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

Exp Gerontol. 2020 Apr;132:110831. doi: 10.1016/j.exger.2020.110831. Epub 2020 Jan 7.

Abstract

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.

Keywords: Ageing; Cellular energetics; NAD+; Nicotinamide; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Aging / metabolism*
  • Animals
  • Humans
  • Inflammation / metabolism
  • Mice
  • NAD / metabolism*
  • Neurodegenerative Diseases / metabolism
  • Niacinamide / analogs & derivatives
  • Niacinamide / metabolism
  • Nicotinamide Mononucleotide / metabolism
  • Oxidative Stress
  • Pyridinium Compounds
  • Rats
  • Risk Assessment

Substances

  • Pyridinium Compounds
  • nicotinamide-beta-riboside
  • NAD
  • Nicotinamide Mononucleotide
  • Niacinamide