NAD+

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. ^[1] NAD+ is a coenzyme found in all living cells that serves both as a critical coenzyme for enzymes fuelling reduction-oxidation reactions and as a cosubstrate for other enzymes such as the sirtuins and poly(ADP-ribose) polymerases. ^[2] Beyond its classical redox function, NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38, and poly(ADP-ribose) polymerases. ^[1]

NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence, and immune cell function. ^[1] NAD+ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. ^[3] NAD+ biosynthesis is mediated particularly by nicotinamide phosphoribosyltransferase (NAMPT), and NAD+ works together with the NAD+-dependent deacetylase SIRT1 to regulate metabolism and circadian rhythm. ^[4]

Ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. ^[1] This decline in NAD+ levels has been linked to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia, and frailty, and in preclinical settings various strategies to increase NAD+ levels have shown beneficial effects. ^{[1] [5]} In a systematic review of 10 randomized clinical trials with a total of 489 participants across conditions such as chronic fatigue syndrome, Parkinson's disease, and Alzheimer's disease, supplementation with NADH and precursors was well tolerated and had a low incidence of side effects. ^[6] Much about the biology of NAD+ remains poorly understood, and there are ongoing controversies about the limitations, assumptions, and risks of NAD+ supplementation

Many ageing-associated diseases linked to the NAD+ decline can be slowed down and even reversed by restoring NAD+ levels, so targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease and extend healthspan and lifespan. ^[1] Alterations in NAD+ homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes, and cancer. ^[5] The conceptual evolution of NAD+ from a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metabolism and longevity, including the sirtuin family, has driven a competitive race to discover NAD+ boosters to improve healthspan and lifespan. ^[5]