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.