Decoding the immune regulation of ovarian aging: mechanisms and therapeutic strategies.

Abstract

Ovarian aging is among the earliest functional declines in humans and acts as a pacemaker of female aging. It encompasses both physiological age-related ovarian decline and pathological accelerated aging, exemplified by premature ovarian insufficiency (POI). Increasing evidence positions the immune system as both a regulator of ovarian homeostasis and a driver of ovarian dysfunction. Age-related immunosenescence and chronic low-grade inflammation (inflammaging) coordinately drive ovarian aging through bidirectional crosstalk between systemic immunity and the ovarian immune microenvironment. POI frequently coexists with autoimmune disorders, reinforcing the central role of the immune-ovarian axis in reproductive aging. Elucidating this interplay may enable targeted immunomodulatory strategies to preserve reproductive longevity and mitigate systemic consequences of ovarian decline. The aim was to synthesize current evidence on (i) immune regulation of normal ovarian physiology; (ii) immune alterations in physiological ovarian aging, including systemic immunosenescence and ovarian immune microenvironment remodelling; (iii) autoimmune dysregulation in POI; and (iv) the translational potential of immunomodulatory interventions for mitigating ovarian aging. Original articles published up to April 2026 were identified through PubMed using combinations of the terms 'immune system', 'ovarian function', 'inflammation', 'immune cell', 'ovarian aging', 'menopause', 'primary ovarian insufficiency', and 'therapeutics'. Immune cells and cytokine networks form a specialized regulatory axis that governs folliculogenesis, ovulation, and luteal dynamics. This review synthesizes emerging evidence showing that this immune-ovary axis undergoes profound remodelling during reproductive aging and that immune dysregulation is a causal driver of ovarian functional decline. Systemically, the menopausal transition accelerates immunosenescence and amplifies pro-inflammatory cytokine production. Locally, the aging ovary exhibits chronic inflammation, NLRP3 inflammasome activation, and accumulation of senescent cells with a senescence‑associated secretory phenotype. These changes coincide with a shift from tissue‑resident to monocyte‑derived macrophages and expansion of inflammatory γδ and double‑negative T cells. This progressive loss of immune homeostasis promotes follicular depletion, stromal fibrosis, and impaired steroidogenesis. POI represents a pathological extreme of this axis, characterized by autoimmune comorbidities, B cell-driven humoural abnormalities, T cell dysregulation, and genetic variants affecting immune pathways. Comparative analysis reveals both conserved inflammatory signatures shared with physiological aging and POI-specific immune features that reflect overt immune-mediated ovarian injury. By integrating systemic, local, and disease-specific immune mechanisms, this review reframes ovarian aging as a modifiable immunological process. Therapeutically, emerging immunomodulatory strategies range from molecular agents targeting inflammatory mediators and senescence programs, through cell-based immune reprogramming with stem cells, regulatory T cells, and senolytic immune effectors, to lifestyle-driven systemic immunomodulation. These strategies show promise in restoring ovarian immune homeostasis and extending the reproductive lifespan, with several of these approaches now advancing toward early-phase clinical evaluation. Collectively, the current evidence positions immune dysregulation as a mechanistic driver, rather than a secondary correlate, of ovarian aging. Integrating immune biomarkers into predictive frameworks and designing stratified immunomodulatory trials may shift ovarian aging management from symptomatic hormone replacement toward mechanism-based intervention. Reframing ovarian aging as a modifiable immune-mediated process offers new opportunities to extend female reproductive longevity and the female health span. N/A.