WALS: Mechanisms of Ovarian Aging: A Target for Geroprotection in Women

The ovary is the first organ to undergo early-onset aging in the human body, with profound consequences for both fertility and overall health in women. However, the biological mechanisms driving ovarian aging remain poorly understood. To understand the molecular, cellular, and genetic basis of ovarian aging in humans, we performed integrative single-nucleus multi-omics analyses of young and reproductively aged human ovaries, uncovering coordinated changes in gene regulation across all ovarian cell types. We found that ovarian aging is marked by transcriptomic and chromatin accessibility signatures of the canonical Hallmarks of Aging. By integrating our multi-omics data with genome-wide association study (GWAS) variants linked to age at natural menopause, we demonstrate how functional genetic variants shape gene regulatory networks across ovarian cell types. Our work provides a comprehensive multimodal landscape of human ovarian aging and mechanistic insights into inherited variation influencing the timing of menopause. Our results raise the hope that geroprotectors targeting the “Hallmarks of Aging” may be used to delay ovarian aging, thereby promoting reproductive health and extending healthspan and longevity in women. Building on this research, we have initiated a clinical trial (NCT05836025) to test low-dose rapamycin, a well-known geroprotector, as an intervention strategy against aging in the ovary to explore the potential for rapamycin to delay ovarian aging and improve reproductive health.