Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMAs), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMAs includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMAs improved the AD-associated histological parameters in the animals. Finally, 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. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group...Our results show that treating AD patients with CMAs leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases.

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...

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.

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.

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

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.

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.

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 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.

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.

We have selected a number of neurodegenerative disorders that are known to involve mitochondrial dysfunction in their pathogenesis. We have further selected a number of nutrients that have a key role in mitochondrial function. We then correlated data on the deficiency (Table 1) and supplementation of these nutrients (Table 2) in the said neurodegenerative disorders. In this review, we have therefore provided a rationale for a combination of CoQ10, B-vitamins/NADH, l-carnitine, vitamin D, and alpha-lipoic acid to support the future treatment of these neurodegenerative disorders.

During regeneration, muscle stem cells (MuSCs) from [mice with both NRK1 and NRK2 knocked out] hyper-proliferate but fail to differentiate. Double NRK Knockout also alters the recovery of NAD+ during muscle regeneration as well as mitochondrial adaptations and ECM remodeling required for tissue repair. These metabolic perturbations result in a transient delay of muscle regeneration which normalizes during myofiber maturation at late stages of regeneration via over-compensation of anabolic IGF1-Akt signaling.

...Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing progression of diabetic kidney disease.

Interestingly, mice supplemented with NA revealed a significant delay in the onset of imbalance, whereas NR supplementation showed a trend towards delaying the median age of onset of tremors. Furthermore, NR significantly extended median lifespan by approximately 25% or 5 weeks, while animals receiving NA lived about as long as control-fed animals.

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

...Recent studies have expanded on the role of circadian rhythms and the core clock factors that maintain them in the regulation of NAD+ levels in the heart. This has revealed that NAD+ pools and their use are tightly linked to cardiac function, but also heart failure. The convergence of these fields, namely, clock regulation, heart disease, and NAD+ metabolism present a complex network ripe with potential scientific and clinical discoveries, given the growing number of animal models, recently developed technology, and opportunity for safe and accessible precursor supplementation...

...The objective of this study was to investigate if supplementation with nicotinamide riboside and pterostilbene (NRPT) promotes skeletal muscle regeneration after muscle injury in elderly individuals by improved recruitment of MuSCs...Daily supplementation with 1,000 mg NR and 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly individuals.

Our results demonstrate that NR supplementation results in a significant increase in cancer prevalence and metastases of TNBC to the brain. These results outline the important role of powerful nutraceuticals like NR in cancer metabolism and the need to personalize their use in certain patient populations.

NR treatment not only restored MII oocyte quality but also enhanced early embryonic development potential of postovulatory oocytes via alleviating mitochondrial dysfunction and maintaining normal spindle/chromosome structure. ...NR supplementation increases the oocyte quality and early embryonic development potential in post-ovulatory oocytes which could potentially increase the successful rate in assisted reproductive technology.

Oral nicotinamide (NAM) supplementation has been shown to decrease the incidence of keratinocyte carcinoma (KC) in high-risk skin cancer patients. NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and thus directly leads to increased NAD+. This increase in NAD+ is believed to be responsible for NAM’s impact on keratinocyte carcinoma risk. NAD+ has protective cellular effects and is a necessary cofactor for DNA repair, helping to prevent potentially oncogenic mutations. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ intermediates like NAM...

Increasing NAD+ levels with nicotinamide riboside can alleviate the exercise intolerance associated to ANT1-deficiency, indicating the therapeutic potential of NAD+-stimulating compounds in mitochondrial myopathies.

Addressing aging at the cellular level is now critically important. Many surgical procedures rely on the healing and regenerative capacity of the skin which is known to decline with age, leading to disappointing results or negative postsurgery outcomes. Improving health and resilience at the cellular level with NAD+ restoration could be harnessed as a way to ensure consistent results and recovery irrespective of patient age. It should also be noted that the efficacy of many nonsurgical aesthetic procedures such as microneedling and laser technologies ultimately rely on the activation of cellular stress pathways to trigger the clearance of damaged cells and stimulate the production of new collagen. Many of these pathways require adequate NAD+ levels for optimal function, meaning NAD+ restoration before treatment could be a strategy to ensure the underlying cells are in an optimal condition to respond to the treatment.

