Ovarian aging accelerates through cellular senescence cascades: primordial follicle depletion, SASP-driven stromal inflammation, mitochondrial dysfunction, PI3K/AKT/mTOR nutrient-sensing dysregulation, epigenetic drift, and NLRP3 inflammasome activation collectively collapse the follicular niche. This review systematically maps senolytic agents—dasatinib+quercetin, navitoclax, fisetin—and senomorphics—rapamycin, metformin, melatonin—against these pathways, evaluating their preclinical capacity to preserve ovarian reserve, suppress SASP-mediated fibrosis, and extend measurable reproductive function in animal models.
The significance here extends well beyond fertility. Ovarian senescence is increasingly recognized as a pacemaker for systemic female aging—accelerated cardiovascular risk, bone loss, and cognitive decline track closely with follicular exhaustion, not merely chronological age. That framing makes ovarian geroscience a genuinely strategic longevity target, not a niche reproductive medicine concern. However, this is a narrative review, not a clinical trial, and the translational gap remains wide: nearly all mechanistic evidence is preclinical, dosing regimens optimized for mice are poorly validated in women, and systemic senolytics carry meaningful off-target toxicity risks that ovary-directed delivery systems aim—but have not yet managed—to solve. Biomarkers proposed for clinical translation (AMH, AFC, exosomal RNAs, follicular fluid SASP analytes) are promising but lack prospective validation as senotherapy endpoints. For now, this review's value is architectural—it integrates scattered mechanistic threads into a coherent intervention framework—rather than immediately actionable. Incremental but strategically important.
