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Nicotinamide riboside (NR) is a newly-researched vitamin B3 analog and the most efficient precursor to nicotinamide adenine dinucleotide (NAD+). NAD+ is a key component of glycolysis, the citric acid cycle, and the electron transport chain, which are all involved in mitochondrial production of ATP for energy. In addition to its importance in cellular energy production, NAD+ is a critical substrate for several enzymes, including sirtuins, which play key roles in numerous biological functions that affect stress responses, aging, metabolism, and other cellular activities. In addition to sirtuins, NAD+ is necessary for other key enzyme classes – ADP-polyribose polymerases (PARPs), ADP-ribose transferases (ARTs), and cADP-ribose (cADPR) synthases. PARPs and ARTs are primarily involved with DNA repair and apoptosis (programmed cell death), while cADPR synthases are mainly involved in calcium mobilization.1-3 Collectively these are all referred to as NAD+ consumers. It is important to elucidate this NAD+ “consumer” function in humans. NAD+ and NADP+ (nicotinamide adenine dinucleotide phosphate) – as their reduced forms NADH and NADPH – are typically viewed as hydrogen donors and, thus, heavily involved in redox reactions. In this form, NAD+ can be more easily regenerated and the basic NAD+ substrate remains intact. However, given the numerous reactions that consume fundamental components of the NAD+ molecule (such as the ribose and adenine moieties), there is an increased need for NAD+ precursors from the diet.1

In addition, the activity of the primary, rate-limiting enzyme that regenerates NAD+ – nicotinamide phosphoribosyltransferase (Nampt) – is reduced by aging,4 deconditioning.5 pathway that restores NAD+ status can be diminished to the extent it has clinical implications. Because NAD+ is closely linked to mitochondrial biogenesis, this is one reason why mitochondrial numbers can be reduced in these situations.

Why Nicotinamide Riboside Instead of Other NAD+ Precursors?

Professor Anthony Sauve of Weill Medical College at Cornell University: “We have discovered that nicotinamide riboside can provide very large enhancements in cellular NAD+ levels, and is a new form of vitamin B3 that is more potent than nicotinamide or niacin for this purpose.”

Nicotinamide riboside is found in trace amounts in various foods, including the whey fraction of milk.6 precursors are identified, there are differences in their effectiveness. Administration of nicotinamide riboside has been shown to increase intracellular NAD+ levels in murine and human cell lines.7 researchers demonstrated that oral administration of nicotinamide riboside increased tissue levels of NAD+ in a mouse model. 

Furthermore, NAD+ increases led to up-regulation of two key sirtuins involved in aging and metabolism – SIRT1 and SIRT3.7 NAD+ levels more effectively than niacin, niacinamide, or nicotinamide mononucleotide.6 as much as a 270-percent increase in NAD+ after NR administration.8 In addition to more efficient NAD+ production, NR can provide additional benefits over other NAD+ precursors. Niacin is known to cause side effects such as flushing, and, when used in high doses, it can have side effects such as elevated liver enzymes, dysglycemia, and gout. Niacinamide, although it does increase NAD+ levels, can have an inhibitory effect on sirtuin activities, the exact opposite of the desired effect. In addition, NR seems to be the preferential precursor of NAD+ in neurons, suggesting an advantage of NR over niacin or niacinamide for protection from neurological degeneration.9 remain more stable after NR supplementation compared to niacin.10 

Potential Clinical Indications for Nicotinamide Riboside

Healthy Aging

Cellular aging is associated with NAD+ depletion via a number of mechanisms. The effect of aging on NAD+ levels and metabolism has been tested in an animal model in which the researchers demonstrated a significant decrease in NAD+ and NAD+:NADH ratios by middle age (12 months in rats) in the heart, lung, liver, and kidneys. This status was associated with increased levels of oxidative stress and decreased SIRT1 activity. The study’s authors concluded that, “Strategies targeted toward maintaining adequate NAD+ content during the aging process may prove a novel and potentially effective mechanism for retarding oxidative stress mediated cell degeneration and age associated disorders.”11 Calorie restriction is known to afford significant increases in human lifespan, in part via up-regulation of sirtuins. Resveratrol, one of the most-researched sirtuin activators, up-regulates human SIRT1 and has been shown to extend the lifespan in some organisms. In a seminal study, nicotinamide riboside elevated NAD+ levels, up-regulated sirtuin activity, and extended lifespan in a yeast model.10 Building on this study using a yeast model, researchers at the University of California Davis found that calorie restriction-associated increases in lifespan and stress resistance were dependent on adequate amounts of endogenous nicotinamide riboside.12 Mitochondrial dysfunction, which can manifest as a decrease in number or function of mitochondria, is a hallmark of aging. In a mouse study, increasing NAD+ levels for one week in a 22-month-old mouse resulted in mitochondrial function and muscle biochemical markers being restored to that of a six-month-old mouse.13

