Tier 3 — preclinical

Safety and efficacy of long-term nicotinamide mononucleotide supplementation on metabolism, sleep, and nicotinamide adenine dinucleotide biosynthesis in healthy, middle-aged Japanese men

Shintaro Yamaguchi, Junichiro Irie, Masanori Mitsuishi, Yuichi Uchino, Hideaki Nakaya, Ryo Takemura, Emi Inagaki, Shotaro Kosugi, Hideyuki Okano, Masato Yasui, Kazuo Tsubota, Kaori Hayashi, Jun Yoshino, Hiroshi Itoh
Endocrine Journal 2024 71(2):153-169

Bibliography

PubMed
PMID 38191197
DOI
10.1507/endocrj.EJ23-0431
Funding
Supported by internal institutional budgets, including the Program for the Advancement of Research in Core Projects on Longevity of the Keio University Global Research Institute. Oriental Yeast Company, Ltd. provided the placebo and NMN capsules.
Competing interests
Emi Inagaki, Hideyuki Okano, and Kazuo Tsubota were awarded Japanese Patent No. 7090336, 'Utilization of NAD-related metabolites.' Jun Yoshino is an inventor on NMN-related patent applications US20180228824 and JP2018131418A. Hiroshi Itoh received research funding from Oriental Yeast Company, Ltd. The authors state that potential conflicts were managed according to the Keio University School of Medicine IRB recommendations.

Study snapshot

DesignSingle-center, single-arm, open-label study with a 4-week placebo lead-in, a washout period, and an 8-week NMN treatment phase; there was no concurrent randomized placebo group.
ModelEleven healthy middle-aged Japanese men.
Sample28 volunteers were screened and 14 were eligible. One withdrew before starting study medication; 13 entered the placebo lead-in. One withdrew during placebo, one after washout, and two during NMN treatment. Twelve entered the NMN phase, 11 had measurements after NMN initiation, and 9 completed the full study and contributed the primary longitudinal analyses.
InterventionFour-week placebo lead-in followed by washout, then NMN 250 mg/day (two 125-mg capsules once daily before breakfast) for 8 weeks. Placebo and NMN capsules were supplied by Oriental Yeast Company, Ltd.
Duration12-week follow-up framework comprising a 4-week placebo lead-in, washout, and an 8-week NMN treatment phase.
EndpointsPBMC NAD+; Biochemical and metabolic measures; Oral glucose tolerance; Ophthalmologic measures; Sleep quality; Safety

What the study showed, in plain terms

This was not a randomized placebo-controlled trial. Healthy middle-aged Japanese men first completed a placebo lead-in and washout, then received 250 mg/day NMN for eight weeks in an open-label single-arm phase. Twenty-eight men were screened, 14 were eligible, and nine completed the full protocol used for the main longitudinal analyses.

PBMC NAD+ increased over the NMN phase. Overall glucose and insulin measures did not significantly improve; an exploratory subgroup of three participants with baseline insulin oversecretion showed a possible attenuation of postprandial hyperinsulinemia. Pittsburgh Sleep Quality Index scores did not significantly improve.

Key findings

  • PBMC NAD+ increased over the NMN treatment period in the nine full-protocol completers.
  • Overall glucose, insulin, HOMA-IR and related OGTT measures were not significantly changed by NMN.
  • A subgroup of three participants with insulin oversecretion showed an exploratory attenuation of postprandial hyperinsulinemia.
  • PSQI sleep-quality scores did not significantly improve during NMN supplementation.
  • Two participants withdrew during the NMN phase, one after transient liver-enzyme elevations and one after increased intraocular pressure; the authors judged overall adverse-event incidence comparable with pre-NMN periods.

What this study can and cannot tell us

The study was open-label and single-arm, with a sequential placebo lead-in rather than a concurrent control. Only nine participants completed the full protocol for the primary longitudinal analyses. The postprandial-hyperinsulinemia signal came from only three participants, and sleep quality did not significantly improve. These design and sample-size limitations prevent strong efficacy conclusions.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology