Nicotinamide Improves Aspects of Healthspan, but Not Lifespan, in Mice

The role in longevity and healthspan of nicotinamide (NAM), the physiological precursor of NAD⁺, is elusive. Here, we report that chronic NAM supplementation improves healthspan measures in mice without extending lifespan. Untargeted metabolite profiling of the liver and metabolic flux analysis of liver-derived cells revealed NAM-mediated improvement in glucose homeostasis in mice on a high-fat diet (HFD) that was associated with reduced hepatic steatosis and inflammation concomitant with increased glycogen deposition and flux through the pentose phosphate and glycolytic pathways. Targeted NAD metabolome analysis in liver revealed depressed expression of NAM salvage in NAM-treated mice, an effect counteracted by higher expression of de novo NAD biosynthetic enzymes. Although neither hepatic NAD⁺ nor NADP⁺ was boosted by NAM, acetylation of some SIRT1 targets was enhanced by NAM supplementation in a diet- and NAM dose-dependent manner. Collectively, our results show health improvement in NAM-supplemented HFD-fed mice in the absence of survival effects. Interventions that increase NAD⁺ bioavailability are of therapeutic interest for the improvement of healthspan and lifespan. Mitchell and Bernier et al. show that chronic treatment with nicotinamide, an NAD⁺ precursor, is associated with health improvements and lower inflammation in the absence of lifespan extension in high-fat-diet-fed mice.