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 mortality and healthspan. The current study investigated the connection between reproductive profiles, epigenetic aging and mortality among post-menopausal women (50-85 years) with data from the National Health and Nutrition Examination Survey across the United States (N=770). Using latent profile analysis, we identified four distinct reproductive profiles: high gravidity but average parity (Class 1); high gravidity and parity (Class 2); early menopause (Class 3); 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 early menopause may have altered epigenetic aging trajectories. Pace of aging may be more sensitive to the impact of reproductive profile variations than the status of biological age as indicated by PhenoAge or GrimAge. Clinically monitoring the pace of biological aging among women with early menopause and an appropriate application of hormone replacement therapy may minimize the negative consequence of accelerated biological aging and reduce premature mortality. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study did not receive any funding. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All the data used in this study are publicly downloadable from the website of the National Center for Health Statistics (https://www.cdc.gov/nchs/nhanes/index.html). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All the data used in this study are publicly downloadable from the website of National Center for Health Statistics (https://www.cdc.gov/nchs/nhanes/index.html).