The evolution of aging and lifespan.

The extensive variation in lifespan among organisms provides a natural dataset to probe the evolutionary tradeoffs that constrain and mold this phenotype across taxa. Several key pathways repeatedly emerge as the targets of selection from comparative genomics of long-lived species. Overall, these pathways exhibit increased constraint in long-lived species and reduced constraint in short-lived species with distinct signatures of diversifying selection observed in individual taxa. Large cohort studies demonstrate that even late-acting deleterious alleles appear to be under strong purifying selection in human populations. Somatic mutation rates scale with lifespan and are significantly higher than matched germline mutation rates. Cell culture models of extreme agers are beginning to facilitate characterization of key genotype–phenotype interactions in biological aging. Aging is a nearly inescapable trait among organisms yet lifespan varies tremendously across different species and spans several orders of magnitude in vertebrates alone. This vast phenotypic diversity is driven by distinct evolutionary trajectories and tradeoffs that are reflected in patterns of diversification and constraint in organismal genomes. Age-specific impacts of selection also shape allele frequencies in populations, thus impacting disease susceptibility and environment-specific mortality risk. Further, the mutational processes that spawn this genetic diversity in both germline and somatic cells are strongly influenced by age and life history. We discuss recent advances in our understanding of the evolution of aging and lifespan at organismal, population, and cellular scales, and highlight outstanding questions that remain unanswered. [ABSTRACT FROM AUTHOR]