NR supplementation blunts Th1 and Th17 immune responsiveness in healthy volunteers and in psoriasis...This study has expanded our understanding of NAD+ boosting in the adaptive immune system with the focus on NR blunting Th17 immune activity...The finding from this study that NR blunts Th1 and Th17 immune responsiveness in an ex vivo study supports that the utilization of NAD+ boosting could potentially be employed as a supplemental therapy in this disease. The concept is now being explored in vivo, where mild to moderate psoriasis patients are being investigated in a placebo-controlled study...

NAD + precursors prevent COVID-19 plasma-induced endothelial cell dysfunction and hold promise as therapies for COVID-19-related vascular dysfunction...Co-incubation with NR abolished COVID-19-induced reductions in NO production and oxidative stress (both p > 0.05 vs. control). Co-treatment with NMN produced similar results. Our findings suggest the circulating milieu of patients with COVID-19 promotes endothelial cell dysfunction, characterized by lower NO bioavailability, greater ROS bioactivity, and NAD(+) depletion. Supplementation with NAD(+) precursors may exert a protective effect against COVID-19-evoked endothelial cell dysfunction and oxidative stress.

This mouse study is the first to show NR's potential to be a therapeutic agent for delayed effects of acute radiation exposure in patients receiving radiotherapy and exposed populations.

This mouse study is the first to show NR's potential to be a therapeutic agent for delayed effects of acute radiation exposure in patients receiving radiotherapy and exposed populations.

The aim is to slow down Alzheimer's disease by using personalized dietary NMN to affect the composition of the AD intestinal flora

Niacin is associated with improved body composition (characterized by increased muscle mass and decreased fat content) and improved glucose homeostasis in dietary doses. Dietary niacin supplementation is a feasible way to alleviate age-related muscular loss.

Pharmacologic treatments that target oxidative stress, inflammation, and mitochondrial exhaustion may provide neurologic benefit in ataxia-telangiectasia.

We used human umbilical vein endothelial cells (HUVECs) to demonstrate that NMN inhibits oxidative stress-induced damage by activating the sirtuin 1 (SIRT1)/NAD(P)H: quinone oxidoreductase 1 (NQO-1) axis. We found that NMN inhibited H2O2-induced cytotoxicity and senescence-associated protein expression, such as p16 and p21. Furthermore, NMN prevented H2O2-induced actin cytoskeletal disorganization via inhibiting reactive oxygen species (ROS) production. NMN increased NQO-1 mRNA and protein expression that in turn was abrogated by SIRT1 inhibition, suggesting that NMN-inducible NQO-1 was associated with SIRT1 activity. SIRT1 and NQO-1 inhibition attenuated the inhibitory effect of NMN on H2O2-inducible cytotoxicity, senescence-related protein upregulation, and actin cytoskeletal disorganization. Our findings provide new insights into the mechanism by which NMN exerts protective effects against vascular oxidative stress.

The present study revealed that oral NR administration (1000 mg/kg daily) exerted substantial axonal protection in ocular hypertension optic nerve damage. We also found apparent protective effects on retinal nerve fibers in this model... to our knowledge, this is the first study demonstrating axonal protection of NR against glaucomatous damage in both the optic nerve and retina...Since axonal degeneration precedes RGC body death in glaucoma, oral NR administration may help to inhibit further axonal degeneration, thereby preventing additional RGC death.

We have identified NAMPT as a dependency in rhabdomyosarcoma (RMS), a malignancy for which novel therapies are critically needed. Here we describe the effect of NAMPT inhibition on RMS proliferation and metabolism in vitro and in vivo….Most cell lines experienced profound depletion of ATP with subsequent irreversible necrotic cell death. Importantly, loss of NAD and glycolytic activity were confirmed in orthotopic in vivo models, which exhibited complete tumor regressions...RMS is highly vulnerable to NAMPT inhibition.

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.

Meta-analyses of [29 random controlled trials with 8,664 participants]...indicated a significant reduction in systolic...and diastolic blood pressure...with the NAD+ precursors supplementation compared with the control group. In addition, a greater effect of supplementation with NAD+ precursors in reducing blood pressure (BP) were observed with the highest dose (≥2 g) and duration of the intervention (>12 weeks)...These findings suggest that NAD+ precursor supplementation might have a beneficial effect on cardiovascular risk factors such as blood pressure, C-reactive protein concentration and carotid intima-media thickness.

