Summary Nicotinamide Adenine Dinucleotide (NAD) levels decrease during aging, and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.

Purpose Here, we describe a novel interplay between NAD synthesis and degradation involved in pancreatic tumor growth. Experimental Design We used human pancreatic cancer cells both in vitro (cell culture experiments) and in vivo (xenograft experiments) to demonstrate the role of NAD synthesis and degradation in tumor cell metabolism and growth. Results We demonstrated that pharmacological and genetic targeting of Nampt, the key enzyme in the NAD salvage synthesis pathway, inhibits cell growth and survival of pancreatic cancer cells. These changes were accompanied by a reduction of NAD levels, glycolytic flux, lactate production, mitochondrial function, and levels of ATP. The massive reduction in overall metabolic activity induced by Nampt inhibition was accompanied by a dramatic decrease in pancreatic tumor growth. The results of the mechanistic experiments showed that neither the NAD-dependent enzymes PARP-1, nor SIRT1 play a significant role on the effect of Nampt inhibition on pancreatic cancer cells. However, we identified a role for the NAD degradation pathway mediated by the NADase CD38 on the sensitivity to Nampt inhibition. The responsiveness to Nampt inhibition is modulated by the expression of CD38; low levels of this enzyme decrease the sensitivity to Nampt inhibition. In contrast, its overexpression decreased cell growth in vitro and in vivo and further increases the sensitivity to Nampt inhibition. Conclusions Our study demonstrates that NAD metabolism is essential for pancreatic cancer cell survival and proliferation and that targeting NAD synthesis via the Nampt pathway could lead to novel therapeutic treatments for pancreatic cancer.

Background: DBC1 is a key regulator of SIRT1 activity, although it is unknown how the SIRT1-DBC1 interaction is regulated. Results: PKA and AMPK activate SIRT1 by disrupting the interaction between SIRT1 and DBC1. Conclusion: We provide mechanistic evidence on how the SIRT1-DBC1 complex is regulated. Significance: The SIRT1-DBC1 complex constitutes a target for the development of drugs to activate SIRT1.