- 1 Nicotinamide benefits
- 2 What is nicotinamide riboside?
- 3 Side effects
- 4 Studies on boosting NAD with NR
- 5 Is Niagen worth buying?
As co-director of the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging at Harvard Medical School, much of Sinclair’s longevity research this decade has been focused on an aging factor which purportedly might be reversible; the restoring of NAD+ levels.
In a nutshell, it’s about communication within your cells.
Scientists claim that as we age, there are various events – communication – taking place between a cell’s nucleus and mitochondria. The nucleus contains the genetic information or instructions for the cell, while the mitochondria is where its energy is created. As we age, communication between the two becomes less efficientand as a result, there is an acceleration of aging (7).
In studies where a certain compound – nicotinamide mononucleotide – is given to elderly mice, that lost communication is reportedly restored. Sinclair describes it as:
“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down, and just like with a couple, restoring communication solved the problem.”
What is the difference between resveratrol and nicotinamide riboside? Both are believed to be sirtuin activators, but they operate in different ways.
Natural resveratrol from plants, as well as similar synthetic versions, are not naturally found in the human body.
Contrast that to nicotinamide mononucleotide (NMN), which is a molecule naturally found in your cells and is said to be responsible for levels of nicotinamide adenine dinucleotide (NAD). Those levels of NAD are what declines with age.
In summary, resveratrol is a foreign substance which is hoped to be an activator of SIRT1 and other sirtuins linked to aging. NAD levels are believed to be a direct cause for the activation of sirtuins.
If the research is correct and a decline in natural NAD+ is a known cause of cellular aging, then obviously the logical question would be how to increase those levels?
You already know about niacin (nicotinic acid), which is one of the essential B vitamins. Most multivitamin contain a synthetic form while both meat and plant food sources contain a natural form.
What you may not know though is that niacin is only one form of vitamin B3. The other form is nicotinamide.
Is nicotinic acid the same as nicotinamide? No. The difference is that nicotinic acid is a precursor to nicotinamide. Both can address vitamin B3 deficiency, but the difference with nicotinamide is that it generally doesn’t carry the nasty side effects associated with a niacin supplement overdose, such as unbalanced uric acid levels, skin flush, rapid heart beat, abdominal pain, and more (8). This is because those side effects are caused by the conversion process.
Only some nicotinic acid converts to nicotinamide. From that, a tiny fraction converts to NAD.
In other words, niacin is two conversions away from NAD while nicotinamide is only one. Does that mean it’s a NAD booster?
Well one form in particular has been heavily researched and many believe it may be the best precursor or “booster” there is…
What is nicotinamide riboside?
In your diet, you consume many precursors to NAD. These include the amino acid tryptophan, aspartic acid, nicotinic acid (Na), nicotinamide (Nam), and nicotinamide riboside (NR). When you hear Niagen is referenced, that’s merely the brand name for NR and is molecularly the same.
Among those Nam and NR may be the closest, but many studies suggest that NR may be the best known precursor to NAD in terms of efficiency.
Nicotinamide riboside was actually discovered a long time ago. In 1944 it was described as a “growth factor” for a type of bacterium that lives in the blood. Among the precursors, NR was said to be the one that causes the most rapid growth of the bacterium (9).
Below is an image from a research paper titled “NAD+ and Sirtuins in Aging and Disease” which depicts a good visual explanation of how NAD+ works within the cell as we age (10). That paper was authored by two highly respected big names in the field; Leonard Guarente, Ph.D. (MIT) and Shin-ichiro Imai, M.D., Ph.D. (Washington University).
Excerpt from the image caption: During the aging process, DNA damage accumulates in the nucleus, causing PARP activation and NAD+ reduction. Consequently, SIRT1 activity is reduced, resulting in increased PGC-1α acetylation and decreased TFAM levels. These nuclear events might reduce mitochondrial function in old mitochondria.
You can buy other precursors in a plethora of supplements on the market and those are nothing new, but a nicotinamide riboside supplement is new. Similar to how a Japanese company owns the process for synthesizing ubiquinol (the best form of ubiquinone/CoQ10), there’s only one company on the market the owns the patents for synthesis of NR.
Those synthesis processes were developed in academia by Cornell, Dartmouth, and Washington University. The company ChromaDex has snapped up that IP in recent years through exclusive licensing agreements with them. In 2013, they began producing and selling NR under the brand name Niagen.
You can buy ubiquinol from many different companies like Jarrow Formulas, Doctor’s Best, Now Foods, Life Extension, Qunol, and numerous other name and generic brands.
