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Evolutionary and Genetic Aspects and the Human Condition

George M. Martin

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Departments of Pathology and Genetics, University of Washington, Seattle, WA 98195

Senescence can be defined as the constellation of phenotypes that have escaped the force of natural selection. The ages at which such phenotypes unfold among species varies as functions of the ecological hazards under which the species evolved. Two types of non-adaptive gene actions are implicated. JBS Haldane and Peter B. Medawar envisioned a variety of constitutional mutations, the effects of which failed to reach a phenotypic level of expression until late in the life course. We might refer to these idiosyncratic types of modulations of senescence as private, as their frequencies in any population would be related to genetic drift. George C. Williams conceived an alternative mode of relevant gene action, called antagonistic or negative pleiotropy. He invoked alleles which act early in the life course to enhance reproductive fitness, but which have late deleterious effects. Such allelic modulations might be referred to as public, in that they are likely to spread within a population. An argument can be made that these variants may often be part of polymorphic series of alleles.

Dr. Martin will discuss several important implications of the evolutionary theory of senescence as well as challenges to that theory from research on demography, single gene mutations in C. elegans, caloric restriction in mammals, and the Weibull analysis of the time-to-failure of complex systems.

Finally, he will briefly review progress in defining the very large numbers of potentially relevant loci in man, with emphasis upon the Werner helicase gene (WRN), null mutations at which result in the Werner syndrome (WS), a striking segmental progeroid syndrome. The many clinical and cell biological discordances between WS and usual aging lead to the conclusion that it most likely represents an example of a private modulation of aging. The impact on human senescence of heterozygosity for nulls, of leaky mutations, and of polymorphisms at WRN remains to be determined, however, especially given the potential for interactions with endogenous and exogenous genotoxic agents.

Dr. Martin is Professor of Pathology and Director of the Alzheimer Disease Research Center at the University of Washington School of Medicine. He received his B.S. and M.D. from the University of Washington in 1949 and 1953, respectively. He is a member of Sigma Xi, an elected Fellow of the American Association for the Advancement of Science, and a member of the National Academy of Sciences' Institute of Medicine. He received the Allied Signal Achievement Award in Aging (1990), the Research Medal from the American Aging Association (1992), the Robert W. Kleemeier Award from the Gerontological Society of America (1993), and the Irving Write Award of Distinction of the American Federation for Aging Research (1996).

He recently served on the Board of Scientific Counselors of the National Institute on Aging, was Vice President of the American Federation for Aging Research Executive Committee, and Chairman of the American Federation for Aging Research's Scientific Review Committee. He currently serves as a member of that Federation's selection committee for the Paul Beeson Physician Faculty Scholars Program.