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Oxford University Press
A Means to an End: The Biological Basis of Aging and Death / Edition 1

A Means to an End: The Biological Basis of Aging and Death / Edition 1

by William R. ClarkWilliam R. Clark


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Why do we age? Is aging inevitable? Will advances in medical knowledge allow us to extend the human lifespan beyond its present limits? Because growing old has long been the one irreducible reality of human existence, these intriguing questions arise more often in the context of science fiction than science fact. But recent discoveries in the fields of cell biology and molecular genetics are seriously challenging the assumption that human lifespans are beyond our control.
With such discoveries in mind, noted cell biologist William R. Clark clearly and skillfully describes how senescence begins at the level of individual cells and how cellular replication may be bound up with aging of the entire organism. He explores the evolutionary origin and function of aging, the cellular connections between aging and cancer, the parallels between cellular senescence and Alzheimer's disease, and the insights gained through studying human genetic disorders--such as Werner's syndrome--that mimic the symptoms of aging. Clark also explains how reduction in caloric intake may actually help increase lifespan, and how the destructive effects of oxidative elements in the body may be limited by the consumption of antioxidants found in fruits and vegetables. In a final chapter, Clark considers the social and economic aspects of living longer, the implications of gene therapy on senescence, and what we might learn about aging from experiments in cloning.
This is a highly readable, provocative account of some of the most far-reaching and controversial questions we are likely to ask in the next century.

Product Details

ISBN-13: 9780195153750
Publisher: Oxford University Press
Publication date: 02/28/2002
Series: Biological Basis of Aging and Death
Edition description: New Edition
Pages: 256
Product dimensions: 9.10(w) x 6.10(h) x 1.10(d)

About the Author

Professor Emeritus of Immunology at UCLA and an internationally recognized authority on cellular immune reactions, William R. Clark is the author of The New Healers: Molecular Medicine in the Twenty-First Century, Sex and the Origins of Death, and At War Within: The Double Edged Sword of Immunity, all published by OUP.

Read an Excerpt

Chapter One

Aging, Senescence, and Lifespan

    We are all aware of aging in humans from our earliest years, through normal, daily contacts with family members, neighbors, and others who have reached an advanced age. Perhaps because aging seems such an intuitively obvious phenomenon, it was quite late in becoming an object of formal study. Magical cures and restorative waters aside, the first serious scientific studies of aging did not get under way until the early part of the present century. The initial pace of research in the entire field of aging was slow; respectable scientists and physicians were doubtless deterred by the unsavory history of quack remedies and practices aimed at increasing human lifespan that had characterized the previous several centuries, as well as the first part of the twentieth century.

    Perhaps we felt we didn't need a bunch of highly trained professionals telling us about getting old. We recognize it when the first signs appear in our own bodies—usually earlier than we might have expected from observing others. Elderly people look and behave differently than people in the early and peak years of their lives (Table 1.1). They become wizened and gray, and slower to respond both physically and mentally to things around them. They appear smaller and, in fact, are: Both skeletal and muscle mass decrease, often significantly, after age fifty or so. Even the brain gets smaller, shrinking by up to 10 percent in women, and slightly more in men. All of the major organs and physiological systems undergo a gradualdecline with increasing age. None of these changes is in itself a cause of aging; they are all the result of the aging process.

    Some age-dependent changes are psychologically distressing but have little clinical impact; degeneration of the skin is a good example. Skin changes are one of the most externally visible and irrefutable signs of aging. Skin becomes thinner with age, largely because of loss of subcutaneous fat. It loses elasticity and tone because of changes in collagen, the major protein of all connective tissue, and becomes wrinkled because of both collagen changes and an increased production of a protein called elastin. Uneven distribution of the pigment melanin can result in so-called "age spots," and the skin becomes increasingly dry as sweat and oil glands gradually lose function. All of these changes associated with the normal aging process are greatly accelerated by exposure to sunlight; compare the texture of the skin on the buttocks of an elderly person with skin on the face or arms, for example. But aside from occasional skin cancers, which (with the exception of deadly malignant melanoma) are relatively harmless and easily treated, aged skin is biologically nearly as effective as young skin, and causes no threat to health or well-being.

