Abstract
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.
Highlights
Female fertility declines dramatically with age, primarily due to the loss of oocyte number and quality (Findlay et al, 2018)
For Nlrp3−/− mice, the concentration of TNF-α and IL-18 in serum at 18 months, and IL-6 at all ages, was not determined due to lack of serum availability. These data indicate that deletion of adaptor protein ASC, but not NLR Family Pyrin Domain Containing 3 (NLRP3), attenuates the levels of systemic inflammatory cytokines observed in mice during reproductive aging
Recent studies have suggested that the NLRP3 inflammasome has a major influence on inflammaging, which is proposed to underlie a range of pathologies associated with the normal aging process (Goldberg and Dixit, 2015; Latz and Duewell, 2018)
Summary
Female fertility declines dramatically with age, primarily due to the loss of oocyte number and quality (Findlay et al, 2018). A woman’s lifetime supply of oocytes is stored in her ovaries in structures called primordial follicles. Most primordial follicles are dormant, but a few at a time become activated to begin folliculogenesis, which is characterized by growth of the oocyte, plus the proliferation, and differentiation of the granulosa cells that support oocyte development. The number of primordial follicles steadily declines as consequence of follicle recruitment, follicle atresia, and the normal aging process. The supply of healthy follicles becomes so low that females become infertile and undergo menopause. In addition to natural ovarian aging, follicles can be depleted much earlier than expected, leading to premature
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