By Benjamin V. Treadwell, Ph.D.
By now avid Juvenon Health Journal readers are familiar with the potential health benefits of vitamin B3/niacin, as we've touched upon this important topic frequently. In this month's Juvenon Health Journal we explore exciting new findings on this vitamin with emphasis on a recently isolated niacin metabolite, nicotinamide riboside.
Niacin's Key Role in Metabolism
Niacin is the core constituent of two key biomolecules: nicotinamide adenine dinucleotide, NAD(H), and nicotinamide adenine dinucleotide phosphate, NADP(H), both critical for maintaining optimum health. The (H) designates that these biomolecules can be in a form without hydrogen or in a reduced form (with hydrogen). Like drill-bits are essential to the mechanics of a drill, these co-factors are essential to cellular machines, and are required for energy production, as well as the synthesis of virtually all our structural components -- lipids, carbohydrates, and proteins.
In addition, they provide many of the vital health maintenance services. For example, they serve as caretakers of important cellular antioxidants, such as glutathione, and superoxide dismutase (SOD). These antioxidants help neutralize body-damaging free radicals and other disease-producing oxidants. The ability of NAD(H) and NADP(H) to fine-tune metabolism has been documented in experimental data reported over the previous decade or more.
Why Restrict Calories?
From diabetes and heart disease to cancer and dementia, the health benefits of restricting one's calorie intake (CR diet) have been extensively studied and reported over the past two decades.
Virtually all animals, including humans, benefit from a reduced-calorie diet, and now it is becoming clear why it improves health. The reason? One family of enzymes, the sirtuins, appears to be at least partly responsible for eliciting the health effects of a CR diet. The sirtuins remove specific molecules, acetyl groups, from key regulators of metabolism. One such regulator is the enzyme, AMPK (adenosine monophosphate-activated protein kinase) that acts to inhibit a key enzyme, ACC, (Acetyl-CoA carboxylase) in fat synthesis, resulting in a decrease in fat production.
The inhibition of fat production promotes the utilization of fat for energy production, and ultimately the removal of fat from the body. Therefore, the sirtuins not only prevent fat production, but also burn the fat present in the body for energy. Furthermore, specific sirtuins switch-on a host of cell-protective antioxidant genes that protect against toxic oxidants, which are produced during the conversion of fat, and/or other foods, to energy.
In addition to these positive health effects, the sirtuins act to improve the function of the pathway active in removing toxic sugar from our blood, the insulin pathway. The consequence is an increase in insulin sensitivity as the insulin receptor is returned to a more youthful-like, highly sensitive state.
New Research Discovers CR-Mimicking Vitamins
Truthfully, diets that severely restrict calories (30-40% less than the typical caloric recommendation) can be challenging. But what if there was a way to mimic a CR diet with vitamin supplementation? Exciting new research indicates that one can obtain similar CR benefits by taking the vitamin niacin (N), or the newly discovered niacin derivative, nicotinamide riboside (NR). This vitamin-like molecule is present in milk and beer, and probably other foods in our diet. Both of these vitamins act on the liver and muscles to increase amounts of the key regulator of metabolism, Nicotinamide Adenine Dinucleotide. NAD+ is elevated in a calorie-restricted diet and fine-tunes our metabolic machinery for maximum health and energy.
Niacin and Healthy Cholesterol
Clinical studies over the previous six decades have established niacin's benefits on triglycerides and cholesterol when taken in pharmacological doses See Juvenon Health Journal, Volume 11, Number 4,"Niacin: Is the First Cardio Health Therapeutic Still the Best?"), but no one really understood how this vitamin worked its magic. The studies with niacin and NR, described above, provide important new information pertinent to niacin's positive action on our lipids. The action of these two substances is to increase NAD+ levels, which is the key regulator of energy metabolism. Supplemental niacin or NR primes the cell to burn fat and improve insulin sensitivity. These two nutrients may also prevent some diseases such as diabetes and heart disease, as well as other diseases associated with metabolic imbalance.
Nicotinamide Riboside: Better than Niacin?
The newly discovered vitamin, NR, is being touted as better than niacin because of the fact that NR, unlike niacin, does not bind to the niacin receptor found on certain cells (Langerhan's cells of the skin, macrophages and fat cells). Binding to this receptor is what triggers the production of prostaglandins, and promotes the unpleasant side effects of niacin (itching, flush etc). However, the lack of itching and flushing with NR does not mean it is better overall. Importantly, there is recent evidence in support of niacin-induced prostaglandins as agents to help prevent dangerous platelet activation and clot formation. Fortunately, most people can avoid unpleasant side effects by taking extended release niacin, which binds to the niacin receptor, but at a more steady-state rate.
