Tissue-specific effects of exercise as NAD⁺-boosting strategy: current knowledge and future perspectives

Nicotinamide adenine dinucleotide (NAD⁺) is an evolutionarily highly conserved coenzyme with multi-faceted cell functions, including energy metabolism, molecular signaling processes, epigenetic regulation, and DNA repair. Since the discovery that lower NAD⁺ levels are a shared characteristic of various diseases and aging per se, several NAD⁺-boosting strategies have emerged. Other than pharmacological and nutritional approaches, exercise is thought to restore NAD⁺ homeostasis through metabolic adaption to chronically recurring states of increased energy demand. In this review we discuss the impact of acute exercise and exercise training on tissue-specific NAD⁺ metabolism of rodents and humans to highlight the potential value as NAD⁺-boosting strategy. By interconnecting results from different investigations, we aim to draw attention to tissue-specific alterations in NAD⁺ metabolism and the associated implications for whole-body NAD⁺ homeostasis. Acute exercise led to profound alterations of intracellular NAD⁺ metabolism in various investigations, with the magnitude and direction of changes being strongly dependent on the applied exercise modality, cell type, and investigated animal model or human population. Exercise training elevated NAD⁺ levels and NAD⁺ metabolism enzymes in various tissues. Based on these results, we discuss molecular mechanisms that might connect acute exercise-induced disruptions of NAD⁺/NADH homeostasis to chronic exercise adaptions in NAD⁺ metabolism. Taking this hypothesis-driven approach, we hope to inspire future research on the molecular mechanisms of exercise as NAD⁺-modifying lifestyle intervention, thereby elucidating the potential therapeutic value in NAD⁺-related pathologies.