In a clinical study examining human pelvic tissue that had been surgically removed for reasons unrelated to the trial, declining NAD+ levels were associated with aging in both males and females. This was shown to be at least partially due to increased PARP activity (more evident in males than females), which is necessary for DNA repair. NAD+ is the sole substrate for PARP and is consumed when PARP is involved with DNA repair. This study also found SIRT1 activity was negatively correlated with increasing age in males, but not females. The authors concluded that NAD+ depletion probably plays a role in the aging process by interfering with DNA repair, gene signaling, and energy production.14

Neurodegenerative Conditions: Parkinson’s Disease, Multiple Sclerosis, Optic Neuritis, Peripheral Neuropathy, Ischemic Stroke, Traumatic Brain Injury, Alzheimer’s Disease

Progressive axon degeneration (Wallerian degeneration) takes place in a number of neurodegenerative diseases, including peripheral neuropathy, Parkinson’s disease, and Alzheimer’s disease. Researchers at Washington University School of Medicine in St. Louis, Missouri, discovered that NAD+ pretreatment of injured axons – either from physical injury or chemotherapy-induced (vincristine) injury – protected against further nerve degeneration via SIRT1 up-regulation.15 Further research demonstrated exogenous application of NAD+ at the time of axon injury prevented degeneration.16 Some of these same researchers sought to determine whether NAD+ precursors could provide protection from neurodegeneration. In an elaborate set of experiments, niacin, niacinamide, nicotinamide riboside, and several intermediate molecules in the biosynthetic pathway to NAD+ were tested. Nicotinamide riboside was the only dietary constituent of the NAD+ pathway that provided axon protection; no protection was offered by niacin or niacinamide. Furthermore, the enzyme Nrk2 that converts NR to nicotinamide mononucleotide (which is then converted to NAD+) was increased 20-fold after neuronal injury, indicating NR’s significance in this process.17 Optic neuritis is an inflammation of the myelin sheath of the axons that make up the optic nerve and is often associated with multiple sclerosis (MS). Symptoms include vision loss, fading color vision, and pain; and a histological sign is loss of retinal ganglion cells. In an experimental MS murine model, intravitreal injections of either nicotinamide riboside or resveratrol helped prevent loss of retinal ganglion cells, most likely via SIRT1 activation, since the effect was blocked by a SIRT1 inhibitor. Further research is needed to determine whether oral administration would offer the same protection. The authors suggest these findings help confirm that, “SIRT1 activation is important for neuroprotection in CNS [central nervous system] demyelinating disease.”18 NAD+ depletion might be central to brain damage associated with ischemic stroke or traumatic brain injury. The proposed mechanism is the up-regulation of PARP in order to repair DNA. PARP is a NAD+ consumer, however, so if the area is flooded with PARP, then a relative NAD+ deficiency could occur.19 In an animal model of traumatic brain injury, intranasal NAD+ protected hippocampal neurons from destruction.20 It remains to be determined whether oral administration of nicotinamide riboside can provide such neuroprotection. 

