Long-Term Administration of Nicotinamide Mononucleotide Mitigates High-Fat-Diet-Induced Physiological Decline in Aging Mice

Background: Nicotinamide adenine dinucleotide (NAD+) levels decline with age, and boosting it can improve multi-organ functions and lifespan. Objectives: Nicotinamide mononucleotide (NMN) is a natural NAD+ precursor with the ability to enhance NAD+ biosynthesis. Numerous studies have shown that a high-fat diet (HFD) can accelerate the process of aging and many diseases. We hypothesized that long-term administration of NMN could exert protective effects on adipose, muscle, and kidney tissues in mice on an HFD act by affecting the autophagic pathway. Methods: Mice at 14 mo of age were fed an HFD, and NMN was added to their drinking water at a dose of 400 mg/kg for 7 mo. The locomotor ability of the mice was assessed by behavioral experiments such as grip test, wire hang test, rotarod, and beam-walking test. At the end of the behavioral experiments, the pathological changes of each peripheral organ and the expression of autophagy-related proteins, as well as the markers of the senescence and inflammaging were analyzed by pathological staining, immunohistochemical staining, and western blotting, respectively. Results: We found that NMN supplementation increased NAD+ levels and ultimately attenuated age- and diet-related physiological decline in mice. NMN inhibited HFD-induced obesity, promoted physical activity, improved glucose and lipid metabolism, improved skeletal muscle function and renal damage, as well as mitigated the senescence and inflammaging as demonstrated by p16, interleukin 1 beta, and tumor necrosis factor alpha levels. In addition, the present study further emphasizes the potential mechanisms underlying the bidirectional relationship between NAD+ and autophagy. We detected changes in autophagy levels in various tissue organs, and NMN may play a protective role by inhibiting excessive autophagy induced by HFD. Conclusions: Our fi ndings demonstrated that NMN administration attenuated HFD-induced metabolic disorders and physiological decline in aging mice.