Macrophage polarization in ovarian inflammaging: mechanisms, mediators, and therapeutic targets

Ovarian aging is characterized by progressive follicle depletion, declining oocyte quality, and transition into menopause. Increasing evidence suggests that chronic low-grade inflammation, termed “inflammaging,” contributes to this process, with macrophages representing a major immune cell population in the ovarian microenvironment. This review examines the cellular and molecular mechanisms by which macrophage polarization may contribute to ovarian inflammaging. We integrate findings from single-cell transcriptomics, spatial analyses, genetic mouse models, and interventional studies to summarize macrophage ontogeny, phenotypic transitions, upstream signaling pathways, downstream cellular effects, and therapeutic implications. Available studies support age-associated changes in ovarian macrophage composition and signaling, including shifts in resident-like and monocyte-derived programs, increased pyroptosis-associated signatures, and accumulation of multinucleated giant cells in aged stroma. Candidate upstream pathways include cGAS-STING signaling, the NLRP3 inflammasome, and the S100A8/A9-TLR4-NF-kB axis. Downstream, macrophage-associated inflammatory signaling has been linked to granulosa-cell dysfunction, fibroinflammatory stromal remodeling, and altered follicular homeostasis. Environmental exposures such as microplastics, particulate matter, and metabolic stress may further amplify these processes in experimental models. Macrophage polarization is an important and potentially modifiable component of ovarian aging biology. Pharmacologic, metabolic, and extracellular-vesicle-based interventions have shown preclinical promise, but most evidence remains model-specific and requires further validation in human ovarian aging. Single-cell and spatial approaches are likely to refine mechanistic understanding and guide future biomarker and therapeutic development.