Guest guest Posted June 2, 2005 Report Share Posted June 2, 2005 Hi All Arking maybe should be requested to review Walford's new CR book, based on the below. It is from a not yet in Medline review. CR forms much of the discussion of the review. BIOLOGY, FRUIT FLIES, AND HUMANS: CAN EXTENDED LONGEVITY STRETCH FROM ONE TO THE OTHER? Review Essay by Arking Gerontologist. 2005 Jun;45(2): 418-425. The Biology of Death: Origins of Mortality, by André Klarsfeld and Frédéric Revah (translated from French by Lydia Brady). Cornell University Press, Ithaca, NY, 2004, 211 pp., $29.95 (cloth). " How should we live our lives? " is an age-old question. " Should we actively seek to live a longer life? " is a more recent question now in the process of being answered. " How should we live an extended life? " is a newborn question just beginning to be addressed. Just as there is a multiplicity of views regarding the proper answer to the first question, so there are differing views regarding the latter two questions. While these divergent and competing views may be judged by some as an inappropriate cacophony, others may view them as an ongoing discussion and commentary on the most personal of all things—our lives and their shape. The three books reviewed in this essay ostensibly address the second question, although their authors' views can be interpreted as pointing towards some still-forming response to the third question. A Dinner Conversation: Death and Longevity A stimulating dinner conversation is stated to have been the inspiration for The Biology of Death: Origins of Mortality, by André Klarsfeld and Frédéric Revah. They have written a short but pointed summary of recent scientific findings regarding death and longevity for the intelligent lay person. People tend not to dwell too much on death except to believe that it must be a biological necessity, if only to justify the unfairness of that personal extinction that awaits us all. This book is the authors' response to that common but flawed perception. Originally published in French in 2000, this translation captures the flavor of the French writings on this topic. I for one thank Lydia Brady for her efforts, which make only too clear the loss of access to all those untranslated writings which afflict us unsuspecting monolinguists. The authors start off with a concise overview of prior biological concepts of aging and death, winding up with August Weismann and Elie Metchnikoff and the beginnings of the evolutionary concepts of aging. Following a discussion of the demographic methods of measuring longevity (complete with charts and tables), they engage in a comparative examination of the rapid and gradual modes of aging. Only then do they segue into a continuation and elaboration of the evolutionary theory of aging, one in which they weave the essence of the theoretical arguments and their supporting empirical data into an engaging story (with minimal jargon) that culminates in the disposable soma theory and the purposelessness of death. In a mere 30 pages Klarsfeld and Revah summarize the current state of our knowledge of the mechanisms underlying aging in a manner such that a careful lay reader could hold her own at that dinner table conversation. Following a discussion of apoptosis, they delve into an examination of the ways in which one might significantly slow the aging process. In the few years since Klarsfeld and Revah wrote this well-crafted slim volume in French, our knowledge of aging mechanisms and potential interventions has qualitatively increased. So this portion of the translated text is the most dated (although the French version must have been quite current when published). They recap the conversation by concluding that " the priority of living organisms cannot be to devote all of their efforts to their own survival; they must also keep resources to reproduce, to transmit their genes. Aging and natural death arise from this compromise, not automatically by a direct link but through the work of natural selection; they are simply particularly adverse side effects, from a human point of view " (pp. 193–194). In this, they agree with the now-accepted view based on the prior conclusions of scholars such as Rose (1991), Kirkwood (1987), (1957), Medawar (1952), and Bidder (1925, 1932) regarding the role of reproduction in bringing about the lack of somatic maintenance, which is the ultimate cause of death. The evolutionary approach to understanding aging is the only concept that has allowed us to construct a coherent and empirically proven explanation as to why organisms possessed of an elaborate synthesis and repair apparatus should inevitably—and otherwise inexplicably—fail to maintain themselves and so inexorably lose function, decay, and die. Klarsfeld and Revah's dinner companions must have been fascinated by their conversation, as much by the light it shed on the problem of death as by the method of its analysis. As Rose has well written elsewhere, " And for those who would know and understand the long story of life on earth, Darwinism is the great searchlight in the darkness. For the modern world to go on without Darwin's Spectre would be to lose our way in a twilight of the mind " (Rose, 1998, p. 211). Not all celebrate the intellectual triumph of this materialist approach to the deep questions of life, for many are uncomfortable with the absence of a compassionate creator. The supposed consolations of death and finitude have been put forth in moral terms, most notably by Leon Kass (2004). (For a specific rebuttal to his arguments see Arking, in press.) They have also been expressed in supposedly biological terms, the latter exemplified by Klarsfeld and Revah's summary of the precepts of the Thanatology Society, which posits that " ... the death of individuals ensures not only the perennity of the species but also its rejuvenation: it is hence not only a necessity but a benefit " (M. Marois, p. 192). There is some truth to this statement, involving the calculation of Darwinian fitness in changing environments. But we now realize that an increase (or a decrease) in the frequency of some allele which we pass on to our offspring has no moral meaning. It offers us no beneficial recompense for our death. " What compensation would the immortality of the species bring to the individual stalked by death? ... What good does it do me that the future world will survive if I won't be there? " (V. Jankelevitch, p. 193). This individualist and materialist rejection of mortality's alleged benefits was not only voiced by others, but is becoming more widespread in our society as evidenced by a recent article by Kaufman, Shim, and Russ (2004). They argue that biomedical improvements make the improbable treatment routine, change the expectations for the quality of life at older ages, and bind hope to the normalization of life-extending techniques. In effect, the alleged benefits of death are being refuted by every individual who takes the new drug or undergoes the new surgical interventions that modern data-based medicine suggests will likely extend his or her life. It seems as if ordinary people are exerting their autonomy by opting for life rather than for death. The intellectual validity of their optimistic actions is supported by the prolongevity philosophy put forth by Overall (2003, 2004). A materialistic explanation of human origins in an uncaring universe will likely resonate only with that subset of people who can be comfortable with the cold comfort of logic and who can derive " ought " from " is " (see Bronowski, 1956). In contrast, those desirous of a purposeful universe overseen by a compassionate creator may consider such a view as devoid of meaning and incapable of giving a moral coherence to life. The political future of prolongevity interventions will likely rest on our ability to truthfully present to both groups the information necessary for them to individually view such interventions as supportive of life and, thus, of their own philosophy. Prolonged Senescence In the current societal state of affairs, life expectancy is being extended by adding years onto the latter part of the life span. The social and ethical discussions swirl about this one strategy only, although other and better strategies are available (as will be discussed below). This current strategy works only because social organisms may receive enough support from their group to enable them to survive past the time when they would otherwise have been able to survive on their own. Such supportive behavior was selected for in humans by both cultural and biological means as Crews (see below) points out in much detail. But such amelioration, even though it is an intrinsic part of our species' life history strategy, does not defer senescence but lengthens it. What might we expect to happen if we continue to follow this strategy of extending senescence? There is good news, and there is bad news (Baltes & , 2003). The good news is that people in the 65–85 age bracket (which constitute about 12.8% of the population of developed countries) are much healthier and more productive today than they were in the past, and they have high levels of physical and mental well-being. Moreover, there is still substantial latent potential for better mental and physical fitness among them. For these reasons, people in the 65–75 age bracket have been termed the " young–old " in recognition of their ability to maintain function into what was traditionally considered the frail and morbid years of being " old. " Many of these young–old adults could continue to contribute to society and enrich it by continuing to work, by developing new social roles, and by contributing in various ways to the resources needed for their own medical care. In fact increasing numbers already do so, and our society will likely change for the better as this trend continues. The bad news is that the " oldest–old, " the people in the 85–100 and older age bracket (which constitute about 1.5% of the population in developed countries), are not in as good a condition. Many have some sort of functional physical or cognitive loss and have also lost their social contacts as spouses and relatives and friends die. These oldest–old adults are, for the most part, lonely women, most of whom will die alone in a hospital or nursing home. This group may not be numerically large now, but their numbers will substantially increase if we just maintain our current practices of biomedical intervention at the end of life. They are a harbinger of our future. Such a prospect should give even an optimist pause, for the joys of living long are nullified by the loss of dignity and control suffered by the oldest–old. If all that our vaunted knowledge of the biology of aging can do is to increase the odds that one would live into the oldest–old group without devising any way to buffer one against the inevitable functional losses seen in this group, then perhaps it would be better for biogerontologists not to continue their research. It is enough to make one wonder whether there should be limits to life. Kaufman and colleagues (2004) point out that " A price is paid for hope and expectation invested in biomedical technique " (p. 737), and that price seems to be one of deficits, disappointment, and despair when the hopes of " eternal " health do not materialize, as indeed they cannot. Delaying the Onset of Aging But there is another strategy available, and it grows out of modern biogerontological research. One of the major purposes of using laboratory models for research is to discover mechanisms and responses that may not be obvious in humans but that can be brought to light by animal studies. Should a new or unusual response be found in mice or primates, then we should consider the possibility of it occurring in humans and the implications. In Methuselah Flies: A Case Study in the Evolution of Aging, by R. Rose, Hardip B. Passananti, and Margarida Matos, the very first research paper is a reprint of an earlier report by Rose on the evolution of postponed senescence in Drosophila (Rose, 1984). This paper was published simultaneously with the independent report of Luckinbill, Arking, Clare, Cirocco, and Buck (1984) showing the same effect. Much work has been done since then elucidating the mechanisms underlying this form of extended longevity, as the new book by Rose and colleagues amply demonstrates. The work that my colleagues and I have since done on Drosophila longevity bears on the development of this alternate strategy. We reported that aging in the Ra strain of wild type flies is rather complex, being characterized by at least three different extended longevity phenotypes, each of which was induced by specific stimuli and had different demographic mortality and survival profiles (Arking, Buck, Novoseltsev, Hwangbo, & Lane, 2002). The first longevity phenotype (Type I) is a delayed onset of senescence which leads to a significant increase in both the mean and maximum life span of the experimental strain. Normally, mortality rates increase as a population ages. It turns out that an extension in life span may be brought about either by an age-independent reduction in the initial mortality rate observed in the youngest members of a population or by an age-dependent reduction in the rate of increase in the mortality rate with age. The former case results in the same rate of increase in the mortality rate as a function of age, but each age cohort is much healthier than is its comparable age cohort in the relevant control population because their starting mortality was so much lower. The net effect is an increase in longevity due to increased health. The latter case results in the population having the same initial mortality rate as the control, but this is coupled with a lower rate of increase in the mortality rate with age. As a result, each age cohort is aging slower than is its comparable age cohort in the control population. The net effect is an increase in longevity due to a slower rate of aging. Demographic analyses of our long-lived La strains shows that they are using the second method, as their rate of aging is reduced by 33% relative to normal-lived controls. This is not true of the other two longevity phenotypes observed in these Ra strain flies. The second (Type II) is characterized by an increased early survival which leads to a significant increase in mean but not in maximum life span. The third (Type III) longevity phenotype is an increased later survival which leads to a change in the maximum but not in the mean life spans. There is no significant alteration in the rate of aging in either of these alternative longevity phenotypes, although there is a transient decrease in mortality in the young (Type II) or the old (Type III) individuals. Moreover, empirical evidence demonstrates that not only do multiple longevity phenotypes exist but that each of them may be induced by a variety of stimuli, some of which may interact in an additive manner. The Type I delayed onset of senescence phenotype may be induced in flies by (a) caloric restriction (Pletcher, Mac, Marguerie, Certa, Stearns, Goldstein, et al., 2002), ( the down regulation of the insulin-like signaling pathway (Clancy, Gems, Harshman, Oldham, Stocker, Hafen, et al., 2001; Tatar, Kopelman, Epstein, Tu, Yin, & Garofalo, 2001), © up regulation of the antioxidant defense system (ADS) plus altered mitochondrial properties (Arking et al., 2002), (d) different alterations through pharmaceuticals of the patterns of adult gene expression (Kang, Benzer, & Min, 2002; Zhao, Sun, Lu, Li, Chen, Tao, et al., 2005), and (e) alteration of steroid hormone levels (Simon, Shih, Mack, & Benzer, 2003). These different stimuli in flies probably exert varied specific effects, but all seem to lead to high levels of somatic maintenance and thus to a significant delay in the onset of observable loss of function. The mechanisms likely involved are discussed elsewhere (Arking, in press; see also Rose and colleagues, as discussed below). Furthermore, this diversity of longevity phenotypes is not restricted to insects. All three phenotypes are known in mice. However, only the three longevity phenotypes of Types II and III are known to occur in humans. The mouse data, when combined with the conservation of aging mechanisms across species (see below), strongly imply their parallel existence in humans. There is every reason to believe that the Type I phenotype can be expressed in primates as a delayed onset of senescence. For example, it certainly appears as if the Type I phenotype is expressed in calorically restricted macaque monkeys (Roth, Lane, Ingram, Mattison, Elahi, Tobin, et al., 2002) and humans (Fontana, Meyer, Klein, & Holloszy, 2004; Walford, Mock, Verdery, & MacCullum, 2002). An underappreciated outcome of the past century of biological research is the discovery that fundamental cellular and homeostatic traits are common to almost all species and are very often controlled by the same basic molecular mechanisms. Evolution may be said to be frugal in its invention of new molecular mechanisms but extravagant in the number of species employing them. Against that conceptual background, these findings almost certainly imply the existence of an evolutionarily conserved longevity mechanism and its corresponding longevity phenotype. If so, then it should be possible for us to induce the delayed onset of senescence phenotype in humans using stimuli other than a 30% reduction in caloric intake. Such efforts are underway in various labs and biotech companies (Hadley, Lakatta, on-Bogorad, Warner, & Hodes, 2005). Historically, clinical therapeutic efforts focused on alleviating the symptomatic effects of underlying age-related diseases. The increase in our knowledge has fostered recent clinical efforts to more effectively treat the underlying chronic conditions. The effect of these efforts has been to progressively decrease the mortality of senescent adults over the past few decades. That strategy keeps us alive longer than was the case in the past, and I am personally grateful for it; but it does not extend the healthy span of our lives. The failure of humans so far to express a Type I delayed onset of senescence phenotype may be the result of not applying an appropriate stimulus to our bodies rather than being the result of an intrinsic inability of our bodies to respond. With the appropriate stimulus we would be asking our bodies to evoke a response which is already built into our genome. This is by definition a natural response. Such a natural evocation of an innate response would not alter any essential aspect of our human nature. Pharmaceutical interventions have been proved in principle on the basis of work reported with worms and flies and mice. The current goal of the advanced research into the biology of aging is to identify and characterize pharmaceutical inducers of the Type I delayed onset phenotype in mammals, eventually including humans. The success of these efforts will likely weaken the current ethical arguments against extended longevity, based as they presently are on decreasing the mortality of senescent adults. We will pick up this point after we examine the book by Crews below. As noted above, Rose's 1984 seminal paper helped to open the modern phase of biogerontological research. What of the book in which it is recapitulated? Methuselah Flies: A Case Study in the Evolution of Aging is a most unusual volume. It is not the usual festschrift, lovingly assembled at the end of a mentor's career. Nor is it the usual edited assemblage of varied individual contributions hopefully focused on some common theme. This is instead a deliberately crafted compilation of 29 scientific papers by Rose and his colleagues, all of which are focused on the analysis of his well-known normal-lived ( and long-lived (O) strains of Drosophila melanogaster. Note that Rose has authored a minimum of 40 peer-reviewed articles on these strains over the past 20 years, in addition to a large number of review papers, which makes it apparent that this is not a mere pastiche of his reprint files. This book represents a deliberate overview of the knowledge gained from the past 20 years of work with these long-lived fruit flies. This organization of their knowledge resulted in six lacunae, and so six papers were written especially for this volume. They underwent an independent peer-review process under the guidance of Margarida Matos, which resulted in the rejection of one of them. The remaining 5 newly vetted articles and the 24 previously published articles are organized around six general themes (each preceded by a short introductory section) as follows: Creation and long-term evolution of Methuselah flies; Stress, resistance, physiology, and aging; Reproduction, nutrition, and aging; Genetics and molecular biology of Methuselah flies; Reverse evolution of Methuselah flies; Aging, development, and crowding. This is not a book for the uninitiated lay person, but it is one with which an experimental gerontologist can curl up. I found the introductory essays useful and the compiled papers convenient to compare. The goal of the book is to emphasize the value of the research on the array of long-lived flies created by Rose and his collaborators. The perception of that value has been eclipsed in recent years as work done with single-gene mutants of yeast, nematodes, flies, and mice has allowed the identification and characterization of the genetic and molecular pathways regulating the organism's stress resistance and, hence, longevity. This book is an effort to bring attention back to the focused work done by Rose and his collaborators through a convenient collection. Much of that value stems from the fact that few labs have focused such a variety of experimental techniques on one set of related long-lived and control animals. So what has this work taught us about the mechanisms underlying this delayed onset of senescence phenotype? Other than the creation of the stocks of fruit flies, which was instructive and much imitated, the work done on topics 2, 3, and 5 (listed above) yielded the most useful set of data and concepts. It had long been thought that long-lived animals reworked their physiology so as to increase their caloric investment in somatic maintenance at a cost of early fecundity, only to mobilize their resources for reproduction in later life. The papers in these three topics adduced much of the data that supported that early assumption. Long-lived animals really are physiologically different animals, and we should not be surprised that their reengineered energy metabolism allows them to age slower. The detailed studies on nutrition and stress resistance helped to define the major parameters defining these two important variables which directly affect the onset of aging and senescence. But no one approach is perfect, and the work done with selected strains of fruit flies summarized in part 4 of the Rose volume gives no hint of the powerful effects on longevity of particular single-gene mutants, especially those involved in the insulin-like signaling pathway and its control of stress resistance (Helfand & Rogina, 2003; Kenyon, 2005). The population studies of topic 1 listed above suggested a large number of genes were involved in aging, which is true; but the inability to discern the major reworking of the animal's physiology brought about by the altered expression of individual key regulatory genes and particular pathways led to the underappreciation of the single-gene approach. However, it must be pointed out that the success of the molecular genetic approach depended on the prior existence of Riddle, Swanson, and Albert's (1981) classic analysis of certain stress resistance pathways in the nematode. These were given significance for aging by the later serendipitous finding that certain of these mutants defining a certain type of stress resistance were long-lived (Kenyon, Chang, Gensch, Rudner, & Tabtiang, 1993; Larsen, Albert, & Riddle, 1995) and that one of the key mutant genes carried the information required to synthesize a key component of the insulin-like signaling system. The upshot was the connection of a regulatory system extraordinarily well described in mammals (the insulin-like signaling system) but not in worms or flies, with the well-developed concepts of extended longevity in these invertebrates. The connection of two such different phenomena made no sense unless one understood it to imply the existence of an evolutionarily conserved set of regulatory mechanisms modulating aging in invertebrates and metabolic regulation in vertebrates. The hypothesis that aging and metabolic regulation were connected in both species was rapidly tested and proven correct, and the concept of manipulating aging came to the minds of some (e.g., Guarante, 2003). Fortuitous findings from independent laboratories seem to have trumped a more planned approach, at least in this sphere. Evolutionary Biology and Cultural Factors But how much of this is relevant to us? Humans are not flies, worms, or just featherless bipeds. We share about 98% of our genes with the chimpanzee, who is our closest relative, but we are not just bigger chimps. Crews makes this very clear in Human Senescence: Evolutionary and Biocultural Perspectives, his excellent examination of " the evolutionary biology of human senescence from an evolutionary and biocultural perspective " (p. vii). One