NAD+ repletion with niacin counteracts cancer cachexia

Abstract

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 confirmed that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of different mouse models and cachectic cancer patients. Testing NAD+ repletion therapy in cachectic mice revealed that NAD+ precursor, vitamin B3 niacin, efficiently corrected tissue NAD+ levels, improved mitochondrial metabolism and ameliorated cancer- and chemotherapy-induced cachexia. To examine NAD+ metabolism in a clinical setting, we showed that the low expression of NRK2 in cancer patients correlated with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose a novel therapy target, NAD+ metabolism, for cachectic cancer patients.