·   This clinical study is the first to report the effectiveness of NMN on human health.

·   The researchers show that NMN increases blood cell NAD+ levels and improves muscle insulin sensitivity and structure in aged, prediabetic women.

The molecule nicotinamide mononucleotide (NMN) has garnered attention for its counteracting effects on metabolic deterioration and age-related diseases in rodents. But whether NMN supplementation improves metabolism, let alone aging, in people has not been looked at, until now.

Klein and colleagues from the Washington University School of Medicine in St. Louis published a report in Science showing for the first time that NMN improves the muscle insulin sensitivity of prediabetic women. They show that NMN exerts these positive metabolic effects by enhancing insulin’s ability to trigger sugar uptake and increasing the activity of genes involved in muscle structure and remodeling. The Missouri-based research team did not, however, find that NMN improves the levels of fats in the blood, blood sugar levels, or blood pressure. This Science publication provides tantalizing insight suggesting that NMN may help people with age-related disease prevention.

“This is one step toward the development of an anti-aging intervention, though more research is needed to fully understand the cellular mechanisms responsible for the effects observed in skeletal muscle in people,” said co-investigator Shin-Ichiro Imai, MD, PhD, in a press release.

NMN Increases Human Blood Cell NAD+ Levels

NMN is a precursor to a vital molecule for energy production and metabolic health called nicotinamide adenine dinucleotide (NAD+). Many studies have already demonstrated that by increasing NAD+ levels throughout the body in animals, NMN improves metabolic health during aging.

To find out whether NMN really boosts NAD+ levels in human tissue, Klein and colleagues examined the effects of taking 250 mg capsules of NMN per day for 10 weeks on prediabetic women between the ages of 55 and 75 who were overweight. After the treatment course, they found that NMN significantly increased NAD+ levels in blood cells that are also crucial components of the immune system. Although NMN treatment did not elevate NAD+ levels in skeletal muscle, it did significantly increase levels of NMN metabolic byproducts. This suggests that NMN was being converted to NAD+ and that the skeletal muscle utilized the NAD+ at a rapid pace so that NAD+ levels did not increase.

(Yoshino et al., 2021 | Science) NMN treatment increases NAD+ levels in blood cells called peripheral blood mononuclear cells (PBMCs) and NMN metabolites in skeletal muscle. These graphs show the effect of 250 mg NMN for 10 weeks on the levels of NAD+ in PBMCs (left) and NMN metabolites in skeletal muscle (right) in prediabetic, postmenopausal women. The white bars represent NAD+ levels at the beginning of the study, and the grey bars represent NAD+ levels after 10 weeks of treatment. NMN had a major effect on both the levels of NAD+ in PBMCs and the NMN metabolite N-methyl-nicotinamide in skeletal muscle. 

NMN Improves Human Muscle Metabolism and Repair

Then, to see what effects increasing NAD+ levels with NMN in skeletal muscle had on metabolism, Klein and colleagues measured the muscle’s sensitivity to insulin — a hormone that triggers the cellular uptake of sugars. They did so by looking at the rate of insulin infusion-stimulated disposal of a sugar called glucose in muscle tissue and found 10 weeks of NMN treatment triggered about a 25% increase in muscle glucose usage. These findings indicate that NMN increases muscle tissue utilization of sugars to improve metabolism.

(Yoshino et al., 2021 | Science) NMN substantially improved muscle metabolism of sugar. This graph shows the effect of taking 250 mg NMN for 10 weeks in prediabetic, postmenopausal women on the usage of the sugar glucose before (white) and after (grey) infusion with the insulin hormone that triggers glucose cellular uptake. The NMN-treated group had a significantly enhanced glucose clearance rate after insulin infusion compared to the placebo group. These results suggest that NMN improves muscle metabolism in prediabetic postmenopausal women by improving the glucose clearance rate.

To get at how exactly NMN was working, Klein and colleagues looked at a signaling pathway indicative of muscle sugar uptake and remodeling to see whether improved muscle metabolism could translate to better muscle repair. Their findings showed that NMN treatment increased signalling related to muscle metabolism and cell growth. This was consistent with the previous findings showing that NMN improves muscle tissue sensitivity to insulin and muscle metabolism and also indicated that NMN stimulates muscle remodeling pathways.

NMN Increases Gene Activity for Muscle Remodeling

To confirm that NMN improves muscle metabolism and remodeling, Klein and colleagues examined gene activity patterns following NMN treatment. In their analyses, they found NMN promotes the activation of genes involved in muscle remodeling processes, especially increasing gene activity for “Platelet derived growth factor” (PDGF) that regulates muscle cell growth and proliferation. These observations of NMN’s effects on gene expression are in line with NMN improving muscle metabolism, repair, and remodeling.

“The results from our study demonstrate NMN supplementation (250 mg/day) increases skeletal muscle insulin signaling, insulin sensitivity, and muscle remodeling in postmenopausal women with prediabetes who are overweight or obese,” stated Klein and colleagues in their publication. The exact mechanisms by which NMN provides these effects and whether NMN treatment gives similar results in patients with other conditions or diseases remain to be explored. Future studies can examine whether NMN has similar beneficial effects in these other groups of people.

What’s Next For Evaluating NMN in People?

“Although our study shows a beneficial effect of NMN in skeletal muscle, it is premature to make any clinical recommendations based on the results from our study,” said senior investigator Samuel Klein, MD, the William H. Danforth Professor of Medicine and Nutritional Science and director of the Center for Human Nutrition. The researchers caution that more studies are needed to determine whether NMN has beneficial effects in the prevention or management of prediabetes or diabetes in people.

Similar research has shown that another NAD+-boosting molecule, nicotinamide riboside (NR), does not improve human muscle metabolism, at least in men. Finding an explanation behind why NMN has been shown to improve muscle metabolism but NR has not remains open for exploration. Klein and Imai are continuing to evaluate NMN in another trial involving men as well as women.