Reproductive life events and biological aging in women over 50: evidence from DNA methylation clocks

As global aging intensifies, elucidating reproductive health's epigenetic aging associations is crucial. However, the impact of reproductive history on multi-generational DNA methylation (DNAm) clocks remains insufficiently characterized, representing a significant gap in understanding biological vs. chronological aging divergence. This study analyzed 1117 U.S. women aged 50 or older from NHANES 1999-2002 to examine associations between reproductive history and 12 DNA methylation (DNAm) algorithms. Multivariable linear/logistic regression models assessed associations between reproductive indicators and DNAm age acceleration, adjusting for sociodemographic/biological confounders. The β coefficients represent the change in DNAm age acceleration in years. Pregnancy frequency (per additional pregnancy) showed positive associations with PhenoAgeacc (β = 0.14, 95%CI:0.01-0.27) and GrimAge2Mortacc (β = 0.10, 0.03-0.18). Categorical analyses revealed that high pregnancy parity (≥5) significantly increased the odds of GrimAge2Mortacc (OR = 2.34, 95% CI: 1.15-4.71), while high live birth parity (≥5) was associated with increased odds of HannumAgeacc (OR = 2.57, 95% CI: 1.01-6.92). Most primary associations involving second-generation clocks remained robust after false discovery rate correction. While menarche timing showed no significant associations, later menopause and a longer reproductive lifespan were significantly associated with decelerated biological aging after multiple testing correction. These findings suggest that parity and reproductive timing are associated with biological aging trajectories through methylation mechanisms, advancing our understanding of sex-specific aging drivers.