    But of course "clinical impact" does not always adequately describe the tremendous psychological impact many of the changes associated with aging can bring. Mental confusion and slowness to respond to simple questions do not at all imply an unawareness of, or indeed a painful embarrassment about, one's diminished mental capacities. Increasing weakness and a tendency to fall can be not only physically dangerous, but can drive many older individuals to become increasingly immobile through fear of embarrassing themselves. Perhaps most humiliating of all the assaults of old age is urinary incontinence. This condition, affecting some fifteen million Americans, is a major factor in the self-imposed social isolation of many elderly people. The overall loss of the ability to control the image of ourselves seen by others may be one of the most devastating changes of growing old, ranking with the fear of death itself as a psychological toll of aging.

    In terms of human morbidity and mortality, age-associated degenerative changes in the cardiovascular system are probably most critical, for the obvious reason that all of the other cells of the body are dependent on a constant blood supply for food and oxygen. The death of a relatively small number of brain cells through lack of oxygen, and the consequent inability of the brain to coordinate physiological activities in the rest of the body, can occur within minutes of a serious heart attack, and result in death of the entire organism. Cardiovascular disease is the leading cause of death in people over fifty years of age in the United States and most of the industrialized world. To some extent this reflects the fact that other causes of death have been brought under control; each time one cause of death is reduced, another emerges to take its place.

    The vascular changes leading to coronary artery disease can occur in arteries elsewhere in the body as well, resulting in a variety of other serious complications such as stroke or gangrene. These changes are largely due to atherosclerosis (literally, sludge-hardening), in which the inner lining of the arteries delivering blood throughout the body become thicker and less flexible, and the lumen itself becomes clogged with oxidized fatty deposits that include cholesterol. The result is reduced blood flow to all parts of the body. Interestingly, the pumping function of the heart muscle itself, in the absence of cardiovascular disease, does not weaken significantly with age.

    We are also more open to attack from the outside as we get older. The immune system is less able to fight off invasion by microbial pathogens, and even begins slowly to attack the body itself in the collection of disorders known as autoimmune disease. The thymus gland, which plays a key role in the development of an important disease-fighting white blood cell called the T (for thymus-derived) cell, begins to atrophy at about the time of sexual maturity; the loss of this immunological "master organ" doubtless impairs T-cell function in the body over time. In addition to playing a direct role in defense against infectious disease, T cells also play a role in regulating many other components of the immune system. Thus the well-documented diminution of T-cell function with age may be a major cause of decreased immune defense against disease. The increased incidence of autoimmune disease with age could be related to the gradual loss of T-cell regulatory function, or it may be due to production of "self" molecules altered with age that the immune system comes to regard as foreign.

    Reproductive capacity in most species changes markedly with age. It is largely controlled by hormones produced in the pituitary gland of the brain, and the pattern of synthesis and release of these hormones changes in an age-dependent manner. In virtually every species, the degenerative changes associated with aging are substantially held back until reproductive maturity. In mammals generally, the changes in reproductive capacity with age are more pronounced in females than in males. The sudden changes brought on in human females at menopause are a striking example of the close link between reproduction and senescence. But human males also experience a decrease in reproductive ability with age. The necessity to defer age-related physical decline in all systems until reproductive maturity is a key to understanding the basic biology of aging.

    Not only is the aging process complex in terms of the spectrum of changes that occur across multiple organs and tissues, but it also seems to begin at different times in different people, and to proceed at differing paces. We all know of people who look old "before their time," or others who look ten or even twenty years younger than they actually are. Some people turn gray in their thirties, while others die at eighty with a full head of deeply colored hair. Wrinkles set in at different times in different people. Some people in their nineties seem to have lost very little of their hair or their mental capacities (not that the two traits are connected), while others in their fifties cannot recall a friend's name, or remember why they walked into a room. Does this reflect a difference in the aging program itself, or a difference in the interaction of natural aging mechanisms with variable environmental factors? This is one of the most fundamental questions addressed by those who study aging.