Recent research has implicated dysregulation of the sirtuin pathway in the pathogenesis of Alzheimer’s disease (AD). In mouse models, the up-regulation of SIRT1 and increased NAD+ have been shown to prevent amyloid-beta (Aβ) accumulation, the primary components of amyloid plaques found in the brains of individuals with AD.21,22 The effect of dietary nicotinamide riboside was tested in an AD mouse model. Mice supplemented with 250 mg/kg/day NR for three months demonstrated a diminution of cognitive deterioration. Amyloid-beta production was attenuated by NR via up-regulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), an important regulator of Aβ generation. The authors concluded, “Our study provides a novel aspect of a potential application of NR in AD treatment.”23

Mitochondrial Myopathy

Mitochondrial disorders, among the most common forms of inherited metabolic disorders, tend to be progressive and often fatal due to the lack of available treatment. Mitochondrial disease involving the muscles is referred to as mitochondrial myopathy and is associated with deficiencies of energy production in the electron transport chain. Histological aspects of myopathy include depletion of the mitochondrial NAD+ pool, structural abnormalities in skeletal muscle mitochondria, decreased mitochondrial number, and ultimately decreased ATP production.

In a just-completed study in a mouse model of mitochondrial myopathy (demonstrating the abnormalities cited above), nicotinamide riboside attenuated several of the devastating consequences of this disease. Genetically diseased and healthy mice were given 400 mg/kg/day NR or control chow diet, prior to disease manifestation to test its preventive capacity, and after disease manifestation to test whether it could halt disease progression. After 16 weeks of treatment with NR, the diseased mice showed improved biochemistry in muscle fibers, increased mitochondrial mass, normalized mitochondrial structure (dense cristae and matrices), and enhanced ATP production. NR significantly delayed the progression of the disease in both its early and advanced stages.24

Metabolic Derangements: Obesity, Metabolic Syndrome, and Diabetes

In an animal model nicotinamide riboside directly increased NAD+ levels in muscle, the liver, and brown adipose tissue, and mediated several aspects of metabolic syndrome. Mice were fed either a normal diet or a high-fat diet and supplemented (or not) with NR at a dose of 400 mg/kg/day. NR prevented obesity in the high-fat fed mice, but did not affect dietary intake or exercise patterns, indicating NR resultedin better energy expenditure. NR also decreased liver triglyceride accumulation in the high-fat diet group, which has implications for prevention of fatty liver. NR feeding also lowered fasting insulin levels, improved glucose disposal, and enhanced insulin sensitivity. In addition, NR partially prevented high-fat diet-induced elevations in total- and LDL-cholesterol, without affecting HDL-cholesterol levels. Other improved metabolic findings in the NR groups included increased thermogenesis, greater muscle endurance (particularly in the high-fat diet group), and increased cristae density in brown adipose mitochondria.7

In the above study NR increased NAD+, which in turn increased SIRT1 and SIRT3 activity in NAD+-accumulating tissues – muscle, liver, and brown adipose. Up-regulation of these two sirtuins has positive implications for metabolic syndrome. The authors speculated that increased NR-stimulated SIRT1 activity in the liver might be the mechanism behind lowered cholesterol.7

Another group of researchers investigated the effect of decreased SIRT3 activity on the development of metabolic syndrome. They found that feeding mice with a high-fat diet resulted in the down-regulation of SIRT3 activity. In addition, mice lacking SIRT3, when placed on a high-fat diet, experienced acceleration of obesity, insulin resistance, hyperlipidemia, and fatty liver. These same researchers found a correlation between a genetic polymorphism in humans that decreases SIRT3 activity and increased risk of developing metabolic syndrome. Their research uncovered a single nucleotide polymorphism (SNP) in SIRT3 that was associated with an increased risk for metabolic syndrome in a group of Caucasians with fatty liver.25

The metabolic targets of SIRT1 and SIRT3 were further elucidated in an extensive review.26 Among the key mechanisms associated with metabolic syndrome, SIRT1: (1) inhibits hepatic glucose production in obesity; (2) prevents liver lipid accumulation in hyperglycemic conditions; (3) enhances production of HDL-cholesterol; (4) regulates insulin release from the pancreas, improving glucose tolerance; (5) protects pancreatic beta-cells from destruction; and (6) attenuates insulin resistance and obesity-associated inflammation by increasing adiponectin. A review of SIRT3’s effects on metabolism shows: (1) inhibition of lipid accumulation in hepatocytes; (2) promotion of mitochondrial biogenesis in skeletal muscle, and (3) increased thermogenesis in brown adipose tissue associated with higher levels of SIRT3.

