Immune-metabolic-endocrine crosstalk in ovarian aging: mechanisms, biomarkers, and translational opportunities

Ovarian aging has traditionally been attributed to follicular depletion and declining sex hormone production. However, accumulating evidence suggests that it is associated with broader changes across immune, metabolic, and endocrine networks. Positioned at the intersection of these regulatory systems, the ovary responds to signals from multiple organs and systemic pathways, which may contribute to the progression of ovarian aging. In this review, we propose that ovarian aging may be conceptualized as a progressive reorganization of immune–metabolic–endocrine regulation. At the intraovarian level, metabolic stress and mitochondrial dysfunction are associated with inflammatory signaling, cellular senescence, and impaired steroidogenesis. At the systemic level, signals from the brain, adipose tissue, intestine, bone, and skeletal muscle may influence ovarian function through metabolic, immune, and endocrine pathways. Cytokines, growth factors, and metabolic mediators have been implicated in linking local ovarian changes with systemic physiological processes. This network-based perspective may provide a framework for understanding the heterogeneity of ovarian aging and the limitations of individual biomarkers. Emerging therapeutic strategies targeting inflammatory signaling, metabolic pathways, and cytokine-mediated regulation may offer potential approaches for improving the assessment and management of ovarian aging.