    While the changes associated with aging are quite obvious in humans, it is rare to observe the aging process at work in animal populations living in the wild, because of the very high level, in most species (including pre-modern humans), of accidental death. Accidental death will be an important concept in our considerations of the aging and longevity of individual organisms. We will explore accidental death below in some detail in terms of its associated cellular events, but here let us define it at the organismal level simply as death from causes lying outside the individual organism—things like being eaten by a predator, starvation or infectious disease, as well as fatal physical accidents. It is to be distinguished from what we might call, for lack of a better term, natural death—death that results from purely internal causes such as genetic disease, heart attack, cancer, or other age-related disorders.

    When talking about the basic biology of aging, as opposed to its outward physical and behavioral manifestations, it is common to talk about something called senescence. Senescence is here defined as the increasing likelihood of death of an individual with advancing age. On one level, such a statement may seem so intuitively obvious that it scarcely bears writing down, let alone dedicating an entire book to its explanation. Yet as we will see, senescence is in fact one of the least understood processes in all of biology, and thus one of the least understood aspects of human medicine. The simplest statements about it often provoke seemingly endless debate and discussion among those who study it.

    What precisely is meant by "an increasing likelihood of death with advancing age?" What we mean is that for any defined increment of time—a calendar year of life in the case of humans, for example—the probability of death in the n+1 time increment is demonstrably greater then the probability of death in the nth increment; the probability of death in the n+2 increment is greater than the probability in the n+1 increment; and so on. But notice that this definition of senescence does not mention any of the characteristics that we associate with aging per se; it mentions only death. This has important implications for understanding the evolution of senescence. One of the things we will try to establish about the various forms of natural death—death from senescence—is that ultimately all of them involve information embedded in and controlled through our DNA. Senescence can be explained and understood at the cellular and molecular level, as well as appreciated in the context of the whole organism.

    Most humans in industrialized societies die either directly or indirectly from the causes of senescence, as do some wild animals kept in zoos or laboratories where they are largely protected from accidental death. From a purely biological point of view, senescence is nature's backup plan; if we do not die from external accidental causes, then ultimately we will die from the cumulative effects of internal senescence. But accidental and natural death are intimately intertwined in the life history of every species; individuals die from one cause or the other, but very often senescence—in the form of cancer or cardiovascular disease or a genetic disorder—increases an organism's susceptibility to disease and accidental death. The gradual physical weakening that accompanies aging will make an animal more likely to be caught by a predator; diminished immune capacity can make us more susceptible to infectious disease. Moreover, different forms of senescence can interact; decreased immune function, for example, can also make us more susceptible to purely internal diseases such as cancer. It is complications like these that are best sorted out by beginning our study of aging and death not at the cellular or molecular level, but at the very opposite end of the biological spectrum—in large populations.

Death in a crowd: Senescence and lifespan in populations

     At a population level, aging and death are often analyzed in terms of survival curves, examples of which are shown in Figure 1.1. In these curves, we are looking at the survival over time of some large initial number—a cohort—of newborn members of the same species. Such curves display death from both accident and senescence inextricably mingled together; in populations living in the wild it is rarely possible to separate them. Curve A in this figure is thus entirely theoretical, and would never obtain in the real world. It is what we would imagine a survival curve to look like if senescence were the only cause of death in a population. There would be little or no death from senescence until that point in their overall lifespan where individuals in the cohort normally produce at least a replacement number of offspring, that is, the number of offspring needed to provide enough reproductively competent adult individuals to maintain or expand the species in its natural habitat. That point in life (set here arbitrarily at about 70 percent of lifespan), and the number of requisite offspring, is different in different species, and can even change within a species as conditions in the environment change. But already we have incorporated an important theoretical point into our hypothetical curve: Significant senescence does not set in until reproductive maturity has been achieved, or if it does, it must be offset by processes that effectively neutralize it.

