Nicotinamide Riboside

Nicotinamide riboside (NR) is a precursor of the cofactor nicotinamide adenine dinucleotide (NAD+) and, together with nicotinamide mononucleotide, is one of the two key NAD+ intermediates studied as supplements. ^{[1] [2]} NR is a marketed NAD+ biosynthetic intermediate, and NMN is its phosphorylated form. ^[3] Like other dietary vitamin B3 components, NR feeds the synthesis of NAD+, and it has been found in vegetables, meat and milk, either in free form or as a metabolite of digested NAD+. ^{[3] [4]} NR, NR co-administered with pterostilbene, and NMN are the most common NAD+-boosting compounds investigated for improving physiological function in humans. ^[5] The first clinical trial of NR, testing the safety and efficacy of human supplementation, was conducted in 2016. ^[1]

NAD+ is a redox coenzyme and also regulates NAD+-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs) and the CD38/157 ectoenzymes. ^[6] NAD+ levels decline during aging, which may cause defects in nuclear and mitochondrial function and contribute to age-associated pathologies. ^[6] Dietary NAD+ precursors such as NR can promote NAD+ biosynthesis and increase intracellular NAD+ levels, which is the rationale for supplementation. ^[4] The pharmacokinetics and metabolic fates of NR and NMN are still under investigation and appear to depend on the tissue distribution and expression of NAD+ biosynthetic enzymes, nucleotidases and presumptive transporters. ^[2] The gut microbiome

In old or diseased animals, restoring NAD+ levels can promote health and extend lifespan. ^[9] A systematic review that identified 80 eligible rodent studies of NAD-related compounds found that NAD+ augmentation in rodent models was frequently associated with improvements in metabolic, mitochondrial, inflammatory and functional outcomes, although effects varied across models and endpoints. ^[10] In the same review of 33 human intervention studies (28 randomized), oral NR and NMN consistently raised circulating or cellular NAD-related metabolites and were generally well tolerated over weeks to months. ^[10] In those human studies, effects on functional, metabolic, vascular and other healthspan-relevant outcomes were heterogeneous and often null or endpoint-specific, so clinical effectiveness for anti-aging outcomes remains inconclusive. ^[10] A critical review of the 25 published research articles on human NR supplementation

NAD+-boosting supplementation with compounds such as NR is safe, tolerable and can increase NAD+ and related metabolites in multiple tissues. ^[5] Dosing regimens and study durations vary greatly across human trials, and small sample sizes limit interpretation of physiological outcomes. ^[5] Data on NAD+ dynamics in human tissues remain sparse, and extrapolating rodent findings to humans is not straightforward. ^[8] Some NAD(H) catabolites generated after precursor supplementation have emerged as biomarkers in physiological disorders and might not be innocuous. ^[3] Much of NAD+ biology remains poorly understood, and unappreciated factors might limit the success or contribute to risks of NAD+ supplementation. ^[7]