The Biology of Aging This page intentionally left blank The Biology of Aging Observations and Principles Third Edition Robert Arking 1 2006 3 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford New York Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With offices in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam Copyright © 1998 Sinauer Associates, 2nd edition Copyright © 2006 by Oxford University Press, Inc. Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Arking, Robert The biology of aging : observations and principles / by Robert Arking. — 3rd ed. p. cm. ISBN-13 978-0-19-516739-9 ISBN 0-19-516739-2 1. Aging. 2. Physiology, Comparative. I. Title. [DNLM: 1. Aging—genetics. 2. Aging—physiology. WT 104 A721b 2006] QP86.A75 2006 612.6'7—dc22 2005030674 1 3 5 7 9 8 6 4 2 Printed in the United States of America on acid-free paper To Lucy, who encouraged and For David and Deanne, Jonathan and Carolyn, Ben, Jared, and Rachel; Joshua and Emily— who will know. Theory without fact is fantasy, but fact without theory is chaos. C.W. Whitman, 1894 Seek simplicity and distrust it. Alfred North Whitehead (cited in Gilbert, 2000, p. xvii) The effort to understand the universe is one of the very few things that lifts human life a little above the level of farce, and gives it some of the grace of tragedy. Steven Weinberg, The First Three Minutes, 1977 This page intentionally left blank Preface to the Third Edition There were two inspirations for writing this third the matrix of public mechanisms via which lon- edition. The first was the qualitative change in gevity seems to be regulated (i.e., metabolic con- our understanding of the genetic basis for longev- trol of several types, stress resistance, genetic ity and senescence which occurred since 1998 stability, reproductive effects). This framework when the second edition was printed. When that seems to accommodate diverse data without ob- text could no longer serve by itself as an adequate vious strain, and so it offers an obvious pragmatic text for my own classes, I realized that the time value in assisting readers to conceptualize the had come to take on that task once again. The information and make it theirs. second inspiration was the generosity of the re- Third, our increased knowledge of aging cells viewers and colleagues who commented on the allows me to put forth in chapter 9 some ideas as second edition in a mostly positive manner. No to how a cell transitions from a healthy state to a good deed goes unpunished, and so many of those senescent state, but in such a manner as to still same individuals have had to trudge though an- allow for high levels of intra- and interspecific other review or critique. variability. Fourth, the renaming of aging mecha- Experienced readers will, I hope, note that nisms as senescent mechanisms, which is the there are at least six important conceptualchanges emphasis of part IV of the text, is a name change that have been made in the presentation of the that I think will help the reader understand that data. Perhaps the most important is the stron- aging is a nonprogrammatic loss of function that ger distinction drawn between the biological is, however, somewhat plastic and that can be mechanisms involved in longevity determination modulated. As before, I have grouped these losses (mostly described in chapter 7) and those in- under the rubric of damage to the gene interac- volved in senescent processes (mostly described tion networks arising from stochastic damage, in chapters 9–13). And these processes are de- from mitochondrial damage, and from degrada- fined in a time-independent manner in chapter 1: tion of both intra- and intercellular regulatory “If aging is a series of increasingly different and systems. Recent data have forced a reevaluation less functional molecular and physiological sig- of the roles these various senescent processes play natures, then senescence comprises the processes such that we may see mulitple mechanisms at that are responsible for the changes in those sig- play here. natures.” That first chapter also sets up the be- Fifth, the standard evolutionary story does not ginning of an integrated theory of aging over the fully explain the evolution of social organisms, life span, which is updated as the text progresses. and so I have incorporated recent work that deals A second change emerged from my wrestling with with intergenerational resource transfers into a the interesting and insightful genetic data pub- discussion of human longevity. I am intrigued by lished in the past half-dozen years. The sheer the possibility that extended longevity may well mass of this information forced me to develop a have played a mostly unappreciated role in our conceptual framework on which to mentally hang becoming quintessentially human. Sixth and last, all these facts, if only to avoid the deterioration if both longevity-determining mechanisms and of this book into a laundry list of unrelated items. senescent mechanisms are plastic and can be sig- And so the organization of chapter 7 is based on nificantly modulated in the laboratory, then the viii Preface to the Third Edition demand to move these anti-aging interventions have built on the shoulders of my colleagues who into the human arena will inevitably grow. Dis- have conceived and executed informative experi- cussions about longevity extension