NAD plus therapy in age-related degenerative disorders: A benefit/risk analysis

Nicotinamide adenine dinucleotide (NAD +) is an essential pyridine nucleotide that is present in all living cells. NAD + acts as an important cofactor and substrate for a multitude of biological processes including energy production, DNA repair, gene expression, calcium-dependent secondary messenger signalling and immunoregulatory roles. The de novo synthesis of NAD + is primarily dependent on the kynurenine pathway (KP), although NAD + can also be recycled from nicotinic acid (NA), nicotinamide (NAM) and nicotinamide riboside (NR). NAD + levels have been reported to decline during ageing and age-related diseases. Recent studies have shown that raising intracellular NAD + levels represents a promising therapeutic strategy for age-associated degenerative diseases in general and to extend lifespan in small animal models. A systematic review of the literature available on Medline, Embase and Pubmed was undertaken to evaluate the potential health and/or longevity benefits due to increasing NAD + levels. A total of 1545 articles were identified and 147 articles (113 preclinical and 34 clinical) met criteria for inclusion. Most studies indicated that the NAD + precursors NAM, NR, nicotinamide mononucleotide (NMN), and to a lesser extent NAD + and NADH had a favourable outcome on several age-related disorders associated with the accumulation of chronic oxidative stress, inflammation and impaired mitochondrial function. While these compounds presented with a limited acute toxicity profile, evidence is still quite limited and long-term human clinical trials are still nascent in the current literature. Potential risks in raising NAD + levels in various clinical disorders using NAD + precursors include the accumulation of putative toxic metabolites, tumorigenesis and promotion of cellular senescence. Therefore, NAD + metabolism represents a promising target and further studies are needed to recapitulate the preclinical benefits in human clinical trials.