In the same way, ChromaDex licenses their NR to different supplement manufacturers. Some choose to feature the Niagen brand name, while others refer to it as nicotinamide riboside, however both are the same thing. A few products currently using it include:
- Jarrow Formulas Nicotinamide Riboside, 100 mg per 1 tablet (60 tabs)
- Live Cell Research Niagen, 250 mg per 1 capsule (30 capsules)
- Nectar7 Niagen NAD+ Activator, 250 mg per 2 capsules (60 capsules) (also sold in higher quantities)
As to which is the best nicotinamide riboside supplement on the market to buy, really the decision should be based on price. This is because any reputable brand such as those listed above (and others) should be of equal quality, given that they are all using the same source for the active ingredient; ChromaDex.
As with any supplement, it’s important to be aware of what possible adverse reactions may result from taking them, so you can be on guard for if and when they arise. As far as nicotinamide riboside side effects are concerned, much of the findings are said to be quite positive.
A review was published in 2013 by the Albert Einstein College of Medicine and Weill Cornell Medical College (11). The prior animal model studies were analyzed for this review and the authors suggested these claims in their summary:
“It has properties that are insulin sensitizing, enhancing to exercise, resisting to negative effects of high-fat diet, and neuroprotecting.”
The neuroprotective results were at least in part referencing nicotinamide research in Alzheimer’s disease. Again, we stress these things are about animal studies and only preliminary scientific conclusions.
An international peer reviewed journal, Human and Experimental Toxicology (HET), published a study in 2016 which specifically looked at nicotinamide riboside safety (12). In the study, they used a several methods:
- bacterial reverse mutagenesis assay (Ames)
- in vitro chromosome aberration assay
- in vivo micronucleus assay
- acute 14 and 90 day rat toxicology studies
Niagen was not found to be genotoxic. Its toxicity and side effects were found to be similar to regular nicotinamide.
A nicotinamide riboside dosage of 1,000 mg/kg/day was said to the lowest observed adverse effect level. They did not state the exact overdose symptoms, but the liver, kidney, ovaries, and testes were the “target organs” that they were looking for toxicity in, so presumably the side effects were related to one or more of those. If we had to guess which was affected at that dose, we would presume the liver, since that is by far the most common organ affected from drug toxicity and often, supplement overdosing too.
300 mg/kg/day was the no observed adverse effect level.
If that 300 mg/kg level was the same in a 150 lb human, it would be the equivalent dose of 20,400 mg per day. Many of the Niagen supplements on the market are 250 mg per capsule with an instructed serving size of 1 or 2 capsules per day. You would have to be taking approximately 40 times that amount to reach the 20,400 mg.
There are over 150 articles on PubMed which mention nicotinamide riboside and we are not aware of any that mention serious side effects (13).
On a forum, we did read someone claim that if you have a methylation defect, higher NAD may cause neuropathy, fatigue, and pain. One comment we saw was by a person on 122mg dose of levothyroxine (medication for treating hypothyroidism). He said that after a couple weeks of taking a NR supplement, he experienced peripheral neuropathy, joint and muscle pain.
Everyone should talk with their doctor before taking not just a dietary supplement like Niagen, but any supplement.
Studies on boosting NAD with NR
Even though the ability to isolate and synthesize NR is new, there has already been a great deal of research about it. Much of it within just the past 5 years. David Sinclair is only one of many who are researching this. Keep in mind that most involve animal models.
A study conducted at the University of North Carolina and published in a 2014 edition of Cell Metabolismclaims that nicotinamide activates a SIRT3 pathway that reduces neurite degeneration. This reportedly helps protect against noise-induced hearing loss (14).
The study claims that in cultured neurons, axon-protection is seen with it. They say the ability to prove that in vivo (in a live human) is difficult due to “poor cell permeability and serum instability.” However they were able to demonstrate it in a mouse model, where they were able to create noise reduced hearing loss in the control group, but less occurred in the the mice receiving nicotinamide riboside powder.
Diabetic side effects and lipid profiles
There are two studies, one in 2015 and the other in 2016, which looked exclusively at the effect NR had on diabetic rodents.
The earlier study was conducted by two universities in South Korea. 8 week old male mice were divided into a control group and a group receiving nicotinamide riboside supplementation through an osmotic pump for 7 days.
Weight gain and liver function were not affected by the NR, but they do state that the oral glucose tolerance test (OGTT) and levels of insulin in the blood were improved in the mice receiving the supplement.
