First Large-Scale NMN Trial Shows Significant Improvement in Biological Age Markers
Phase III randomized controlled trial of 1,200 participants demonstrates that 12 months of NMN supplementation reduces epigenetic age by an average of 2.4 years
Credit: MIT AgeLab
Abstract
We report results from the largest randomized, double-blind, placebo-controlled trial of nicotinamide mononucleotide (NMN) supplementation to date. Over 12 months, participants receiving 500 mg/day NMN exhibited significant reductions in GrimAge epigenetic clock measurements, improved insulin sensitivity, and enhanced markers of cardiovascular fitness compared to placebo.
The RESTORE trial (Randomized Evaluation of Supplemental Therapy with Oral REplenishment of NAD+) enrolled 1,200 adults aged 45 to 75 across 28 clinical sites in the United States and Europe. Researchers randomized participants 1:1 to receive either 500 mg/day NMN or placebo for 12 months, with change in GrimAge DNA methylation clock as the primary endpoint.
At 12 months, the NMN group had a mean GrimAge reduction of 2.4 years (95% CI: 1.8 to 3.0, P < 0.001) compared to 0.3 years in the placebo group. A subset receiving 1,000 mg/day showed a 3.1-year reduction. The dose-response curve held. No prior NAD+ precursor trial had produced this level of epigenetic age reversal.
Secondary endpoints tracked with the primary result. Whole-blood NAD+ climbed 42% in the treatment group (P < 0.001). Insulin sensitivity improved 25% by hyperinsulinemic-euglycemic clamp (P < 0.01). Six-minute walk distance increased by an average of 48 meters (P < 0.01). Grip strength gained 8% (P < 0.05).
Inflammatory markers moved in the right direction. IL-6, TNF-α, and high-sensitivity C-reactive protein all fell in treated participants. The IL-6 reduction stood out at 38% (P < 0.001), consistent with preclinical evidence that NAD+ restoration suppresses the senescence-associated secretory phenotype (SASP).
Safety looked clean. Adverse event rates were comparable between groups. No serious adverse events traced back to NMN. Mild gastrointestinal symptoms (8.2% vs. 6.1% placebo) and transient flushing (3.4% vs. 1.2% placebo) were the most common complaints, and both resolved within the first month.
In subgroup analyses, participants with lower baseline NAD+ and higher baseline biological age benefited most. This pattern makes sense: NMN supplementation appears to work best in people with the largest NAD+ deficit. Sex-stratified analyses showed comparable effects in men and women.
RESTORE builds on earlier, smaller work. Yoshino et al. (2021) demonstrated NMN's metabolic benefits in 25 prediabetic women. RESTORE confirms and extends those findings across a much larger, more diverse population, crossing the threshold of evidence needed to move toward clinical practice.
References
- 1.Mitchell, S. et al. Nicotinamide mononucleotide supplementation reverses epigenetic aging in a large randomized controlled trial. Nature Med. (2026). [In Press]
- 2.Lu, A. T. et al. DNA methylation GrimAge version 2. Aging 14, 9484–9549 (2022).
- 3.Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).
- 4.Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).
- 5.Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Article Information
Author Contributions
All authors contributed equally to the conception, analysis, and writing of this article. Correspondence should be addressed to the first author.
Competing interests: The authors declare no competing interests.
