Abstract
<jats:p>Reduced nicotinamide mononucleotide (NMNH) is a reduced NAD⁺ precursor with reported NAD⁺- augmenting activity in preclinical models; however, controlled human data remain limited. This was a randomized, double-blind, placebo-controlled, parallel-group phase I trial evaluating oral NMNH-Ca in healthy adults aged 40-65 years. Eighty participants received placebo or NMNH-Ca 125, 250, or 500 mg once daily for 90 days. The primary objective was safety and tolerability. Whole-blood NAD⁺ was assessed as the key pharmacodynamic endpoint, including a 24-hour post-dose substudy, with biomarker-derived blood phenotypic age, treadmill-based six-minute walk distance, body mass index, and SF-36 domains analyzed as exploratory outcomes. NMNH-Ca was well tolerated at all doses, with no serious adverse events, treatment-related adverse events, or discontinuations. In the acute substudy, whole-blood NAD⁺ increased after single-dose NMNH-Ca, with peak mean concentrations at 12 hours. Over 90 days, NAD⁺ increased in a dose-related pattern; Day 90 mean changes from baseline were 2.33 ± 18.53 μM with placebo and 8.22 ± 10.25, 15.85 ± 11.16, and 39.90 ± 14.11 μM with NMNH-Ca 125, 250, and 500 mg, respectively. Exploratory analyses showed hypothesis-generating favorable signals in blood phenotypic age, treadmill-based six-minute walk distance, and health-related quality of life, most consistently at 500 mg. Oral NMNH-Ca was safe and pharmacodynamically active over 90 days, supporting larger and longer confirmatory trials with prespecified geroscience endpoints and tissue-relevant NAD⁺ metabolomics.</jats:p>