Main Research Findings

1) Nicotinamide riboside was shown to increase cerebral NAD levels and improve brain metabolism, indicating a potential neuroprotective treatment for Parkinson’s disease.

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

 

Selected Data
1) The NADPARK study conducted by the research team of Brakedal et al was designed as a randomized, double-blind, placebo-controlled Phase I clinical trial to evaluate the safety, tolerability, brain penetration, and biological effects of oral nicotinamide riboside (NR) supplementation in individuals with newly diagnosed Parkinson’s disease (PD). The primary objective was to determine whether oral NR could increase nicotinamide adenine dinucleotide (NAD+) concentrations within the brain while producing measurable changes in cerebral metabolism. Secondary objectives included assessing the safety profile of NR, evaluating changes in Parkinson’s disease symptoms, characterizing alterations in systemic NAD metabolism, and investigating molecular pathways associated with mitochondrial function, inflammation, and cellular homeostasis [1].
Thirty participants with newly diagnosed Parkinson’s disease were enrolled after screening thirty-six individuals for eligibility. Eligible participants had not yet begun dopaminergic therapy, allowing investigators to examine the biological effects of NR without interference from standard Parkinson’s medications. Participants were randomly assigned in a 1:1 ratio to receive either oral nicotinamide riboside or an identical placebo. Those assigned to the intervention group received 1,000 mg of NR daily for approximately thirty days, while the placebo group received visually identical capsules containing inactive ingredients. Both participants and investigators remained blinded throughout the study to minimize bias during treatment administration, clinical evaluations, laboratory analyses, and data interpretation. Drug adherence was monitored through capsule counts and participant reporting, demonstrating excellent compliance in both groups throughout the intervention period.
The primary endpoint focused on determining whether orally administered NR could penetrate the central nervous system and increase cerebral NAD levels. To accomplish this, investigators employed phosphorus-31 magnetic resonance spectroscopy (P-MRS), a noninvasive imaging technique capable of quantifying phosphorus-containing metabolites in living brain tissue. Spectroscopy measurements were performed before treatment initiation and repeated following the intervention period. The imaging protocol enabled researchers to quantify cerebral NAD relative to ATP while simultaneously measuring additional phosphorylated metabolites involved in brain energy metabolism. Because Parkinson’s disease is characterized by mitochondrial dysfunction and impaired cellular bioenergetics, demonstrating an increase in cerebral NAD represented a critical mechanistic outcome of the trial [1].
To evaluate changes in functional brain metabolism, participants also underwent fluorodeoxyglucose positron emission tomography (FDG-PET) before and after treatment. FDG-PET measured regional glucose utilization throughout the brain, allowing investigators to determine whether increased NAD availability altered neuronal metabolic activity. Advanced multivariate image analysis using ordinal trends/canonical variates analysis and principal component analysis was applied to identify treatment-related metabolic networks associated with NR supplementation. These analyses enabled researchers to compare metabolic changes between treatment groups while correlating imaging findings with clinical outcomes [1].
Clinical efficacy was assessed using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), including total scores and individual subsections evaluating nonmotor experiences of daily living, motor experiences of daily living, and motor examination. Disease severity was also evaluated using the Hoehn and Yahr staging scale. Safety monitoring included documentation of adverse events, physical examinations, vital signs, routine laboratory testing, and treatment compliance throughout the study period. These assessments ensured that any biological effects of NR supplementation could be interpreted alongside its safety profile.
To investigate systemic effects of NR supplementation, researchers collected cerebrospinal fluid (CSF), skeletal muscle biopsies, peripheral blood mononuclear cells (PBMCs), and blood samples before and after treatment. Comprehensive metabolomic analyses were performed to quantify NAD+, NADH, nicotinamide mononucleotide (NMN), nicotinic acid adenine dinucleotide (NAAD), nicotinamide metabolites, and multiple downstream degradation products associated with NAD biosynthesis. Measuring these metabolites across several tissues allowed investigators to determine whether NR supplementation effectively enhanced NAD metabolism both centrally and peripherally while providing biochemical evidence of treatment adherence [1].
To explore molecular mechanisms underlying NR supplementation, RNA sequencing was performed on skeletal muscle and PBMC samples collected before and after treatment. Differential gene expression analysis identified genes and biological pathways influenced by NR administration. Gene ontology and pathway enrichment analyses were subsequently conducted to determine whether treatment altered pathways related to mitochondrial function, oxidative phosphorylation, protein degradation, lysosomal activity, ribosomal function, RNA processing, antioxidant defense, or cellular metabolism. These transcriptomic analyses provided insight into whether increases in NAD availability translated into broader biological adaptations associated with neuroprotection.
Finally, investigators measured circulating biomarkers associated with mitochondrial dysfunction and neuroinflammation. Serum and cerebrospinal fluid concentrations of growth differentiation factor-15 (GDF15), fibroblast growth factor-21 (FGF21), neurofilament light chain (Nf-L), and an extensive panel of inflammatory cytokines were quantified before and after treatment. Statistical analyses compared baseline and post-treatment values within each treatment group and between groups using paired statistical tests, permutation testing, correlation analyses, and false discovery rate corrections where appropriate. These analyses allowed researchers to evaluate not only biochemical and imaging outcomes but also relationships among cerebral NAD changes, metabolic network activity, inflammatory signaling, and clinical improvement. Together, this multimodal methodology enabled the investigators to characterize the pharmacological, metabolic, molecular, and clinical effects of nicotinamide riboside supplementation in early Parkinson’s disease [1].
2) 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 [2].
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 [2].
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 [2].
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 [2].
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 [2].

