Comparing epigenetic puberty and epigenetic clocks as biomarkers of adult biological aging and health

Recent lifespan frameworks of aging theorize that pubertal development and cellular aging are governed by overlapping pathways, but the time lag between adolescence and older adulthood complicates the study of shared molecular mechanisms. Here we compare a DNA-methylation-based epigenetic index of pubertal development to epigenetic clocks, which were designed to measure biological aging, as a putative biomarker of adult aging and health in two adult cohorts: 3,642 older Americans in the Health and Retirement Study (HRS; age range, 56 to 100 years; 2,106 females) and 18,676 adults from Generation Scotland (GS; age range, 18 to 98 years; 10,974 females). Epigenetic puberty was correlated with chronological age in both cohorts, moderately in the older HRS sample (r = 0.51 in females, r = 0.51 in males) and strongly across the wider adult age range of GS (r = 0.82 in females, r = 0.86 in males). In both cohorts, age-residualized epigenetic puberty was associated with accelerated biological aging as measured by epigenetic clocks and other aging biomarkers (standardized coefficients: HRS, 0.13 to 0.47, all P < 0.005; GS, 0.05 to 0.40, all P < 0.001). Epigenetic puberty was linked with multiple health outcomes: mortality in HRS in both sexes (ORs, 1.39 and 1.46, both P [&le;] 0.001) and in GS among females (HR, 1.12, P = 0.003); 10-year onset of diabetes, any cancer and lung disease in GS (HRs, 1.12 to 1.19, all P < 0.005); and with multimorbidity, functional limitations and BMI in females in HRS (standardized coefficients, 0.10 to 0.16, all P < 0.001). It also accounted for a unique, albeit smaller, proportion of variance in aging-related outcomes beyond that explained by epigenetic clocks. These findings indicate that the epigenetic puberty index reflects pro-aging underlying biology, showing overlapping molecular pathways between pubertal development and cellular aging, and support a lifespan-based approach to studying biological aging.