The NAD+/PARP1/SIRT1 Axis in Aging

Rejuvenation Res. 2017 Jun;20(3):244-247. doi: 10.1089/rej.2017.1980.

Abstract

NAD+ levels decline with age in diverse animals from Caenorhabditis elegans to mice. Raising NAD+ levels by dietary supplementation with NAD+ precursors, nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN), improves mitochondrial function and muscle and neural and melanocyte stem cell function in mice, as well as increases murine life span. Decreased NAD+ levels with age reduce SIRT1 function and reduce the mitochondrial unfolded protein response, which can be overcome by NR supplementation. Decreased NAD+ levels cause NAD+-binding protein DBC1 to form a complex with PARP1, inhibiting poly(adenosine diphosphate-ribose) polymerase (PARP) catalytic activity. Old mice have increased amounts of DBC1-PARP1 complexes, lower PARP activity, increased DNA damage, and reduced nonhomologous end joining and homologous recombination repair. DBC1-PARP1 complexes in old mice can be broken by increasing NAD+ levels through treatment with NMN, reducing DNA damage and restoring PARP activity to youthful levels. The mechanism of declining NAD+ levels and its fundamental importance to aging are yet to be elucidated. There is a correlation of PARP activity with mammalian life span that suggests that NAD+/SIRT1/PARP1 may be more significant than the modest effects on life span observed for NR supplementation in old mice. The NAD+/PARP1/SIRT1 axis may link NAD+ levels and DNA damage with the apparent epigenomic DNA methylation clocks that have been described.

Keywords: DBC1/CCAR2; NAD+; PARP1; SIRT1; epigenome.

MeSH terms

  • Aging / metabolism*
  • Animals
  • DNA Damage
  • Humans
  • Mice
  • NAD / metabolism*
  • Poly(ADP-ribose) Polymerases / metabolism*
  • Signal Transduction*
  • Sirtuin 1 / metabolism*

Substances

  • NAD
  • Poly(ADP-ribose) Polymerases
  • Sirtuin 1