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

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.