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BOOK REVIEW |
George M. Martin, MD Professor of Pathology Adjunct Professor of Genome Sciences University of Washington Box 357470 Seattle, WA 98195
Focus on Modern Topics in the Biology of Aging: Annual Review of Gerontology and Geriatrics, Volume 21, edited by Vincent J. Cristofalo and Richard Adelman. Springer Publishing Company, New York, 2002, 320 pp., $58.00 (cloth).
Surprisingly, it has been almost one generation of human beings and close to 24,000 generations of the gerontologist's favorite roundworm since Volume 1 of the Annual Review of Gerontology and Geriatrics series appeared (Eisdorfer et al., 1980). That book devoted a significant proportion of its content to the biology of aging and thus permits us to make some comparisons with the contents of the most recent volume in this series, Focus on Modern Topics in the Biology of Aging, edited by Vincent J. Cristofalo and Richard Adelman. Perhaps we can thereby make some general conclusions about how much progress has been made since 1980.
Many of our friends and neighbors have expected a great deal, given the generous use of their tax monies for the funding of biomedical research by the National Institutes of Health (NIH) since the appearance of this book's predecessor in 1980. A convenient tabulation of the NIH budget is available for the period 1988 through 1997 (NIH, 1998). Total expenditures for that 10-year period were approximately $100 billion. But we must immediately inform our friends and neighbors that, first of all, this figure pales in comparison with the predicted expenditures for health care. By the year 2020, it is estimated that the yearly costs merely for Part A of Medicare will be over a trillion dollars in constant year 2000 dollars (White House, 2001, chart 5). Second, we must inform them that the funding of research devoted to the elucidation of basic biological mechanisms of aging has been and continues to be a trivial fraction of the NIH's total budget. The estimate for total NIH funding for fiscal year (FY) 2002 is approximately $23.6 billion; that for the National Institute on Aging (NIA) is $896 million (NIH, 2002). Although it is difficult to make an estimate of the amount of FY 2002 funding for research on fundamental biological mechanisms of aging, my best guess is that it is of the order of $200–500 million. That would yield a figure of between 0.85–2.1% of the NIH budget that is devoted to basic research on aging. Given the fact that such research has the potential to make a major impact upon the lion's share of the NIH agenda (cancer, heart disease, stroke, Type 2 diabetes, Parkinson disease, Alzheimer disease, cataracts, age-related macular degeneration, hearing loss, osteoporosis, osteoarthritis, sarcopenia, benign prostatic hyperplasia, etc.), this is a surprisingly small figure. Moreover, the elimination of such diseases will do very little to extend overall health span and life span as compared to potential breakthroughs that address basic processes of aging. For example, a pill that will mimic the effects of caloric restriction might provide postponement of all major causes of death and substantial increases in life span (Miller, 2002).
So how have our ideas about the nature of biological aging changed since 1980? The introductory chapter to that 1980 volume, a review of various theories of aging, was by the late George A. Sacher, a former president of The Gerontological Society of America. In it, virtually no attention was given to the evolutionary theory of aging. This was not surprising to me, as I was quite aware of George's distaste for that theory, particularly the version that has come to be known as the "mutation accumulation" theory (or, more properly, the accumulation of heritable, late acting deleterious constitutional mutations, as distinct from somatic mutations). If I had to identify the single most significant shift in the dominant paradigm of biogerontological thinking since 1980, it would be the widespread acceptance of evolutionary theory as the most satisfying explanation for why aging happens. In the present volume, this message comes through loud and clear in the chapters by Tom Kirkwood and Steve Austad and has clearly reached the physiologists and even the demographers, judging from the chapters, respectively, by Ed Masoro and by Jay Olshansky and Bruce Carnes. (The Austad chapter, which is concerned with the comparative biology of aging, is not to be missed. It includes the most succinct, intelligent, comprehensive, and critical evaluation of sex differences in longevity that has ever been published.)
Despite the efforts of Kirkwood, Austad, and others, most notably the special initiatives by Michael Rose (e.g., Rose & Graves, 1989) to inform our community regarding evolutionary theory, there are colleagues who remain skeptical. The views of our champion skeptics and my good friends, Harriet and David Gershon, are well represented in this 2002 volume of the Annual Reviews. They rail against most of our popular model systems for the study of aging and, judging from their criteria for what constitutes a useful model, have either not fully digested or fully accepted the evolutionary model. We need such iconoclasts, however. They raise some very important criticisms, such as the dangers of making generalizations from experimental results with a single highly inbred species that has been adapted to life in the laboratory. At the risk of antagonizing the male coauthor, who is a tough former Israeli Army tank officer, let me outline some of our points of disagreement. First, let us examine certain of their criteria for deciding what is a basic mechanism of aging—specifically the argument that, in order to decide that a putative fundamental process of aging is valid, it must occur in all members of a species and among all species. Evolutionary theory states that senescent phenotypes emerge because of the decline in the force of natural selection with respect to the age of gene effects. There is no necessity for universality of phenotypes. Some mechanisms may indeed be "public" but others can be "private," reflecting patterns of decline in structure and function that are idiosyncratic to the individual or to the species (Martin, Austad, & Johnson, 1996; Partridge & Gems, 2002). Several categories of gene action may underlie such differences within and between species in how aging plays out (Martin, 2002). To give a concrete example, the age-specific incidence of dementias of the Alzheimer type rises exponentially after about the age of 60 (Jorm & Jolley, 1998). In a number of independently studied White populations, almost half of women over the age of 95 years and only slightly fewer men develop at least mild forms of the disorder; the figures would be much higher if one were to tally questionable cases (Hy & Keller, 2000). These are phenotypes that have clearly escaped the force of natural selection. The underlying mechanisms of aging that lead to this marked increase in susceptibility with age remain to be fully elucidated. Whatever they are, there are likely to be sufficient differences in gene–gene and gene–environmental interactions both within and between species. Old rodents, for example, do not develop these lesions in the absence of some transgenic manipulations.