Lifespan, a book by Harvard scientist David Sinclair, has become an influential source of misinformation on longevity, featuring counterfactual claims about longevity genes being conserved between yeast and humans, the existence of supposed activators of these genes, and claimed successful age reversal in mice based on partial reprogramming. The book has popularized a stack of drugs and supplements with significant potential to harm the general public.The reviewer suggests that scientists and physicians emphasize to the general public that aging is known to be a highly polygenic developmental process and that the most important things that people can do to age better are to maintain high physical and mental activity.

While sirtuins carry out interesting biochemical reactions and perform important functions for organisms, their degree of regulation is modest compared to most other enzymes that function in the NAD system. In addition, the degree of hype, framing, and nonreproducibility in the sirtuin literature is persistently misleading. Dispassionate analysis of their functions does not support assignment as longevity enzymes or as principal mediators of the effects of NAD repletion.

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

Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic β-cell function in pathophysiological conditions...

NAD+ repletion can delay several hallmarks of aging and suppress the deterioration of age-related diseases[95]. This suggests a significant potential for the treatment of cardiac diseases in the elderly population with supplementation of NAD+ precursors. Indeed, the dietary intake of NAM could reduce cardiac hypertrophy and diastolic dysfunction in aged mice

The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD+) and NADH levels. Raising NAD+ levels with the NAD+ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD+ levels...

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing globally on a path to becoming the most frequent cause of chronic liver disease. Novel strategies for the prevention and treatment of NAFLD are urgently needed. A 6-month prospective, randomized, double-blind, placebo-controlled clinical trial was conducted to assess the efficacy of daily NRPT (commercially known as Basis; a combination of nicotinamide riboside and pterostilbene) supplementation in 111 adults with NAFLD...This study demonstrates that NRPT at the recommended dose is safe and may hold promise in lowering markers of hepatic inflammation in patients with NAFLD.

The rate of infertility continues to rise in the world for several reasons, including the age of conception and current lifestyle. We list in this paper potential non-invasive and invasive techniques to assess oocyte quality. We searched the database PubMed using the terms “oocytes AND quality AND evaluation”. In the first part, we study the morphological criteria, compartment by compartment, to then focus in a second part on more objective techniques such as genetics, molecular, apoptosis, or human follicular fluid that contain biologically active molecules. The main criteria used to assess oocyte quality are morphological; however, several other techniques have been studied in women to improve oocyte quality assessment, but most of them are invasive and not usable in routine.

Leigh syndrome is the most common form of mitochondrial disease in children. The mechanisms underlying its pathogenesis are not fully understood and no therapies are approved for the treatment of patients with LS. In a new study, Yoon and colleagues1 shed light on the pathophysiological mechanisms of cardio-encephalomyopathy in LS and demonstrates that nicotiname riboside (NR) provides significant amelioration in disease models of LS

Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer’s and Parkinson’s Disease. It has also been beneficial against noise induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL...

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

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

A large body of preclinical research supports the potential effectiveness of NAD+ precursor supplementation for preserving cognitive health across a variety of disease contexts, with the strongest evidence presented for Alzheimer’s disease and other forms of dementia.

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

Our study reveals direct mechanistic explanations of the observed cardiac bradyarrhythmia, diastolic dysfunction and neuronal apoptosis in mouse and human induced pluripotent stem cells (iPSC) models of Leigh Syndrome….Metabolic rescue by nicotinamide riboside (NR) supplementation increased intracellular NAD+/ NADH, restored metabolic derangement, reversed protein hyperacetylation through NAD+‐dependent Sirtuin deacetylase, and ameliorated cardiomyopathic phenotypes...NR also attenuated neuronal apoptosis and microglial activation...

Using the NAD precursor NRH to raise NAD levels in an incurable type of brain cancer (Glioblastoma multiforme or GBM) significantly increased the effectiveness of a type of chemotherapy (Temozolomide or TMZ) that is commonly used to treat GBM.

The antioxidant N-acetylcysteine (NAC) could alleviate cellular senescence only by a minimal degree, whereas supplementation with nicotinamide mononucleotide (NMN) strongly ameliorated RPE senescence through the alleviation of DNA damage and the maintenance of mitochondrial function. The protective effects of NMN were demonstrated to rely on undisturbed Sirt1 signaling. Moreover, both the expression of senescence markers of RPE and subretinal inflammatory cell infiltration were decreased by NMN treatment in vivo. Our results indicate that RPE senescence induced by NaIO3 acquired several key features of AMD. More importantly, NMN may potentially be used to treat RPE senescence and senescence-associated pre-AMD changes by restoring the NAD+ levels in cells and tissues.

