Senescent cells promote tissue NAD + decline during ageing via the activation of CD38 + macrophages

Nat Metab. 2020 Nov;2(11):1265-1283. doi: 10.1038/s42255-020-00305-3. Epub 2020 Nov 16.

Abstract

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Publication types

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

MeSH terms

  • ADP-ribosyl Cyclase / metabolism
  • ADP-ribosyl Cyclase 1 / genetics*
  • Adipose Tissue, White / metabolism
  • Aging / metabolism*
  • Animals
  • Antigens, CD / metabolism
  • Cellular Senescence*
  • Cytokines / metabolism
  • Female
  • GPI-Linked Proteins / metabolism
  • Gene Expression
  • Glycolysis / genetics
  • Humans
  • Liver / metabolism
  • Macrophage Activation*
  • Male
  • Membrane Glycoproteins / genetics*
  • Metabolome
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • NAD / metabolism*
  • NAD+ Nucleosidase / metabolism

Substances

  • Antigens, CD
  • Cytokines
  • GPI-Linked Proteins
  • Membrane Glycoproteins
  • NAD
  • ADP-ribosyl Cyclase
  • ADP-ribosyl cyclase 2
  • Cd38 protein, mouse
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1