Reproductive ageing in females is defined by a progressive decline in follicle number and oocyte quality. This is a natural process that leads to the loss of fertility and ovarian function, cycle irregularity and eventually menopause or reproductive senescence. The factors that underlie the natural depletion of follicles throughout reproductive life are poorly characterised. It has been proposed that inflammatory processes and fibrosis might contribute to ovarian ageing. To further investigate this possibility, we evaluated key markers of inflammation and immune cell populations in the ovaries of 2, 6, 12 and 18-month-old C57BL/6 female mice. We report that the decrease in follicle numbers over the reproductive lifespan was associated with an increase in the intra-ovarian percentage of CD4 + T cells, B cells and macrophages. Serum concentration and intra-ovarian mRNA levels of several pro-inflammatory cytokines, including IL-1α/β, TNF-α, IL-6, and inflammasome genes ASC and NLRP3, were significantly increased with age. Fibrosis levels, as determined by picrosirius red staining for collagen I and III, were unchanged up to 18 months of age. Collectively, these data suggest that inflammation could be one of the mechanisms responsible for the age-related regulation of follicle number, but the role of fibrosis is unclear. Further studies are now required to determine if there is a causative relationship between inflammation and follicle depletion as females age.

Ovarian aging is a natural process characterized by follicular depletion and a reduction in oocyte quality, resulting in loss of ovarian function, cycle irregularity and eventually infertility and menopause. The factors that contribute to ovarian aging have not been fully characterized. Activation of the NLRP3 inflammasome has been implicated in age-associated inflammation and diminished function in several organs. In this study, we used Asc−/− and Nlrp3−/− mice to investigate the possibility that chronic low-grade systemic inflammation mediated by the inflammasome contributes to diminished ovarian reserves as females age. Pro-inflammatory cytokines, IL-6, IL-18, and TNF-α, were decreased in the serum of aging Asc−/− mice compared to WT. Within the ovary of reproductively aged Asc−/− mice, mRNA levels of major pro-inflammatory genes Tnfa, Il1a, and Il1b were decreased, and macrophage infiltration was reduced compared to age-matched WT controls. Notably, suppression of the inflammatory phenotype in Asc−/− mice was associated with retention of follicular reserves during reproductive aging. Similarly, the expression of intra-ovarian pro-inflammatory cytokines was reduced, and follicle numbers were significantly elevated, in aging Nlrp3−/− mice compared to WT controls. These data suggest that inflammasome-dependent inflammation contributes to the age-associated depletion of follicles and raises the possibility that ovarian aging could be delayed, and fertile window prolonged, by suppressing inflammatory processes in the ovary.