Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men

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Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men was a study which assessed single oral doses of 100 mg, 250 mg, and 500 mg NMN. Given the promising in vitro and pre-clinical data underlying NMN supplementation, the authors undertook a first assessment of the pharmacokinetics of orally administered NMN in humans. The authors found no significant changes in vital signs (blood pressure, temperature, heart rate) in the 5 hours following a single dose of NMN. Importantly, the authors found significant, dose-dependent elevation in plasma NMN metabolites following a single dose of enteral NMN. Findings from this study also support speculation NMN administration increases tissue NAD+ and its metabolic byproducts. Blood plasma levels of bilirubin increased while insulin levels decreased. The authors noted that these changes were consistent with expected fasting changes in these serum levels; however, without a control group they were unable to ascertain if the changes were due to NMN or fasting effects. Other serum values, like AST/ALT, creatinine, amylase, and white blood cell count were unchanged in the five hours following the single oral dose of NMN.[1]

Article abstract

Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans has remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.

Implications

This study has several important implications. First, it supports that oral NMN supplementation in humans results in significant, measurable increases in blood levels of NMN metabolites. This corroborates previous animal studies which also established that oral dosing appeared to be effective in raising levels of NMN and its metabolites in mice. Metabolite level data also support speculation that NMN administration increases tissue NAD+ levels. Additionally, this study revealed a range of doses from 100 mg – 500 mg appeared to be tolerable, with no short-term side effects noted.

Additional research to be conducted

This study opens the door for future human studies of the effects of NMN supplementation. The authors note that they are already planning follow-up studies examining the effects of oral NMN supplementation on plasma NMN and NAD+ levels in peripheral blood cells. Additionally, they note they hope to biopsy and record tissue-specific levels of NMN metabolites in skeletal muscle or adipose tissue as part of their next series of tests with oral NMN supplementation.

Institution

Dr. Hiroshi Itoh has published extensively on the biologic underpinnings surrounding NMN. His lab had a landmark paper in Nature Medicine which examined the role of sirtuins in diabetic kidney injury.[2] Additionally, the Itoh group has published several additional papers investigating sirtuins, NMN, and their effects in renal and vascular tissues. [3][4][5][6]

Funding

This study was funded by internal grants from Keio University. The authors did not report any industry sponsorship or other extramural sources of funding.

Authors/ Researchers

  • Junichiro Irie – Department of Endocrinology, Keio University
  • Emi Inagaki – Department of Ophthalmology & Department of Physiology – Keio University / Japan Society for the Promotion of Science
  • Masataka Fujita - Department of Endocrinology, Keio University
  • Hideaki Nakaya - Department of Endocrinology, Keio University
  • Masanori Mitsuishi - Department of Endocrinology, Keio University
  • Shintaro Yamaguchi - Department of Endocrinology, Keio University
  • Kazuya Yamashita - Department of Ophthalmology, Keio University
  • Shuhei Shigaki – Biomarker Research and Development, Shionogi & Co.
  • Takashi Ono – Drug Discovery, Shionogi & Co.
  • Hideo Yukioka - Drug Discovery, Shionogi & Co.
  • Hideyuki Okano – Department of Physiology & Global Research Institute, Keio University
  • Yo-ichi Nabeshima – Department of Gerontology, Institute for Biomedical Research and Innovation, Kobe, Japan
  • Shin-ichiro Imai - Department of Gerontology, Institute for Biomedical Research and Innovation, Kobe, Japan / Department of Developmental Biology, Washington University
  • Masato Yasui - Global Research Institute & Department of Pharmacology, Keio University
  • Kazuo Tsubota - Global Research Institute & Department of Ophthalmology, Keio University
  • Hiroshi Itoh – Department of Endocrinology & Global Research Institute, Keio University

References

  1. ↑ Irie J, Inagaki E, Fujita M, et al. Effect of oral administration of nicotinamide mononucleotide on clinical parameters and nicotinamide metabolite levels in healthy Japanese men. Endocr J. 2020;67(2):153-160.
  2. ↑ Hasegawa K, Wakino S, Simic P, et al. Renal tubular sirt1 attenuates diabetic albuminuria by epigenetically suppressing claudin-1 overexpression in podocytes. Nat Med. 2013;19(11):1496-1504.
  3. ↑ Irie J, Itoh H. [Aging and homeostasis. Age-associated diseases and clinical application of NMN(Nicotinamide Mononucleotide).]. Clin Calcium. 27(7):983-990.
  4. ↑ Wakino S, Hasegawa K, Itoh H. Sirtuin and metabolic kidney disease. Kidney Int. 2015;88(4):691-698.
  5. ↑ Homma K, Sone M, Taura D, et al. Sirt1 plays an important role in mediating greater functionality of human ES/iPS-derived vascular endothelial cells. Atherosclerosis. 2010;212(1):42-47.
  6. ↑ Hasegawa K, Wakino S, Yoshioka K, et al. Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function. J Biol Chem. 2010;285(17):13045-13056.
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