Deletion of enzymes for de novo NAD⁺ biosynthesis accelerated ovarian aging.

Abstract

Recent advances highlight the pivotal role of nicotinamide adenine dinucleotide (NAD⁺ ) in ovarian aging. However, the roles of de novo NAD⁺ biosynthesis on ovarian aging are still unknown. Here, we found that genetic ablation of Ido1 (indoleamine-2,3-dioxygenase 1) or Qprt (Quinolinate phosphoribosyl transferase), two critical genes in de novo NAD⁺ biosynthesis, resulted in decreased ovarian NAD⁺ levels in middle-aged mice, leading to subfertility, irregular estrous cycles, reduced ovarian reserve, and accelerated aging. Moreover, we observed impaired oocyte quality, characterized by increased reactive oxygen species and spindle anomalies, which ultimately led to reduced fertilization ability and impaired early embryonic development. A transcriptomic analysis of ovaries in both mutant and wild-type mice revealed alterations in gene expression related to mitochondrial metabolism. Our findings were further supported by the observation of impaired mitochondrial distribution and decreased mitochondrial membrane potential in the oocytes of knockout mice. Supplementation with nicotinamide riboside (NR), an NAD⁺ booster, in mutant mice increased ovarian reserve and improved oocyte quality. Our study highlights the importance of the NAD⁺ de novo pathway in middle-aged female fertility.