Sustained NAD⁺ augmentation by high-dose nicotinamide mononucleotide supplementation in older adults: a 24-week randomized, double-blind, placebo-controlled trial

Abstract

Abstract In animal studies, the administration of nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD⁺), can ameliorate aging-related diseases by increasing tissue and blood NAD⁺ levels. However, human data on this intervention are limited. In this study, we investigated whether chronic oral supplementation with high-dose NMN could elevate blood NAD⁺ concentrations and alter physiological dysfunction in healthy older adults. In a placebo-controlled, randomized, double-blind, parallel-group trial, participants aged ≥65 years received 1250 mg of NMN daily for 24 weeks. Chronic high-dose NMN supplementation was generally well tolerated, although careful safety monitoring is warranted, and did not induce significant adverse effects. Metabolomic analysis of whole blood samples confirmed that oral high-dose NMN supplementation significantly increased concentrations of NAD⁺ and related metabolites. No significant improvement was observed in the primary endpoint of auditory function or in physical performance measures. Nominal changes were observed in certain body composition, lipid-related, and dietary behavior measures; however, these findings did not remain significant after correction for multiple testing and should be considered exploratory. Taken together, long-term high-dose NMN supplementation robustly increases circulating NAD-related metabolites, whereas evidence for broader physiological benefit remains limited. Trial registration: Japan Registry of Clinical Trials (jRCT), jRCTs031220373, registered on October 11, 2022.