We here present the effect of nicotinamide riboside in another individual with ataxia…Given the absence of adverse effects, we strongly encourage to consider nicotinamide riboside in all individuals with ataxia telangiectasia.

NAPRT displays marked tissue [specificity] and is mostly present in several catabolic healthy mammalian tissues including the heart, kidney, liver, and small intestine. In tissues that express the NAPRT protein, NA is the preferred precursor of NAD.

The last decade has seen a strong proliferation of therapeutic strategies for the treatment of metabolic and age-related diseases based on increasing cellular NAD+ bioavailability. Among them, the dietary supplementation with NAD+ precursors—classically known as vitamin B3—has received most of the attention. Multiple molecules can act as NAD+ precursors through independent biosynthetic routes. Interestingly, eukaryote organisms have conserved a remarkable ability to utilize all of these different molecules, even if some of them are scarcely found in nature. Here, we discuss the possibility that the conservation of all of these biosynthetic pathways through evolution occurred because the different NAD+ precursors might serve specialized purposes.

...It has recently been found that gavage application of a precursor of nicotinamide adenine dinucleotide, nicotinamide riboside, for 12 days can increase brain Oxytocin (OT) in mice. Here, we review the evaluation of the new concept that RAGE is involved in the regulation of OT dynamics at the interface between the brain, blood, and intestine in the living body...

This work demonstrates for the first time that NARH can act as a NAD+ precursor in mammalian cells and how different NAD+ precursors can interact and influence each other when co-administered...NARH achieved synergistic effects with NR in increasing NAD+ levels, but not with any of the other NAD+ precursors tested...The effect was remarkable, given the fact that NR or NARH had limited effects on NAD+ levels in these two cell lines when used as single treatments...The synergistic action of NR and NARH could be confirmed in vivo...NR degradation to NAM was not a critical step, as NAM and NARH did not lead to cooperative increases in NAD+ levels...The vigorous increase in NAD+ levels observed when combining NR and NARH was reminiscent of the effects of NRH...The simplest explanation for this would be that the combination of NR and NARH led to the production of NRH...The results showed that, when used together, NR and NARH increased the intracellular levels of NRH...Simply adding the two molecules to a vial of water at room temperature was enough to generate NRH

We show that NR, an NAD+ precursor and pharmacologic activator of SIRT2, effectively prevents and alleviates CIPN in mice. We present in vitro and in vivo genetic evidence to illustrate the specific dependence on SIRT2 of NR-mediated CIPN mitigation. Importantly, we demonstrate that NAD+ mediates SIRT2-dependent neuroprotection without inhibiting cisplatin cytotoxic activity against cancer cells. NAD+ may, in fact, further sensitize certain cancer cell types to cisplatin.

This pilot study provides significant evidence that NAD infusions are beneficial in the treatment of Substance Use Disorder.

The objective of this study was to investigate the clinical evidence of NR's mitigation of inflammation in humans. We identified 5 clinical trials of oral NR supplementation that measured inflammation. There was substantial heterogeneity in inflammatory endpoints evaluated. NR dose and treatment duration ranged from 1–2 g/day and 5-d– 6-wks, respectively. Participants varied in age (18–78 years) and health status. In one study, NR was given as part of a nutritional cocktail, while NR was the sole intervention in the remaining studies. Of the 3 studies assessing circulating inflammatory markers, two investigated IL-6 and reported significant reductions in its levels with NR treatment, while effects on MCP-1 and TNF-α were inconsistent. NR significantly lowered gene expression of IL-6 and IL-18, but not NLRP3 or IL-1B in peripheral blood mononuclear cells in one study...Preliminary evidence suggests that NR may improve some inflammatory measures, with potential for more robust effects among populations with compromised NAD + and higher inflammation status, e.g., elderly or diseased...

In this review, we focus on the role of the nucleotide NAD(P)(H) and NAD+-dependent sirtuin deacetylases as integrators of circadian and metabolic cycles, as well as the implications for this interrelationship in healthful aging.

