Main Research Findings

1) Treatment with nicotinamide riboside in patients with peripheral artery disease improved endurance, emphasizing the compound’s potential to reduce oxidative stress.

2) Administration of nicotinamide riboside was shown to reduce levels of circulating inflammatory cytokines without altering mitochondrial bioenergetics.

 

 

Selected Data
1) The NICotinamidE riboside with and without resveratrol to improve functioning in peripheral artery disease (NICE) study performed by McDermott et al was designed as a randomized, double-blind, placebo-controlled clinical trial to determine whether oral NR, either alone or in combination with resveratrol, could improve walking performance and skeletal muscle health in individuals with lower extremity peripheral artery disease (PAD). The study was conducted using a parallel-group design in which participants were randomly assigned to receive one of three interventions for six months: 1,000 mg of nicotinamide riboside daily, 1,000 mg of nicotinamide riboside combined with 125 mg of resveratrol daily, or a matching placebo. The primary objective was to determine whether increasing NAD+ availability through NR supplementation could improve functional walking capacity in patients with PAD, while also examining whether resveratrol provided additional benefit by enhancing SIRT1 activity and mitochondrial function [1].
Participants were recruited through multiple community-based strategies, including advertisements on public transportation, mailed postcards to adults aged 50 years and older, and direct contact with individuals who had previously participated in PAD-related research and expressed interest in future studies. Eligibility required documented peripheral artery disease, defined primarily by an ankle-brachial index (ABI) of 0.90 or less in either leg or by objective evidence of significant lower extremity arterial disease obtained from vascular laboratory testing or angiographic imaging. Additional vascular criteria, including abnormal toe-brachial index values, duplex ultrasound findings demonstrating at least 70% arterial stenosis, or significant post-exercise declines in ABI, were also accepted. Importantly, participants with or without classic intermittent claudication symptoms were eligible because many individuals with PAD experience atypical or no exertional leg symptoms despite having significant functional impairment [1].
Exclusion criteria were extensive and included critical limb ischemia, major lower extremity amputation, inability to ambulate independently, active foot ulcers, severe kidney or liver disease, pregnancy, dementia, recent participation in supervised exercise programs or clinical trials, planned vascular surgery, recent revascularization procedures, and recent use of high-dose nicotinamide riboside, vitamin B3, niacin, or resveratrol supplements. These criteria ensured a relatively homogeneous study population while minimizing factors that could confound treatment effects.
Before randomization, all participants completed a two-week placebo run-in period designed to identify individuals unlikely to comply with study procedures. During this phase, participants were instructed to take five placebo capsules daily, corresponding to the dosing schedule used during the intervention. Individuals who consumed less than 70% of the prescribed placebo capsules were excluded before randomization. Those who successfully completed the run-in were randomly assigned in equal proportions to one of the three treatment groups using a computer-generated randomization schedule based on randomly permuted block sizes of four and six. Participants assigned to the NR group received two 250-mg NR capsules twice daily, while those assigned to the combined treatment group received the same NR regimen plus one 125-mg resveratrol capsule daily. Participants in the placebo group received visually identical placebo capsules according to the same dosing schedule. Medication adherence was monitored through pill counts, medication logs, and scheduled follow-up visits at three and six months [1].
The primary outcome of the trial was the change in six-minute walk distance from baseline to six months. The six-minute walk test was conducted using a standardized protocol in which participants walked repeatedly along a 100-foot hallway for six minutes while attempting to cover the greatest possible distance. The investigators identified an improvement of approximately eight meters as the minimum clinically important difference and twenty meters as a large clinically meaningful improvement. Secondary outcomes included changes in six-minute walk distance after three months, maximal treadmill walking time measured using the Gardner-Skinner treadmill protocol, self-reported walking ability assessed using the Walking Impairment Questionnaire (WIQ) distance score, objectively measured daily physical activity using ActiGraph accelerometers, and several skeletal muscle biopsy outcomes. Exploratory outcomes included WIQ speed and stair-climbing scores, Short Form-36 Physical Functioning scores, and additional skeletal muscle measurements. These multiple outcome measures allowed investigators to evaluate both objective and subjective changes in physical function while exploring potential biological mechanisms underlying treatment effects.