are as old as ments that made things clear and/or wrote use- Methuselah, but the past few years have wit- ful reviews that astutely summarized an area and nessed a growing discussion of this topic in diverse made it easier to grasp. I thank them for their venues. These public discussion have rambled all efforts and point out that the references cited over the field, with the consequence that argu- clearly reflect more the limits of my mind and my ments and questions get muddled. I have included desk rather than the limits of what has been done. here a full discussion of my own opinions on the And so I apologize to those whose work was over- biological, social, and ethical aspects of one highly looked, and I look forward to them bringing me focused aspect of this debate. My striking a clear up to date. position is not meant to propagandize but rather I will say again that I am fortunate in the acu- to encourage readers to argue with me and reach ity of my critics. Their sharp eyes have saved me their own conclusions, but without abandoning once again from embarrassment or errors, whether what we can all agree are the demonstrated facts. of omission or of commission. I accepted willingly There are many words in this book (too and gratefully most of their suggestions and criti- many, some will say). And yet I think that the cisms, for they were made in a spirit of collegial- main ideas underlying this text are summed up ity. These colleagues were generous with their time in three graphics (figures 1.6, 9.6 and 14.9). If and knowledge in critiquing the draft of this third that last statement is true, then why did it take edition. I must particularly thank the reviewers so many words and chapters to describe these who so capably critiqued these chapters and made central ideas? One reason is that this is a data- many useful suggestions and corrections: Robert based textbook, and so the basic statements must Avila, Daniel Callahan, James Carey, Vince be well supported by robust data. In an emerg- Cristofalo, Aubrey de Grey, Michael Fossel, Mark ing field such as is biogerontology, capable people Greene, Barry Halliwell, Nikki Holbrook, Don may obtain differing results or interpret the same Ingram, Nicole Jenkins, Tom Kirkwood, Christiaan results differently, and so the disagreements of the Leeuwenburgh, Jeff Leips, Gordon Lithgow, field should also be laid out for students to read George Martin, Gawain McColl, S. Jay Olshansky, and ponder and reach their own decision. An- John Papaconstantinou, Serguei Scherbov, and other reason is the need to point out things that Ron Woodruf. might not be fully clear to a person just entering I must also thank Craig Giroux and Michael the field, such as relationships between appar- Fossel, among others, who shared with me their ently unrelated variables or to illustrate interac- logic and passion in the quest to understand the tions between the different complexity levels of cell. But stubbornness dies hard: I did not accept the cell or organism. Finally, I believe some of the every suggestion, and so I must accept full respon- many words are necessary to describe the broad sibility for any errors or inaccuracies in the work. scope and deep richness of the data now avail- And of course I must once again acknowledge the able and the predictive hypotheses that now exist. sometimes vocal assistance of the students in my I fervently hope that my readers will more or less Biology of Aging classes at Wayne State Univer- agree with this rationalization. Even so, not all sity, who pointed out to me the strengths and the words could fit into this book, and so I have weaknesses of the revised text as I was preparing constructed a website where both supplemen- it. The text is again more readable because of their tal and updated material may be found (http:// efforts. bio.wayne.edu/profhtml/arking/textbook/ I thank Kirk Jensen for his enthusiasm for the supplement.html idea of publishing with Oxford University Press, If this text offers a useful view of the processes and Peter J. Prescott for his skill in bringing the and mechanisms underlying the biology of aging, project to reality—in large part by gently remind- then that view was made possible only because I ing me of the virtues of brevity. Some may believe Preface to the Third Edition ix I didn’t listen, but that is not the case. Only Kaity tents. Although a full understanding requires the Cheng’s organizational capabilities kept this pro- students to address each of these questions, there ject from becoming an embodiment of chaos is sufficient material in the several key chapters theory. I am truly grateful to Andy Sinauer for so that each instructor can, by means of judicious making available to me the text and artwork of the choices and emphases, impart their own inter- second edition. The current work owes much to his pretation to their course. The point is to tell a co- generosity and goodwill. Matthew Garin deserves herent and realistic story that will reliably guide full credit for translating my crude sketches and the students’ future thinking on the topic. If this marked-up photocopies into distinctive figure files. book achieves that goal, I will be satisfied. The organization of the book has changed again, for it is now divided into the answers to Robert Arking the five questions contained in the Table of Con- October 2005