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NRC NIAGEN BIOCEUTICAL 10 GRAMS

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Nicotinamide Riboside Chloride (NRC NIAGEN)

Nicotinamide Riboside Chloride (NRC) is a stable, crystalline form of Nicotinamide Riboside (NR) that has been extensively evaluated both preclinically and clinically.

CAS: 1341-23-7

Nicotinamide Riboside is a special form of vitamin B3 and naturally-sourced trace nutrient which functions as a direct precursor to nicotinamide adenine dinucleotide (NAD+), which is a crucial mediator of cellular metabolic energy transformation and redox potential which has been shown to promote an incredibly wide-range of health benefits:

  1. Cellular energy metabolism in mice and humans [1]–[6]
  2. Neuroprotection [7]–[11]
  3. Telomere protection and extension (i.e. anti-aging) [12], [13]
  4. Lifespan extension [14]–[17]
  5. Resistance to negative effects of high-fat diet [18]–[20]
  6. Protection from alcohol-induced liver damage [21]–[23]
  7. Enhancement of benefits from exercise [24], [25]
  8. Enhanced stem cell hematopoiesis (i.e. new blood cell generation) [26]
  9. Protection from noise-induced hearing loss [27]

Background

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The therapeutic strategy of replenishing or elevating NAD+ to combat metabolic disease and aging has been extensively explored for over half a century. While all tissue produce NAD+ Importantly, despite homeostatic systems and dietary intake of NAD+ precursors, it is now known that the levels of NAD+ co-enzymes are continuously challenged by metabolic stress. For instance, in overfed and diabetic mice, levels of NAD+ are dramatically depressed [19]. Similar results have been observed animal models of noise-induced hearing loss, heart failure, peripheral nerve damage, central brain injury, and the livers of a stressed mouse, in which NAD+ levels are significantly compromised. Furthermore, NAD+ levels decline in response to DNA damage, alcohol use, and normal aging. Furthermore, the activation of specific enzymes required for necessary NAD+ regeneration naturally declines with aging and chronic inflammation. Taken together, these results demonstrating the strong relationships between NAD+ metabolic stress and aging, nutritional scientists are now investigating whether the ingestion of higher levels of special, stable forms of vitamin B3 such as NRC should be part of an evidence-based approach to optimize health.

Selected preclinical research findings

NR has demonstrated a phenomenal array of benefits in the preclinical setting, especially with regard to lifespan extension and muscle maintenance:

  1. “NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice”

The oxidized form of cellular nicotinamide adenine dinucleotide (NAD+) is critical for mitochondrial function, and its supplementation can lead to increased longevity. In this study, Zhang et al. found that feeding the NAD+ precursor nicotinamide riboside (NR) to aging mice protected them from muscle degeneration. NR treatment enhanced muscle function and also protected mice from the loss of muscle stem cells. The treatment was similarly protective of brain and skin stem cells, which may have contributed to the extended life span of the NR-treated animals.

Adult stem cells (SCs) are essential for tissue maintenance and regeneration yet are susceptible to senescence during aging. We demonstrate the importance of the amount of the oxidized form of cellular nicotinamide adenine dinucleotide (NAD+) and its effect on mitochondrial activity as a pivotal switch to modulate muscle stem cell (MuSC) senescence (i.e. cellular exhaustion). Treatment with the NAD+ precursor nicotinamide riboside (NR) induced the mitochondrial unfolded protein response and synthesis of prohibitin proteins, and this rejuvenated muscle stem cells in aged mice. NR also prevented muscle stem cell exhaustion in a mouse model of muscular dystrophy. We furthermore demonstrate that NR delays cellular exhaustion of neural stem cells and skin stem cells and increases mouse life span. Strategies that conserve cellular NAD+ may reprogram dysfunctional stem cells and improve life span in mammals.

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Fig. 1 Graphical overview of the NAD+ cycle with respect to muscle energetics. In the case of skeletal muscle, a gradual decline in mass, strength, and oxidative capacity increases the susceptibility of middle-aged adults to frailty and metabolic diseases, which can be prevented with NR supplementation.

