Impairment of an Endothelial NAD +-H 2 S Signaling Network Is a Reversible Cause of Vascular Aging

Cell. 2018 Mar 22;173(1):74-89.e20. doi: 10.1016/j.cell.2018.02.008.

Abstract

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.

Keywords: NAD(+); aging; angiogenesis; endurance; exercise; hydrogen sulfide; ischemia; nicotinamide mononucleotide; sirtuins; skeletal muscle capillaries.

Publication types

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

MeSH terms

  • Aging*
  • Animals
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism
  • Humans
  • Hydrogen Sulfide / metabolism*
  • Mice
  • Mice, Knockout
  • Microvessels / metabolism
  • Mitochondria / metabolism
  • Muscle, Skeletal / metabolism
  • NAD / metabolism*
  • Neovascularization, Physiologic
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / metabolism
  • Physical Conditioning, Animal
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Receptors, Notch / metabolism
  • Signal Transduction
  • Sirtuin 1 / antagonists & inhibitors
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • RNA, Small Interfering
  • Receptors, Notch
  • Vascular Endothelial Growth Factor A
  • NAD
  • Sirtuin 1
  • Hydrogen Sulfide