Assessing mechanisms and evidence of a causal role for cellular senescence and somatic mutations in aging

Understanding the primary molecular and cellular drivers of aging and how they trigger systemic functional decline remains a fundamental challenge. This review focuses on two proposed drivers of aging, cellular senescence and somatic DNA mutations, critically discusses the evidence for their association with organismal aging, and appraises their causal contribution to it. Several studies support the notion that cellular senescence can cause aging, acting through cell-intrinsic and, likely more significantly, cell-extrinsic mechanisms such as the senescence-associated secretory phenotype. Differently, the mutational burden is strongly correlated with aging, but we argue that the causal contribution of altered DNA sequences to age-related functional decline remains difficult to untangle from its originating genotoxic events.