To investigate the physiological effects of NR supplementation, gastrocnemius muscle biopsies were obtained from a subset of participants at baseline and after six months of treatment. Muscle samples were collected from the medial gastrocnemius under local anesthesia, immediately frozen, and stored for laboratory analysis. High-performance liquid chromatography was used to quantify skeletal muscle NAD+ concentrations, while immunohistochemical techniques measured muscle satellite cell abundance and muscle fiber composition using established antibodies targeting Pax7, type I myosin, and laminin. Additional baseline measurements included height, weight, body mass index, ankle-brachial index, smoking history, medical comorbidities, leg symptom classification, and health-related quality of life. Participants also completed validated questionnaires assessing walking impairment and underwent treadmill testing, although some treadmill assessments were limited because of restrictions imposed during the COVID-19 pandemic. Throughout the study, investigators collected information regarding adverse events and serious adverse events using standardized monthly questionnaires to evaluate the safety and tolerability of the interventions [].
Statistical analyses followed the intention-to-treat principle, with participants analyzed according to their randomized treatment assignment regardless of adherence. Mixed models for repeated measures were used to analyze changes in six-minute walk distance across baseline, three-month, and six-month assessments while adjusting for age, sex, race, and baseline walking performance. Analysis of covariance was used for secondary outcomes, including treadmill performance, Walking Impairment Questionnaire scores, physical activity, and muscle biopsy measurements, with adjustments for baseline values and demographic variables. Additional post hoc analyses examined outcomes among participants demonstrating at least 75% adherence to the prescribed study medications, providing insight into the relationship between treatment compliance and clinical response. Overall, the comprehensive study design combined rigorous clinical assessments, objective functional testing, muscle biology, and statistical methodology to evaluate whether nicotinamide riboside supplementation could improve mobility and skeletal muscle health in patients with peripheral artery disease [1].
2) The study by Elhassan et al was designed as a randomized, double-blind, placebo-controlled crossover clinical trial to determine whether oral NR supplementation could increase the skeletal muscle NAD⁺ metabolome in older adults and whether these biochemical changes would influence mitochondrial function, muscle metabolism, physical performance, and systemic inflammation. Previous animal studies had demonstrated that NR supplementation improved mitochondrial function, enhanced skeletal muscle health, and restored declining NAD⁺ concentrations associated with aging. However, evidence in humans was limited, particularly regarding whether orally administered NR could effectively reach skeletal muscle and produce measurable physiological effects. Therefore, the investigators designed a carefully controlled experimental medicine study to examine both the metabolic and functional consequences of short-term NR supplementation in healthy older men [2].
Twelve healthy men between 70 and 80 years of age were recruited for participation. The investigators specifically selected an elderly population because age-related declines in NAD⁺ metabolism have been proposed as an important contributor to mitochondrial dysfunction, sarcopenia, and reduced physiological resilience. Participants were generally healthy, with a median age of approximately 75 years and a median body mass index of 26.6 kg/m², placing most individuals within the slightly overweight range. Individuals with significant metabolic disease, uncontrolled cardiovascular disease, or other major illnesses that could influence skeletal muscle metabolism were excluded to minimize confounding variables. Baseline demographic characteristics, routine laboratory values, and clinical assessments confirmed that participants represented a relatively healthy aging population, allowing investigators to examine the direct biological effects of NR supplementation independent of severe underlying disease [2].
The trial employed a randomized crossover design in which every participant completed both the nicotinamide riboside and placebo treatment periods, thereby allowing each individual to serve as his own control. Participants were randomly assigned to begin with either NR or placebo and then crossed over to the alternate treatment following a 21-day washout period intended to eliminate any residual treatment effects. Both investigators and participants remained blinded to treatment allocation throughout the study. Nicotinamide riboside chloride (Niagen) and placebo capsules were supplied in identical 250-mg capsules. Participants received a total daily dose of 1 g NR by taking two capsules each morning and two capsules each evening for 21 consecutive days. Compliance was monitored throughout the intervention, and all twelve participants successfully completed every study visit and experimental assessment according to the study protocol without withdrawals or protocol violations.
