The interplay among reproductive, molecular, and chronological age in relation to aging-related conditions in women: a longitudinal study - SUMMARY/ABSTRACT Aging confers increased risk for most chronic diseases as well as declines in cognitive and physical function. While chronological age cannot be altered, the pace of reproductive and biological markers of aging may vary dramatically. Human aging is a sexually dimorphic process, with females having a slightly longer expected total lifespan but substantially shorter reproductive lifespan than males. Many diseases of aging, including dementia and cardiovascular disease, show sex-specific patterns. Across their reproductive years, on average females have lower risk for aging-related chronic diseases and more optimal markers of brain and cardiovascular health, such as lipids and blood pressure. However, common risk factors including obesity, tobacco use, diabetes mellitus, and hypertension are more strongly associated with chronic diseases in women compared with men. Moreover, menopause, which signals the end of female reproductive potential, also marks the start of rapidly escalating trajectories in multiple aging-related chronic conditions including physical frailty, dementia, and cardiometabolic diseases. The extent to which reproductive aging presages healthy lifespan beyond chronological age among females remains uncertain. The overall goal of the proposed project is to disentangle distinct aspects of aging – reproductive, biological, and chronological – in relation to aging-related chronic diseases among females. We will leverage existing high-quality data and biosamples from a well-phenotyped population of over 850 women followed from recruitment in early pregnancy in 1999-2002 for over 2 decades, making this proposal both fiscally and temporally efficient as well as highly rigorous and feasible. Our specific aims are to examine associations of different aging-related measures with chronic disease risk factors in midlife females. Exposures include reproductive aging reflected by clinical measures (ages at menarche and menopause and their difference) as well as molecular markers (AMH measured in the mid- reproductive years and midlife) of gonadal aging; biological aging reflected by epigenetic age deviation (EAD), mitochondrial DNA copy number, and telomere length; and chronological aging reflected by calendar age at outcome. Outcomes include objectively measured and self-reported cognitive function, measures of physical frailty, and cardiometabolic risk factors. We will also examine interactions among reproductive, biological, and chronological aging measures in relation to the outcomes above. This application is directly responsive to NOT-OD-24-079 and addresses high priority research areas of NIA. Its importance derives from its scientific focus on common and highly morbid chronic conditions of aging, whose sex-specific patterns are poorly understood. Results will inform precision estimation of chronic disease risks for women that extend beyond chronological age.
