Ovarian aging: A central driver of systemic aging in females

Ovarian aging occurs significantly earlier than the overt aging of most somatic organs, indicating that it is not merely a passive consequence of systemic aging but a potential upstream regulator of female organismal decline. This review aims to comprehensively synthesize current evidence on the cellular, molecular, and systemic mechanisms underlying ovarian aging, to clarify how intra-ovarian changes reshape intercellular communication networks, and to elucidate how ovary-derived signals contribute to aging in distant organs. The ovary is a unique organ integrating reproductive and endocrine functions, maintaining a finite follicular reserve while secreting hormones such as estrogen, inhibin, anti-Müllerian hormone, and diverse bioactive factors. Unlike most somatic tissues, ovarian aging begins early, with a marked decline in ovarian reserve typically observed in women in their early thirties. Emerging single-cell and multi-omics studies reveal that ovarian aging is a dynamic, multicellular process involving coordinated dysfunction across oocytes, granulosa cells, theca cells, endothelial cells, stromal cells, immune cells, and neuro-glial networks. These cell types exhibit distinct yet interconnected aging phenotypes, including altered differentiation trajectories, inflammatory activation, fibrosis, and impaired vascular and metabolic support. At the molecular level, four convergent hallmarks dominate: genomic instability, epigenetic and transcriptional reprogramming, loss of proteostasis, and energy metabolic dysfunction. These mechanisms interact to create a self-reinforcing microenvironment characterized by oxidative stress, inflammation, hypoxia, and extracellular matrix remodeling. Critically, ovarian aging disrupts key intra-follicular communication systems—metabolic coupling, paracrine signaling, and steroidogenesis—leading to progressive follicular failure. Beyond the ovary, aging-related endocrine changes, senescence-associated secretory phenotype, and extracellular vesicles act systemically, promoting cardiovascular disease, osteoporosis, neurodegeneration, and metabolic disorders. Both clinical and experimental evidence supports a causal role, with timing-dependent effects observed in interventions such as hormone replacement therapy. We propose that ovarian aging functions as a central regulatory hub in female systemic aging. Future research should focus on high-resolution spatial multi-omics, computational modeling of intercellular networks, and development of human-relevant models such as ovarian organoids. Identifying critical transition points and early biomarkers will be essential for designing precise, time-sensitive interventions aimed at preserving ovarian function and extending female healthspan.