Nicotinamide adenine dinucleotide (NAD⁺): essential redox metabolite, co-substrate and an anti-cancer and anti-ageing therapeutic target

Nicotinamide adenine dinucleotide (NAD⁺) and its reduced form NADH are essential coupled redox metabolites that primarily promote cellular oxidative (catabolic) metabolic reactions. This enables energy generation through glycolysis and mitochondrial respiration to support cell growth and survival. In addition, many key enzymes that regulate diverse cell functions ranging from gene expression to proteostasis require NAD⁺ as a co-substrate for their catalytic activity. This includes the NAD⁺-dependent sirtuin family of protein deacetylases and the PARP family of DNA repair enzymes. Whilst their vital activity consumes NAD⁺ which is cleaved to nicotinamide, several pathways exist for re-generating NAD⁺ and sustaining NAD⁺ homeostasis. However, there is growing evidence of perturbed NAD⁺ homeostasis and NAD⁺-regulated processes contributing to multiple disease states. NAD⁺ levels decline in the human brain and other organs with age and this is associated with neurodegeneration and other age-related diseases. Dietary supplementation with NAD⁺ precursors is being investigated to counteract this. Paradoxically, many cancers have increased dependency on NAD⁺. Clinical efforts to exploit this have so far shown limited success. Emerging new opportunities to exploit dysregulation of NAD⁺ metabolism in cancers are critically discussed. An update is also provided on other key NAD⁺ research including perturbation of the NAD⁺ salvage enzyme NAMPT in the context of the tumour microenvironment (TME), methodology to study subcellular NAD⁺ dynamics in real-time and the regulation of differentiation by competing NAD⁺ pools.