Overall, we show that the increased myelin production that follows NAM treatment in vivo is accompanied by a decrease in both astrocyte and microglia accumulation at the lesion site. Our data indicate that NAM influences astrocytes and microglia directly, in favor of the remyelination process by promoting a less inflammatory environment.

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.

This study demonstrated that...NAD+ metabolism governs the anti-inflammatory function of mesenchymal stem cells during inflammation.

Increasing the level of NAD+ in psoriatic lesions could be considered as a therapeutic option. We have already shown that the topical composition of NAD+ can effectively be used for treatment of psoriasis, with effects comparable to conventional therapy with anthralin. More recent research has confirmed that the augmentation of NAD+ can result in amelioration of psoriasis-like dermatitis . This effect is linked to elevated Sirt1 activity, which is an NAD+-dependent process.

NR administration improves the stemness-related genes expression in ASCs and mitigates their propensity for adipocyte differentiation. These results suggest that NR treatment holds promise as a potential strategy to rejuvenate the stemness of aged adipose-derived stem cells.

Inhibiting the rate-limiting enzyme nicotinamide phosphoribosyl transferase (NAMPT) to block NAD+ synthesis has been extensively studied preclinically to restrain tumor growth. However, early-phase clinical trials of NAMPT inhibitors yielded modest results with significant toxicities. Alternative methods, such as identifying sensitive populations and combining NAMPT inhibitors with other therapies, are warranted. Furthermore, recent studies have revealed new concepts of NAD+ metabolism, including its involvement in signal transduction, posttranslational modifications, and epigenetic regulation. For instance, NAD+ promoted the expression of programmed cell death 1 ligand 1 (PD-L1) through epigenetic mechanisms in hepatocellular carcinoma (HCC), contributing to tumor immune evasion. Combining NAD+ replenishment with anti-PD-L1 therapy effectively repressed tumor growth in preclinical models. The controversial role of NAD+ metabolism reflects the complexity of regulating redox metabolism for cancer therapy.

While most COVID-19 therapeutic efforts have understandably focused on vaccines from the public health perspective, less emphasis was directed at other therapeutic options either independently or conjointly with vaccination. Current evidence strongly suggests that theKynurenine pathway of tryptophan metabolism is the top target of COVID-19 infection and a major determinant of its pathophysiology... Depletion of NAD+ and ATP are the end result of COVID-19 infection...Replenishing NAD+ levels (in COVID) can be achieved by using suitable NAD+ precursors. Careful choice of precursors is however important. Use of Trp is inadvisable for two reasons: increased production of Kyn metabolites and the powerful AhR agonist IPA. Similarly, nicotinic acid is unlikely to contribute to NAD+ replenishment, given that the Preiss-Handler pathway will also be blocked. This leaves nicotinamide or its riboside...

Nicotinamide riboside...is a different form of vitamin B3, which in the brain promotes the formation of NAD+, which usually declines with aging and neurodegeneration. A phase I clinical trial studied the effects of nicotinamide riboside (NR) oral intake (1000 mg for 30 days) in individuals with PD (clinicaltrials.gov: NCT03816020). Overall, NR treatment was well tolerated, promoting increased NAD levels in the brain (MRI scan and CSF) and increased brain glucose metabolism . The clinical benefits were associated with increased NAD levels and increased mitochondrial activity. This study advanced to phase II where the PD patients will take NR for up to 1 year; the results of this study are expected in 2024.

We demonstrate a significant depletion in the NAD + levels within the intestinal epithelium of mice undergoing experimental colitis, as well as humans with ulcerative colitis...Treatment of mice undergoing experimental colitis with an NAD + precursor reduced the severity of colitis, restored mitochondrial function, and increased active PGC1α levels

Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States...Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing the progression of diabetic kidney disease.

We found that NR eased symptoms of disease by activating the mitochondrial unfolded protein response (UPRmt) via the transcription factor atfs-1. Similarly, in a proteasome inhibitor, lactacystin, -induced mouse model of PD, NR rescued mitochondrial dysfunction and behavioural deficits caused by lactacystin lesion. However, long-term NR supplementation, in conjunction with proteasome inhibition, resulted in decreased DA levels in both the lesioned and unlesioned sides of the substantia nigra with concomitant downregulation of key genes in DA metabolism. Our results suggest specific endpoints that should be monitored in ongoing NR clinical trials.

