Regulation of and Challenges in Targeting NAD Metabolism

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.