Tissues and organs, in physiology, agree to cooperate in a certain way and this cooperative scheme can be unraveled by disrupting the interactions and therefore putting end to life. As indicated in the coda, the basic parts of organisms—the cells—evolved from cells that used to live autonomously. Throughout evolution, these (future) parts came to produce a novel, collective individual, and the evolved (mostly by natural selection) capacities of these cells—including PCD—were involved in the possibility of this evolution. That is how PCD has been recruited in multicellularity, allowing first the defense of the organisms against free-riding cells (namely, cells that become cancerous) and defective cells that hamper the functioning of the whole—and, second, morphogenesis. Hence the outstanding importance of the question of death and its evolution with respect to the general question of what is organismality, understood as a specific relationship between parts and wholes, as Kant suggested a long time ago. (3) Death of the organism has been explained through physiology since Bichat. Experiments on pathological death make manifest as a temporal sequence the event of death previously supposed to be instantaneous. This deployment in time allows the physiologist to make sense of the spatial conditioning between effects of parts in an organism, as argued in the first section. Hence, what is death—in the sense of “how death functions”—is supposedly accounted for by physiologists. Considering that violent death is used by physiology to understand death in general, the confrontation of the two sides of my inquiry acquires

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a novel meaning. The Bichatian legacy in physiology of death uses experiments on death—hence, violent death—to mimic the processes of death after alteration of a specific organ (lungs, heart, brain), in order to explain death in general, and, ultimately, the functioning of life. In evolutionary biology, the explanandum is rather natural death itself: the fact of death, the longevity, the mortality curves, both at the individual (i.e. chances of death) and population levels. But, as I extensively demonstrated, this natural death, to which any living organism is destined once it’s born, is explained in turn (through the shadow of selection) by a reference to accidental death, which of course is violent death (predation, starvation, etc.). Thus, epistemologically, the articulation between the two approaches of death, physiological and evolutionary, between proximate and ultimate explanations revolves around this circular connection between mortality, natural death, and pathological death. As a consequence, biologically speaking, “death” is not a simple object: –– First it is torn between two meanings, death of parts (or “death of organs,” as Bichat used to say) and death of an organism. Parts, in turn, viewed in an evolutionary perspective, descend from free living cells, hence, from lower-level wholes formerly reproducing for themselves, which “invented” a specific way of dying for themselves, thanks to a still controversial selective process. –– Second, “death” means at the same time a necessary property of living beings—Bichat: “living bodies become ill and die”—and a contingent accident happening to them because of scarce resources and predation; and these two facts and their explanations are epistemologically related, in a way described all along the present enquiry. (4) Regarding philosophy, a major lesson of this examination is that the metaphysical weight of death is somehow lightened. The traditional metaphysical framework for thinking of death—whose robustness has been indicated at the opening of the second section—is challenged by evolutionary biology. There, natural death is less an intrinsic essential property of life, needing some justification, than a result to be explained. The epistemologically and ontologically original fact, from which death as an inherent property derives—this property alluded to by Bichat in the phrase I just quoted—is actually extrinsic death: being eaten, affected by a

