What is the Proximal Cause of Aging

In spite of exciting new insights into regulatory mechanisms that modulate the aging process, the proximal cause of aging remains one of the unsolved big problems in biology. An evolutionary analysis of aging provides a helpful theoretical framework by establishing boundary conditions on possible mechanisms of aging. The fundamental insight is that the force of natural selection diminishes with age (Medawar, 1952; Comfort, 1956; Williams, 1957). This does not preclude senescence (age-related decrease in individual fitness) from occurring in natural populations (Nussey et al., 2012). Senescence can develop because some genes have non-separable, but typically different or opposite, functions in reproductive-age and in old individuals (antagonistic pleiotropy; Williams, 1957). Such genes, selected according to their “youthful” function, may thus impose a distinct senescent phenotype in old age. In general, however, unless a controversial formulation of group selection (Nowak et al., 2010; Wilson, 2012) is invoked, traits that would become manifest only in old age cannot evolve. This precludes the evolutionary emergence of aging programs, which have been sometimes postulated to exist (Goldsmith, 2012; Mitteldorf, 2012) in analogy to developmental and other biological programs. (By the same token, selective pressure that diminishes with age would also prevent extreme longevity from evolving, if “extreme” denotes a potential life span much longer than that imposed by extrinsic mortality in a given environment.) This and other arguments against the existence of an aging program have been discussed previously (e.g., Zimniak, 2008; Kirkwood and Melov, 2011).