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

Anthony J. Covarrubias, Abhijit Kale, Rosalba Perrone, Jose Alberto Lopez-Dominguez, Angela Oliveira Pisco, Herbert G. Kasler, Mark S. Schmidt, Indra Heckenbach, Ryan Kwok, Christopher D. Wiley, Hoi Shan Wong, Eddy Gibbs, Shankar S. Iyer, Nathan Basisty, Qiuxia Wu, Ik Jung Kim, Elena Silva, Kaitlyn Vitangcol, Kyong Oh Shin, Yong Moon LeeRebeccah Riley, Issam Ben-Sahra, Melanie Ott, Birgit Schilling, Morten Scheibye-Knudsen, Katsuhiko Ishihara, Stephen R. Quake, John Newman, Charles Brenner, Judith Campisi, Eric Verdin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1265-1283
Number of pages19
JournalNature Metabolism
Volume2
Issue number11
DOIs
StatePublished - Nov 2020

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Cell Biology
  • Physiology (medical)

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