From a biochemist's perspective, NR holds an edge over NMN since cells cannot directly absorb NMN, and NMN must be converted to NR before entering cells. Thus, [NMN's greater popularity among consumers] may be attributed to the fact that NMN is a more direct precursor in the biosynthesis pathway of NAD+ when viewed from a layman's standpoint. This illusion, probably further fanned by the manufacturers, is responsible for the hyped demands and sales of NMN for consumers that causes more people to be exposed to NMN compared to other NAD+ precursors.

This review provides a comprehensive summary (through Q1 of 2023) of the literature that makes the case for the consumption of NR as a dietary supplement. It then summarizes the challenges of delivering quality NR to consumers using standard synthesis, manufacture, shipping, and storage approaches. It concludes by outlining the advantages of NR borate in these processes.

Nicotinamide riboside may play a role in the reduction of inflammatory states and has shown some potential in the treatment of diverse severe diseases.

NR is more effective than NMN in maintaining DNA integrity in cisplatin-treated cells.

We demonstrate that mice primarily rely on the nicotinamide and NR salvage pathways to generate NAD+ from NMN, while the uptake of intact NMN plays a minimal role.

We report the discovery of a cell-permeable SIRT5 activator, nicotinamide riboside (NR), which activates SIRT5 deacetylase activity with synthetic peptide and physiological substrates. This activation is selective for SIRT5 as it is the only sirtuin family member being activated by NR.

NMN and NR demonstrated protect against diabetes, Alzheimer disease, endothelial dysfunction, and inflammation. They also reverse gut dysbiosis and promote beneficial effects at intestinal and extraintestinal levels.

Most previous studies have shown that exogenous NMN cannot be directly used by cells and needs to be decomposed into NAM and NR.... In our study, the results were in accordance with those of previous studies…

We investigated the effect of NR supplementation on DNA methylation in a double blinded, placebo-controlled trial of 29 human subjects with Parkinson's Disease, in blood cells and muscle tissue. Our results show that NR had no impact on DNA methylation homeostasis, including individuals with common pathogenic mutations in the MTHFR gene known to affect one-carbon metabolism.

NAD+ and 1-methylnicotinamide (MeNAM), which are produced from nicotinamide (NAM), differentially affect human health and aging. Metabolite tracing with 2H4-NAM unveiled the metabolic fates of exogenous NAM and NAD+-derived NAM in cultured cells, mice, and humans. Exogenous NAM produced NAD+ and MeNAM. NAD+- derived NAM was a poor precursor for MeNAM.

Both NAD levels and autophagy activity decline with age, and genetically or pharmacologically boosting either promotes lifespan extension and attenuates age-related pathology in laboratory animals...It was recently shown that autophagy deficiency induces fatal depletion of NAD+/NADH, that is rescuable by NAD precursor supplementation, suggesting a role of autophagy in NAD maintenance. Therefore, NAD and autophagy form a bidirectional feedback relationship which may be linked to longevity and age-related disease, and could represent a target for therapeutic intervention.

NMN administration in overweight or obese, middle-aged and older adults safely increased circulating NAD levels, and significantly reduced total LDL and non-HDL cholesterol, body weight, and diastolic blood pressure.

This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.

CD38 inhibition can be suggested as a strategy to boost NAD+ and would not negatively affect hepatic functions during thermogenesis.

Mitochondrial dysfunction, insulin resistance, metabolic dysregulation and neuroinflammation that contribute to cognitive decline in Alzheimer's Disease...The findings of this study suggest that SIRT3 is a potential therapeutic target for the treatment of AD. Sirtuins, including SIRT3, require NAD+ as a cosubstrate. Administration of NR, a precursor of NAD+, leads to increase in the cellular level of NAD+. In this study, we demonstrate that NR increases the levels of IDE as well as neprilysin and decreases the levels of BACE1 in vivo. Interestingly, NR also increases the levels of SIRT3, probably by autoregulation. NR has been reported to reverse insulin resistance and glucose intolerance in a mouse model for type 2 diabetes. NR has been shown to be effective in reducing neuroinflammation and improve cognition in Alzheimer’s mouse models. Therefore, NR-based treatment can be considered for the treatment of AD with comorbidities.

Ablation of the microbiome by antibiotic treatment increases the uptake and conversion of orally delivered NMN into the NAD metabolome, and that isotope labelled NMN overwhelmingly presents in intestinal tissue in the form of NR. Contrary to the assumption that exogenous NMN treatment raises NAD+ levels solely through its direct incorporation into the NAD metabolome, we show that treatment with isotope labelled NMN increases the levels of endogenous, unlabelled NAD metabolites....Given this evidence for the decomposition of NMN into free Nam prior to its uptake, a key question for the field is why downstream precursors in NAD+ synthesis such as NMN and NR lead to different outcomes compared to Nam alone...

Accumulating evidence unequivocally establish NR far ahead of other NAD+ precursors in improving human wellness. The future will reveal whether ample preclinical investigations can be translated into clinical applications.

Nicotinamide-riboside shifts the differentiation of human primary white adipocytes to beige adipocytes impacting substrate preference and uncoupling respiration through SIRT1 activation and mitochondria-derived reactive species production

The circadian clock is a time-tracking endogenous system which anticipates and coordinates adaptation to daily environmental fluctuations. Circadian misalignment leads to obesity, which is accompanied by reduced levels of the clock-controlled metabolite NAD+. Concomitantly, increasing NAD+ levels is emerging as a therapy for diet-induced obesity and type 2 diabetes; however, the impact of daily fluctuations of NAD+ on these therapies remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ as a therapy for diet-induced metabolic disease in mice...

Alterations in cellular nicotinamide adenine dinucleotide (NAD+) levels have been observed in multiple lifestyle and age-related medical conditions. This has led to the hypothesis that dietary supplementation with NAD+ precursors, or vitamin B3s, could exert health benefits. Among the different molecules that can act as NAD+ precursors, Nicotinamide Riboside (NR) has gained most attention due to its success in alleviating and treating disease conditions at the pre-clinical level. However, the clinical outcomes for NR supplementation strategies have not yet met the expectations generated in mouse models. In this review we aim to provide a comprehensive view on NAD+ biology, what causes NAD+ deficits and the journey of NR from its discovery to its clinical development...