cannot reliably translate the laboratory findings on laboratory model organisms to humans without a full understanding of the nature of our evolutionary differences compared to other hominids and primates or of the huge but hitherto underappreciated role which our cultural adaptations (e.g., intergenerational transfers of resources) play in allowing us to be described as being very long-lived hominids with a generally high (albeit variable) level of postreproductive vitality not seen in other forms. Crews' slender but informationally dense book does an excellent job of linking the findings of human anthropology to those of biogerontology (and vice versa). Perhaps this book can be viewed as a continuation of the Klarsfeld–Revah dinner conversation, only now focusing on the nitty-gritty details that differentiate fact from fiction. Following two introductory chapters, Crews moves into detailed discussions of human variation in growth and life history (chapter 3), as well as chronic diseases, risk factors and senescence (chapter 4), and thence segues into a discussion of human life span and life extension (chapter 5), before ending with an overview and perspective of all the material (chapter 6). Although Crews points out that we are unarguably different from other primates, there are arguably no unique human qualities. Instead our uniqueness stems from an unusual array of interrelated adaptations that improve the adaptability of each quality. These include bipedality, large brains, high visual dependence, verbal communication, culture, manual dexterity, complete infant dependency, growth and development patterns quite different from those of our primate cousins, and long life. Consider our growth patterns. Our intrauterine growth period of 9 months is comparable to that of chimpanzees and gorillas, but it results in big-brained, comparatively large—but helpless—infants who cannot even cling to their mothers but do have " a well-developed ability to be heard, after which they are continually held to the breast by the free upper limbs of their mothers " (Crews, p. 85). Even though our infants are twofold larger at birth than are our primate cousins, they are weaned at half the age. The human postnatal growth period is unlike those of other primates, which have neither midchildhood nor adolescent growth spurts nor even such life stages. Compared to chimpanzees, we have a much slower physical development both in utero and postnatally, coupled with a comparatively slow pattern of neural development. For example, our brains attain about 25% of the adult weight by birth, attain adult weight by around 10 years, but continue developing until we are 20 years old, at least. We become sexually mature at about age 14, much later than do great apes (around 7–10 years), but significantly before we are fully developed (around age 20), and much parental distress follows from that asymmetry. All of this developmental discussion is especially interesting because of the comparative format in which Crews has placed it. As Crews points out, longevity in modern humans did not evolve directly but rather is secondary to the evolutionary trends listed above. Culture, communication, and language allow us to maintain relatively constant microenvironments and thus play crucial roles in our reproductive success. These biocultural responses restructure our genetic variation and alter existing gene–environment relationships, allowing long-lived, postreproductive survivors to contribute to the success of their children and extended kin, thus further enhancing the longevity-favoring aspects of these biocultural adaptations. It is this biocultural adaptability that makes human life history different from other mammals. This phenomenon makes some question whether the extended longevity discussed above (e.g., the Type I delayed onset of senescence) can be reasonably translated from laboratory data to the human condition, or whether this scenario is just another snake-oil salesman's fairy tale of forbidden hope. In his discussion of this question, Crews rightly emphasizes the complex differences between humans and other hominids, particularly the fact that we are already a very long-lived species with an unexpectedly long postreproductive life, often significantly longer than our reproductive life. But because our history has already made us long lived, then perhaps we are already at the limits of our innate longevity; and if so, then perhaps the longevity interventions generally operative in simpler laboratory model organisms will not be operative in us. The tricks that let laboratory animals live long may not be effective in us if they have been superseded by our unique biocultural adaptations. There is no conclusive answer yet available to this question. So Crews leaves the issue formally open, as indeed the data would dictate that he should. But after reviewing the evidence, he does conclude that " According to all available evidence, calorie restriction instituted during childhood should retard [senescence] and increase average life span for humans .... [it] may