It was also said to “significantly” benefit the hepatic proinflammatory markers (15). In the liver, the total cholesterol concentration was decreased.
The 2016 study was conducted at the University of Iowa. It looked at prediabetic mice who were on a high fat diet and showing signs of insulin resistance and neuropathy. The same mice were then also administered an agent to induce full on type 2 diabetes (16).
(a) NR reduced weight gain on high-fat diet independent of streptozotocin (a substance used to induce diabetes)
(e) NR lowered circulating cholesterol
(f) NR depressed fasting glucose in both models
The mice on a high fat diet were found to lose weight and experience better glucose tolerance and protection again neuropathy.
In the type 2 diabetic mice, the nicotinamide riboside was said to “greatly reduce” blood glucose, both fasting and non-fasting levels. Hepatic steatosis, weight gain, and neuropathy were also said to benefit.
The last sentence of the abstract stated “The data justify testing of NR in human models of obesity, T2D and associated neuropathies.”
Obesity and weight loss or gain
While the diabetic studies touched on the topic of weight loss/gain, there have been other studies which focused specifically on that.
A Swiss study which was published in a 2012 edition of Cell Metabolism looked at the side effects of nicotinamide riboside on mammalian cells and mouse tissues, which included brain, muscle, and liver. It was claimed to activate the SIR1 and SIRT3, which help protect against metabolic abnormalities caused by a high-fat diet (17). It appears the NR acted as a NAD booster based on the results in the graph.
An even more exciting study involved humans. A press release put out at the end of 2015 from the National Institutes of Health. The title of it was (18):
NIH researchers find potential target for reducing obesity-related inflammation
They talk about a human study which was published in The Journal of Clinical Nutrition which found that SIRT3 “could potentially prevent or reverse obesity-associated diseases of inflammation” (19). The lead researcher, Dr. Michael N. Sack, is quoted as saying:
“Previous research has shown that intermittent fasting or intermittent calorie restriction — by way of eating fewer calories for a few days a month — reduces inflammation, we found through our study that this effect is mediated, in part, on a molecular level when SIRT3 blocks the activity of another molecule known as the NLRP3 inflammasome.”
How did the human participants reportedly have their SIRT3 activated? By nicotinamide riboside.
The same NIH study mentioned above also touches on asthma. Although they did not evaluate asthma in the study, they said the increase in asthma rates is making it more difficult for obese people to exercise and lose weight (if they have asthma). They’re currently conducting a follow-up study to see if bronchial inflammation can be improved with nicotinamide riboside.
Cognitive decline and Alzheimer’s
Published in 2013 and conducted by the Department of Neurology at Mount Sinai School of Medicine, this study looked at Alzheimer’s disease mice models (20). The goal was to find out how nicotinamide adenine dinucleotide/NAD+ (which “has been identified as a key regulator of the lifespan-extending effects”) would be affected by NR.
(A) Treatment with NR 250 mg/kg/day in Tg2576 mice for 3 months improves cognitive function. Object recognition memory test, performed as described by Bevins and Besheer (21)
(B) The NR treatment significantly increased the levels of NAD+ levels measured by NAD/NADH Assay Kit (Abcam).
(C) PGC-1a mRNA levels in brain.
The findings were that the nicotinamide riboside supplement benefits PGC-1a function and the ubiquitin proteasome system, both of which play important roles in Alzheimer’s disease. It was said to improve the plasticity in the hippocampal CA1 region.
Although not part of the study, it does mention in passing how that same PGC-1a function is also associated with age-related dementia and diabetic metabolic disorders.
Mitochondrial and stem cell function
Much of the research done does not necessarily focus on only one disease or condition, but rather looks at the broader picture of how NAD+ levels might affect cellular health in general. These studies are quite useful and logical, because similar to CoQ10, anything that is potentially used in every cell of the body may be linked to any number of things.
An excellent study was published in a 2016 edition of Science Magazine (22). The title of the article was:
“NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice”
A number of known researchers were part of it, most coming from Switzerland along with one from Brazil and one from Canada. The paper suggests that using the NAD+ precursor, nicotinamide riboside, protects aging mice against muscle degeneration. Similar effect were also seen in neural stem cells.
Speaking of muscles, another study from 2014 suggested that restoration of healthy NAD+ levels resulted in a partial reversal of skeletal muscle aging in old mice (23).
A few people have asked whether Niagen is thought to benefit hair loss or grey hair, however we are aware of no studies – neither animal or human – on those topics.
Is Niagen worth buying?