Second, let us examine their arguments against the validity, for aging research, of simple model systems such as genetically defined laboratory strains of fruit flies and roundworms. It is not clear when their manuscript was written, but they may well have missed the big biogerontological news of 2001—namely the evidence that comparable signal transduction pathways in C. elegans, D. melanogaster, and, possibly, M. musculus domesticus are involved in mutations leading to prolonged life spans (reviewed by Partridge & Gems, 2002). Some biologists, including myself, have struggled with attempting to reconcile such results with the evolutionary theory of aging, which predicts a highly polygenic substrate and multiple mechanisms. The same concern applies to the observations that a simple environmental manipulation like caloric restriction can provide substantial increments in the life spans of many different organisms. I no longer have such concerns, however. I believe that these mutations are in pathways involved in mechanisms of life course modulation that have been under strong selection. These are collectively known as diapauses. They are "time-outs" from the business of reproduction necessitated by environmental stresses such as food deprivation. As such they can be considered to be subtexts of a larger picture of aging—the picture that invokes gene actions that have indeed escaped the forces of natural selection.
Another chapter, by R. G. Allen, Arthur Balin, and Vincent Cristofalo, gives a very competent and up-to-date consideration of replicative senescence. Here again, it is instructive to compare this contribution with one on the same subject by Hayflick in the 1980 volume. The significance of the in vitro model of replicative senescence has now been questioned, mainly because of the experiments by Cristofalo and colleagues showing that mass cultures of skin fibroblast-like cells from normal donors do not exhibit any age-related declines in replicative potentials (Cristofalo, Allen, Pignolo, Martin, & Beck, 1998). In contrast to the review of that model by the Gershons, where it is essentially dismissed without qualifications, Allen and colleagues do indeed give qualifications. They point out that the methodology employed for their negative studies, involving established mass cultures, could not examine the very large number of cells that did not contribute to the establishment of the culture, as there is very strong selection in favor of the best growing cells. Even methods such as clone size distribution, if initiated after the establishment of the cultures, would fail to evaluate a potentially significant decline in replicative potential in the vast majority of cells that exist in vivo. Moreover, the Gershons do not cite in vivo studies that do indicate declines in the replicative potentials of a variety of somatic cell types, in particular the work of Norman Wolf, William Pendergrass, and colleagues (reviewed in Wolf & Pendergrass, 1999).
The final word has yet to be written about the significance of altered replicative potential of somatic cells during aging. Every pathologist will tell you that the tissues of old people at autopsy exhibit varying degrees of atrophy. It is also interesting that one also observes multifocal proliferations and hyperplasias. There clearly seems to be an alteration of proliferative homeostasis during aging, the significance of which needs further study. The excellent chapter by Zahra Zakeri and Richard Lockshin on apoptosis and other forms of cell death deals with an area of research that is slowly but surely elucidating underlying mechanisms for this altered proliferative homeostasis.
In keeping with the times, the theme of genetics dominates this volume. Readers will find very helpful summaries of methods of genetic analysis and a tabulation of "longevity genes" so far discovered in yeast and in C. elegans. We are also privileged to have a chapter on the genetics of behavioral aging by the pioneer in this field, Gerald E. McClearn. But the role of environment is not neglected. Jim Joseph and his colleagues bring us up to date on the surprising results of nutritional interventions on rodent cognition. One fringe benefit of their results is that we now are treated to blueberries during the breaks in our scientific meetings, thanks to the generous donations of vendors who have been delighted with these results! Jim tells me that, to get the full benefit of the anti-oxidant flavinoids in blueberries, one should heat them somewhat, to make them more available, but then one should refrigerate them. To my delight, this is exactly what my wife has been doing with her blueberry tarts for years!
Finally, it is a pleasure to discover a book on the biology of aging that includes chapters by demographers. They have been increasingly interested in biological explanations of their findings. The demographers who have contributed to this volume are among the very best in the field—Ken Manton, Jay Olshansky, and Bruce Carnes.
References
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