Ovarian remodeling and aging-related chronic inflammation and fibrosis in the mammalian ovary.

BACKGROUND: The female ovary undergoes constant follicular atresia from birth, as well as ovulation and corpus luteum (CL) regression during reproductive age, leading to recurrent ovarian remodeling and ultimately resulting in ovarian aging. However, aging-related cellular and molecular changes in the ovary remain poorly explored. RESULTS: Using ovarian transcriptomics, we characterized the changes in gene expression in the ovaries of young (2-month-old), middle-aged (6-month-old) and old (12-month-old) mice. Our analyses revealed that the stromal cell markers THY1 and CD44 were significantly upregulated, whereas the markers of oocytes, granulosa cells and theca cells were markedly downregulated in old mice; thus, endocrine dysfunction occurred. We also found that MAPK pathway- and inflammation response-related genes were enriched and that the populations of Tregs, macrophages and NK cells notably decreased in aged ovaries, which was confirmed by flow cytometry. However, during superovulation, the proportions of macrophages and NK cells steadily increased as the follicles developed and ovulated, whereas the proportion of macrophages sharply decreased after ovulation. We further verified these ovarian changes in specific cell markers and rate-limiting enzymes for steroid hormone synthesis by immunohistochemistry (IHC) and collagen deposition by Masson's trichrome staining in pre- and postmenopausal women. CONCLUSIONS: These results from clinical samples demonstrated that aging-associated changes were similar to those observed in mice and were strongly correlated with the age of the woman. Therefore, this report provides critical insights into aging-related cellular and molecular changes in the ovary.