Setting the Pace of Epigenetic Aging in Mammals: A Hierarchy from Species to Individual

Epigenetic clocks have transformed aging research by providing accurate molecular measures of biological age, but the factors regulating their pace across mammals remain unclear. This review proposes a hierarchy of regulation: species-level determinants that set intrinsic aging rate and lifespan, as well as individual-level modifiers acting within species. Comparative analyses show developmental tempo, rather than body mass, anchors species differences. Across individuals, caloric restriction and other perturbations of the insulin-like growth factor 1 nutrient-sensing axis alter epigenetic aging rate, whereas torpor models suggest body temperature, rather than metabolic rate per se, acts as the pacemaker. Gonadal hormones, reproduction, social environment, and ecology also contribute, with applications in livestock and wildlife conservation highlighted as means to capitalize on age-associated traits and exposures. Together, this work shows epigenetic clocks are far more than a yardstick for biological time; they reveal the multifaceted biology, and its hierarchy, that sets the pace of aging in mammals.