In adults, tissue homeostasis is highly dependent on stem cell (SC) function. Adult SCs are not only essential in continuously proliferating tissues (like the blood, intestinal, and skin systems) but also in normally non-proliferative tissues (such as skeletal muscle and the brain) that require regeneration after damage or exposure to disease. Aging is accompanied by a decline in adult SC function, termed SC senescence (i.e. cellular exhaustion), which leads to the loss of tissue homeostasis and regenerative capacity.

Homeostasis and regeneration of skeletal muscle depend on normally non-proliferative muscle stem cells which are activated upon muscle damage to expand and give rise to differentiated myogenic cells that regenerate damaged muscle fibers. These responses are blunted in aged muscle, probably because of the reduced number and function of muscle stem cells. In aging, muscle stem cell dysfunction may be caused by outside signals, intrinsic cellular exhaustion signaling pathways, or both. One general regulator of cellular senescence, CDKN2A, shows increased expression in geriatric muscle stem cells, which causes permanent cell cycle withdrawal and senescence of muscle stem cells in very old mice (28 to 32 months of age). However, reductions in muscle stem cell number and function can already be observed before this stage, indicating that MuSC exhaustion may be initiated at an earlier time point. Pre-geriatric mice, approximately 2 years old, can exhibit features of muscle stem cell exhaustion, and this is particularly relevant to middle-aged humans. However, the early mechanisms that instigate muscle stem cell senescence are still largely unknown.

One of the hallmarks of overall aging is the appearance of mitochondrial dysfunction. Induced by calorie-dense diets or aging, mitochondrial dysfunction can result from depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+), whereas NAD+ repletion, with precursors such as nicotinamide riboside (NR), can reverse this process. Stem cells are thought to rely predominantly on glycolysis for energy, a process that incidentally reduces cellular concentrations of NAD+. Mitochondrial function is linked to stem cell maintenance and activation, yet its role in cellular exhaustion is still largely unknown.

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Fig. 2. NR increases lifespan of aged mice.

CD=chow diet (normal diet); NR=nicotinamide riboside supplemented diet

Oxidative stress, partially caused by mitochondrial respiration, is thought to be circumvented in stem cells by their reliance on glycolysis as a primary energy resource. However, this study demonstrates that mitochondrial oxidative respiration is important for the functional maintenance of multiple types of adult stem cells during aging. In fact, the reduction in cellular NAD+ ultimately leading to a loss of mitochondrial homeostasis with a concurrent reduction in the number and self-renewal capacity of muscle stem cells. Accordingly, by boosting the muscle stem cell concentration of NAD+, toxic stress resistance may be restored. In turn, this effect will improve mitochondrial homeostasis, protecting muscle stem cells from exhaustion and safeguarding muscle function in aged individuals. Furthermore, maintaining healthy mitochondria by replenishing NAD+ stores seems to have beneficial effects beyond muscle stem cells, as it appears to protect both neural stem cell and skin stem cell populations from aging.

These results demonstrate that the depression of mitochondrial function can be reversed in aging by using a nutritional intervention to boost NAD+ concentrations in stem cells. Additionally, these findings suggest that NAD+ boosting may be revealed as an attractive strategy for lengthening mammalian life span.

  1. “Nicotinamide Riboside Promotes Sir2 Silencing and Extends Lifespan via Nrk and Urh1/Pnp1/Meu1 Pathways to NAD+” [16]

Although NAD+ biosynthesis is required for replicative lifespan, alterations in NAD+ precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside (NR) is a newly discovered NAD+ precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that oral nicotinamide riboside promotes Sir2-dependent repression of DNA recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD+ synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD+ metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD+ and increases Sir2 function which leads to increased longevity.


  1. “Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer’s disease model mice” [28]

Nicotinamide adenine dinucleotide (NAD+) supplementation to repair disabled mitochondria is a promising strategy for the treatment of Alzheimer’s disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD+ precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of Alzheimer’s disease mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.


