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.wisepoqder beta-Nicotinamide mononucleotide powder
Historically unprecedented worldwide trends in population aging are predicted to become an incessant burden on governmental healthcare finances (OECD, 2013). To make the process of aging healthy and prevent expensive age-associated health problems, efforts to develop effective, affordable, anti-aging interventions have recently been intensified, leading to some promising compounds, such as metformin, rapamycin, and SIRT1 activators (Barzilai et al., 2016, Hubbard and Sinclair, 2014, Lamming et al., 2013). Whereas these compounds were originally developed as pharmaceutical drugs, some endogenous compounds might also have the potential to achieve healthy and productive lives even at a very old age (Imai, 2010, Imai and Guarente, 2014).
Nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), key NAD+ intermediates in mammals, could be such candidates (Imai, 2010). NMN is synthesized from nicotinamide (Nic), an amide form of vitamin B3, and 5′-phosphoribosyl-pyrophosphate (PRPP) by nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in this particular NAD+ biosynthetic pathway (Cantó et al., 2015, Imai and Guarente, 2014). NR is phosphorylated to NMN by nicotinamide riboside kinases (NRKs) (Belenky et al., 2007). Once NMN is synthesized, it is converted to NAD+ by three NMN adenylyltransferases, NMNAT1-3. The short-term administration of either NMN or NR has been reported to have remarkable therapeutic effects on metabolic complications and other disease conditions. For example, we have shown that NMN ameliorates impairments in glucose-stimulated insulin secretion in aged wild-type mice and some genetic mouse models (Ramsey et al., 2008, Revollo et al., 2007). NMN treatment also significantly improves both insulin action and secretion in diet- and age-induced type 2 diabetic or obese mouse models (Caton et al., 2011, Yoshino et al., 2011). Furthermore, NMN protects the heart from ischemia/reperfusion injury by preventing NAD+ decrease induced by ischemia (Yamamoto et al., 2014), maintains the neural stem/progenitor cell population, and restores skeletal muscle mitochondrial function and arterial function in aged mice (de Picciotto et al., 2016, Gomes et al., 2013, Stein and Imai, 2014), ameliorates mitochondrial function, neural death, and cognitive function in Alzheimer’s disease rodent models (Long et al., 2015, Wang et al., 2016). NR is also able to ameliorate mitochondrial dysfunction in obese mouse models (Cantó et al., 2012, Gariani et al., 2015, Lee et al., 2015) and various mitochondrial disease models (Cerutti et al., 2014, Khan et al., 2014), attenuate cognitive deterioration in Alzheimer’s disease model mice (Gong et al., 2013), prevent DNA damage and hepatocellular carcinoma formation (Tummala et al., 2014), improve noise-induced hearing loss (Brown et al., 2014), and maintain muscle stem cell function (Zhang et al., 2016). Collectively, these findings strongly suggest that enhancing NAD+ biosynthesis by administering NMN or NR is an efficient therapeutic intervention against many disease conditions (Imai and Guarente, 2014).
Interestingly, it has been demonstrated that enhancing NAD+ biosynthesis extends lifespan in yeast, worms, and flies (Anderson et al., 2002, Balan et al., 2008, Mouchiroud et al., 2013). In rodents and humans, a number of studies have reported that NAD+ content declines with age in multiple organs, such as pancreas, adipose tissue, skeletal muscle, liver, skin, and brain (Gomes et al., 2013, Massudi et al., 2012, Mouchiroud et al., 2013, Stein and Imai, 2014, Yoshino et al., 2011, Zhu et al., 2015). Thus, enhancing NAD+ biosynthesis with NMN or NR is expected to provide significant preventive effects on various pathophysiological changes in the natural process of aging. To address this critical question, long-term administration studies need to be performed under normal conditions in wild-type mice.
To examine whether long-term administration of NMN shows preventive effects on age-associated pathophysiological changes, we treated regular chow-fed wild-type mice for 12 months with two different doses of NMN in their drinking water. We assessed a variety of functional traits, as well as long-term safety and toxicity, and found that NMN is remarkably capable of ameliorating age-associated physiological decline in mice. Our findings from this long-term administration study provide a proof of concept to develop NMN as an effective anti-aging compound that prevents age-associated physiological decline, hoping to translate the results to humans.