A rare mutation that disorganizes keratin filaments, and causes skin blistering and liver injury, can be treated with parthenolide, which has the effect of upregulating SIRT2. Giving mice NMN had a protective effect similar effect to parthenolide.

Recent studies have revealed the significant contribution of mitochondrial dysfunction and disrupted energy metabolism to the pathogenesis of osteoarthritis. Impaired mitochondrial function leads to the accumulation of reactive oxygens species, which contribute to cartilage degradation and chondrocyte apoptosis...Compounds capable of modulating mitochondrial metabolism and improving mitochondrial function, such as nicotinamide riboside and pyrroloquinoline quinone, have also been investigated in the context of osteoarthritis. These compounds promote mitochondrial biogenesis, enhance mitochondrial respiration, and reduce oxidative stress and inflammation in chondrocytes, ultimately preserving the integrity of the cartilage matrix...

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

In acute kidney injury and chronic kidney disease, de novo NAD+ biosynthesis is impaired, and substantial decreases in the levels of NAD+ can reduce energy generation. More recently, NAD+ augmentation through supplementation with nicotinamide mononucleotide (NMN) or nicotinamide (NAM), an NAD+ precursor, has been proposed as for the prevention of numerous kidney illnesses, including AKI, CKD, the AKI-to-CKD transition, and diabetic nephropathy. Our experimental results showed that NAD+ lowered TGF-β1-induced extracellular matrix deposition in kidney organoids produced from hiPSCs, confirming its therapeutic efficacy in chronic kidney disease....In conclusion, activation of Insig1 in PTCs markedly attenuated CKD, possibly by maintaining NAD+ homeostasis and controlling ER expansion via the transcriptional repression of Aldh1a1 in PTCs.

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

In our study, NAM prevented osteoblast DNA damage and cell death caused by oxidative stress. Therefore, NAM can prevent the acceleration of musculoskeletal aging caused by oxidative stress.In summary, the present study shows that NAM significantly enhances osteoblast differentiation by relieving mitochondrial oxidative stress. NAM increases mitochondrial respiration and the expression of antioxidant enzymes via SIRT3, FOXO3A and PGC1A activation, facilitating osteoblast differentiation both in normal physiological conditions and under oxidative stress. On the basis of this study, NAM could be a therapeutic or prophylactic drug to improve bone health or therapeutic agent for the bone diseases caused by reactive oxygen species (ROS).

NAM supplementation prevented brain inflammation and microglial activation inthe brains of diabetic mice.

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.

In this study, the role of NAD+ supplementation, specifically the administration of NR, was investigated as a potential therapeutic strategy to alleviate the pathological changes in Alpers’ syndrome...we provide evidence that NAD+ supplementation, specifically through NR therapy, could present a promising clinical avenue for neuroprotection not only in Alpers’ disease, but also in a broader spectrum of mitochondrial disorders.

NMN is protective against sepsis-induced memory dysfunction, and the inflammatory and oxidative injuries in the hippocampus region of septic mice. The NAD+/SIRT1 pathway might be involved in one of the mechanisms of the protective effect.

This review summarizes recent studies on the effect of oral NMN on the enhancement of NAD+ in vivo and the improvements in mitochondrial autophagy abnormalities in AD through aerobic exercise, focusing on (1) how oral NMN improves the internal NAD+ level; (2) how exercise regulates the content of NAD+ in the body; (3) the relationship between exercise activation of NAD+ and AMPK; (4) how SIRT1 is regulated by NAD+ and AMPK and activates PGC-1α to mediate mitochondrial autophagy through changes in mitochondrial dynamics. By summarizing the results of the above four aspects, and combined with the synthesis of NAD+ in vivo, we can infer how exercise elevates the level of NAD+ in vivo to mediate mitochondrial autophagy, so as to propose a new hypothesis that exercise interferes with Alzheimer’s disease (AD).

Our studies demonstrate that administration of NR during pregnancy in mice can prevent severe developmental defects caused by genetic inhibition of NAD production. In view of the multiple clinical syndromes already linked to defective NAD production, our findings raise hope of their attenuation and perhaps prevention.

These results demonstrate the beneficial effect of NR on sepsis and T cell exhaustion

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.

NR averted cisual field sensitivity worsening in progressing glaucoma although it did not show a neuroenhancement effect.

Our findings indicated that nicotinamide riboside diminished ovarian injury in sepsis via inhibiting tissue infiltration and increasing endogenous antioxidant capacity. Nicotinamide riboside administration may represent a new treatment approach for the prevention of sepsis-induced ovarian injury.

Nicotinamide riboside is beneficial for treating social impairments in young and aged people, some of which are based on impairments of oxytocin and/or oxytocin release;...CD157KO and CD38KO mice displayed no social preference (that is, more interest towards a novel mouse than a familiar one) behavior. This defect was rescued after oral gavage administration of nicotinamide riboside for 12 days in CD157KO mice, but not in CD38KO mice. Social memory was not observed in CD157KO and CD38KO mice...Nicotinamide riboside is less harmful and has beneficial effect on defects in recovery from social behavioral, for which CD38 is required in mice.

The decreased NAD+ levels in the blood of CMT patients, compared to healthy subjects, suggest that the patients may benefit from the administration of NAD+ precursors. The NAD+ biosynthetic intermediates, such as nicotinamide riboside, may decelerate the progression of CMT disease with age.

In this double blinded, placebo-controlled trial, we treated stable COPD patients with the NAD precursor nicotinamide riboside (NR) for 6 weeks and followed up 12 weeks after. NAD levels were lower in COPD patients compared with lung-healthy controls and correlated with lung function. NR significantly increased NAD levels, reduced lung inflammation, and cellular senescence in vivo and in vitro. Our findings suggest that NR could be a viable treatment option for COPD patients.

RA patients display altered NAD+ metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD+ boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.

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…

Treatment of mice undergoing experimental colitis with an NAD+ precursor [nicotinamide riboside (NR), 500 mg/kg/day] decreased the severity of colitis, restored mitochondrial function, and increased active PGC1α levels.

Here, we show that NAMPT-dependent control over the molecular clock varies substantially between tissues...our findings reveal that peripheral molecular clocks and metabolic biorhythms are shaped in a highly tissue-specific manner by NAMPT-dependent NAD+ synthesis.

Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet-induced metabolic disease in mice. Increasing NAD+ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD+ immediately before the rest phase selectively compromised these responses....In humans, clinical trials aiming to boost endogenous NAD+ for treatment of metabolic diseases are increasing, showing promising results... However, all these studies mostly overlook the time of drug intake, which is selected based on practicalities or attempting to displace side effects from the patient’s active phase. Considering our results, we propose that time of treatment dictates the amplitude of metabolic benefits from rising NAD+ levels, which ideally outlines the basic strategy of chronobiology-based NAD+ therapy.

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.

In this study, we report for the first time that nicotinamide riboside (NR) supplementation could alleviate cancer metastasis in tumor-bearing mice and enhance the maintenance of body weight at the late stage of cancer. Our results reveal that NAD precursor may be a novel treatment for the prevention of HCC progression....,NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice...NR supplementation decreased metastasis to the bone and liver...NR supplementation also significantly decreased the size of allografted tumors and extended the survival time... In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of liver cancer progression.

NR treatment led to functional improvement in total gastrointestinal transit time in induced diabetic animals. This was associated with neuroprotection in the myenteric plexuses of both small and large intestines of induced diabetic rats. This represents an important first step in showing NR’s benefit as a treatment for diabetic enteric neuropathy.

To delay or prevent optic nerve damage in glaucoma, two forms of vitamin B3, nicotinamide (NAM) and nicotinamide riboside (NR) are emerging as viable adjuvant therapies.

Defective nicotinamide adenine dinucleotide (NAD+) metabolism is involved in various diseases. A study in Nature Metabolism identifies the cytosolic mitochondrial-RNA sensing system as a mediator that links NAD+ deficiency to kidney disease in humans and mice.

Here we show that NAD+ deficiency drives mitochondrial dysfunction causing inflammation and kidney disease development...Supplemental NR or NMN restores NAD+ levels and improved kidney function.

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.

