CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

Cell Metab. 2016 Jun 14;23(6):1127-1139. doi: 10.1016/j.cmet.2016.05.006.

Abstract

Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.

Keywords: CD38; NAD(+); aging; glucose intolerance; mitochondrial function.

Publication types

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

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism*
  • Aging / metabolism*
  • Animals
  • Diet, High-Fat
  • Mammals / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism*
  • Mitochondria / ultrastructure
  • NAD / metabolism*
  • NAD+ Nucleosidase / genetics
  • NAD+ Nucleosidase / metabolism
  • Niacinamide / analogs & derivatives
  • Niacinamide / metabolism
  • Organ Specificity
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Sirtuin 3 / metabolism*

Substances

  • RNA, Messenger
  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1
  • Sirtuin 3