title: A theory of age-dependent mutation and senescence.
abstract: Laboratory experiments show us that the deleterious character of accumulated novel age-specific mutations is reduced and made less variable with increased age. While theories of aging predict that the frequency of deleterious mutations at mutation-selection equilibrium will increase with the mutation's age of effect, they do not account for these age-related changes in the distribution of de novo mutational effects. Furthermore, no model predicts why this dependence of mutational effects upon age exists. Because the nature of mutational distributions plays a critical role in shaping patterns of senescence, we need to develop aging theory that explains and incorporates these effects. Here we propose a model that explains the age dependency of mutational effects by extending Fisher's geometrical model of adaptation to include a temporal dimension. Using a combination of simple analytical arguments and simulations, we show that our model predicts age-specific mutational distributions that are consistent with observations from mutation-accumulation experiments. Simulations show us that these age-specific mutational effects may generate patterns of senescence at mutation-selection equilibrium that are consistent with observed demographic patterns that are otherwise difficult to explain.
authors.affiliation: Department of Genetics, University of Georgia, Athens, Georgia 30602-7223, USA. jmoorad@uga.edu
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Moorad
authors.forename: Daniel E L
authors.initials: DE
authors.lastname: Promislow
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D005075:Biological Evolution; D006801:Humans; D008136:Longevity; D008957:Models, Genetic; D009154:Mutation