NAD + repletion with niacin counteracts cancer cachexia

Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD + ) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD + and downregulation of Nrk2 , an NAD + biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD + repletion therapy in cachectic mice reveals that NAD + precursor, vitamin B3 niacin, efficiently corrects tissue NAD + levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD + in the pathophysiology of human cancer cachexia. Overall, our results propose NAD + metabolism as a therapy target for cachectic cancer patients.