Reproductive Ageing: Inflammation, immune cells, and cellular senescence in the aging ovary

Abstract

In brief: Recent reports suggest a relationship between ovarian inflammation and functional declines, although it remains unresolved if ovarian inflammation is the cause or consequence of ovarian aging. In this review, we compile the available literature in this area and point to several current knowledge gaps that should be addressed through future studies.

Abstract: Ovarian aging results in reduced fertility, disrupted endocrine signaling, and an increased burden of chronic diseases. The factors contributing to the natural decline of ovarian follicles throughout reproductive life are not fully understood. Nevertheless, local inflammation may play an important role in driving ovarian aging. Inflammation progressively rises in aged ovaries during the reproductive window, potentially affecting fertility. In addition to inflammatory markers, recent studies show an accumulation of specific immune cell populations in aging ovaries, particularly lymphocytes. Other hallmarks of the aging ovary include the formation and accumulation of multinucleated giant cells, increased collagen deposition, and increased markers of cellular senescence. Collectively, these changes significantly impact the quantity and quality of ovarian follicles and oocytes. This review explores recent literature on the alterations associated with inflammation, fibrosis, cell senescence, and the accumulation of immune cells in the aging ovary.

Figure 1

Schema of age-related changes in ovarian cellularity and biomarkers of functional declines. Ovarian aging is characterized by a decline in follicular reserve and an increase in pro-inflammatory mediators, collagen deposition, oxidative stress, mitochondrial dysfunction, and accumulation of multinucleated giant cells. Some reports suggest that senescent cells accumulate in the aged ovary. Recent findings indicate that these hallmarks of ovarian aging correspond to changes in immune cellularity. The ratio of alternatively activated to classically activated macrophages increases with age and type 1 and type 17 T lymphocytes accumulate in parallel. It remains unclear if the changes in immune cell populations underlie the aforementioned ovarian aging hallmarks. Therefore, additional studies are needed to disentangle this potential relationship. This figure was created with Biorender.com.