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parasite, infected by a virus, starving, etc. This might be used as an argument against what one could call the death-maximalists: no grandiose metaphysic should be triggered by the facts of death and its necessity. Nothing will redeem death through a higher purpose, because at the beginning was contingent death—the one that can’t be justified. In Chap. 7 I had reconstituted what I called a “providentialist metaphysics,” upon which thinkers like Aristotle, Schopenhauer, Hegel, and biologists like Weismann concurred, and according to which the death of organisms is explained because it is justified by the higher good it provides—a good for our species, for the Universal. Such providentialist metaphysics is implausible once Darwinism is taken seriously. We— humans, animals, organisms in general—don’t die for the sake of the species, or for the manifestation of the concept and its universality, or as Hegel’s Encyclopedia fascinatingly concluded, for the rise of the “spirit.” Long story short: we—humans, animals, plants—die because life is short, brutish, and harsh, and naturally, intrinsically dying is what eventually happens in this world to entities whose existence is governed by natural selection, even if death is not itself produced by natural selection. Most of our characteristics as living beings are explained by selection, while death, longevity, and senescence are explained by the “shadow of selection,” if one wants to employ a recurrent metaphor used by evolutionists since Haldane. Yet this may not be the whole story. I have devoted a whole chapter (Chap. 11) to trade-offs about and within fitness. I argued that the very nature of fitness (a measure of evolutionary success, which is also the untranslatable major concept of evolutionary theory) implies trade-offs between survival and reproduction that make death necessary, under the guise of senescence as an increasing probability of death with time, possibly modeled by Gompertz law or one of its rivals. Whereas traditional metaphysics thought about a sort of providential economics, where death occurs as the price of something grand (the Species, the Concept, the Spirit, hence generally the Universal—namely, as Hegel understood it, what the individual by definition can’t be by itself), Darwinians, post-Medawar and Williams, increasingly subscribed to another economy, another kind of trade-off, between reproducing now or surviving longer, or between reproducing now or reproducing later. In a word, a trade-off intrinsic to time. Granted, someone could say that after all Darwinians just shifted the nature of the main trade-off, but that their theoretical insights and modeling acknowledge the deepest economical nature of life and death, or

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captured the truth of the old providentialist economic interpretation, namely that death is a price to pay. And, as I recalled in several places, the economic thinking is entrenched within evolutionary biology, and, from Darwin’s emphasis on scarcity of resources to Alan Grafen’s “Maximizing agent analogy,” a parallel runs between these two sciences, and mostly revolves around the idea that both of them concern the optimal allocation of rare resources.2 At the highest level of generality, this notion of a general continuity within the theory of death could not be wrong. After all, any disruption in the history of thought, approached from a more general viewpoint, may appear as a continuity, which simply shows us that the very question of absolute novelty and disruption in the course of ideas is just a delusional question. But it could still be much more interesting to focus on what, within this continuous economic take on life and death, appears deeply novel within Darwinian accounts, as I did in this book. Even though, I have to highlight two things that this whole inquiry has made salient regarding this economics. First, while contemplating trade-offs that are explanatory with respect to all death-related explanantia, and issues raised about the proper currency in which all hypothetical trade-offs are formulated, I also saw that there are some limits to the explanatory power of those trade-offs. It is very possible that constraints also explain some of the phenomena that are named when we talk about death—at least, in some clades. I recalled that, regarding sex, another riddle in evolution, featuring issues sometimes analogous to the problem of death, historical constraints appear in some cases as an explanation. Thus, I paid some attention to the idea that, if a death program exists, whatever the explanation of its origin, it may subsist as a constraint in many metazoan clades. Epistemologically speaking, this means that, in the same time that evolutionary accounts of death manifest what one could call, paraphrasing Darwin, “the paramount power of economics,” they also suggest us what the boundaries of this power could be. And, even more than that, they allow us to formulate perhaps the ultimate question regarding this paramount power, namely, the question of the distinction between trade-offs and constraints. Classically, constraints are rigid and trade-offs are modulable according to environmental demands— but, as we saw, it may not be always the case. Sometimes it’s hard to know whether we face a constraint or a trade-off. And, above all, the timescale is 2

 For analyses of this parallel see Okasha (2018), André et al. (2022).