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AD= Alzheimer’s disease

This study demonstrates that the supplementation of NR ameliorated selective cognitive impairment and the chronic brain neuro-inflammation in aged mice, and ameliorated selective cognitive impairment and plaque accumulation in Alzheimer’s disease model mice. The beneficial effects of NR regiment on Alzheimer’s model mice has been reported, for example in a DNA repair-deficient mouse model. This classic study shows that supplementation of NR for 3 months significantly attenuates cognitive deterioration, which coincides with an increase in the steady-state levels of NAD+ in the cerebral cortex [10]. Intriguingly, these data showed that the supplementation of NR improved the contextual fear memory of mice. They also found that NR also inhibited the accumulation of brain plaques, similar to the previous reports [11]. In addition, the Alzheimer’s mice showed a decreasing density of brain cell astrocytes in the hippocampus, and miraculously NR supplementation prevented such decreasing. The supplementation of NR decreased plaque accumulation, which may result in the inhibition of the unwanted migration of astrocytes.

The supplementation of NR rescued the contextual fear memory but not cue fear memory. It has been known that the contextual fear memory is hippocampus dependent, and the cued fear memory is non-hippocampus dependent. This may imply that the oral uptake of NR has selective effects on distinct neurons or brain regions with unknown reasons. We do not know whether this is due to the different permeability of blood-brain barrier in different brain region for the transport of NR, or due to the penetration and metabolism of NR in selective neurons.

The protective effects of NAD+ boosting supplementation have been reported in aged organs, such as non-alcoholic fatty liver, skeletal muscle, and blood vessels. These authors found that the supplementation of NR also has beneficial effects on aged brain. The supplementation of NR improved the novel object recognition, and inhibited the chronic neuroinflammation of aged mice. It should be noted that NR did not affect the anxiety-like behavior of aged mice. However, the supplementation of NR only improved the short memory with 30–60 min interval between the training and testing, but failed to rescue the fear memory, which has 24 h interval between training and testing. The effects of NR supplementation on memory seems distinct from the low locomotor activity of aged mice, because NR supplementation did not change their overall locomotor activity. In general, the sedative effect of aging may increase the freezing time; however, they found that the freezing time significantly decreased in aged mice with or without NR supplementation. Thus, NR did not show sedative effect, and the sedative situation of aged mice did not affect the result of NR supplementation on cognition.

Interestingly, the treatment of NR inhibited the increase of the NAMPT enzyme in serum of aged-mice. NAMPT can be secreted by multiple cells, serving as an inflammatory cytokine, and the serum NAMPT level is elevated in inflammatory diseases, age-related diseases, and aging. Thus, NR may show anti-inflammatory effect of aged and Alzheimer’s mice via the inhibition of the elevation of serum NAMPT. And NR may also protect the peripheral organs in aged mice and ameliorate chronic inflammation by inhibit NAMPT release. Yet, the serum NAMPT also increased in Alzheimer’s mice, which was not inhibited by the supplementation of NR. This may imply that the sources of NAMPT or the mechanism of NMAPT secretion can be different, yet both remains unknown. Another surprised benefit of NR supplementation is the inhibition of body weight gain of aged mice. It has been reported that the increase of NAD+ is associated with weight loss. Intriguingly, NR supplementation significantly attenuated high-fat diet induced body fat gain, which was related with the NAD+ levels.

It is clear from this study that the effects of NR supplementation on aged mouse versus Alzheimer’s mice were different, which may arise from distinct mechanisms of action. Aging is a natural process that is accompanied with the depletion of NAD+ and dysfunction of mitochondria, which may result in dementia. The supplementation of NR directly replenishes NAD+ and restores the function of mitochondria. In contrast, in the Alzheimer’s mice, the supplementation of NR may enhance the function of mitochondria differently, with the ultimate result being a stronger clearance of brain plaques and an improvement in cognitive ability.

In summary, the 3 months of NR supplementation had benefits to both the aged brain and the brain of Alzheimer’s mice. This implies that NR may possess beneficial effects to prevent dementia with particular mechanisms. Thus, the oral uptake of NR is clearly a promising strategy for the prevention of dementia due to Alzheimer’s disease.

Selected clinical research findings

NAD+ is a pivotal metabolite involved in cellular bioenergetics, genomic stability, mitochondrial homeostasis, adaptive stress responses, and cell survival. Multiple NAD+ dependent enzymes are involved in synaptic plasticity and neuronal stress resistance. Excitingly, there are emerging findings that reveal key roles for NAD+ and related metabolites in the adaptation of neurons to a wide range of physiological stressors and in counteracting processes in neurodegenerative diseases, such as those occurring in Alzheimer’s, Parkinson’s, and Huntington diseases, and amyotrophic lateral sclerosis (ALS). Advances in understanding the molecular and cellular mechanisms of NAD+ based neuronal resilience will lead to novel approaches for facilitating healthy brain aging and for the treatment of a range of neurological disorders.

