Evaluation of reproductive profiles, epigenetic aging, and mortality in post-menopausal women

Abstract Evolutionary theories of aging indicate trade-offs between reproduction and longevity. Epigenetic clocks, such as PhenoAge, GrimAge, and DunedinPoAm, were designed to reflect biological age and be used as surrogates for healthspan and mortality. The current study investigated the connection between reproductive profiles, epigenetic aging, and mortality among post-menopausal women (N=770; 50-85 years of age) with data from the National Health and Nutrition Examination Survey across the United States. Using latent profile analysis, we identified four distinct reproductive profiles: high gravidity but average parity (Class 1); high gravidity and high parity (Class 2); premature menopause (Class 3); and an average profile (Class 4). Women of Class 3 had an accelerated pace of aging as indicated by DunedinPoAm, but not an older epigenetic age as measured by PhenoAge or GrimAge. The association was significant among women who had ever used female hormones (β = 0.521; 95% CI: 0.014-1.027). Women of Class 1 or 2 did not exhibit accelerated epigenetic aging. Women of Class 3 had higher mortality (HR = 1.40, 95% CI: 1.08-1.81), and 36.3% of the effect was mediated through accelerated DunedinPoAm. Findings suggest that women with reproductive profiles characterized by premature menopause may have altered epigenetic aging trajectories. Pace of aging may be more sensitive to the impact of reproductive profile variations than biological age as indicated by PhenoAge or GrimAge. Clinically monitoring the pace of biological aging among women with premature menopause and an appropriate application of hormone replacement therapy may minimize the negative consequence of accelerated biological aging and reduce premature mortality.