 

Discussion
1) The NADPARK trial by Brakedal et al demonstrated that oral NR supplementation was safe, well tolerated, and produced measurable biological effects in patients with newly diagnosed Parkinson’s disease. Thirty participants completed the study, with fifteen randomized to receive NR and fifteen receiving placebo. Adherence to the intervention exceeded 97% in both groups, and the average treatment duration was approximately thirty-two days. No clinically significant abnormalities were observed in laboratory values or vital signs, supporting the tolerability of daily administration of 1,000 mg NR in this patient population [1].
The study’s primary finding was that NR supplementation significantly increased cerebral NAD+ levels, demonstrating that orally administered NR successfully crossed the blood-brain barrier and enhanced brain NAD metabolism. Using P-MRS, investigators observed a significant increase in the brain NAD-to-ATP ratio in the NR group, whereas no change occurred in participants receiving placebo. Although the treatment effect was statistically significant overall, individual responses varied considerably. Ten of the thirteen participants with analyzable imaging data exhibited measurable increases in cerebral NAD, with nine demonstrating increases greater than 10% above baseline. These individuals were classified as MRS responders and became the focus of additional metabolic and clinical analyses. The variability in cerebral NAD elevation suggested that individual biological responsiveness may influence the therapeutic effects of NR supplementation and highlighted the importance of monitoring cerebral NAD levels in future clinical trials.
Functional brain imaging further demonstrated that increased cerebral NAD levels were associated with measurable alterations in brain metabolism. FDG-PET analyses identified a novel NR-related metabolic pattern characterized primarily by reduced glucose metabolism within the caudate nucleus, putamen, globus pallidus, thalamus, and several cortical regions, including the precuneus, medial frontal cortex, anterior cingulate cortex, and posterior cingulate gyrus. This metabolic network was observed almost exclusively in participants who experienced increases in cerebral NAD and was absent in the placebo group. Importantly, greater expression of this treatment-induced metabolic pattern correlated with larger improvements in motor function, suggesting that the observed metabolic changes reflected biologically meaningful adaptations rather than random imaging variability. Furthermore, the newly identified NR metabolic network overlapped with several regions involved in the established Parkinson’s disease-related metabolic pattern, indicating that NR may partially normalize disease-associated alterations in cerebral energy metabolism. These findings support the hypothesis that increasing brain NAD availability can modify neuronal metabolic activity in regions critically involved in Parkinson’s disease pathology [1].
Although the overall MDS-UPDRS scores did not significantly improve across the entire NR-treated group, clinically meaningful trends emerged among participants who exhibited substantial increases in cerebral NAD. These MRS responders demonstrated reductions in total MDS-UPDRS scores, reflecting improvements in both motor and selected non-motor symptoms. When analysis was restricted to participants whose cerebral NAD levels increased by more than 10%, the improvement became statistically significant. Improvements were most apparent within the motor examination and non-motor symptom components of the rating scale, suggesting that enhanced cerebral NAD metabolism may translate into modest clinical benefits in responsive individuals. While these findings should be interpreted cautiously because of the study’s small sample size and short treatment duration, they provide preliminary evidence linking increased brain NAD concentrations with functional neurological improvement [1].
