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.