The study protocol consisted of five separate clinical visits. The initial visit included participant screening, medical evaluation, informed consent, and baseline laboratory testing. Visits two, three, and five involved extensive physiological testing before and after each intervention period, while visit four occurred following the washout phase and included collection of fasting blood and urine samples before participants crossed over to the alternate treatment. At the primary assessment visits, participants underwent fasting blood collection, gastrocnemius skeletal muscle biopsy, oral glucose tolerance testing, indirect calorimetry, venous occlusive plethysmography to assess muscle blood flow, and arteriovenous sampling techniques to quantify skeletal muscle substrate utilization. This comprehensive protocol enabled investigators to examine biochemical, molecular, physiological, and functional responses to NR supplementation within the same participants [2].
A major component of the investigation focused on determining whether oral NR increased skeletal muscle NAD⁺ metabolism. Muscle biopsy specimens were obtained using a percutaneous needle biopsy technique under local anesthesia. Samples were immediately processed and stored for detailed metabolomic analyses. Targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to quantify multiple metabolites within the NAD⁺ metabolic pathway, including nicotinamide riboside, nicotinamide mononucleotide (NMN), nicotinic acid adenine dinucleotide (NAAD), nicotinamide (NAM), NAD⁺ itself, and several downstream methylated nicotinamide metabolites. Similar metabolomic analyses were performed using fasting whole blood and 24-hour urine samples, allowing investigators to compare tissue-specific responses to NR supplementation while evaluating systemic NAD⁺ metabolism and metabolite clearance. Because blood, skeletal muscle, and urine samples were all analyzed using the same targeted analytical platform, investigators were able to comprehensively characterize changes in NAD⁺ metabolism throughout the body.
To investigate whether changes in the NAD⁺ metabolome influenced skeletal muscle biology, RNA sequencing was performed on muscle biopsy specimens collected before and after NR supplementation. Differential gene expression analysis identified genes that were significantly upregulated or downregulated following treatment. Gene Set Enrichment Analysis (GSEA) and Gene Ontology analyses were subsequently used to determine whether specific biological pathways were significantly altered by NR administration. Quantitative real-time polymerase chain reaction (qPCR) was performed to validate selected transcriptional changes, while immunoblotting confirmed expression of several proteins associated with glycolytic metabolism, mitochondrial function, and NAD⁺-related pathways. These molecular techniques allowed investigators to determine whether increased NAD⁺ availability translated into coordinated alterations in skeletal muscle gene expression [2].
The investigators also conducted an extensive evaluation of mitochondrial function using several complementary physiological techniques. High-resolution respirometry was performed on permeabilized skeletal muscle fibers to quantify oxidative phosphorylation supported by complex I and complex II substrates, maximal respiratory capacity, and fatty acid oxidation. Citrate synthase enzyme activity and mitochondrial DNA copy number were measured as indicators of mitochondrial content and density. Western blotting was used to quantify proteins involved in the electron transport chain as well as global protein acetylation, providing indirect assessment of sirtuin activity. Muscle strength was evaluated using standardized hand-grip dynamometry, while indirect calorimetry measured whole-body energy expenditure and respiratory exchange ratio during fasting and following oral glucose administration. Investigators further assessed forearm muscle blood flow using venous occlusive plethysmography and employed arteriovenous difference techniques to measure oxygen consumption, carbon dioxide production, glucose uptake, and lactate release across skeletal muscle.
Systemic metabolic responses were evaluated using oral glucose tolerance testing, measurements of insulin, nonesterified fatty acids, blood pressure, lipid profiles, and homeostatic model assessment of insulin resistance (HOMA-IR). Finally, circulating inflammatory biomarkers were quantified to determine whether NR exerted anti-inflammatory effects. Collectively, these biochemical, molecular, physiological, and metabolic methodologies enabled investigators to comprehensively evaluate the effects of oral nicotinamide riboside supplementation on skeletal muscle metabolism and systemic physiology in healthy older adults [2].

