Nicotinamide adenine dinucleotide, in its oxidized (NAD⁺) and reduced (NADH) forms, is a reduction–oxidation (redox) co-factor and substrate for signalling enzymes that have essential roles in metabolism. The recognition that NAD⁺ levels fall in response to stress and can be readily replenished through supplementation has fostered great interest in the potential benefits of increasing or restoring NAD⁺ levels in humans to prevent or delay diseases and degenerative processes. However, much about the biology of NAD⁺ and related molecules remains poorly understood. In this Review, we discuss the current knowledge of NAD⁺ metabolism, including limitations of, assumptions about and unappreciated factors that might influence the success or contribute to risks of NAD⁺ supplementation. We highlight several ongoing controversies in the field, and discuss the role of the microbiome in modulating the availability of NAD⁺ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), the presence of multiple cellular compartments that have distinct pools of NAD⁺ and NADH, and non-canonical NAD⁺ and NADH degradation pathways. We conclude that a substantial investment in understanding the fundamental biology of NAD⁺, its detection and its metabolites in specific cells and cellular compartments is needed to support current translational efforts to safely boost NAD⁺ levels in humans.

烟酰胺腺嘌呤二核苷酸，以氧化 （NAD⁺） 和还原 （NADH） 形式存在，是一种还原-氧化 （redox） 辅助因子，也是在新陈代谢中起重要作用的信号酶的底物。认识到 NAD⁺ 水平会随着压力而下降，并且可以通过补充剂轻松补充，这引起了人们对增加或恢复人类 NAD⁺ 水平以预防或延缓疾病和退行性过程的潜在好处的极大兴趣。然而，人们对 NAD⁺ 和相关分子的生物学特性知之甚少。在这篇综述中，我们讨论了目前对 NAD⁺ 代谢的了解，包括可能影响 NAD⁺ 补充剂成功或导致风险的局限性、假设和未被重视的因素。我们强调了该领域正在进行的几个争议，并讨论了微生物组在调节 NAD⁺ 前体的可用性中的作用，例如烟酰胺核苷 （NR） 和烟酰胺单核苷酸 （NMN），存在具有不同 NAD⁺ 和 NADH 库的多个细胞区室，以及非经典的 NAD⁺ 和 NADH 降解途径。我们得出的结论是，需要对了解 NAD⁺ 的基础生物学、其检测及其在特定细胞和细胞区室中的代谢物进行大量投资，以支持当前安全提高人类 NAD⁺ 水平的转化工作。