NAD ⁺ Precursors in Human Health and Disease: Current Status and Future Prospects

Significance: Nicotinamide adenine dinucleotide (NAD + ) acts as a cofactor in many important biological processes. The administration of NAD + precursors increases the intracellular NAD + pool and has beneficial effects on physiological changes and diseases associated with aging in various organisms, including rodents and humans. Recent Advances: Evidence from preclinical studies demonstrating the beneficial effects of NAD + precursors has rapidly increased in the last decade. The results of these studies have prompted the development of clinical trials using NAD + precursors, particularly nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). In addition, in vivo studies of NAD + metabolism have rapidly progressed. Critical Issues: Several studies have demonstrated that the oral administration of NAD + precursors, such as NR and NMN, is safe and significantly increases NAD + levels in humans. However, the efficacy of these NAD + precursors is lower than expected from the results of preclinical studies. In addition, the identification of the contribution of the host–gut microbiota interactions to NR and NMN metabolism has added to the complexity of NAD + metabolism. Future Directions: Further studies are required to determine the efficacy of NAD + precursors in humans. Further in vivo studies of NAD + metabolism are required to optimize the effects of NAD + supplementation. There is also a need for methods of delivering NAD + precursors to target organs or tissues to increase the outcomes of clinical trials. Antioxid. Redox Signal. 39, 1133–1149.