 

Discussion
1) The NICE trial completed by researchers McDermott et al demonstrated that NR supplementation produced clinically meaningful improvements in walking performance among individuals with lower extremity PAD, while the addition of resveratrol did not provide any significant advantage over NR alone. The primary outcome of the trial was the change in six-minute walk distance after six months of treatment. Participants receiving nicotinamide riboside alone experienced a mean improvement of approximately seven meters from baseline, whereas participants assigned to placebo declined by more than ten meters during the same period. After adjustment for baseline characteristics, the between-group difference favored NR by 17.6 meters, meeting the investigators’ prespecified threshold for statistical significance and representing a clinically meaningful improvement in functional walking capacity [1].
In contrast, participants receiving nicotinamide riboside combined with resveratrol demonstrated only a modest improvement relative to placebo, with a between-group difference of approximately 3.7 meters that did not reach statistical significance. These findings indicated that NR alone effectively improved walking endurance in individuals with PAD, whereas adding resveratrol did not enhance the treatment response. Because walking impairment is one of the most disabling manifestations of PAD, these results suggest that increasing NAD+ availability through NR supplementation may improve functional mobility in this patient population.
Secondary outcome analyses further supported the beneficial effects of nicotinamide riboside on physical performance. After only three months of treatment, both the NR-alone group and the NR plus resveratrol group demonstrated significant improvements in six-minute walk distance compared with placebo, improving by approximately 22.4 meters and 20.6 meters, respectively. These gains exceeded the established minimum clinically important difference for the six-minute walk test, suggesting that participants experienced noticeable functional benefits relatively early during treatment. At six months, participants receiving NR alone also demonstrated significantly greater improvements in maximal treadmill walking time compared with placebo, increasing endurance by approximately two additional minutes. However, neither NR alone nor the combined therapy significantly improved Walking Impairment Questionnaire distance scores, objectively measured daily physical activity, or accelerometer-derived activity counts. Thus, although NR enhanced supervised measures of walking endurance, these improvements were not accompanied by measurable increases in participants’ habitual physical activity or self-reported walking ability during everyday life [1].
When investigators combined participants from both NR treatment groups for additional analyses, they observed similar overall trends. The combined NR-treated participants exhibited significantly greater improvements in six-minute walk performance after three months and significantly longer treadmill walking times after six months compared with placebo-treated participants. However, when evaluating six-month six-minute walk performance using the combined treatment groups, the overall improvement did not quite reach the prespecified significance threshold because the relatively poorer adherence among participants receiving NR plus resveratrol reduced the overall treatment effect. Likewise, no significant improvements were observed in Walking Impairment Questionnaire scores or objectively measured physical activity for the combined intervention groups. These findings suggested that the beneficial effects of NR were most apparent when participants consistently adhered to supplementation and when walking performance was measured under standardized testing conditions rather than through self-reported or free-living activity measures [1].
Muscle biopsy analyses provided important mechanistic insights into the biological effects of nicotinamide riboside supplementation. Compared with placebo, participants receiving NR alone demonstrated a significant increase in gastrocnemius muscle satellite cell abundance, indicating enhanced regenerative capacity within skeletal muscle. Satellite cells play an essential role in muscle repair, adaptation, and maintenance, suggesting that NR may improve muscle health independently of measurable changes in muscle metabolism. In contrast, neither NR alone nor NR combined with resveratrol significantly altered skeletal muscle NAD+ concentrations or muscle fiber composition, including the proportion of type I muscle fibers. Similarly, there were no significant improvements in exploratory outcomes such as Walking Impairment Questionnaire speed scores, stair-climbing scores, or health-related quality of life measured using the Short Form-36 Physical Functioning scale. Although these findings indicate that NR produced only modest changes in skeletal muscle biology, the increase in satellite cell abundance supports the possibility that improved muscle regeneration contributed to enhanced walking performance.
Among participants who consumed at least 75% of their prescribed study medication, nicotinamide riboside alone improved six-minute walk distance by approximately 31 meters compared with placebo after six months, while NR combined with resveratrol improved walking distance by nearly 27 meters. These improvements were considerably larger than those observed in the primary intention-to-treat analysis and exceeded thresholds generally considered to represent large clinically meaningful improvements in walking performance. Participants with high adherence in both treatment groups consistently improved their walking endurance, whereas individuals with lower adherence experienced declines similar to those observed in the placebo group.
Overall, the NICE trial provided the first randomized clinical evidence that nicotinamide riboside supplementation can improve objective walking performance in patients with peripheral artery disease. Participants receiving NR demonstrated clinically meaningful improvements in six-minute walk distance and treadmill walking endurance, along with increased skeletal muscle satellite cell abundance, suggesting beneficial effects on both physical function and muscle regeneration. The addition of resveratrol did not improve efficacy beyond NR alone, and researchers concluded that the findings justify larger clinical trials to confirm the therapeutic potential of nicotinamide riboside as a novel intervention for improving mobility and physical function in individuals with peripheral artery disease [1].