Our data suggested that normalizing NADH:NAD+ ratio with NR may be a potential treatment for glycolytic and fatty acid β-oxidation defects in citrin deficiency in the liver. Additionally, increasing cytoplasmic NAD+ levels may be useful for the treatment of other monogenic mitochondrial diseases involving the aspartate malate shuttle and mitochondrial transporters

NR recovered fetal growth by increasing blood glucose levels when artificial hypoglycemia was induced during pregnancy. Our study revealed the glucose-metabolic function of NR in hypoglycemic pregnant animals, suggesting NR as a dietary supplement to improve fetal growth. Because diabetic women suffer from hypoglycemia due to insulin therapy, NR has therapeutic potential for use as a glycemic control pill.

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.

The coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth.

Supplementation of NAD+ through NR in water improved longevity and partially enhanced olfaction in aged mice. Our studies provide mechanistic and biological insights into the olfaction decline during aging and highlight the role of NAD+ for preserving smelling function and general health.

We investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment...Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD+ precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD+ precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD+ precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD+ precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset.

Our work suggests that a clear association exists between NAD+ and health status in human aging.

A 12-week randomized, double-blind, placebo-controlled, parallel-group clinical trial was conducted. A total of 36 healthy middle-aged participants received one capsule of either 125 mg NMN or placebo twice a day. Among the NAD+ metabolites, the levels of nicotinamide in the serum were significantly higher in the NMN intake group than in the placebo group. Pulse wave velocity values indicating arterial stiffness tended to decrease in the NMN intake group. However, no significant difference was found between the two groups. Long-term NMN supplementation at 250 mg/day was well tolerated and did not cause adverse events. NMN safely and effectively elevated NAD+ metabolism in healthy middle-aged adults. Additionally, NMN supplementation showed potential in alleviating arterial stiffness.

Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis....Taken together, our results show that hepatic Nampt deficiency aggravates dyslipidemia and liver damage in HFD fed mice. Hepatocyte Nampt can be a protective target against dyslipidemia and fatty liver.

Our data showed a trend for increase in NAD+-levels in blood; only in the D2-mdx NR-treated mice the NAD+-levels were slightly increased. These markers were elevated in mdx models compared to controls, but not affected by the NR treatment. Histological analysis of muscle tissues indicated a mild treatment effect in D2-mdx mice. Based on our results, testing NR treatment in clinical trials in DMD patients is not warranted.

"...Vitamin B3 supplementation has been shown to alleviate various symptoms associated with PD...Mechanistically, vitamin B3 promotes the biosynthesis of the classical enzyme cofactor nicotinamide adenine dinucleotide (NAD) and mediates the release of nicotinamide by poly-ADP ribosylation. This generates an anti-inflammatory response, which alleviates DA-ergic neurodegeneration caused by neuroinflammation. These findings suggest that dietary supplementation with vitamin B3 may ameliorates oxidative stress and neuroinflammation, which would therefore prevent the death of DA-ergic neurons..."

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.

Glyoxolase 1 (GLO1) [a rate-limiting enzyme for detoxification of methylglyoxal, which has been implicated in Type 2 diabetes (T2D) and other age-related disorders] is decreased in muscle from individuals with obesity prior to the development of T2D. In vitro modeling of this molecular milieu via GLO1 KD in human immortalized myotubes suggest that muscle lacking GLO1 is characterized by inflammation, stress, fibrosis, and muscle dysfunction. Mechanistic experiments in human myotubes and implicate SIRT2, NAMPT, and NAD+ as potential regulators of GLO1 protein and activity and suggest that NR or other NAD precursors may be able to augment GLO1....The findings presented here demonstrating that nicotinamide riboside NR can promote GLO1 transcripts, and activity, as well as NRF2 are perhaps the most exciting data which warrant further exploration of NR as a potential therapy for the prevention and treatment of metabolic dysfunction.

Although future studies are required to better clarify the potential of targeting NAD+ homeostasis, the strategies based on administering NAD+ precursors or inhibiting NAD+-dependent enzymes seem to be an attractive approach for reducing chronic low-grade inflammation, enhancing mitochondrial biogenesis, and improving oxidative metabolism in vascular cells.

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.

This study shows that NAMPT inhibition concomitant to NAD restoration significantly attenuate experimental liver damage.

