Senotherapeutic strategies for ovarian aging: Mechanistic insights and translational perspectives.

Ovarian aging manifests as progressive depletion of the primordial follicle reserve and declining oocyte quality, culminating in menopause and associated systemic comorbidities. Cellular senescence emerges as a central driver of this process, exerting effects through cell-cycle arrest pathways and a proinflammatory senescence-associated secretory phenotype (SASP) that disrupts the follicular niche and stromal architecture. However, current senolytic and senomorphic interventions for ovarian aging remain largely at the mechanistic and preclinical stages, and their translational potential in humans is still uncertain. This review synthesizes the molecular hallmarks of ovarian senescence-encompassing genomic instability, mitochondrial dysfunction, dysregulated nutrient sensing (PI3K/AKT/mTOR), proteostatic failure, epigenetic drift, and inflammasome activation-into a unified framework for therapeutic intervention. We critically evaluate the preclinical efficacy of senolytics (eg, dasatinib + quercetin, navitoclax, fisetin), and senomorphics (eg, rapamycin, metformin, melatonin, NLRP3 inhibitors) in preserving ovarian reserve, mitigating SASP-driven inflammation and fibrosis, and extending reproductive lifespan. Emphasis is placed on multimodal biomarkers (AMH, AFC, SASP analytes, follicular fluid signatures, exosomal RNAs) essential for clinical translation, alongside ovary-directed delivery systems to enhance specificity and safety. By bridging ovarian geroscience with emerging senotherapeutics, this review charts a roadmap for advancing these strategies from bench to bedside, offering potential to combat ovarian aging and safeguard women's reproductive and systemic health.