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of the essence here, because constraints may become trade-offs at a longer timescale. So, the question of the limits of the economical scheme in evolution, made urgent and manifest by an exploration of the evolutionary theories of death, also culminates in this open problem: is there a genuine distinction (arguably timescale-dependent) between trade-offs and constraints, or is this distinction wholly conventional? Of course, I’ll stop here and leave this open, hence, not concluding anything about the paramount power of economics in Darwinian biology, as it is manifested by the phenomenon of death evolutionarily understood. Second, recall that trade-offs were not only temporal ones. The last consideration developed in the second section pushed to the fore the dimension of sociality. If death is explained by trade-offs, those can’t be complete if they don’t articulate temporal trade-offs—between now and later—and what I called social-trade-offs—between me and the others. Each of them embodies a specific discounting rate—between past and future, between ego and others. The theoretical and empirical determinations of these rates are still under-investigated. Even more under-­investigated is their combination, and the possible trade-offs—or meta-trade-offs—that may eventually occur between these two dimensions. Clearly the present investigation calls for further examinations about both the two key points I just indicated, and the general relations between evolution of death and proximate mechanisms of death. I just wanted to substantially explore the topic, formulate epistemological and methodological riddles involved in the evolutionary accounts, as well as their assumptions, the modeling choices they embody, and the philosophical consequences one can draw. I mostly intended to address epistemological issues but consequences are of course massive regarding metaphysics, as I tried to emphasize in this conclusion. Because of these consequences, I still hope that philosophy as such can have an interest in the present investigations and the biological theories that were their objects. I am not sure that biology can overcome a tradition of thought that is much entrenched in philosophy, but it can help questioning it. As a matter of fact, Scheffler’s (2013) strong argument about our existential interest in afterlife, namely, the embedding of valuing itself within a relation toward those that are not yet born, finds a clear echo in the dialectics of trade-offs within time, which evolutionary biology puts at center stage of any account of death. (Even though I can’t yet characterize this echo further.)

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Moreover, thinking that death, as a biological phenomenon, is rooted within trade-offs that are also social trade-offs, in whatever species or population one considers, can’t leave philosophers uninterested. If biological modeling indeed establishes that death, as a phenomenon intrinsic to the biological individual, is also explained by social properties and collectives to which this individual belongs, then, philosophers can’t remain immune to this knowledge, since it promises to ground novel insights within philosophy about aging and ultimately death, which may not any more represent—using (and distorting) Medawar’s phrase—“the uniqueness of the individual.”

References André, J. B., Cozic, M., DeMonte, S., Gayon, J., Huneman, P., Martens, J., & Walliser, B. (2022). From evolutionary biology to economics and back. Parallels and crossings between economics and evolution. Springer. Carmona-Gutierrez, D., Eisenberg, T., Büttner, S., Meisinger, C., Kroemer, G., & Madeo, F. (2010). Apoptosis in yeast: Triggers, pathways, subroutines. Cell Death and Differentiation, 17(5), 763–773. Okasha, S. (2018). Goals and agents in evolution. Oxford University Press. Scheffler, S. (2013). Death and the Afterlife. Oxford University Press.

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Author Index1

A Abrams, Peter, 208, 245, 289, 291–294, 292n30, 296–301, 321, 363, 461 Austad, Steve, 179, 195, 208, 236, 244, 261, 261n5, 272, 306, 344, 393, 394 B Bapteste, Eric, 248, 361 Baudisch, Annette, 208, 242, 243, 296, 321, 333, 348, 348n6, 349, 358 Bernard, Claude, 3, 35, 58, 61, 71, 85, 100, 106, 126, 131, 132, 134, 136–163, 138n10, 139n11, 139n12, 141n17, 141n18, 143n20, 153n38, 313, 361, 403, 484, 491

1

Bichat, Xavier, 2, 41, 65–83, 85, 99–127, 131–164, 170, 211, 254, 391, 442, 484, 490 Blagoskonny, Mikhail, 208–209 Bordeu, Theophile de, 53, 54, 56, 59, 60, 67, 71, 77, 78, 100, 103, 104, 109n20, 134, 139, 143 Buffon, George Louis, 51, 74, 90, 96, 97, 97n13, 97n14, 100, 101, 101n4, 106, 116n33, 154, 155, 220 C Cuvier, Georges, 48, 67, 69, 74n20, 86, 87n2, 113, 114, 114n30, 125, 134, 143, 147, 159, 160, 160n45, 176

