The stromal microenvironment and ovarian aging: mechanisms and therapeutic opportunities

For decades, most studies of ovarian aging have focused on its functional units, known as follicles, which include oocytes and granulosa cells. However, in the ovarian stroma, there are a variety of somatic components that bridge the gap between general aging and ovarian senescence. Physiologically, general cell types, microvascular structures, extracellular matrix, and intercellular molecules affect folliculogenesis and corpus luteum physiology alongside the ovarian cycle. As a result of damage caused by age-related metabolite accumulation and external insults, the microenvironment of stromal cells is progressively remodeled, thus inevitably perturbing ovarian physiology. With the established platforms for follicle cryopreservation and in vitro maturation and the development of organoid research, it is desirable to develop strategies to improve the microenvironment of the follicle by targeting the perifollicular environment. In this review, we summarize the role of stromal components in ovarian aging, describing their age-related alterations and associated effects. Moreover, we list some potential techniques that may mitigate ovarian aging based on their effect on the stromal microenvironment.