Metabolomic analyses confirmed that NR supplementation substantially enhanced NAD metabolism throughout the body. Cerebrospinal fluid demonstrated marked increases in Me-2-PY, a well-established metabolite of NR and a biomarker of successful NAD biosynthesis, providing additional evidence that NR reached the central nervous system. Skeletal muscle exhibited significant increases in several NAD-related metabolites, including NAAD, Me-Nam, nicotinamide N-oxide, Me-2-PY, and Me-4-PY. Peripheral blood mononuclear cells showed similar elevations in NAAD and Me-Nam. Interestingly, despite these widespread metabolic changes, steady-state concentrations of NAD+ itself remained relatively unchanged in muscle and blood cells, suggesting that NR supplementation increased NAD turnover and metabolic flux rather than simply accumulating NAD within tissues. Importantly, these peripheral metabolic responses occurred in nearly all NR-treated participants regardless of whether measurable increases in cerebral NAD were detected, indicating that systemic NAD metabolism responded more consistently than brain NAD levels.
RNA sequencing further demonstrated that NR supplementation produced widespread molecular adaptations consistent with improved cellular function. In skeletal muscle, fifty-eight genes were differentially expressed following treatment, while thirteen genes were significantly altered in peripheral blood mononuclear cells. Gene enrichment analyses revealed upregulation of pathways involved in mitochondrial respiration, oxidative phosphorylation, antioxidant defense, lysosomal activity, proteasomal degradation, ribosomal function, RNA processing, and protein quality control. Several genes associated with protection against oxidative stress and maintenance of mitochondrial integrity were also significantly increased. These findings suggest that NR supplementation not only alters metabolite concentrations but also activates transcriptional programs supporting mitochondrial health, cellular maintenance, and resistance to oxidative damage, all of which are processes believed to deteriorate during Parkinson’s disease progression [1].
The investigators also observed evidence that NR supplementation may reduce systemic and central nervous system inflammation. Several inflammatory cytokines decreased in both serum and cerebrospinal fluid following treatment, although reductions in cerebrospinal fluid appeared more specific to the NR-treated group. Serum concentrations of GDF15, a biomarker associated with mitochondrial dysfunction, also declined modestly after NR administration, suggesting improved mitochondrial health. In contrast, FGF21 and Nf-L, a marker of neuronal injury, remained unchanged during the study. Collectively, these biomarker findings indicate that NR supplementation may exert anti-inflammatory effects while improving mitochondrial function, although longer studies will be necessary to determine whether these biological changes translate into slower disease progression.
Overall, the NADPARK trial provided the first clinical evidence that oral nicotinamide riboside effectively increases cerebral NAD levels in individuals with Parkinson’s disease while producing measurable metabolic, molecular, and inflammatory changes associated with neuroprotection. The treatment was safe, demonstrated excellent compliance, altered brain energy metabolism, enhanced systemic NAD biosynthesis, activated genes supporting mitochondrial and lysosomal function, and showed preliminary associations with clinical improvement in participants who achieved robust increases in cerebral NAD [1].
2) 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 [2].
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 [2].
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 [2].
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 [2].

 

Disclaimer

**LAB USE ONLY**
*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] Brakedal B, Dölle C, Riemer F, et al. The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease. Cell Metab. 2022;34(3):396-407.e6. doi:10.1016/j.cmet.2022.02.001

[2] 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

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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