...Here, we studied the long-term programming effects of mild NR supplementation during the suckling period on lipid and oxidative metabolism in skeletal muscle and liver tissues using an animal model. ...These pre-clinical findings suggest that mild NR supplementation in early postnatal life beneficially impacts lipid and energy metabolism in skeletal muscle and liver in adulthood, serving as a potential preventive strategy against obesity-related disorders characterized by ectopic lipid accumulation.

...We previously reported that NR supplementation prevented the development of liver fibrosis in male mice. However, whether NR exerts a similar effect in females is unknown. Therefore, we determined whether NR supplementation can prevent obesity-induced inflammation and fibrosis in the liver and white adipose tissue (WAT) by providing NAD+ in obese female mice...Our results indicated that NR supplementation exerted an anti-obesity effect and prevented the development of inflammation and fibrosis in the white adipose tissue of old, but not young, female mice with diet-induced obesity.

...CD38 expression is consistently silenced by methylation in prostate cancer and progressively downregulated in advanced castration-resistant prostate cancer, suggesting a connection between NAD+ and prostate carcinogenesis as well as prostate cancer progression. ...In this study, we...demonstrate that CD38 overexpression resulted in growth suppression and apoptosis accompanied by cleavage of poly (ADP-ribose) polymerase 1 (PARP1). CD38 overexpression also dramatically reduced intracellular NAD+ levels and decreased mitochondrial respiration as measured by oxygen consumption rate. We further show that some but not all of these CD38-induced phenotypes could be rescued by exogenous NAM. Treatment of cells with NAM rescued CD38-induced apoptosis and mitochondrial stress but did not restore intracellular NAD+ levels. We also found that NAM demonstrated biphasic effect on mitochondria function, a finding that can be explained by the dual role of NAM as both a precursor of NAD+ and also as a suppressor of a number of NAD+-dependent enzymes...

...This randomized, triple-blind, placebo-controlled, crossover pilot study assessed the efficacy and safety of a combination of nicotinamide with D-ribose (RiaGev) for NAD metabolome enhancement and related benefits in healthy middle-aged adults...

Here, we show that supplementation with the NAD+ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD+ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.

NMN oral supplementation at 250 mg/day in healthy older men for 12 weeks was safe and well-tolerated and significantly increased the levels of NAD + and NAD +-related metabolites in whole blood. Furthermore, NMN administration partly improved muscle performance, evaluated using gait speed and grip strength, in healthy older men...NMN did not affect the skeletal muscle mass of participants in our study...Thus, the chronic oral administration of NMN could be a therapeutic strategy for aging-related disorders in humans, such as sarcopenia.

Diabetic peripheral neuropathy (DPN) is a common neurological complication of diabetes. Currently, there is no therapy that permanently prevents or reverses neuropathy. ...Correction of NAD+ depletion [with dietary NR] in dorsal root ganglion neurons may be sufficient to prevent diabetic peripheral neuropathy, but does not significantly affect glucose tolerance, insulin levels, or insulin resistance.

We aimed to determine whether long-term nicotinamide riboside (NR) supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twins from 22 BMI-discordant monozygotic pairs were supplemented with an escalating dose of NR (250-1000 mg/day) for 5 months (clinicaltrials.gov entry NCT03951285). NR improved blood and tissue NAD+ metabolism, muscle mitochondrial number, myoblast differentiation and gut microbiota composition independent of BMI. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.

The level of NAM in large follicles was significantly higher than that in small follicles. In mature FF, the NAM concentration was positively correlated with the rates of oocyte maturation and fertilization. Five mM NAM treatment during IVM increased maturation rate and fertilization rate in the oxidative stress model, and significantly reduced the increase of ROS levels induced by H2O2 in mice oocytes. Higher levels of NAM in FF are associated with larger follicle development. The supplement of 5 mM NAM during IVM may improve mice oocyte quality, reducing damage caused by oxidative stress...However, we found that an excessive NAM concentration inhibited the maturation and fertilization of oocytes.

...Many extra-pulmonary symptoms of COVID-19 strikingly resemble those of pellagra, vitamin B3 deficiency (e.g., diarrhea, dermatitis, oral cavity and tongue manifestations, loss of smell and taste, mental confusion). In most developed countries, pellagra is successfully eradicated by vitamin B3 fortification programs. Thus, conceivably, it has not been suspected as a cause of COVID-19 symptoms. Here, the deregulation of the NAD+ metabolism in response to the SARS-CoV-2 infection is reviewed, with special emphasis on the differences in the NAD+ biosynthetic pathway’s efficiency in conditions predisposing for the development of serious COVID-19... The robustness of the host’s NAD+ salvage pathway, prior to the SARS-CoV-2 infection, is an important determinant of COVID-19 severity and persistence of certain symptoms upon resolution of infection.

