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Nicotinamide adenine dinucleotide metabolism and arterial stiffness after long-term nicotinamide mononucleotide supplementation: a randomized, double-blind, placebo-controlled trial

Takeshi Katayoshi, Sachi Uehata, Noe Nakashima, Takahisa Nakajo, Natsuko Kitajima, Masakatsu Kageyama, Kentaro Tsuji-Naito
Scientific Reports 2023 13, 2786

Bibliography

PubMed
PMID 36797393
PubMed Central
PMC9935856
DOI
10.1038/s41598-023-29787-3
Funding
Supported by a research grant from DHC Corporation.
Competing interests
The authors declare no competing interests.

Study snapshot

DesignRandomized, double-blind, placebo-controlled, parallel-group trial with 1:1 block randomization.
ModelHealthy middle-aged men and women, primarily 40-59 years old in the enrolled sample; eligibility allowed ages 40-65.
Sample36 randomized; 18 per group. One participant in each group was lost to follow-up, leaving n=17 NMN and n=17 placebo for the full analysis set.
InterventionNMN 125 mg twice daily after meals (250 mg/day total) for 12 weeks versus matched placebo.
Duration12 weeks.
EndpointsSerum nicotinamide (NAM), NMN and NAD+; Brachial-ankle pulse wave velocity (baPWV); Ankle-brachial index (ABI); Blood pressure and routine hematology/chemistry; SIRT1 mRNA; Urinary 8-OHdG; Skin advanced glycation end products

What the study showed, in plain terms

This 12-week randomized trial tested 250 mg/day of NMN against placebo in healthy middle-aged adults, with a focus on NAD+-related metabolites, safety and vascular stiffness.

Serum nicotinamide rose significantly with NMN, which the authors interpreted as evidence that NAD+ metabolism had been affected. Direct serum NAD+ and NMN concentrations were below the assay's lower limit of quantification, so the study could not show a measurable increase in those serum analytes.

Average brachial-ankle pulse wave velocity moved downward in the NMN group but was not significantly different from placebo overall (p=0.097). Significant reductions appeared in exploratory subgroups with above-average BMI or glucose, but baseline vascular differences and the small sample make those subgroup signals hypothesis-generating.

Key findings

  • Twelve weeks of 250 mg/day NMN was well tolerated; no adverse events were reported and routine hematology, chemistry and hormone measures showed no concerning between-group changes.
  • Serum nicotinamide increased in the NMN group relative to placebo (ANCOVA p=0.037).
  • Serum NMN and NAD+ were detectable but below the lower limit of quantification, preventing meaningful between-group comparison.
  • Average baPWV decreased by about 25.1 cm/s in the NMN group, but the overall between-group difference was not statistically significant (p=0.097).
  • Exploratory subgroups with above-average BMI or blood glucose showed larger baPWV reductions with NMN; no such significant change was seen in the above-average blood-pressure subgroups.
  • SIRT1 mRNA, urinary 8-OHdG and skin advanced glycation end products did not differ significantly between groups.

What this study can and cannot tell us

The NMN group began with lower baPWV values, including a significant baseline difference for left-side baPWV, complicating vascular interpretation.

Serum rather than whole blood or PBMCs was used to quantify NAD+ metabolism, and NAD+ and NMN values were below quantification limits.

Participants were allowed to continue pre-existing supplements, which differed between groups and could have affected vascular outcomes. The sample was also small and the subgroup analyses were exploratory.

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