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535

536 

AUTHOR INDEX

D Darwin, Charles, 24, 36, 153n38, 157, 163, 175–185, 187–190, 209, 275, 276, 322, 332, 395, 477–483, 495 De Magalhaes, Joao Pedro, 223n2, 385, 385n4, 438–441, 438n9 Descartes, René, 43–45, 48, 49, 51, 319 Dobzhansky, Theodosius, 163, 182, 187, 188 Durand, Pierre, 169n1, 192n6, 413n21, 413n22, 423, 447–449, 447n11, 453, 456n12, 461, 469, 472, 478, 483 F Fisher, Ronald, 187, 188, 188n1, 197, 198, 206, 222, 237, 270n16, 275, 285, 295, 296, 298, 335, 338, 365, 371, 372 H Haldane, J.B.S., 187, 192, 197, 395, 494 Haller, Albrecht von, 42, 49, 51, 56–60, 71, 72, 75, 92, 101, 101n4, 104, 106, 107, 109, 132–134, 154, 161 Hamilton, William, 201n22, 202n23, 205, 225, 237, 238, 287, 288, 292, 297, 298, 371, 371n15, 373, 455, 466, 468, 473, 483n7 Hayflick, Leonard, 184, 208, 387–389, 391, 392n8, 396, 407, 446 Hegel, G.W.F., 3, 19, 20, 70n15, 125, 170, 172–176, 375, 485, 494

K Kant, Immanuel, 46, 48, 60, 60n26, 95–97, 111, 111n24, 113, 114, 138, 147, 170, 477–483, 492 Kenyon, Cynthia, 256, 258–260, 264, 265, 306, 307 Kirkwood, T.B., 215, 223n1, 229, 235, 237, 238, 279, 302–305, 315, 341, 394, 395, 437 L Lamarck, Jean-Baptiste, 48, 69, 76n22, 96, 97, 101, 101n4, 111, 146, 154 Levins, Richard, 207, 312n41, 339, 340, 348, 349, 360, 441 Lewontin, Richard, 87n2, 188, 207, 283, 287, 296, 357, 374 M Magendie, François, 35, 58, 61, 85, 100, 126, 131–136, 139, 153 Mayr, Ernst, 32, 161–163, 187, 310, 412n20 Medawar, Peter, 24, 184, 187–212, 215, 216, 227, 228, 233, 238, 279, 288, 301, 313, 322, 371, 372, 375, 387, 395, 466, 485, 490, 497 O Okasha, Samir, 188n1, 296, 305, 312n40, 338, 366n14, 372n16 R Rera, Michael, 385, 442–444, 457

  AUTHOR INDEX 

S Schopenhauer, Arthur, 3, 70n15, 94, 95, 171–175, 171n4, 180, 494 Sober, Elliott, 290, 340 Stahl, Georg Ernst, 45–48, 50, 51, 59, 67, 126, 127, 132, 141, 154, 154n40, 162 W Weismann, August, 35, 175–185, 345, 396, 437, 461, 494

537

Williams, Bernard, 21 Williams, George, 24, 36, 182–184, 187–212, 216, 220, 226–228, 233, 237, 260, 279, 282, 284, 288, 296, 301, 306, 308, 322, 331, 332, 334, 341–342, 349–352, 355, 358, 363, 365, 371–375, 390, 395, 396, 405, 406, 437, 438n9, 446, 448, 461, 466, 468, 494 Wright, Sewall, 182, 187, 188, 197, 198, 338

Subject Index1

A Anatomy, 2, 35, 41, 42, 56, 58, 60, 65, 70–74, 72n17, 74n20, 77, 80, 83, 87, 111, 111n24, 114, 114n30, 117–119, 118n41, 122–126, 125n56, 134, 137, 147, 151, 160, 160n45, 244, 477, 490 Animal life, 55, 65, 66n2, 68n10, 69, 70n15, 73, 77, 85–97, 91n5, 100, 104, 105, 107, 108, 112, 114, 115, 147, 148 Antagonistic pleiotropy (AP), 36, 184, 193–203, 212, 215, 218, 220, 221, 227, 235, 237, 242, 245, 248, 258, 260, 261, 268, 269, 270n15, 271, 275, 277, 279–289, 285n25, 291–301, 306–318, 310n38, 311n39, 317n49, 319n51, 322, 332, 333, 340, 344, 348–350, 354, 356–358, 363, 370, 372, 374,