Destruction of pancreatic beta-cell function is the hallmark of type 1 diabetes. However, progressive deterioration of pancreatic beta-cell function in the elderly is also being increasingly implicated in the pathogenesis of type 2 diabetes. NAD+-stimulated SIRT1 has been shown to up-regulate glucose-stimulated insulin secretion in pancreatic beta-cells. SIRT1 also improves insulin sensitivity in skeletal muscle. This is significant because skeletal muscle accounts for approximately 75 percent of insulin-stimulated glucose uptake in the body.27

As discussed above, Nampt is the rate-limiting enzyme in the pathway from nicotinamide to nicotinamide mononucleotide (NMN) and on to NAD+. A group of researchers at Washington University School of Medicine (St. Louis, Missouri) found that synthesis of NAD+ via Nampt is severely compromised by a high-fat diet. If this step is bypassed, however, by direct application of nicotinamide mononucleotide, then NAD+ levels are restored along with improved glucose tolerance, enhanced hepatic insulin sensitivity, and decreased inflammation and oxidative stress, all mediated by SIRT1.28 Because nicotinamide riboside bypasses the rate-limiting and high-fat diet depleted enzyme Nampt, it would appear to be a likely candidate for supplementation to improve insulin sensitivity. As noted above, NR increases NAD+ levels more effectively than niacin, niacinamide, or NMN.6


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2. Yang T, Sauve A. NAD metabolism and sirtuins: metabolic regulation of protein deacetylation in stress and toxicity. AAPS J 2006;8:E632-E643.

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7. Canto C, Houtkooper R, Pirinen E, et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab 2012;15:838-847.

8. Yang T, Chan N, Sauve A. Syntheses of nicotinamide riboside and derivatives:effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells. J Med Chem 2007;50:6458-6461.

9. Bogan K, Brenner C. Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition. Annu Rev Nutr 2008;28:115-130.

10. Belenky P, Racette F, Bogan K, et al. Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+. Cell 2007;129:473-484.

11. Braidy N, Guillemin G, Mansour H, et al. Age related changes in NAD+ metabolism oxidative stress and SIRT1 activity in Wistar rats. PLoS One 2011;6:e19194. 

12. Lu S, Kato M, Lin S. Assimilation of endogenous nicotinamide riboside is essential for calorie restriction-mediated life span extension in Saccharomyces cerevisiae. J Biol Chem 2009;284:17110-17119.

13. Gomes A, Price N, Ling A, et al. Declining NAD(+) induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell 2013;155:1624-1638.

14. Massudi H, Grant R, Braidy N, et al. Age-associated changes in oxidative stress and NAD+ metabolism in human tissue. PLoS One 2012;7:e42357.

15. Araki T, Sasaki Y, Milbrandt J. Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration. Science 2004;305:1010-1013.

16. Wang J, Zhai Q, Chen Y, et al. A local mechanism mediates NAD-dependent protection of axon degeneration. J Cell Biol 2005;170:349-355.

17. Sasaki Y, Araki T, Milbrandt J. Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy. J Neurosci 2006;26:8484-8491.

18. Shindler K, Ventura E, Rex T, et al. SIRT1 activation confers neuroprotection in experimental optic neuritis. Invest Ophthalmol Vis Sci 2007;48:3602-3609. 

19. Ying W, Xiong Z. Oxidative stress and NAD+ in ischemic brain injury: current advances and future perspectives. Curr Med Chem 2010;17:2152-2158.

20. Won S, Choi B, Yoo B, et al. Prevention of traumatic brain injury-induced neuron death by intranasal delivery of nicotinamide adenine dinucleotide. J Neurotrauma2012;29:1401-1409.

21. Qin W, Yang T, Ho L, et al. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J Biol Chem 2006;281:21745-21754.

22. Bonda D, Lee H, Camins A, et al. The sirtuin pathway in ageing and Alzheimer disease: mechanistic and therapeutic considerations. Lancet Neurol 2011;10:275-279.

23. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated β-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging 2013;34:1581-1588.

24. Khan N, Auranen M, Paetau I, et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3. EMBO Mol Med 2014 April 6. [Epub ahead of print]

25. Hirschey M, Shimazu T, Jing E, et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell2011;44:177-190.

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28. Yoshino J, Mills K, Yoon M, Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 2011;14:528-536.



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