    Once individuals have reached sexual maturity, and have had an adequate opportunity to reproduce, senescence would begin to operate, and individuals would start to die, either directly or indirectly, from senescence. These deaths would occur more or less randomly, across some fairly brief period of time. Survival curves of this type approximate a rectangle, the deviation of the descending leg from the vertical indicating the efficiency of the senescence process; human females may live fifty or more years beyond menopause, whereas a female salmon may live only a day or two after spawning. We assume that in a natural population, death from accidental causes will continue and perhaps even accelerate during this portion of the curve as well. And it is in the descending portion of the curve that the definition presented earlier about senescence is in full operation; for an individual managing to survive to any point on this descent, the likelihood of death will be greater at subsequent time points than it was at preceding time points.

    Curve B in the figure is also entirely theoretical, and typifies a population in which death from senescence does not occur at all. Death of the entire cohort in this case results from accidental causes, such as starvation, predation, or physical trauma, and is essentially exponential; if it were plotted logarithmically, instead of arithmetically as shown here, the survival curve would be a straight line as long as environmental conditions remain constant. What this means is that across any fixed interval of time, beginning at the moment of birth, a constant proportion of the surviving members of the selected cohort will die. The shape of this curve of course could be altered somewhat if, for example, older members of the species have a reduced susceptibility to accidental death because of increased size or some age-dependent physiological change. The survival curves for some invertebrate organisms, particularly certain insects and aquatic species like Hydra and most sea anemones, actually approach curve B rather closely.

    Interestingly, curve B looks very much like a survival curve for inanimate objects that wear out from mechanical usage. In a study described in Alex Comfort's book, The Biology of Senescence, a virtually identical curve was generated by following the "survival" of a large cohort of glass tumblers in a public cafeteria. A fairly constant proportion of glasses disappeared each week from accidents—dropping by customers or employees, and breakage in the cleaning or drying process. Similar "exponential decay" curves would be generated by following the fate of any number of other objects subjected to random destruction through accident.

    Curve C is a reasonable facsimile of the expected survival of human beings born in the United States in the last decades of the twentieth century; like most survival curves, it displays death caused by a mixture of accident and senescence. We can expect in the twenty-first century that many people will continue to die by accidental means—infectious disease, physical accidents, and the like—but that the majority will die of senescence, and because of increased susceptibility to accidental death caused by senescence. Note that this curve is much closer in shape to curve A than curve B; it is more "rectangularized." That is because senescence is a major factor in human mortality today. Were we to plot survival curves for certain other large mammals, such as whales or elephants, they would approximate that of humans more than they would the survival curves for invertebrates, or even small mammals such as field mice or voles, which also look more like curve B. Curve C is also similar to the survival exhibited by many animals maintained in zoos, or even invertebrates reared in the laboratory. By protecting these organisms from predators and providing them with food and an opportunity to exercise, their survival curves can be radically shifted from a curve A-like to a curve B-like form. Finally, curve C is similar to curves plotting the survival of complex mechanical devices such as automobiles, where there would be a limited amount of loss from accident at all stages in the "life history" of a cohort of cars, compounded by losses from a variety of internal mechanical failures beginning at some point, leading to a sharp decline in the survival rate.

    The point of initiation of senescence in curve C is not obvious; we are plotting only the disappearance of individuals with age, from the cumulative effects of accident and senescence; we have arbitrarily set the point at which senescence becomes a major factor in mortality at about 60 percent of total lifespan, which is probably not far off for humans. We do not know exactly when significant senescence per se sets in in humans; tests of athletic ability in males suggest physical performance begins to decline noticeably somewhere in the late twenties. Senescence resulting in significant mortality is delayed in all species until at least the beginning of the reproductive period. Given that humans are sexually mature in their early teens, and ten years is probably a reasonable reproductive period, we might expect to see senescence setting in at around the mid- to late twenties. On the other hand, it was pointed out early in this century that the growth rate of human cells in vitro ("in glass"; i.e., outside the human body) slows down substantially almost immediately after birth, which might indicate the onset of some sort of senescent program. Because we do not have an unambiguous test or "marker" for senescence, particularly in humans, we cannot at present detect its onset. Its conclusion, on the other hand, is quite clear.