1

376, 381, 382, 390, 392, 395, 437–441, 438n9, 447, 449, 463, 464, 466, 468, 473, 474, 476, 483, 489 Anti-aging, 17, 265, 391, 392n8, 436 Apoptosis, 267, 396–403, 408–414, 423, 424, 424n4, 427, 429, 429n6, 433, 457, 479, 481 B Bacteria, 13, 26–29, 31, 203, 220, 362, 392, 403–412, 414, 421, 423–425, 424n4, 436, 451, 453–456, 470, 479n5 Behavioral ecology, 200, 224, 225, 227, 276, 299, 311, 312, 312n41, 332, 339, 340, 371n15, 420, 475 Brain, 9–11, 13, 14, 16, 32, 53, 66n2, 69, 71, 76, 82, 85–87, 90, 93–95, 99, 100, 104, 106–110,

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539

540 

SUBJECT INDEX

109n20, 112–115, 147, 148, 267, 318, 319, 434, 485, 493 C Calorie restriction, 254, 266n11, 435, 436 Cell senescence, 305, 384, 420–426, 435, 481 Clinical medicine, 57, 58, 72n17, 80, 119n44, 137–138 Constraints, 191, 204, 243, 268, 271, 280, 291, 296, 337, 339, 352–358, 373, 374, 376, 381, 437, 445–448, 456, 457, 473, 474, 491, 492, 495, 496 Currency, 173, 322, 352–363, 365, 368–370, 373, 474, 495 D Daf-2, 256–266, 285, 382 Death, apparent, 102–106, 108n19 Death, criteria of, 8–11 Design argument, 88, 109 Discounting rate, 365–372, 473–477, 496 Disposable soma theory (DST), 215, 223n1, 260, 267, 270n15, 279, 287, 301–317, 319n51, 332, 333, 341–350, 355–357, 362, 363, 370, 374, 376, 381, 382, 384, 389, 390, 392, 395, 397, 407, 408, 426, 432, 437, 465, 466, 473, 476, 490 E Economics, 36, 55, 173, 176, 179, 180, 234, 276, 277, 277n20, 331, 332, 363, 374–376, 374n17, 381, 494–496

Economics of death, 169–185, 322, 331–376 Encyclopédie, 52, 54, 55, 57, 103 Experimental physiology, 2, 3, 25, 32, 35, 60, 85, 89, 99–127, 131–164, 244, 490–492 F Fitness, definition of, 222 Fitness, inclusive, 205, 225, 363n13, 450, 455, 462 Fundamental Theorem of Natural Selection (FTNS), 188n1, 270n16, 288–300, 371, 372 G Gene regulatory network (GRN), 211, 248, 249, 355, 438 Genetic drift, 265n9 Gompertz law, 229, 232–236, 239, 392, 494 H Hallmarks of aging, 202n24, 319n52, 383–385, 385n3, 443, 445 Heart, 9, 10, 13, 15, 16, 43, 69, 85, 86, 92, 99, 100, 106, 107, 109, 110, 112–115, 147, 155, 198, 256, 345, 348, 371, 434, 468, 475, 490, 493 I Insulin pathway, 256–264 K Kin selection, 201, 205, 225, 297, 298, 426, 429, 430, 446–457, 463, 470, 473–475

