Nicotinamide Riboside Supplementation Alleviates Testicular Aging Induced by Disruption of Qprt‐Dependent NAD+ De Novo Synthesis in Mice

ABSTRACT Recent studies have shown that disruptions in the nicotinamide adenine dinucleotide (NAD + ) de novo synthesis pathway accelerate ovarian aging, yet its role in spermatogenesis remains largely unknown. In this study, we investigated the impact of the NAD + de novo synthesis pathway on spermatogenesis by generating Qprt ‐deficient mice using CRISPR‐Cas9 to target quinolinate phosphoribosyl transferase ( Qprt ), a key enzyme predominantly expressed in spermatocytes. Our results revealed that the deletion of Qprt did not affect NAD + levels or spermatogenesis in the testes of 3‐month‐old mice. However, from 6 months of age onward, Qprt ‐deficient mice exhibited significantly reduced NAD + levels in the testes compared to wild‐type (WT) controls, along with a notable decrease in germ cell numbers and increased apoptosis. Additionally, these mice demonstrated mitochondrial dysfunction in spermatocytes, impaired progression through prophase I of meiosis, defective double‐strand break (DSB) repair, and abnormal meiotic sex chromosome inactivation. Importantly, supplementation with the NAD + precursor nicotinamide riboside (NR) in Qprt ‐deficient mice restored NAD + levels and rescued the spermatogenic defects. These findings underscore the critical role of NAD + de novo synthesis in maintaining NAD + homeostasis and highlight its importance in meiotic recombination and meiotic sex chromosome inactivation in spermatogenesis.