Reduced Akr1b7 signaling drives ovarian aging and reproductive dysfunction

Natural ovarian aging is associated with a progressive decline in female fertility. Here, we comprehensively analyzed RNA expression during ovarian aging in mice during the estrous cycle following ovulation stimulation. The transient activation of the Aldo-keto reductase <i>Akr1b7</i> pathway observed in the ovaries of young mice was absent in older mice. <i>Akr1b7</i> ^-/- mice exhibit attenuated oocyte Akt activation, impaired follicular development, an increased proportion of ovulated immature oocytes, and decreased litter size. The estrous cycle is extended in <i>Akr1b7</i> ^-/- mice due to a prolonged diestrous stage, driven by sustained progesterone levels. This elevation in progesterone was associated with the reduced expression of <i>Cyp17a1</i>, a progesterone-metabolizing enzyme in the <i>Akr1b7</i>-positive theca cell layers. Together, these findings identify <i>Akr1b7</i> as a regulator of ovarian signaling, hormone homeostasis, and reproductive function, with the disruption of this pathway producing phenotypes associated with declining fertility.