These findings indicate that oocytes of advanced maternal age suffer from oxidative damage and mitochondrial dysfunction.

We designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMAs improves cognitive functions in AD patients...We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.

Here, we show that NAD+ supplement suppresses tumor metastasis in a Triple Negative Breast Cancer Model...Overall, we demonstrate that NAD+ supplementation executes its anti-tumor function via activating the SIRT1-p66Shc axis, which highlights the preventive and therapeutic potential of SIRT1 activators as effective interventions for TNBC.

NAD production is an ideal target for neuroprotection in glaucoma and other age-related ophthalmic diseases...While the retina favors the NAD-salvage pathway, the anterior chamber favors the Preiss-Handler pathway and nicotinamide riboside as an alternative substrate to the NAD-salvage pathway...

NAFLD is the most common form of liver disease, but there are no licensed medications available for its treatment. The progression of NAFLD is closely related to chronic inflammation, insulin resistance, and lipid accumulation. NAD+ is currently considered as a potential therapeutic target for NAFLD. As the critical NAD+ degrading enzyme in mammals, inhibiting of CD38 can significantly increase NAD+ levels and prevent NAFLD progression. These ideas have been confirmed in animal studies, but clinical trials still need to be verified.

Administration of the NAD+ precursor, NR, to elevate NAD+ within the injured spinal cord mitigates the tissue damage and functional decline that occurs following spinal cord injury….administration of NR enhances NAD+ levels within the injured rat spinal cord, reduces tissue damage, and improves locomotor recovery after a thoracic spinal cord contusion injury in rats. Collectively, the results show that NR is a safe and effective bioavailable agent that can mitigate spinal cord damage.

NMN and NR can be expected to have broad-spectrum effects in the treatment of neurodegenerative diseases by activating these sirtuins.

Our findings indicated that nicotinamide riboside diminished ovarian injury in sepsis via inhibition of tissue infiltration and incresing of endogenous antioxidant capacity. Nicotinamide Riboside administration may represent a new treatment approach for the prevention of sepsis induced ovarian injury.

NR supplementation holds a promising therapeutic potential for myocardial infarction-induced acute kidney injury

Boosting NAD by Nicotinamide Riboside (NR) prevents ethanol-induced intestinal dysfunction by activation of epithelial mitochondrial function. The protective effects of NAD on intestinal barrier depend on the activation of SirT1 to a considerable extent. NR acts as a good NAD precursor without side effects and is able to regulate mitochondrial function via activating the SirT1 signaling pathway, maintain intestinal epithelial tight junctions stability and ultimately reverse ethanol-induced damage to the intestinal epithelial barrier.

The study underscores the importance of amino acid and NAD+supplementation as promising strategies in fatty liver disorder.

NMN significantly increased tissue levels of NAD+ and its metabolites and improved survival and bodyweight loss in both experimental models. In addition, NMN protected against Doxo-induced cardiotoxicity and loss of physical function in acute and chronic studies, respectively. In the heart, NMN prevented Doxo-induced transcriptomic changes related to mitochondrial function, apoptosis, oxidative stress, inflammation and p53, and promyelocytic leukemia nuclear body pathways. Overall, our results suggest that NMN could prevent Doxo-induced toxicity in heart and skeletal muscle.

Just one month of every-other-day fasting was sufficient to improve oocyte quality [in mice]...Positive impact of intermittent fasting on aged oocytes was mediated by restoration of the nicotinamide adenine dinucleotide (NAD+)/Sirt1-mediated antioxidant defense system, which eliminated excessive accumulated ROS to suppress DNA damage and apoptosis.

We showed that combined metabolic activators [including nicotinamide riboside] administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the Alzheimer's Disease and Parkinson's Disease animal models and is a promising treatment for improving the metabolic parameters and brain functions in neurodegenerative diseases.

We report the first study examining [extracellular vesicles enriched for neuronal origin or "NEV"] NEV biomarkers in response to oral NR supplementation. Our primary analysis of NAD+ and NADH in NEVs suggests an increase in neuronal NAD+ concentration in response to oral NR supplementation....We demonstrate that oral NR supplementation [in humans] increases NAD+ levels in NEVs ...These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans.