  SUBJECT INDEX 

L Life history theory, 210, 224, 225, 227, 269, 315n45, 332–335, 334n2, 337, 339, 371n15 Lifespan, 18, 26, 33, 91n5, 92, 178, 179, 182, 193, 195–197, 201, 211, 219, 223–228, 232, 235, 236, 239, 241, 242, 244, 245, 254–258, 255n3, 260–267, 261n5, 267n13, 269–271, 273, 273n19, 274, 279, 280, 283, 286–289, 291–297, 300, 301, 306–309, 311–313, 315–318, 316n48, 320n53, 333, 343–345, 347, 348, 350, 358–363, 368, 370, 373, 382, 383, 391, 391n6, 392, 396, 406, 407, 420, 424, 427, 430–431, 438, 442, 462–464, 466, 467, 469, 473, 476, 491 Lungs, 9, 10, 57, 69, 85–87, 99, 100, 106–110, 112–115, 140, 147, 397, 405, 493 M Mechanism, 43–52, 55, 59, 59n25, 60, 70, 134, 138, 141, 144, 145, 145n25, 149–151, 184, 190, 202n24, 210, 212, 219, 220, 235, 236, 239, 253–323, 255n3, 302n32, 311n39, 320n53, 342–346, 350, 355–357, 383, 384, 386, 387, 391, 402n13, 407, 410, 412, 414, 414n24, 421, 426, 427, 429n6, 437–439, 441, 447, 449–451, 456, 463, 464, 471n1, 476, 479, 479n5, 481, 496 Molecular biology, 184, 205, 208, 227, 401, 442, 477 Multi-level selection, 478n4

541

Mutation accumulation (MA), 184n14, 193–196, 202, 212, 215, 217, 218, 221, 227, 235, 242, 245, 248, 258, 268, 269, 275, 277, 279–282, 285–289, 291–293, 294n31, 300–302, 308, 309, 312–314, 316, 317, 317n49, 321, 322, 370, 372, 388, 392, 395, 439, 463, 464, 466, 473, 483, 489 N Nematode, 26, 237, 238, 255, 257–259, 263–266, 268, 278, 284, 306, 350, 382, 383, 404n15, 443 O Organic life, 65, 66n2, 69, 70n15, 73, 75, 75n21, 77, 85–88, 87n3, 90–95, 95n10, 97, 100, 104, 105, 109, 114, 115, 133, 147, 148 P Pathological anatomy, 2, 65, 72, 72n17, 80, 117–119, 117n37, 118n41, 122, 123, 125, 126, 137 Phenomenology, 3 Population genetics, 187, 196n15, 198, 207, 208, 228, 284, 354, 371, 372, 445 Population structure, 36, 446–457, 456n12, 461, 462, 464, 466, 470, 473, 475 Preferences, 23, 56, 269, 277 Prokaryotes, 211, 248, 362, 396, 404, 405, 408–410, 413, 414, 419, 420, 424, 425, 431, 446, 447,

542 

SUBJECT INDEX

447n11, 456, 456n12, 469, 475, 476, 478, 479, 482, 483 Providentialism, 172, 173, 321, 322

406, 407, 432, 437, 441, 447, 456, 457, 462, 467, 471, 471n1, 473–476, 490, 494–497

R Rationality, 82, 276, 277, 277n20, 332, 332n1, 366n14, 374, 375

U Utility, 60, 276, 332, 363, 366n14, 374

S Selection Shadow, 227, 321, 395, 396, 461 Sex, 29, 175, 176, 180, 187, 189–192, 201, 201n20, 205, 248, 273, 302n32, 373, 446, 495 Stochasticity, 305, 352–362, 419, 483 Systems biology, 211, 346, 355

V Virus, 202n24, 361, 362, 451, 454, 479n5, 494 Vitalism, 44, 46, 49, 52, 53, 55, 56n20, 58, 59, 68, 73, 76, 83, 86, 87, 103, 105n14, 108n18, 110, 118, 132, 134, 136, 137, 139–145, 147, 149, 157, 158, 161

T Trade-offs, 36, 91, 180, 225, 271, 273, 279, 280, 283, 286, 287, 296, 302, 303, 305n36, 306–310, 310n38, 311n39, 313, 315, 316n47, 321, 322, 331–376, 381, 382, 388, 395,

Y Yeast, 26, 31, 255n3, 261, 263–265, 305n36, 306, 383, 386, 403–414, 413n22, 414n24, 420, 423–427, 424n4, 429, 435, 447, 490