2) The study conducted by Elhassan et al demonstrated that oral NR supplementation was safe, well tolerated, and effectively enhanced the NAD⁺ metabolome in healthy older adults, although these biochemical changes did not translate into measurable improvements in skeletal muscle mitochondrial function or systemic metabolic health over the three-week intervention period. All participants successfully completed both treatment phases of the randomized crossover trial, resulting in complete follow-up data for every subject. Compliance with supplementation was excellent, and no clinically significant adverse events occurred during either the NR or placebo periods. Routine hematological measurements and clinical chemistry analyses, including assessments of renal, hepatic, and thyroid function, remained within normal ranges throughout the study, confirming the favorable safety profile of 1 g/day of nicotinamide riboside in elderly individuals [2].
Targeted metabolomic analyses confirmed that oral NR substantially altered NAD⁺ metabolism within skeletal muscle, whole blood, and urine, demonstrating that orally administered nicotinamide riboside successfully reached human skeletal muscle tissue. Although skeletal muscle NAD⁺ concentrations themselves were not significantly increased after supplementation, several metabolites indicative of enhanced NAD⁺ biosynthesis increased markedly. The concentration of nicotinic acid adenine dinucleotide (NAAD), regarded as a highly sensitive biomarker of increased NAD⁺ synthesis, approximately doubled following NR supplementation compared with placebo. Likewise, several downstream nicotinamide clearance metabolites increased dramatically within skeletal muscle, indicating enhanced NAD⁺ turnover and metabolism rather than simple accumulation of NAD⁺ itself. These findings provided the first direct evidence that oral NR effectively augments the skeletal muscle NAD⁺ metabolome in older humans, despite relatively stable tissue NAD⁺ concentrations.
Comparable metabolic changes were observed in circulating blood and urine. Whole blood analyses demonstrated more than a two-fold increase in circulating NAD⁺ concentrations following NR supplementation, accompanied by significant elevations in NMN, NAAD, and several methylated nicotinamide metabolites. In contrast, circulating nicotinamide concentrations remained unchanged, suggesting that orally administered NR increased NAD⁺ synthesis without causing sustained elevations in nicotinamide itself. Urinary metabolomic analyses similarly demonstrated substantial increases in nicotinamide riboside, NAR, nicotinamide, and multiple downstream clearance products, indicating enhanced excretion of excess NAD⁺ metabolites. Together, these findings confirmed robust systemic activation of NAD⁺ metabolism following supplementation and established that skeletal muscle, blood, and urine each exhibited distinct but coordinated metabolic responses to oral NR administration [2].
RNA sequencing of skeletal muscle biopsies revealed widespread transcriptional adaptations following NR supplementation. Differential gene expression analysis identified 690 significantly upregulated genes and 398 significantly downregulated genes relative to baseline. Gene set enrichment analysis demonstrated that the most consistently downregulated pathways involved mitochondrial function, glycolysis, oxidative phosphorylation, tricarboxylic acid cycle activity, oxidation-reduction processes, and broader cellular energy metabolism. Conversely, genes involved in cell adhesion, actin cytoskeleton organization, cellular motility, and biological adhesion were significantly upregulated. Quantitative PCR confirmed many of these transcriptional changes, while immunoblotting showed no corresponding changes in the abundance of several glycolytic enzymes or proteins involved in NAD⁺ metabolism. These findings suggested that NR altered transcriptional regulation within skeletal muscle despite producing relatively little change in downstream protein expression over the short duration of supplementation [2].
Despite these molecular changes, extensive physiological assessments demonstrated no measurable improvements in skeletal muscle mitochondrial bioenergetics. High-resolution respirometry revealed no significant differences between NR and placebo in complex I-mediated oxidative phosphorylation, complex II-supported respiration, maximal respiratory capacity, or fatty acid-supported mitochondrial respiration. Likewise, citrate synthase activity, mitochondrial DNA copy number, and expression of mitochondrial electron transport chain proteins remained unchanged after supplementation. Measurements of global protein acetylation also showed no evidence that increased NAD⁺ availability enhanced sirtuin-mediated deacetylase activity within skeletal muscle. Functional assessment of muscle performance using hand-grip dynamometry similarly demonstrated no improvement in maximal grip strength or body weight-adjusted strength after three weeks of treatment. Collectively, these findings indicated that although NR significantly altered skeletal muscle NAD⁺ metabolism, these biochemical changes did not translate into detectable improvements in mitochondrial respiratory function or muscle strength during the relatively short intervention period.
Additional physiological investigations further demonstrated that NR supplementation had minimal effects on skeletal muscle metabolism and systemic cardiometabolic function. Venous occlusive plethysmography showed no differences in forearm muscle blood flow between NR and placebo under fasting conditions or following oral glucose administration. Similarly, arteriovenous difference measurements revealed no significant treatment-related changes in skeletal muscle oxygen consumption, carbon dioxide production, glucose uptake, or lactate release. Whole-body metabolic assessments showed no improvements in fasting glucose concentrations, insulin levels, insulin resistance as measured by HOMA-IR, blood pressure, lipid profiles, body weight, respiratory exchange ratio, or metabolic flexibility during oral glucose tolerance testing. These results demonstrated that short-term NR supplementation did not significantly influence substrate utilization, glucose metabolism, or cardiovascular risk factors in this cohort of healthy older adults, despite successfully increasing systemic NAD⁺ availability [2].

