NAD(+) metabolism: Bioenergetics, signaling and manipulation for therapy

Biochim Biophys Acta. 2016 Dec;1864(12):1787-1800. doi: 10.1016/j.bbapap.2016.06.014. Epub 2016 Jun 29.


We survey the historical development of scientific knowledge surrounding Vitamin B3, and describe the active metabolite forms of Vitamin B3, the pyridine dinucleotides NAD+ and NADP+ which are essential to cellular processes of energy metabolism, cell protection and biosynthesis. The study of NAD+ has become reinvigorated by new understandings that dynamics within NAD+ metabolism trigger major signaling processes coupled to effectors (sirtuins, PARPs, and CD38) that reprogram cellular metabolism using NAD+ as an effector substrate. Cellular adaptations include stimulation of mitochondrial biogenesis, a process fundamental to adjusting cellular and tissue physiology to reduced nutrient availability and/or increased energy demand. Several mammalian metabolic pathways converge to NAD+, including tryptophan-derived de novo pathways, nicotinamide salvage pathways, nicotinic acid salvage and nucleoside salvage pathways incorporating nicotinamide riboside and nicotinic acid riboside. Key discoveries highlight a therapeutic potential for targeting NAD+ biosynthetic pathways for treatment of human diseases. A recent emergence of understanding that NAD+ homeostasis is vulnerable to aging and disease processes has stimulated testing to determine if replenishment or augmentation of cellular or tissue NAD+ can have ameliorative effects on aging or disease phenotypes. This experimental approach has provided several proofs of concept successes demonstrating that replenishment or augmentation of NAD+ concentrations can provide ameliorative or curative benefits. Thus NAD+ metabolic pathways can provide key biomarkers and parameters for assessing and modulating organism health.

Keywords: NADH; Nicotinamide adenine dinucleotide; Nicotinamide riboside; Nicotinic acid riboside; Tryptophan; Vitamin B3.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Energy Metabolism
  • Humans
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / therapy
  • Metabolic Networks and Pathways
  • Models, Biological
  • NAD / metabolism*
  • NADP / metabolism
  • Niacin / metabolism
  • Niacinamide / metabolism
  • Nucleosides / metabolism
  • Signal Transduction
  • Sirtuins / metabolism
  • Tryptophan / metabolism


  • Nucleosides
  • NAD
  • Niacinamide
  • Niacin
  • NADP
  • Tryptophan
  • Sirtuins