Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men

Abstract

Preclinical studies have revealed that the elevation of nicotinamide adenine dinucleotide (NAD + ) upon the administration of nicotinamide mononucleotide (NMN), an NAD + precursor, can mitigate aging-related disorders; however, human data on this are limited. We investigated whether the chronic oral supplementation of NMN can elevate blood NAD + levels and alter physiological dysfunctions in healthy older participants. We administered 250 mg NMN per day to aged men for 6 or 12 weeks in a placebo-controlled, randomized, double-blind, parallel-group trial. Chronic NMN supplementation was well tolerated and caused no significant deleterious effect. Metabolomic analysis of whole blood samples demonstrated that oral NMN supplementation significantly increased the NAD + and NAD + metabolite concentrations. There were nominally significant improvements in gait speed and performance in the left grip test, which should be validated in larger studies; however, NMN exerted no significant effect on body composition. Therefore, chronic oral NMN supplementation can be an efficient NAD + booster for preventing aging-related muscle dysfunctions in humans.

Fig. 1. Clinical trial diagrams.

Clinical trial flow chart illustrating the procedures for the selection of study participants and data analyses. Sixty-five potential participants were screened, and 42 eligible participants were selected and randomized in a 1:1 ratio into the two groups. Clinical examinations were performed at the 0-, 6-, and 12-week visits. Deviation from the study protocol was noted in 22 participants after the 6-week visit, and eventually, 20 participants completed the 12-week study.

Fig. 2. Chronic oral NMN administration increases whole blood NAD+ and NAD+-related metabolite levels.

a–g Changes in whole blood NAD+ and NAD+-related metabolite levels (NMN (a), NAD+ (b), NR (c), NAMN (d), NAR (e), NA (f), and NAM (g)) after 12 weeks of placebo (n = 10) or NMN (n = 10) supplementation. Center lines in boxplots are medians. Bounds of boxes are 25- and 75 percentiles. Bounds of whiskers are the minimum and the maximum inside a distance of 1.5 times the interquartile range from the lower or upper quartile. NMN nicotinamide mononucleotide, NAD+ nicotinamide adenine dinucleotide, NR nicotinamide riboside, NAMN nicotinic acid mononucleotide, NAR nicotinic acid riboside, NA nicotinic acid, NAM nicotinamide. ^aInter-group comparisons were performed using an unpaired t test. ^bInter-group comparisons were performed using the Mann–Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001.

Fig. 3. NMN supplementation does not affect metabolic parameters.

a A representative single CT slice at the navel level of an NMN or placebo group participant at the 0- or 12-visit to calculate the visceral fat area; the red region indicates visceral fat, and the blue region indicates subcutaneous fat. b The effect of NMN on the CT L/S ratio, visceral fat area calculated from CT slices, and fat mass (lrb%) measured using the BIA method. c The effect of NMN on HbA1c, FBG, HOMA-β, HOMA-IR, glucose AUC, insulin AUC, and C-peptide AUC. The AUC was calculated from the results of the 75 g OGTT. The numbers in the parentheses indicate the respective sample sizes. ^aTreatment was compared using a mixed-model analysis. The p-value denotes the interaction. ^bTreatment was compared using MMRM. The P value denotes interaction. ^cInter-group comparisons were performed using an unpaired t test (no adjustment for baseline). ^dInter-group comparisons were performed using the Mann–Whitney U test (no adjustment for baseline). ^eInter-group comparisons were performed using ANCOVA for adjusting the baseline. *P < 0.05; **P < 0.01; ***P < 0.001.