    Note also that the survival curve for humans tends to flatten out somewhat at the very end. This feature is real, and not due to careless curve drawing. Detailed analysis of human survival in many countries around the world has shown that the likelihood of death across a given time interval decreases somewhat with very advanced age—those who survive longer survive the longest! The same thing is seen in animal populations. One of the most impressive studies was that reported by James Carey and his associates on Mediterranean fruit flies in 1992. Carey studied the mortality pattern in over one million flies, lending his work a statistical accuracy rarely achieved in biological studies. He found that the mortality rate (the percentage of survivors in a cohort dying at any given time) decreased markedly among the last 0.1 percent of surviving flies. This phenomenon represents an important exception to the definition of senescence set out earlier, as the increased likelihood of death with age; for the last few survivors of any given cohort, the likelihood of death actually decreases with time. It does not, however, go to zero.

    In both flies and humans, the most likely explanation of the "tailing off" effect in populations is genetic heterogeneity within the species. It should be noted that in both cases, the data tell us what is happening at the population level, not at the individual level; it is entirely possible—indeed, likely—that for any given individual, the likelihood of death in fact continues to increase in a more or less steady fashion throughout latter stages of life. As we will discuss throughout the rest of this book, senescence is at least in part under genetic control. There are many reasons for believing this, but one of the simplest is that genetically identical twins die much closer in time to one another than do fraternal twins or non-twin siblings. The slowing of mortality with advanced age might reflect the fact that those alive toward the very end of the human survival curve—the "oldest old"— represent individuals in whom the senescence process has been operating more slowly all along, or who are genetically less susceptible to some of the major senescence factors in humans. We know, for example, that heart failure and cancer as causes of death are up to ten times less frequent in the oldest old; those genetically more susceptible to these diseases presumably succumbed to them during the "normal old" period of sixty-five to eigty-five years of age.

    Curve D is a facsimile of a survival curve for humans born in the last decade of the nineteenth century. What is particularly evident here is the substantially higher rate of infant and childhood mortality, largely caused by infectious diseases, and a somewhat greater rate of loss of individuals in their reproductive years, from a wide range of health problems and workplace accidents. Overall, the curve is much less "rectangular" than curve C. But note that although the average lifespan is quite different from that in curve C, the age of the oldest individuals dying in the cohorts born in the last years of the nineteenth and twentieth centuries is not terribly different, and in fact may not be different at all. That is because in both populations, the individuals dying in the final decade of life are dying largely from senescence, which seems to have a common endpoint for all members of the species.

    This brings up a concept alluded to in our discussion so far, but not fully explained: maximum possible lifespan. Although important to both basic scientists and demographers, maximum lifespan is a bit of a slippery concept. It could be defined as the last documentable point on the survival curve for a species at which an individual has been observed to be alive. It is often defined as the average age of some small proportion—1 percent or so—of the longest living members of a species. We do not know exactly where along the age axis in curves C and D the true maximum lifespan lies for humans; it is certainly closer to the "three-score and ten" of the 90th Psalm than to the 900-plus years attributed to some of the Old Testament patriarchs. Most demographers would probably agree it lies somewhere between 110 and 120 years (Table 1.2).

    Maximum lifespan varies enormously among the species inhabiting the earth today, from a matter of days to hundreds of years. For a few very large mammals, including humans, maximum lifespan can be estimated by observing populations in their natural habitat. Anecdotes and "common wisdom" about human lifespan confused the issue until late in the last century. Although the great French naturalist Georges Buffon had recognized in the mid-eighteenth century that human beings, regardless of their race or social station, only rarely lived beyond a hundred years, accounts of lifespans of as many as 165 years continued to be believed by eminent authorities well into the twentieth century.

    However, a classical and detailed study published in 1873 by the amateur British demographer William Thoms debunked almost every such claim, and, based on his analysis of insurance company records and various birth and death registries, Thoms correctly concluded that Buffon's upper limit of 100 years was substantially accurate. More recent tales of extremely long-lived individuals, for example in the Caucasus region of Georgia and neighboring countries, continue to surface to this day, but do not stand up to close scrutiny. (Josef Stalin was from this region, and apparently enthusiastically promoted claims of unusual longevity by his compatriots.) Demographers examine all such claims meticulously, and find that very old people are often confused about their age. Unimpeachable documentation is required before recognizing the longevity claims of anyone over 100 years old.