...Previous mouse models showed that NMN administration can increase NAD+ in various organs and ameliorate aging-related diseases, such as obesity, diabetes, heart failure, stroke, kidney failure, and Alzheimer’s disease through NAD+-mediated pathways. However, evidence of its effect on humans is still scarce. In this study, we conducted a placebo-controlled, randomized, double blind, parallel-group trial to investigate the safety of orally administered NMN and its efficacy to increase NAD+ levels in thirty healthy subjects...Oral supplementation of NMN for 12 weeks caused no abnormalities in physiological and laboratory tests, and no obvious adverse effects were observed. NAD+ levels in whole blood were significantly increased after NMN administration. We also observed the significant rise in nicotinic acid mononucleotide (NAMN) levels, but not in NMN...These results suggest that oral administration of NMN is a safe and practical strategy to boost NAD+ levels in humans.

Antibiotic therapy down-modulating gut microbiota can restore the anti-cancer efficacy of APO866. Alternatively, NAphosphoribosyltransferase inhibition may restore anti-cancer activity of NAMPT inhibitors in the presence of gut microbiota and of NAM in the diet.

Upon neurofibromin loss, hyperactivation of Ras/MEK/ERK signaling inhibits complex I, causing a decrease in the NAD+/NADH ratio and the ensuing SIRT3 repression. Raising the NAD+/NADH ratio via NDI1 expression has an antineoplastic effect through the enhancement of SIRT3 activity...These findings indicate that tumorigenic growth of NF1-related neoplasms can be impaired both by TRAP1 ablation and by SIRT3 re-activation. Combination of these two approaches reaches maximal efficacy when SIRT3 induction is achieved through a rise in NAD+ precursors...These observations point toward a bona fide tumor suppressor role for SIRT3, which is abrogated by respiratory complex I inhibition and the ensuing decrease of NAD+/NADH ratio in NF1-related tumor cells...We envision that enhancement of SIRT3 activity and replenishment of NAD+ levels result in a multifaceted metabolic rewiring, which can oppose NF1-related cancer growth by affecting multiple bioenergetic pathways.

New possibilities for employing NAD + boosting agents as modulators of the intestinal microbiota should be considered for fostering repopulation of microbiota after decontaminating antibiotic therapy...If certain pathogens increase in abundance, NAD boosting might favor beneficial organisms, particularly in combination with probiotics, prebiotics, or fecal transplantation...If the intestinal microbiota increases the effect of NAD boosting drugs, their concomitant use with antimicrobial agents should be prescribed only in patients where the presence of neoplastic disease can be ruled out.

We found that the supplement of NAD+ precursors seems to have little effect on healthy people, but it has a significant beneficial effect on patients with cardiovascular disease and dyslipidemia. Due to the limitation of the number and quality of included studies, the above conclusions need to be verified by more high-quality studies.

We showed strong evidence that NAM suppresses tumour growth and metastasis in TNBC. These findings indicate a promising potential of repositioning NAM supplement as a novel agent targeting cancer metabolism in TNBC...The activities of the key apoptosis-inducing processes upregulated by NAM are generally decreased in TNBC, supporting a potential therapeutic value of NAM in patients with TNBC.

We conducted a double-blinded phase I clinical trial to establish whether nicotinamide adenine dinucleotide (NAD) replenishment therapy, via oral intake of nicotinamide riboside (NR), is safe, augments cerebral NAD levels, and impacts cerebral metabolism in Parkinson’s disease (PD). Thirty newly diagnosed, treatment-naive patients received 1,000 mg NR or placebo for 30 days. NR treatment was well tolerated and led to a significant, but variable, increase in cerebral NAD levels—measured by 31phosphorous magnetic resonance spectroscopy—and related metabolites in the cerebrospinal fluid. NR recipients showing increased brain NAD levels exhibited altered cerebral metabolism, measured by 18fluoro-deoxyglucose positron emission tomography, and this was associated with mild clinical improvement. NR augmented the NAD metabolome and induced transcriptional upregulation of processes related to mitochondrial, lysosomal, and proteasomal function in blood cells and/or skeletal muscle. Furthermore, NR decreased the levels of inflammatory cytokines in serum and cerebrospinal fluid. Our findings nominate NR as a potential neuroprotective therapy for PD, warranting further investigation in larger trials.

Fasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined. We explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE)...We conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for systemic lupus erythematosus management.

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is a substrate for a number of nonredox enzymes. NAD is fundamental to a variety of cellular processes including energy metabolism, cell signaling, and epigenetics. NAD homeostasis appears to be of paramount importance to health span and longevity, and its dysregulation is associated with multiple diseases. NAD metabolism is dynamic and maintained by synthesis and degradation. The enzyme CD38, one of the main NAD-consuming enzymes, is a key component of NAD homeostasis. The majority of CD38 is localized in the plasma membrane with its catalytic domain facing the extracellular environment, likely for the purpose of controlling systemic levels of NAD. Several cell types express CD38, but its expression predominates on endothelial cells and immune cells capable of infiltrating organs and tissues. Here we review potential roles of CD38 in health and disease and postulate ways in which CD38 dysregulation causes changes in NAD homeostasis and contributes to the pathophysiology of multiple conditions. Indeed, in animal models the development of infectious diseases, autoimmune disorders, fibrosis, metabolic diseases, and age-associated diseases including cancer, heart disease, and neurodegeneration are associated with altered CD38 enzymatic activity. Many of these conditions are modified in CD38-deficient mice or by blocking CD38 NADase activity. In diseases in which CD38 appears to play a role, CD38-dependent NAD decline is often a common denominator of pathophysiology. Thus, understanding dysregulation of NAD homeostasis by CD38 may open new avenues for the treatment of human diseases.

NAD+, as an emerging regulator of immune responses during viral infections, may be a promising therapeutic target for coronavirus disease 2019 (COVID-19). In this Opinion, we suggest that interventions that boost NAD+ levels might promote antiviral defense and suppress uncontrolled inflammation. We discuss the association between low NAD+ concentrations and risk factors for poor COVID-19 outcomes, including aging and common comorbidities. Mechanistically, we outline how viral infections can further deplete NAD+ and its roles in antiviral defense and inflammation. We also describe how coronaviruses can subvert NAD+-mediated actions via genes that remove NAD+ modifications and activate the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Finally, we explore ongoing approaches to boost NAD+ concentrations in the clinic to putatively increase antiviral responses while curtailing hyperinflammation.

In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression...We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.

...It is unknown how dietary supplementation of NR alters the microbiome and if those alterations contribute to deflection of weight gain. In this study, we fed C57BL/6J male mice a high-fat diet (HFD) supplemented with or without NR and performed a fecal material transfer (FMT) to establish a link between NR-conditioned microbiota and NR-induced deflection of weight gain...We also investigated the effects of NR on the microbiome by using metagenomics sequencing. We found that NR-treated mice displayed an altered gut microbial composition relative to controls and that fecal transplant resulted in a distinct functional metabolic profile characterized by enrichment of butyrate-producing Firmicutes...These findings suggest that microbial factors contribute to the beneficial effects of dietary NR supplementation, which may be useful to enhance the therapeutic effects of NR...

...The involvement of the gut microbiome as a factor in NR effects is linked to changes to the gut microbiome and its activity to transform NR and downstream catabolites. This commentary draws attention to these findings and focuses on some puzzling aspects of NAD+ boosters, exploring the still murky interactions between NAD+ metabolism, energy homeostasis, and the gut microbiome.

...Nicotinamide riboside (NR), which is a naturally occurring analogue of Niacin (vitamin B3), is expected to have therapeutic effects on COVID-19 due to its super close structural similarity to the proven RdRp inhibitors...In the current study, the resulted scores from molecular docking and dynamics simulations as the primary determinative factor as well as the observed reliable binding modes have demonstrated that Nicotinamide Riboside and its active metabolite NMN can target human ACE2 and IMPDH, along with the viral Spro, Mpro, PLpro, and on top of all, RdRp as a potential competitive inhibitor.

Coronavirus replication results in expenditure of nicotinamide adenine dinucleotide (NAD+), the central catalyst of cellular metabolism, in the innate response to infection. Repletion of NAD+ levels has the potential to enhance antiviral responses.

