Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice

Abstract

Summary NAD+ availability decreases with age and in certain disease conditions. Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, has been shown to enhance NAD+ biosynthesis and ameliorate various pathologies in mouse disease models. In this study, we conducted a 12 month-long NMN administration to regular chow-fed wild-type C57BL/6N mice during their normal aging. Orally administered NMN was quickly utilized to synthesize NAD+ in tissues. Remarkably, NMN effectively mitigates age-associated physiological decline in mice. Without any obvious toxicity or deleterious effects, NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies. Consistent with these phenotypes, NMN prevented age-associated gene expression changes in key metabolic organs and enhanced mitochondrial oxidative metabolism and mitonuclear protein imbalance in skeletal muscle. These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans.

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

“…Additionally, we found a trending elevation in serum triacylglycerides in FXN-KO mice that was reduced with NMN, along with a reduction in circulating nonesterified FAs (NEFAs) (Supplemental Figure 5, G and H, respectively). These data suggest that NMN reduced global FA availability, a finding consistent with literature that describes reduced serum triacylglycerides and free FAs with long-term administration of NMN in mice (1). Within in the heart, saturated FAs accumulated in the FXN-KO and dKO models (Supplemental Figure 5I), which is also observed in FRDA patients (19).…”

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

“…In addition, NAD + can be generated through de novo synthesis, salvage pathways or through oxidation of NADH by lactate dehydrogenase (LDH) in glycolytic cells. NAD + levels decline during aging, and there is compelling evidence that genetic manipulation of NAD + biosynthesis or supplementation with NAD + precursors can extend lifespan in model organisms spanning yeast, worms and mice [13–18]. While mitochondria appear to be protected against stress-induced decreases in NAD + , they can only retain optimal NAD + levels for a short period of time [19–21].…”

Mitochondria and aging: A role for the mitochondrial transition pore?

“…This was observed in several organs in mice and in Caenorhabditis elegans . There is also evidence of NAD + reduction in aged human tissues (Fang et al., 2014; Massudi et al., 2012; Mills et al., 2016; Mouchiroud et al., 2013; Zhang et al., 2016; Zhu, Lu, Lee, Ugurbil, & Chen, 2015). Conversely, supplementation with NAD + precursors or overexpression of a NAD + synthetic enzyme nicotinamidase have been reported to extend lifespan and to improve healthspan in different species (for review, see Fang et al., 2017).…”