Multiple clinical trials of NAD+ precursors, including NR, in neurological disorders are in progress. NR is orally bioavailable, and it is well tolerated and elevates NAD+ in healthy middle-aged and older adults as well as in old diabetic males. The Brenner group reported oral bioavailability of NR and up to 2.7-fold increased NAD+ levels and 45-fold increase in the intermediate NAAD in human blood after oral NR supplementation (1,000 mg/day for 7 days) [29]. A late clinical trial of NR in combination with the polyphenol pterostilbene (PT) (n = 40 between the ages of 60 and 80 years) led by the Guarente lab showed that this treatment increased whole blood NAD+ levels by 90% with no serious adverse events [6]. Martens and colleagues performed a clinical trial of 1,000 mg NR per day for 6 weeks in 24 healthy adults (average age 65 ± 7), and the data confirmed that NR was bioavailable and safe, with potential cardiovascular benefits [5]. A recent study with NR on diabetic men also showed that NR was safe even at 2,000 mg/day (twice a day) for 12 weeks [30]. Currently, studies on NR in relation to mitochondrial function, bioenergetics, aging (and premature aging), and obesity are conducted or recruiting participants and results from these clinical trials will likely reveal the potential of NR in humans. Thus, at least four independent clinical trials indicate NR supplementation (1–2 g/day for up to 3 months) is orally bioavailable and relatively safe.

Clinical trials with NAD+ precursors in relation to cognitive decline with age are underway. One trial is focused on the effects of NR on memory and brain blood flow in adults with mild cognitive impairment (n = 26, multiple doses from 250 mg/day to 1 g/day for a total of 10 weeks). A similar trial is also in progress (500 mg twice daily, n = 58 for 12 weeks).


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NR has also been in clinical trials for Alzheimer’s disease. An open-label study in 17 Alzheimer’s disease patients (33–84 years, mean age 67.7) reported that NR ingestion (twice a day with a total 10 mg/day) for 8–12 weeks improved cognitive effects. Several decades of clinical studies of NAM for a variety of diseases have been performed, with the clinical data showing NAM is relatively safe (1,000–2,000 mg/day) and is readily absorbed from the gastrointestinal tract with peak serum concentrations in 1 h after oral ingestion. Based on the promising data from Alzheimer’s disease mice [31], a phase II clinical trial of NAM on 15 Alzheimer’s disease patients with mild to moderate dementia (1,500 mg twice daily) for 24 weeks was performed (NCT00580931) [32]. However, NAM did not show any significant effects, though the lack of efficacy may have been due to several contributing factors, such as small sample size and a relatively short treatment period. A new clinical trial with NAM on Alzheimer’s disease is now recruiting with the aim of studying the effect on p-Tau (p-Tau181) and total Tau levels in the cerebrospinal fluid.

Several clinical trials NR in Parkinson’s disease patients have been performed. With relation to Parkinson’s disease, NADH has shown beneficial effects on movement. An early study using NADH (intravenous administration, 25 mg/day) in 34 Parkinson’s disease patients for 4 days, reported that 21 patients (61.7%) showed dramatic benefits, while the remaining 13 Parkinson’s disease patients showed moderate improvement of motor deficits [33]. The benefits were confirmed in a following study with 885 Parkinson’s disease patients, also showing similar benefits between parenteral and oral applications [34]. However, benefits were not seen in a double-blinded study on 5 clinically moderate Parkinson’s disease patients treated with NADH (25 mg) given intravenously once a day for 4 days followed by NADH (25 mg) given intramuscularly after 2 and 4 weeks [35]. Niacin/nicotinic acid (NA) has also been tested in one 78-year-old male Parkinson’s disease patient. This report indicated that 500 mg NA twice a day improved rigidity and bradykinesia. A new clinical trial with NA is currently recruiting Parkinson’s disease patients, with the aim of examining the effects on inflammation and motor function/symptoms in Parkinson’s disease. Since NR is orally bioavailable and has shown no detectable side effects as described above, it would be desirable for clinical trial. Currently, two new clinical trials with NR in Parkinson’s disease are starting, with the aims of investigating the neuro-metabolic profile and motor function after treatment.