represent an untapped source for human life extension .... [N]utritional restriction appears to be humankind's best hope for a fountain of youth " (pp. 209–210). I agree with him and wish to add some recent evidence to his argument. The basic mechanisms underlying the senescent mechanisms that eventually do us in are not unique to us but rather common to all cells. Senescence is the result of a cell-based response to the body's nutritional status (de Cabo, Surer-Galban, Anson, Gilman, Gorospe, & Lane, 2003). Cell-level mechanisms and pathways are highly related across species and often exhibit high levels of functional and structural homology. Interventions acting at the level of the individual cell which delay the onset of these senescent mechanisms should be effective across species because they are not directly affected by the peculiar higher level biocultural adaptations which Crews has described in some detail. The loss of function which underlies senescence mostly (but not entirely) involves the direct and indirect actions of oxidative damage—a sort of biological " rusting " of the subcellular structures. It is often accompanied by a slow but deleterious accumulation of damaged proteins—a sort of " junk accumulation. " This rusting and junk accumulation process is opposed in the model laboratory organisms by a conserved assortment of stress resistance mechanisms and molecules. These resistance mechanisms can be induced by a number of molecules acting more or less directly on the cell (Marsh & , 2004; Morley & Morimoto, 2004) in a cooperative manner ( & Lithgow, 2003). The experimental facts presented in those reports form the basis for our present understanding of the events that cause our cells to transit from a state of high function to a state of lower and decreasing function (see Arking, in press). But can we extrapolate the data? Do our cells react to stress in the same way that other animals' cells do? Although not yet complete, caloric restriction studies on macaque monkeys clearly show that this intervention has altered their physiology such that they appear to be losing function significantly slower than their normally fed cohorts (Roth et al., 2002). The National Institute on Aging (NIA) has recently initiated a study of the effects of caloric restriction on humans, but those data will not be known for some years yet (Heilbronn & Ravussin, 2003). However, some individuals have voluntarily put themselves on a calorically restricted diet, and a recent review of their medical records suggests that humans likely undergo the same physiological changes seen in calorically restricted monkeys (Fontana et al., 2004). Among individuals in good health but not undergoing any known anti-aging intervention, the physiology of those who lived longer than the median age closely resembles the physiology of the calorically restricted macaque monkeys (Roth et al., 2002). Female athletes undergoing intensive physical exercise often cease menstruating, an indication that we still retain the cellular mechanisms whereby the body can shift from a reproductive mode to a somatic maintenance mode under stress conditions not suitable for reproduction. Given these findings, it is not an unreasonable speculation to believe that longevity interventions that enhance our cells' abilities to resist various stresses, and thus to delay the onset of senescence, stand a reasonable chance of forming the basis of a pharmaceutical prolongevity intervention that will be effective in humans. It is likely that such interventions will one day induce the appearance in humans of the " missing " Type I (delayed onset of senescence) phenotype. The social consequences of this intervention are obviously speculative but might well be rather different from what might be expected at first flush. Because such an intervention would be adding healthy years to presenescent individuals, it is open to none of the philosophical criticisms directed towards the biomedical extension of senescence (Kass, 2004). These three books were interesting and informative to me, and I recommend them to all gerontologists and interested observers. The choice of which text you choose might well depend on your familiarity with modern biology and/or your interest in humans as opposed to fruit flies. But each of these texts contains an interesting tale told by masters of their craft, and they are worth the reading. Those individuals who lived throughout most of the 20th century often marveled at the changes they witnessed and the advances in the physical sciences that led to the inventions that transformed their world. There is a reasonable chance that the advances in the biological sciences that will take place in this 21st century will equally transform the world, and do so in ways that perhaps seem unlikely to us today. Now there is a topic for an interesting dinner conversation—and perhaps another book. Al Pater, PhD; email: old542000@... __________________________________ Discover Have fun online with music videos, cool games, IM and more. 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