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 Akr1b7 pathway observed in the ovaries of young mice was absent in older mice. Akr1b7 ^-/- 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 Akr1b7 ^-/- mice due to a prolonged diestrous stage, driven by sustained progesterone levels. This elevation in progesterone was associated with the reduced expression of Cyp17a1, a progesterone-metabolizing enzyme in the Akr1b7-positive theca cell layers. Together, these findings identify Akr1b7 as a regulator of ovarian signaling, hormone homeostasis, and reproductive function, with the disruption of this pathway producing phenotypes associated with declining fertility.