Ovarian aging: Mechanisms and strategies to extend reproductive lifespan

Ovarian aging, a critical challenge to contemporary female reproductive health, has gained increasing prominence due to the global trend of postponed childbearing. This phenomenon not only induces an irreversible decline in female fertility but also strongly correlates with the risk of various chronic diseases, such as osteoporosis and cardiovascular disorders. The pathogenesis of ovarian aging is multifactorial, involving excessive activation and depletion of the primordial follicle pool, decline in oocyte quality linked to chromosomal and mitochondrial abnormalities, genomic instability, epigenetic alterations, chronic inflammation, and fibrosis within the ovarian microenvironment. Through these mechanisms, ovarian aging heightens the risk of miscarriage and offspring anomalies, including aneuploidy, thereby underscoring its consequences to intergenerational health. Although various countermeasures exist, such as lifestyle modifications, antioxidant use, fertility preservation technologies, hormone replacement and emerging stem cell therapies, and senolytic medications, most are limited to delaying or compensating for reproductive functions and are unable to truly reverse the aging process. Future research should focus on leveraging cutting-edge technologies, including high-resolution spatiotemporal omics and artificial intelligence, to comprehensively dissect the underlying mechanisms involved. This could involve the development of ovarian-specific aging clocks and the advancement of individualized, combinatorial precision intervention strategies, with the ultimate objective of significantly extending female reproductive longevity and safeguarding overall health across generations.