 

Figure 1: Changes in systemic metabolic parameters following administration of experimental treatments
One of the most notable findings of the study was the significant reduction in several circulating inflammatory cytokines following NR supplementation. Serum concentrations of inflammatory cytokines decreased significantly after treatment, indicating that NR exerted measurable anti-inflammatory effects even in otherwise healthy older individuals. In contrast, concentrations of interleukin-12, interleukin-8, interferon-gamma, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, and high-sensitivity C-reactive protein remained unchanged. Although the mechanisms responsible for these anti-inflammatory effects were not directly investigated, the authors proposed that increased NAD⁺ availability may suppress age-related inflammatory signaling through pathways involving CD38 activity and improved cellular NAD⁺ homeostasis. Because chronic low-grade inflammation is recognized as a hallmark of biological aging, these findings suggested that the anti-inflammatory actions of NR may represent one of its most clinically relevant biological effects [2].

 

Figure 2: Changes in levels of proinflammatory cytokines following administration of experimental treatments.
Overall, the investigators concluded that oral nicotinamide riboside effectively augments the human skeletal muscle NAD⁺ metabolome and induces widespread transcriptional changes while significantly reducing circulating inflammatory cytokines in healthy older adults. However, these molecular and metabolic adaptations were not accompanied by improvements in mitochondrial bioenergetics, skeletal muscle function, substrate utilization, or systemic cardiometabolic health during the three-week supplementation period. The authors suggested that the absence of physiological improvements may reflect relatively preserved baseline NAD⁺ status in this healthy aging cohort rather than an inability of NR to reach skeletal muscle. They further proposed that greater benefits may be observed in populations experiencing metabolic stress, chronic inflammation, frailty, or age-related disease, where tissue NAD⁺ depletion is more pronounced. Consequently, the study established that nicotinamide riboside is biologically active and well tolerated in older humans while providing important mechanistic evidence supporting future investigations in populations with pathological conditions characterized by impaired NAD⁺ metabolism and chronic inflammation [2].

 

Disclaimer

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*This information is for educational purposes only and does not constitute medical advice. THE PRODUCTS DESCRIBED HEREIN ARE FOR RESEARCH USE ONLY. All clinical research must be conducted with oversight from the appropriate Institutional Review Board (IRB). All preclinical research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA).

 

Citation

[1] McDermott MM, Martens CR, Domanchuk KJ, et al. Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial. Nat Commun. 2024;15(1):5046. Published 2024 Jun 13. doi:10.1038/s41467-024-49092-5

[2] Elhassan YS, Kluckova K, Fletcher RS, et al. Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD+ Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep. 2019;28(7):1717-1728.e6. doi:10.1016/j.celrep.2019.07.043

Mechanisms of NRC Niagen

Nicotinamide riboside, more commonly referred to as niagen, is a vitamin B3 alternative known for its ability to convert to NAD+ As NAD+ levels naturally decrease with age, many supplements that promote substrate conversion to NAD+ are labeled as “anti-aging”. That being said, NAD+ is an important part of many biological processes and helps to combat age-related decline. Additionally, the presence of NAD+ helps to activate various enzymes that are involved in the process of healthy aging. One of the main groups of enzymes are referred to as sirtuins. Evidence has found that sirtuins improve overall health and increase lifespan. Animal-based studies have indicated that sirtuins can potentially repair DNA, improve resistance to stress, and reduce inflammation.

