CD38 ecto-enzyme in immune cells is induced during aging regulating NAD(+) and NMN levels

Decreased nicotinamide adenine dinucleotide (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 increases in CD38 in white adipose tissue (WAT) and 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 decrease 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(+).