Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase CD38 has a central role in age-related NAD decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e CD38 inhibitor, 78c, reverses age-related NAD decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD levels and were reversed by inhibition of NAD synthesis. 78c increased NAD levels, resulting in activation of pro-longevity and health span-related factors, including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD decline and subsequent metabolic dysfunction.

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 + .

Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by CD38 enzymatic activity. In addition, CD38 has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti-CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.