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.
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