Furthermore, NAD+ is crucial to healthy aging of brain cells due to its ability to regulate the production of proliferator-activated receptor-γ coactivators (PGC-1𝜶). PGC-1𝜶 is a protein that is crucial to protecting brain cells against oxidative stress and impaired mitochondrial functioning. This is important to note considering that dysfunction throughout the mitochondria can facilitate the development of diseases such as Parkinson’s and Alzheimer’s.

Amyloid-𝜷 plaques are one of the core components of Alzheimer’s Disease as it has the tendency to trigger neurodegeneration by decreasing expression of the vitamin D receptor (VDR) protein. Researchers Wang et. Al examined how PGC-1𝜶 has the potential to act as a coactivator for VDR in an attempt to protect against oxidative stress. In order to determine the involvement of PGC-1𝜶 in the development of Alzheimer’s Disease, 6 month old mice with deficient levels of PGC-1𝜶 and VDR were studied. Results reported that low expression of PGC-1𝜶 led to decreased VDR expression and increased oxidative stress in the neurons. These mice were then compared to subjects with induced overexpression of PGC-1𝜶. The overexpression led to improvement of VDR expression and a reduction of the amyloid-𝜷 plaques. The results of this study indicate that niagen is capable of reducing instances of Alzheimer’s Disease as the compound is efficiently converted into NAD+, and in turn promotes the expression of PGC-1𝜶 (https://pubmed.ncbi.nlm.nih.gov/33373677/).

This claim was supported by the work of Gong et. Al in which they state that niagen is an NAD+ precursor that increases PGC-1𝜶 levels in the brain. The researchers tested the hypothesis that niagen can potentially treat Alzheimer’s Disease because PGC-1𝜶 is considered a crucial step of Amyloid-𝜷 regulation due to its effects on 𝜷-secretase (BACE-1) degradation. The study was conducted on the Tg2576 AD mouse model and results were measured through use of behavioral analyses, gene silencing, and electrophysiological recordings. Results reported that after daily administration of 250 mg/kg of niagen over the course of 3 months, NAD+ levels in the cerebral cortex had increased while there was a drastic decrease in any measured cognitive deterioration. Additional findings explained that applying niagen to hippocampal slices had the tendency to abolish deficits in long term potentiation as well. Furthermore, the study was able to confirm that niagen promotes the expression of PGC-1𝜶, resulting in enhanced degradation of BACE-1 and decreased production of Amyloid-𝜷. Overall, the researchers were able to conclude that niagen could be an effective treatment for Alzheimer’s Disease due to its mechanism of action (https://pubmed.ncbi.nlm.nih.gov/23312803/).

In addition to niagen’s potential to combat Alzheimer’s Disease, evidence has shown the compound could potentially reverse the degeneration of skeletal muscle due to its role as an NAD+ precursor. Availability of NAD+ is known to decrease during periods of genotoxic stress. While low NAD+ levels in the brain lead to decreased expression of PGC-1𝜶 and can result in the production of Amyloid-𝜷 plaques, the effect of low NAD+ levels in skeletal muscle tissues is unclear. Researchers Frederick et. Al conducted a study to try to understand this pathway. It initially began by depleting Nampt, an enzyme involved in NAD+ salvaging, from the skeletal muscles of mice.

The knockout mice experienced an 85% decrease in NAD+ levels as well as fiber degeneration and a loss of muscle strength and endurance. After observing this change the subjects were administered niagen, which immediately helped improve functional deficits and muscle mass. It’s important to note that these benefits were seen in the animals without a drastic increase in intramuscular NAD+. Further research found that overexpression of Nampt preserved the NAD+ pool as well as the exercise capacity and endurance of the mice. Overall, Frederick et. Al were able to conclude that NAD+ is crucial for maintaining healthy muscle mass and that the compound is regulated through the administration of niagen (https://pubmed.ncbi.nlm.nih.gov/27508874/).

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