The Impact of Scientific Discoveries
Recent studies on the positive health effects of CR helped scientists to understand the importance of the enzymes, sirtuins, as mediators of CR's effects. This discovery inspired investigators to determine how CR activated the sirtuins. They found that when there is a limited supply of food in the diet, as with CR, the ratio of NAD+ / NADH in certain tissues is elevated. Later it was determined that NAD+ could simply be added to cells to activate the sirtuins, and the associated healthy metabolic pathways. In turn, this exciting discovery prompted scientists to look for nutrients (both synthetic and natural) that could increase the sirtuins in cells.
Initial studies demonstrated the sirtuin-activating effects of a number of nutrients including resveratrol, berberine, fisetin and other natural and synthetic compounds. Importantly, experimental results also supported their positive health effects.
Scientists are also investigating another natural bio-molecule with potent, sirtuin-activating properties present in milk, beer, and other foods. NR is interesting because -- like niacin -- when taken in supplement form, it may help correct the inevitable age-associated decline in metabolic balance and associated diseases.
However, more work needs to be performed to determine whether NR, in addition to niacin, is required for maximum health in humans. One important point is that NR, unlike niacin, is currently unavailable as a supplement, yet both vitamins appear to have similar health-promoting properties in animal and cell culture studies.
answers your questions.
question: I take niacin for improving my lipid levels, and it clearly works as my triglycerides and my HDLc improved. I first started taking regular niacin, 500 mg/day. However, because of annoying itching and flush for at least a 20-30 minute period, I had to switch to the extended release niacin, which eliminated the problem. I am intrigued by the fact that a friend of mine takes 500 mg of regular niacin too, and has no side effects (no itching or flushing reaction). Do you have an explanation for this difference in response to niacin?
answer:I am pleased to hear the extended release niacin is working for you and that it is improving your lipid profile with no side effects. The question about your friend's no side effect response to niacin is interesting. The simple answer is that we all have slightly different gene profiles, and that means the enzymes that process drugs, (cytochrome p450s), such as niacin, can have different effects associated with the different gene profiles. There are also differences in gene coding for the receptor, GPR 109 that binds niacin in cells of the skin to produce substances (prostanoids) that elicit the itching response. It is possible that some people have receptors with lower affinity for niacin, and thus less intense side effects.
Interestingly, there are published reports linking certain mental disorders, such as schizophrenia, with a low (or no) side effect to niacin. However, no one should panic as this information is hypothetical and far from proven, but nevertheless interesting.
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Dr. Benjamin V. Treadwell is a former Harvard Medical School professor and member of Juvenon’s Scientific Advisory Board.
Investigators from prestigious institutions in Scandinavia, Europe and the United States, recently published the study results of a new vitamin with significant potential health benefits. The new vitamin, nicotinamide riboside (NR), is a precursor to a key cofactor, nicotinamide adenine dinucleotide (NAD+).
The investigators were aware of previous work demonstrating the importance of NAD+ as a rate-limiting molecule in the regulation of numerous enzymes and DNA transcriptional factors (factors that turn genes on and off), involved in modulating metabolism. They also were aware of reports from other laboratories describing the effects that a precursor to NAD+ had on increasing levels of this rate-limiting metabolic regulator. Past research revealed that under conditions of limited food intake, the ratio of NAD+ /NADH increases. This increase in the relative NAD+ cellular levels activates the sirtuins, which are the metabolic regulators. The NAD+ activated sirtuins, subsequently, act on target proteins involved in the regulation of lipid and carbohydrate metabolism. Additionally, they activate genes and enzymes that improve mitochondria function.
Recently, investigators were intrigued by reports describing the capacity of a newly discovered molecule, NR, to increase cellular NAD+ levels, as well as the life span in yeast. They were curious to find out if this new vitamin-like molecule had similar effects in mammals (mice), as well as human cells (liver and muscle) in culture.
The results clearly showed a positive effect of NR in stimulating NAD+ levels in cells in culture, as well as in mice. They also examined the effects of NR on the activation of sirtuins (SIRT1 and SIRT3) previously shown to be modulators of metabolism. Importantly, the results revealed a significant increase in the activity of the sirtuins. They also demonstrated an increase in mitochondrial activity, with an increase in energy expenditure in the treated cells and mice.
Other studies showed that when NR treated animals were fed a high-fat diet, the insulin and blood glucose stayed at lower-healthy levels, compared to the controls that were not treated with NR. The treated mice had less fat and lower levels of lipids, including cholesterol and triglycerides produced in the liver. Similar positive effects were seen with niacin, a relative of NR.
Although these studies demonstrate the new vitamin's significant positive effects on metabolism, additional studies are needed to determine whether the findings are the same in humans. In the future, boosting NAD+ levels in humans with vitamin-NR may provide an effective therapeutic for health and longevity.
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This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.