For millions of years, life has adapted to shifting environments, with mutation as the engine of this change. The same mutations that fuel evolution also drive genetic diseases, cancer and age-related decline. Comparative analyses now show that somatic mutation rates scale inversely with lifespan across mammals, indicating that long-lived species actively depress annual mutational input to keep lifetime burdens within bounds. Natural experiments in long-lived, cancer-resistant mammals such as naked mole-rats, elephants and bowhead whales reveal reinforced genome-maintenance circuits that enhance repair fidelity and constrain mutation accumulation, supporting a fidelity-based view of life-history design in which organisms balance evolvability with somatic integrity under speed–accuracy, energetic and developmental constraints. This review integrates comparative genomics, molecular mechanisms and evolutionary theory to explain how mutation rates are set, why they differ across species and tissues, and how they shape longevity and cancer risk. We discuss implications for tissue-specific aging trajectories, viral and microbial parallels, and translational strategies, from biomarkers that track in vivo mutation accrual to context-specific, pro-fidelity interventions, and outline testable predictions for the next decade.
Cao et al. (2026) studied this question.