One Giant Step for Mice, One Small Step for Mankind: One Year of NMN Supplementation Slows Down Aging in Mice

Historically unprecedented worldwide trends in population aging are predicted to become an incessant burden on governmental healthcare finances. To make the process of aging healthier and prevent expensive age-associated health problems, efforts to develop effective, affordable, anti-aging interventions have recently been intensified, leading to some promising compounds. Whereas these were originally developed as pharmaceutical drugs, some compounds originating from within an organism might also have the potential to achieve healthy and productive lives even at a very old age.

Nicotinamide mononucleotide (NMN), a key NAD+ intermediate, enhances NAD+ levels critical to cellular energy metabolism and production and ameliorates various pathologies in mouse disease models. Remarkably, a seminal 2016 study from researchers at Washington University School of Medicine, St. Louis showed that 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 aging-related disease-like characteristics.

These effects of NMN highlight the preventive and therapeutic potential of NAD+ intermediates as effective anti-aging interventions in humans. “Our long-term NMN administration study provides compelling support to an effective anti-aging intervention,” concluded the authors in their article. “Given that NMN is contained in a variety of food sources such as vegetables, fruits, and meat, it will be of great interest to translate our study from mice to humans and examine whether this endogenous compound, NMN, is also an effective intervention that prevents age-associated physiological decline in humans.”

Does extending life go through NAD+?

Interestingly, it has been demonstrated that enhancing NAD+ biosynthesis extends lifespan in yeast, worms, and flies. In rodents and humans, several studies have reported that NAD+ content declines with age in multiple organs, such as the pancreas, liver, skin, and brain. So, enhancing NAD+ biosynthesis with precursors like NMN is expected to provide significant preventive effects on various disease-associated changes in the natural process of aging.

To address this critical question, researchers need to perform long-term administration studies of NMN in living animals before being addressed in humans. Along these lines, Mills and colleagues examined whether long-term administration of NMN shows preventive effects on age-associated disease-like changes in mice. To do so, they treated mice for 1 year with two different doses of NMN in their drinking water and then assessed a variety of functional traits, as well as long-term safety and toxicity

NMN supplementation for 1 year mitigates age-associated physiological decline in mice

In this study, Mills and colleagues were able to demonstrate that long-term administration of NMN is capable of mitigating the age-associated physiological decline in otherwise healthy mice. They found that a 12 month-long NMN administration:

• Is well-tolerated without any obvious deleterious effects
• Suppresses age-associated body weight gain
• Enhances food intake, oxygen consumption, energy expenditure, and physical activity
• Improves insulin sensitivity and plasma lipid profile, independent of its effect on body weight
• Improves eye function, bone density, and myeloid-lymphoid composition.
• Prevents age-associated gene-level changes in a tissue-dependent manner
• Enhances mitochondrial respiratory capability in skeletal muscle

It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12 month-long intervention period, suggesting the long-term safety of NMN. Nonetheless, an optimal dose of NMN to maximize its efficacy appears to differ depending on where in the body it is exerting its effects. On the one hand, the effects of NMN on body weight gain, insulin sensitivity, tear production, and bone mineral density were dose-dependent—when the effects change as the dose of the drug is changed. On the other hand, 100 mg/kg/day of NMN improved oxygen consumption, energy expenditure, and physical activity better than 300 mg/kg/day.

NMN is an effective anti-aging intervention that could be translated to humans

This article set the stage for some key questions to be addressed, which are still currently under investigation. Along these lines, research is ongoing regarding how NMN exerts its effects on different tissues and organs. Also, researchers are still trying to understand precisely how NMN is uptaken by cells in different tissues. This will provide critical insight into understanding tissue preferences of this NAD+ precursor and thereby aid in developing effective interventions for age-associated physiological decline by using NMN.

It is of great interest to translate this study from mice to humans and examine whether NMN is also an effective intervention that prevents age-associated physiological decline in humans.  And it’ll be important to figure out the right doses in humans. In this study, since 100 mg/kg each day of NMN was able to mitigate most age-associated physiological declines in mice, an equivalent dose for humans would be around 8 mg/kg each day. A back of the envelope calculation puts this somewhere around 500 mg per day for humans (assuming the global average body weight is 62.5 kg or 137.8 lb).

Along these lines, several clinical trials are currently underway that are investigating the proper dosing and effects of NMN on humans. Perhaps, soon, we will have a better sense of the effects of NMN on human healthspan and longevity. 

References: 

Mills KF, Yoshida S, Stein LR, et al. Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice. Cell Metab. 2016;24(6):795-806. doi:10.1016/j.cmet.2016.09.013