Unveiling uterine aging: Much more to learn

Uterine aging is an important factor that impacts fertility, reproductive health, and uterus-related diseases; however, it remains poorly explored. Functionally, these disturbances have been associated with an abnormal hormonal response in the endometrium and decreased endometrial receptivity. Based on emerging evidence, these alterations are mediated via the senescence of endometrial stem cells and impaired decidualization of endometrial stromal cells. Multiple molecular activities may participate in uterine aging, including oxidative stress, inflammation, fibrosis, DNA damage response, and cellular senescence. Over the past decade, several protective strategies targeting these biological processes have afforded promising results, including stem cell therapy, anti-aging drugs, and herbal medicines. However, the currently available evidence is fragmented and scattered. Here, we summarize the most recent findings regarding uterine aging, including functional and structural alterations and potential cellular and molecular mechanisms, and discuss potential protective interventions against uterine aging. Thereby, we hope to provide a comprehensive understanding of the pathophysiological processes and underlying mechanisms associated with uterine aging, as well as improve fecundity and reproductive outcomes in females of advanced reproductive age.