The end of the beginning

A Means to an End: The Biological Basis of Aging and Deathby William R. ClarkOxford University Press, 2002. 13.50 pbk (234 pages) ISBN 0 19 515375 8Genetics and molecular biology have revolutionized aging research in the past two decades, just as they had developmental biology previously. This historical precedent has had a significant impact on the thinking of many researchers entering the aging field, by fueling their search for a biological aging ‘program’ analogous to the developmental program. The difficulty is that programs have a ‘purpose’. Evolutionary biologists, who constitute another segment of the aging research community, have cogently addressed the lack of purpose in aging, a phenotype that has escaped the force of natural selection through its appearance in post-reproductive individuals. The dilemma then is to acknowledge this, while searching for the proximal causes of aging and the principles that govern its course in various species.In A Means to an End, Clark takes a narrow view of the evolutionists’ position and dismisses it by pointing out the existence of single-gene mutants that have large effects on lifespan and by confidently asserting that there are relatively few genes that govern aging. The word ‘program’, in turn, is usually in quotes in his book, indicating its guarded use. However, clear guidance to its meaning in the context of aging is lacking. The source of this inadequacy could reside in one of the strengths of this book, which treats the cell as the basic aging unit. Replicative senescence and programmed cell death are the terminal phenotypes of the aging cell. The translation of replicative senescence into the aging of the organism is not easy, but Clark does an excellent job in spanning this gap. However, his insistence that programmed cell death causes the demise of the organism is difficult to sell.Aging plays out in individual cells; however, multicellular organisms do not die because all their cells die. The new era opening up before aging research by virtue of the completion of the Human Genome Project, to which Clark often refers, will allow us to bridge the gap between the cell and the organism. This, however, is where the book ends. Cells need not die or even lose most of their function for the organism to senesce. The realization that the organism is a complex system in the nonlinear dynamic sense provides a means for understanding this apparent discrepancy.What is the nature of the genetic determinants of longevity? Three types of gene that influence aging are enumerated by the author: senescence effector, senescence repressor and senescence regulator genes. The first two categories are postulated to be common to all aging species. Clark astutely searches for this commonality in the distant phylogenetic past among the protists. Here, he makes the oft-asserted connection between sex, reproduction and aging, which provides the resolution of the evolutionary dilemma surrounding the origins of aging. This is also where the difficulty with programmed cell death arises. The senescence regulator genes, in contrast to the other two classes of senescence genes, make their appearance throughout phylogeny and determine the characteristic differences between species’ maximum potential lifespans. Statements are made indicating that there is good evidence for these types of genes in different species, including human. This categorization of senescence genes is neat, but there is little, if any, evidence presented to support it.Clark devotes relatively little space to the genetics of aging in invertebrate models. This is surprising given the generic focus on genes. The details of the involvement of the daf-2–age1 pathway in nematode aging were already known when the book was written. (Inexplicably, Clark states that the identity of the age-1 gene is not known.) The omission of the genetics of aging in model systems is a pity, because it would have enhanced the author's otherwise excellent discussion of the role of metabolism and oxidative stress in aging, which includes a nice encapsulation of the life extension and senescence retardation by caloric restriction. This rendition is highlighted by the conclusion that caloric restriction might actually allow the realization of the maximum potential lifespan of the species, rather than altering the maximum lifespan, which would require genetic change if maximum lifespan is a heritable characteristic of a species.A Means to an End is targeted to a lay audience. The citations that would render it more satisfying to the scientist are missing. These citations would have prevented certain inaccuracies and facile statements. There are, however, interesting perspectives and generalizations made by the author that can benefit anyone interested in aging research, once the reader gets past some of the implausible ones.