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.