Nicotinamide riboside suggest an improvement to this article

Nicotinamide riboside (NR) is a precursor molecule for the biosynthesis of nicotinamide adenine dinucleotide, or NAD+, a coenzyme that participates in the production of cellular energy and repair. Two other NAD+ precursors, nicotinic acid (NA) and nicotinamide (NAM, also called niacinamide), along with nicotinamide riboside, are often collectively referred to as niacin (vitamin B3) or niacin equivalents. These precursors are not equally allocated throughout the body, exhibiting preferential distribution among the blood, brain, gut, and other organs. NAD+ can also be produced from tryptophan, an amino acid acquired in the diet, and another dietary compound, nicotinamide mononucleotide (NMN).

NAD+ depletion is one of the hallmarks of aging and likely contributes to the pathophysiology of a wide range of age-related conditions and diseases, such as metabolic dysfunction, neurodegenerative diseases, and cancer. Emerging animal evidence suggests that increasing NAD+ levels via supplementation of its precursors may slow or even reverse several aspects of aging and delay the progression of age-related diseases.

Nicotinamide riboside, nicotinamide, and nicotinic acid help maintain cellular levels of NAD+, thereby facilitating NAD+-dependent cellular activities, such as mitochondrial metabolism, regulation of sirtuins, and PARP activity. They are converted to NAD+ in a stepwise fashion by enzymes specific to their respective pathways. Nicotinamide riboside conversion relies on the kinases Nrk1 and Nrk2, or via enzymes in the body's NAD+ salvaging program. All mammalian cells express Nrk1, but Nrk2 is found only in skeletal muscle and heart and brain tissues.[1] Nrk2's presence in the brain suggests it has potential implications for neurological health.

Nicotinamide riboside is found in cow's milk and beer and is available in dietary supplement form. Upon ingestion, it is incorporated into the body's NAD+ pool.

Learn more about NAD+ in this overview article.

Beneficial health effects

Evidence from animal studies suggests that nicotinamide riboside supplementation may be beneficial to health and may delay or prevent the onset of age-related disease.

Obesity

In a study in which mice were fed a diet that was high in fat and sugar and received a 400-milligram per kilogram of body weight (mg/kg/bw) nicotinamide riboside supplement every day for one week, the mice gained 60 percent less fat, exhibited improved insulin sensitivity, and demonstrated greater endurance and muscle strength, compared to mice that did not receive the supplement.[2]

Mitochondrial health

The depletion of NAD+ in mice promotes severe mitochondrial damage and muscle atrophy similar to muscular dystrophy. Supplementation with nicotinamide riboside, however, reversed mitochondrial damage, increased mitochondrial biogenesis, and reversed muscular atrophy.[3] Similar results were observed in mice with a mitochondrial mutation defect that causes mitochondria to become dysfunctional with age. When the mice were given a 400 mg/kg/bw nicotinamide riboside supplement, their mitochondrial biogenesis (the process by which new mitochondria are made inside cells) increased in both muscle and brown adipose tissue.[4]

Cardiovascular health

In an 8-week long randomized, double-blind, placebo-controlled study involving 120 healthy adults between 60 and 80 years of age, a 250-milligram daily dose of nicotinamide riboside and pterostilbene (a natural compound found in blueberries that activates sirtuins) increased the participants' whole blood NAD+ levels by 40 percent compared to their baseline levels after just four weeks. Participants' whole blood NAD+ levels increased by 90 percent when taking a double dose (500 milligrams). Those who took the lower dose exhibited reduced diastolic blood pressure and lower levels of the liver enzyme alanine aminotransferase, a marker of liver damage.[5] Interestingly, both groups of participants experienced increases in LDL cholesterol. However, findings from clinical trials suggest that pterostilbene increases LDL levels.[6]

A randomized, placebo-controlled crossover trial involving 60 middle-aged and older adults between the ages of 55 and 79 years demonstrated that a 500-milligram dose of nicotinamide riboside twice daily for six weeks was well tolerated and increased NAD+ levels in white blood cells by 60 percent.[7] The study participants also experienced improvements in blood pressure and aortic stiffness but these effects were not statistically significant, possibly due to the size of the dose or the relatively small number of people in the study. Nicotinamide riboside had no effects on metabolic function, motor function, or exercise capacity and performance.