    For mammalian species other than humans, as mentioned earlier, maximum lifespan is normally observed only in animals kept in zoos or maintained in laboratories, where accidental death can be controlled. But the rather startling fact is that it is still there in these latter cases, and it is remarkably constant within a species even though only rarely, if ever, reached in the wild. On the other hand, maximum lifespan can be quite different between physically similar species living in the same ecological niche, and these differences are stably transmitted from one generation to the next. This constancy and heritability of maximum lifespan within a species, and its independence of environmental factors—first recognized by Buffon in the eighteenth century—can be taken as a priori evidence that maximum lifespan is at least in part a genetically determined trait.

    Trying to understand the factors that determine maximum possible lifespan is one of the most puzzling aspects of the overall study of senescence and death. For some single-cell organisms such as yeast, it is not even definable in calendar time, but rather in a total number of cell divisions. That is, at "birth" the cell has a preset average number of divisions that it can undergo before succumbing to the ravages of senescence. The length of time required to complete these divisions may vary considerably; it may be slowed down or speeded up at the extremes of temperature tolerated by the cell. The lifespan of many invertebrate species is also markedly affected by temperature. Moreover, some single-cell organisms are able to form cysts, spore-like structures that are metabolically inert, when conditions in the environment are insufficient to support life, such as ambient temperatures outside the tolerated range, insufficient food or water, or too much or too little salt. Cells can stay in this death-like state for months or years, and when restored to an active form continue the completion of their predetermined number of cell divisions as if nothing had happened. If a cohort were split in half, and half allowed to encyst, the encysted half, when "revived," could still be alive years after all cells in the other half of the cohort had died. This definition of cellular lifespan based on a number of replications rather than calendar time is found in many cells throughout the animal kingdom, including many human cells removed from the body and grown in incubators.

    The variation in maximum lifespan in multicellular animals is, to a first approximation, a function of how long after birth senescence must be delayed in order to permit at least a replacement level of reproductive activity (including protection and rearing of offspring, in those species where this occurs.) As is evident in Figure 1.1, a clear distinction exists between maximum lifespan and average lifespan. The average lifespan in a defined cohort is the age at which 50 percent of the cohort is still alive. Depending on the population under consideration, average lifespan may be determined almost exclusively by accidental cell death or by some combination of accidental death and programmed death (senescence). Maximum lifespan, on the other hand—and this is a very important distinction—is determined solely by the rate and timing of the onset of senescence, and not by accidental death.

    Numerous attempts have been made to correlate maximum lifespan with other attributes of multicellular animals, in order to gain insight into the genetic basis of maximum lifespan. There is a rough correlation of maximum lifespan with body weight (Fig. 1.2), but there are obvious exceptions (compare cows and elephants with humans and rhesus monkeys, for example, or bats and sparrows with mice). August Weismann, the great German biologist and one of the founders of reproductive genetics, pointed out at the end of the nineteenth century that queen ants and the males who breed with them are similar in size, but the former has a maximum lifespan of several years, whereas the males live only a few weeks. The same is true of bees, medflies, and other insects. Birds and small rodents are similar in size, but the former often have maximum lifespans of a dozen years, whereas rats, mice, and voles rarely have maximum lifespan values in excess of three to four years. Weismann correctly inferred that senescence is probably regulated by some internal program that is typical of each species, unrelated in any direct way to the environment, and that greater size results from, rather than causes, delayed senescence. Correlations of size with maximal lifespan improve somewhat when brain size in relation to body weight is factored in, but still leave a great deal to be desired. Moreover, no one has come up with a reasonable proposal of how the size of an organism and/or its brain could affect longevity.

    A second intriguing correlation of maximum lifespan has been found with metabolic rate, the rate at which an organism must burn food and oxygen to produce the energy needed to operate its cells. This parameter, too, correlates roughly with size, in that smaller animals must consume much more food per unit time and per unit body weight than larger animals. This means that they also must deal with a higher level of metabolic waste products per unit time and body weight. As we will see in a later chapter, some of these by-products—especially of oxygen—are toxic, and are a major contributing factor in cellular senescence.