There are fewer clinical trials of treatments that bolster NAD+ levels in ALS patients. Following a clinical trial in healthy elderly people, a trial in ALS patients was recently completed [36]. The trial included 10 ALS patients receiving placebo and 10 patients receiving EH301 for 4 months. The study was a randomized double-blind design and included both males and females. NRPT/EH301 treatment improved ALS functional rating scale revised (ALSFRS-R), increased the MRC grading scale index (grades muscle power), and forced vital capacity (FVC, functional respiratory capacity test), as well as increased electrical activity in muscles. All patients chose to continue the treatment after 4 months, and thus the treatment was finalized after 1-year treatment, with no deterioration. Despite the low level of participants in this study, it sets the stage for the potential for NAD+ augmentation as a treatment for ALS, and large-scale phase trials are certainly warranted.

NAD+ precursors are also being tested for other neurodegenerative conditions including a clinical trial of NR in premature aging diseases based on its significant benefit in cross-species preclinical studies. Additionally, NAM is being tested in two clinical trials for Friedreich’s ataxia, an early-onset autosomal recessive hereditary ataxia caused by a pathological genetic mutation.

While modern, sedentary, and overindulgent lifestyles contribute to brain aging and age-related neurodegenerative diseases, intermittent bioenergetic challenges, as exemplified by exercise, fasting, and intellectual challenges may protect the human brain against age-related dysfunction and disease. Studies on the effects of intermittent metabolic challenges on NAD+ levels, its metabolism, and the activities of the NAD+-dependent enzymes in humans are required. In addition, it will be of considerable interest to compare and contrast the efficacy and safety profiles of NAD+ precursors with the ketone bodies, which elevate NAD+ levels in neurons and has been shown to suppress brain plaque pathologies and ameliorate behavioral deficits in a mouse model of Alzheimer’s disease, and also protects dopaminergic neurons in an animal model of Parkinson’s disease. However, it is important to note that the importance of NAD+ related biogenetics also involves neurons and related pathologies outside the brain. One such example is the group of neurodegenerative diseases termed glaucoma, which is characterized by progressive dysfunction and loss of the retinal ganglion cells. In glaucoma, NAD+ depletion and mitochondrial abnormalities are common, and beneficial effects of NR treatment of mouse models have been reported [37], [38]. Furthermore, the gut-to-brain axis may also show effects of NAD+ augmentation and, hereby, provide a new target of interest in neurodegenerative diseases [39].

Safety and Tolerability

NR has been demonstrated to be safe, a conclusion supported by a rigorous battery of animal toxicology studies [40]. Additionally, NR has been well-tolerated in all published clinical studies. Because regular niacin use is limited by flushing (i.e. temporary facial reddening), it has been of particular interest to assess whether there would be reports of flushing or other treatment related adverse events that are associated with ingestion of NR. For instance, in a randomized, placebo-controlled, double-blind, parallel-group study involving 140 healthy adults, the ingestion of up 1000 mg of NR is not associated with flushing. Limitations of these studies were that it was conducted in predominantly white, middle-aged adults who consumed a diet limited in niacin equivalents.

Since nicotinamide has been studied as a dietary supplement in humans for decades, excellent safety data on long term use is available. The EU Scientific Committee on Food has established an upper limit of 900 mg/day as safe [41] Thus, the nicotinamide safety information coupled with in the sum of clinical trial data detailed above clearly demonstrate that consumption of NR is safe for daily use at reasonable doses.

Conclusion

Nicotinamide Riboside Chloride is a stable form of Nicotinamide Riboside that has the proven ability to raise NAD+ levels in humans. It has been shown to vastly improve cellular energy metabolism, promote neuroprotection in a variety of disease models, maintain and extend telomeres for anti-aging, extend lifespan and healthspan, provide resistance to the negative effects of high-fat diets and excess alcohol consumption, enhance the benefits from exercise, and promote new blood cell generation.

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any diseases. Umbrella Labs remains neutral to third-party intellectual property considerations arising from the non-approved use of any of its products.

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