Physical and cognitive aging

Studies in mice have demonstrated that nicotinamide riboside supplementation enhances longevity, increases neurogenesis, decreases cognitive deterioration and amyloid-beta production, and increases synaptic plasticity.[8] [9]

Whether taking nicotinamide riboside will have the same effects on delaying aging or improving mitochondrial function in humans as it does in animals is unknown. However, when people with type 2 diabetes took a nicotinic acid derivative (an NAD+ precursor), they exhibited improvements in mitochondrial function in their skeletal muscle as well as increased NAD+ levels in their muscles.[10] Interestingly, some findings suggest that nicotinamide riboside is the preferred NAD precursor in mitochondria.[11]

Lactation and breastfeeding

Compelling data from an animal study suggest that nicotinamide riboside supplementation may have far-reaching effects on mothers and their offspring. When nursing-mother mice took a very high dose of nicotinamide riboside supplement (3 grams/kg/bw), they experienced weight loss and improved quantity and quality of their milk.[12] Their offspring demonstrated better motor coordination, better learning and memory, less anxiety, and greater stress resilience than mice whose mothers were not supplemented. The improvements in learning were attributed to increased levels of brain-derived neurotrophic factor, or BDNF, in the mothers' milk. BDNF is a type of neurotrophin – or growth factor – that controls and promotes the growth of new neurons.

Bioavailability

In a pilot study involving one 52-year-old male who took a 1,000-milligram dose of nicotinamide riboside every day for one week, the subject's NAD+ plasma levels increased nearly three-fold.[13] An intermediary molecule involved in NAD+ synthesis, nicotinic acid adenine dinucleotide, increased 45-fold. Further investigation into nicotinamide riboside's bioavailability demonstrated that when 12 healthy adults took varying doses of the precursor (100, 300, or 1,000 milligrams, in a single dose), they exhibited dose-dependent increases in NAD+ levels in plasma.[13] Another study found that a single dose (250 mg) of nicotinamide riboside and pterostilbene increased plasma NAD+ levels by 40 percent and a double dose (500 milligrams) increased levels by 90 percent after four weeks compared to placebo and baseline.[5]

While human studies have shown that oral nicotinamide riboside can raise plasma NAD+ levels, the question still remains whether nicotinamide riboside can reach other tissues intact and directly form NAD+ without going through the salvage pathway. This is an important point because NAD+ produced from the salvage pathway is subject to feedback inhibition and therefore cannot raise NAD+ levels in tissues above a certain level.

When NR was orally administered to animals, NAD+ levels increased in a dose-dependent manner in the liver, kidney, muscle, and the brain. However, all of the orally administered NR was converted to nicotinamide in the liver, so the NAD+ found in other tissues was derived from the salvage pathway and not directly from NR.[14]

Intravenous administration of nicotinamide riboside delivered the intact molecule, which was directly converted to NAD+ into liver, kidney, and muscle tissue in a dose-dependent manner. However, nicotinamide riboside did not cross the blood-brain barrier but did raise brain levels of NAD+ derived from the salvage pathway. These data suggest that if nicotinamide riboside is administered intravenously, it can directly form NAD+ and not be subject to feedback inhibition, possibly raising tissue NAD+ levels to much higher levels than they otherwise would be.

Learn more about NAD+ flux in this overview article.

Supplements and stability

As described above, clinical studies have demonstrated that nicotinamide riboside supplementation in humans markedly increases whole blood and white blood cell NAD+ levels, improves markers of metabolic health in combination with pterostilbene, and is safe, even at high doses.[5] [10] [7]

Nicotinamide riboside supplements are commonly administered in the clinical setting or sold over-the-counter in the compound's synthetic form, nicotinamide riboside chloride. This formulation is fairly shelf-stable at room temperature but shelf life may be extended in cold temperatures.

Although some adverse events have occurred when taking nicotinamide riboside supplements, they were mild and the product is generally considered safe. Side effects included nausea, leg cramps, increased bruising, and flushing, a condition characterized by the sensation of heat and accompanied by redness of the face, neck, and chest.[7] Flushing is a common side effect of niacin supplementation.[15] Of note, study participants taking a placebo reported similar effects.

Identifying the appropriate dose of nicotinamide riboside supplements to elicit improvements in healthspan and lifespan has proven problematic, however. Typical doses in the laboratory setting vary, but the greatest benefit has been observed with 400 mg/kg/bw per day in mice, which is roughly equivalent to 32 mg/kg/bw per day in humans (approximately 2.7 grams for a 180-pound man). Further research will likely inform recommendations for appropriate doses to elicit optimal performance and safety profiles.

Conclusion

Nicotinamide riboside serves as a precursor to NAD+. Data from multiple studies suggest that nicotinamide riboside elicits positive health effects in both animals and humans. In particular, improvements in measures of metabolic, cardiovascular, and neurological health have been observed. Future research will likely elucidate the benefits, safety, and applicability of nicotinamide riboside supplementation.

A COMPREHENSIVE OVERVIEW OF NICOTINAMIDE RIBOSIDE

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