Biological age measured by DNA methylation clocks and reproductive history: Systematic review and meta-analysis

Matthew W Simonson and colleagues synthesized 29 studies covering 550,550 women and examined reproductive history against DNA-methylation measures of biological age. Earlier menopause showed the clearest association with higher epigenetic age acceleration. For GrimAge, each one-year earlier menopause was associated with 0.08 additional years of epigenetic age acceleration (95% CI −0.11 to −0.05; n=5,920). Parity was associated with 0.13 additional PhenoAge years per delivery (95% CI 0.04 to 0.21; n=4,508). Age at menarche was not associated with acceleration in the tested clocks. The findings are relevant to interpretation of GrimAge and PhenoAge in women. They do not show that reproductive history causes faster aging, nor that changing menopause timing or parity will extend life. The evidence is based on cross-sectional studies, with possible confounding by socioeconomic conditions, health, treatment, and cohort composition. All participants were female, and the paper does not test an intervention. The result supports reproductive history as a context variable in biomarker studies, not as a supplement target or clinical prescription. Longitudinal cohorts and trials are needed to determine whether the clock differences predict later outcomes independently of reproductive and health factors.

These findings highlight that aspects of reproductive history are cross-sectionally associated with higher EAA, particularly measured with 2nd generation DNAm clocks (PhenoAge, GrimAge).