Paclitaxel-treated rats developed corneal hypersensitivity to tactile stimuli, enhanced sensitivity to capsaicin but not hyperosmolar saline, and increased basal tear production. Corneal nerve density visualized with anti–β-tubulin or calcitonin gene-related peptide (CGRP) was unaffected. Paclitaxel induced tactile and cool hypersensitivity of the hindpaw and a loss of nonpeptidergic hindpaw IENFs visualized with anti-protein gene product (PGP) 9.5 and CGRP. NR reversed tactile hypersensitivity of the cornea without suppressing tear production or chemosensitivity; it did not alter corneal afferent density. NR also reversed tactile and cool hypersensitivity of the hindpaw without reversing the loss of hindpaw IENFs.

It is well known that female reproduction ability decreases during the forth decade of life due to age-related changes in oocyte quality and quantity; although the number of women trying to conceive has today increased remarkably between the ages of 36 to 44. The causes of reproductive aging and physiological aspects of this phenomenon are still elusive. With increase in the women’s age, during Assisted Reproductive Technologies (ART) we have perceived a significant decline in the number and quality of retrieved oocytes, as well as in ovarian follicle reserves. This is because of increased aneuploidy due to factors such as spindle apparatus disruption; oxidative stress and mitochondrial damage. The aim of this review paper is to study data on the potential role of the aging process impacting oocyte quality and female reproductive ability. We present the current evidence that show the decreased oocyte quality with age, related to reductions in female reproductive outcome...

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.

...This investigation examined the impact of nicotinamide riboside supplementation on whole body energy homeostasis, skeletal muscle mitochondrial function, and corresponding shifts in the acetyl-lysine proteome, in the context of diet-induced obesity using C57BL/6NJ mice. The study also included a genetically modified mouse model that imposes greater demand on sirtuin flux and associated NAD+ consumption, specifically within muscle tissues. In general, whole body glucose control was marginally improved by nicotinamide riboside supplementation when administered at the midpoint of a chronic high-fat diet, but not when given as a preventative therapy upon initiation of the diet. Contrary to anticipated outcomes, the study produced little evidence that NRS increases tissue NAD+ levels, augments mitochondrial function, and/or mitigates diet-induced hyperacetylation of the skeletal muscle proteome.

Compelling evidence suggests that NAD+ homeostasis is required for normal cardiovascular function. Numerous studies suggest that declining NAD+ concomitant with mitochondrial dysfunction is a common trait in myocardial and cardiovascular diseases...Except for NA, which causes some adverse clinical outcomes, vitamin B3 intermediates have been demonstrated to be safe and to have promising beneficial effects in combating cardiovascular diseases in vivo...

Compared with other precursors, NR is gradually becoming a preferred candidate precursor because of its high bioavailability, safety, and ability to increase NAD+ levels. It offers many potential health benefits in diseases such as cardiovascular diseases, neurodegenerative diseases, and metabolic diseases. In summary, NR is a more effective precursor for synthesizing NAD+ and increasing the activity of NAD+-dependent enzymes than NA and NAM...

24 patients with Ataxia telangiectasia (A-T) were treated with NR during four consecutive months. The effects of NR on ataxia, dysarthria, quality of life, and laboratory parameters were analyzed. During treatment, ataxia scores improved; mean total Scale for the Assessment and Rating of Ataxia and International Cooperative Ataxia Rating Scale scores decreased to 2.4 and 10.1 points, respectively. After NR withdrawal, ataxia scores worsened.

This study not only demonstrates nicotinamide as a useful factor for cardiomyocyte production in regenerative medicine, but also implicates that nicotinamide could have a profound impact on embryogenesis if it is prescribed during pregnancy.

...The main route from oral nicotinamide riboside, a widely used nutraceutical, to host NAD is via conversion into nicotinic acid by the gut microbiome. Thus, NAD precursors cycle between the host and gut microbiome to maintain NAD homeostasis.

The present study demonstrated that orally administered NR increased NAD+ levels in a diphasic manner. First, in the early phase (within 1 h after administration), NR was directly taken up by the small intestine and utilized for NAD+ synthesis via the NR salvage pathway. In the late phase (~3 h after administration), NR increased NAD+ levels in a manner dependent on gut microbiota.