We demonstrate supplementing with nicotinamide (NAM) and related components of this pathway improve mitochondrial and overall hepatic metabolic dysfunction. We find that the effects of modulating the TRP-NAD+ pathway are mediated through SIRT1...NAM treatment can either reduce mitochondria degradation or increase its biogenesis in our model of severe malnutrition...NAM was shown to increase SIRT1 levels. The effect was not specific to NAM, as Nicotinamide Riboside (NR) and Tryptophan (TRP) demonstrated a similar effect...In our study, NAM treatment did not significantly restore NAD+ levels whereas NR did...

We demonstrated that CD73 promote tumor growth in a cancer-cell autonomous manner by increasing metabolic fitness. This in turn favors cancer cell adaptation to nutrient-deprived microenvironments and cytotoxic stress by increasing OXPHOS, aspartate biosynthesis and DNA repair. Our study highlights new therapeutic opportunities that may be exploited in novel combination anti-cancer strategies.

Supplementation with a metabolic cocktail including nicotinamide riboside promotes the amelioration of adipose tissue dysfunction observed in the diet-induced obese mouse model...Altogether, this study suggests that the supplements ameliorate adipose tissue dysfunction acting in different pathways affected by obesity, and can be an effective treatment for reducing the incidence of obesity-related metabolic disorders.

In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed.

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

his review details the role of NAD+ metabolism in macrophages and molecular mechanisms during AMD. The selected pathways were identified as potential targets for intervention in AMD, pending further investigation.

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.

...We found that NR supplementation could ameliorate high-fructose-induced lipid metabolism disorder by improving FGF21 resistance in the liver and WAT, which may be related to the regulation of inflammation mediated by the SIRT1/NF-κB signaling pathway.

This specific combination of metabolic cofactors [including nicotinamide riboside] can reverse gut barrier disruption and microbiota dysbiosis contributing to the amelioration of NAFLD progression by modulating key players of the gut-liver axis.

We demonstrated that NR intravenous administration decreases cardiac-muscle fibrous-tissue formation in chronic doxorubicin-induced cardiotoxicity development...Moreover, a pronounced protective effect of NR on the cardiovascular system was demonstrated...Simultaneously, the preventive NR administration had a more significant protective effect on the animal’s body as a whole.

Here, we showed that Metformin (MET) and Nicotinamide Riboside (NR) exhibited a geroprotective effect on aged human stem cells and various tissues in aged rats. Both MET and NR repressed systemic inflammation and inhibited aging markers across multiple tissues in aged rats. MET and NR treatment attenuated aging-associated gene expression across tissues, with the most protective effects in adipose and aortic tissues. We found that that both MET and NR alleviated the aging-associated phenotypes, especially systemic inflammation, tissue fibrosis, and aggresome formation in aged rat tissues. We further showed that both MET and NR partially rescued aging Differentially Expressed Genes in several tissues, and the most remarkable effects were found in adipose and aortic tissues

Metabolic disorders may increase the vulnerability of individuals to SARS-CoV-2 and worsen disease prognosis...Low levels of circulating NAD+ are reported in severe COVID-19...Coronavirus infection can deplete cellular NAD+ levels, and boosting NAD+ with NAD precursors has been shown to enhance the antiviral activities of PARP isozymes...NAD+ is also essential for critical host antioxidant and anti-inflammatory responses. Thus, therapeutic reinforcement of the NAD+ system has been proposed as a potential prophylaxis approach against viruses such as SARS-CoV-2 infection...Ultimately, the outcome of this ‘tug-of-war’ [between the virus and the immune system both drawing down NAD] is likely to be influenced by the nutritional status of the host....

Evidence that has accumulated over the last three decades suggests that renal diseases start in utero...Low nephron number is one of the main contributors to chronic kidney disease (CKD) susceptibility in adulthood...Here, we show that a nephron number deficit and impaired renal architecture of mice born to mothers fed a low protein diet can be restored by NR supplementation during pregnancy through the induction of SIRT3 expression and activity...These findings have huge potential for clinical translation, given that inadequate nephrons at birth increase the risk in adulthood of hypertension and renal diseases. Chronic kidney disease affects over 10% of the adult population worldwide, with rising overall morbidity and mortality rates. In view of this, it is evident that prenatal kidney care is an important global health challenge.