    Although relatively constant for a species living in its natural environment, for many single-cell and even multicellular organisms, maximum lifespan can be shortened or lengthened in the laboratory by manipulations as simple as changing the growth temperature. This is presumably due to alterations in metabolic rates, reinforcing the notion that maximum lifespan is governed at least in part by metabolic processes. Maximum lifespan can also be altered by dietary manipulation, mainly by restricting the intake of calories. Studies of this type began shortly after the turn of the present century. Limiting food intake in a wide range of laboratory organisms—from single-cell organisms through rats and mice—was found to increase maximal lifespan, in some cases up to double the normal maximum lifespan. In warm-blooded animals, it is the only known way to modulate maximum lifespan. The dietary restriction effect was most pronounced if restriction was initiated prior to the reproductive period, although restriction of caloric intake in older animals can also be effective in prolonging lifespan. Extreme restriction, of course, may actually hasten physical decline. Dietary restriction in young animals is almost always accompanied by growth retardation, which is largely restored if normal feeding is resumed. This fact in itself was of great interest when these experiments were first carried out, because they seemed to suggest that achievement of full body size might in some way be linked to onset of senescence. However, as with other correlations of size and longevity, this does not hold up. We will examine the relation of caloric intake to maximum lifespan in detail in Chapter 8.

    Finally, there is the intriguing difference in lifespan between men and women. Currently, men in the United States and most industrialized countries have an average lifespan that is about seven years less than that for women. In Russia, the gap is slightly over ten years. This was not always so in the United States, and it is not true today in some developing countries. Prior to the middle of the last century in this country, men lived longer than women, probably due to a combination of the hazards of childbirth and the greater vulnerability of women to physical harm such as accidents and wartime deprivation. The rate of death among women in the United States giving birth today is less than 10 percent of what it was at the end of the nineteenth century. These factors still compromise the survival of women in some parts of the world.

    The reason for the longer average lifespan of women in a more protected environment is unclear; it may be as simple as the fact that women, at least in the past, have smoked less, consumed less alcohol, and are in general more averse to physical risk. It is now well established that during the child-bearing years women axe protected by hormones from cardiovascular disease, and they appear to have stronger immune systems; these protections are lost at menopause. But it is also possible that women have a slightly longer inherent maximum lifespan. Three of every four centenarians are women. And even at these very oldest ages, women still have a slightly greater life expectancy than do men who somehow manage to live that long. The basis for this effect is entirely unknown, but it is assumed to be related to the more important role of the female in the reproductive process. Intriguingly, a possible survival advantage to human females is seen even before birth. Significantly more fertilization events result in the creation of male embryos than female, but at birth the two sexes are just about even, with 51 percent being male, and 49 percent female.

    The changes wrought in average lifespan through improvements in public health, medicine, and accident prevention are readily understandable, and certainly greatly appreciated. But maximum possible lifespan is a mystery that continues to fascinate us. The causes of human death have changed dramatically during our history as a species, but maximum lifespan, as far as we can tell, has not. As the twentieth century draws to a close, cardiovascular disease and stroke, cancer and pneumonia account for three-quarters of all human deaths. What will happen when these diseases are overcome? Our previous biological history would suggest that maximum lifespan will not change much. But can we be absolutely certain this is true? And what then would we die of? Is there an ultimate cause of human death responsible for the apparent fixity of human maximum lifespan? Or would all human death be accidental? We will explore these questions in the following chapters.

Table of Contents

1. Aging, Senescence, and Lifespan
2. The Nature of Cellular Senescence and Death
3. The Evolution of Senescence and Death
4. Of Embryos and Worms and Very Old Men: The Developmental Genetics of Senescence and Lifespan
5. Human Genetic Diseases That Mimic the Aging Process
6. Cycling to Scenescence
7. Replicative Immortality: Cancer and Aging
8. Caloric Restriction and Maximum Lifespan
9. With Every Breath We Take: Oxidative Stress and Cellular Senescence
10. The Aging Brain
11. A Conditional Benefit

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