Journal
NATURE METABOLISM
Volume 2, Issue 11, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-020-00298-z
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Funding
- Helen Diller Family Foundation
- Ted Nash Long Life Foundation
- Glenn Foundation for Medical Research via the Paul F. Glenn Laboratories for the Biology of Aging at the Mayo Clinic from Calico Life Sciences
- Mayo Foundation
- Noaber Foundation
- NIH National Institute of Aging (NIA) [AG-26094, AG58812, CA233790, AG13925, AG057493, AG016694, P01 AG051449]
- National Institute of Diabetes, Digestive and Kidney disease [DK098656]
- Connor Group
- Colton Center for Auto-Immunity at NYU Langone
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Decreased NAD(+) levels have been shown to contribute to metabolic dysfunction during aging. NAD(+) decline can be partially prevented by knockout of the enzyme CD38. However, it is not known how CD38 is regulated during aging, and how its ecto-enzymatic activity impacts NAD(+) homeostasis. Here we show that an increase in CD38 in white adipose tissue (WAT) and the liver during aging is mediated by accumulation of CD38(+) immune cells. Inflammation increases CD38 and decreases NAD(+). In addition, senescent cells and their secreted signals promote accumulation of CD38(+) cells in WAT, and ablation of senescent cells or their secretory phenotype decreases CD38, partially reversing NAD(+) decline. Finally, blocking the ecto-enzymatic activity of CD38 can increase NAD(+) through a nicotinamide mononucleotide (NMN)-dependent process. Our findings demonstrate that senescence-induced inflammation promotes accumulation of CD38 in immune cells that, through its ecto-enzymatic activity, decreases levels of NMN and NAD(+). Chini et al. demonstrate that CD38(+) expression in immune cells increases during aging, owing to the senescence-associated secretory phenotype of senescent cells, and the ecto-enzymatic activity of CD38(+) affects intracellular NAD(+) levels in vivo by hydrolyzing the NAD(+) intermediate nicotinamide mononucleotide extracellularly.
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