Probably most are in agreement that the body of evidence suggesting NR may be beneficial vastly outweighs anything there ever was for resveratrol, that’s for sure.
But setting aside the suspected health benefits/efficacy for a moment, one of the biggest dietary dosage benefits of nicotinamide riboside supplements is that they are relatively stable. Unlike resveratrol which easily and rapidly degrades from air, heat, and light exposure, NR stability seems to be comparable to many other vitamins and nutrients in terms of shelf life and the amount of potency preserved.
Compare that versus resveratrol bulk powder, tablets, and even the gel caps. With all of those, it’s highly speculative as to how much of the active ingredient are actually in them. Even more so after you repeatedly open and close a jar of resveratrol powder. So before even considering the nicotinamide riboside research, at least you can take comfort in that if you buy it, you’re getting the substance you’re paying for versus some highly oxidized and degraded powder.
Animals vs. humans, study conclusions vs. proof
It’s important to remember that the vast majority of studies involved to date involve animal models taking high dosages. As we all know, not everything that works well in mice or even rhesus monkeys will necessarily translate to human biology.
With those caveats said, it appears the hype – as least as of to date – is justified, given the many promising studies so far suggesting its ability to increase NAD+ levels. However further research and clinical trials will be needed to verify whether or not the benefits are what many researchers suspect them to be.
It’s totally understandable why many say the gamble (as in, the money spent) to buy a nicotinamide riboside supplement or powder is well worth it based on the research.
Even one of the world’s richest – Mr. Li Ka-Shing who is worth an estimated $31 billion – is so compelled in this anti-aging research, that he bought up approximately 20% of ChromaDex in April 2017.
If you do purchase NR, remember that all the brands selling it are buying from ChromaDex. Therefore, you may want to choose based on price rather than your typical go-to brands. Especially since a daily regimen of a higher Niagen dosage will not be cheap.
With the bulk powder, very few sell it. HPN’s Niagen powder (125 mg/60 servings) is the only seller we are currently aware of.
In terms of capsules, you have plenty of competition and therefore, you might get a better value per mg by going that route. It appears Live Cell Research Niagen might be the most popular, based solely on the number of reviews we see on Amazon for each product.
Sinclair told The Washington Post that he was taking 1000 mg of resveratrol a day when he was 45 in 2015 and still had a biological age of 58 according to what he recently revealed in an interview. Before he began taking 500 mg of NMN, he said his blood work showed that his biological age was that of a 58 year old but after the NMN, it had reversed to 32.
This looks like the final nail in resveratrol’s coffin.
DECADES of research have shown that calorie restriction extends lifespan and delays morbidity in many small, short-lived species: yeast, spiders, and various fish and rodents. In humans, though, the benefits of calorie restriction are still unproven, and probably less straightforward. And how calorie restriction slows the aging process is still not well understood. “The interesting thing about calorie restriction is that we used to think the body was in some way slowing down, maybe in the number of heartbeats or production of free radicals,” says professor of genetics David Sinclair. “But it turns out that’s wrong….When we’re calorie restricting, what we’re really doing is telling the body that now is not the time to go forth and multiply. It’s time to conserve your resources, repair things better, fight free radicals, and repair broken DNA.”
Sinclair believes that a compound found in all living cells, nicotinamide adenine dinucleotide (NAD), could be used to mimic these effects in humans without the starvation or decreased reproductive capacity associated with calorie restriction; his human trials of a therapy that could increase NAD levels are due to begin this month. Meanwhile, a similar compound is already being marketed as a supplement by a health start-up with several distinguished scientists (including three Harvard faculty members) on its advisory board—even though there’s still no evidence that the substance works.
Sinclair’s approach is based on a broad view that links diseases of age such as cancer, diabetes, Alzheimer’s, and heart failure to common cellular processes. His lab aims to understand these processes and then use that understanding to develop medical therapies.
Underlying the wide-ranging benefits of calorie restriction, Sinclair explains, are sirtuins—a group of seven genes that appear to be very important in regulating the aging process. “These longevity-gene pathways are turned on by changes in lifestyle” such as exercise and calorie restriction, he says. They “control a variety of protective processes—there’s hundreds of things that they do, and we still don’t know everything. But they protect the chromosomes, they protect stem cells from being lost, they protect cells from senescing.” Sirtuins can be activated by a lack of amino acids or of sugar, or through an increase in NAD. (The compound’s level in the body declines with age.)
Earlier this year, research from Sinclair’s lab showed that feeding mice nicotinamide mononucleotide (NMN)—a related, precursor compound that the body converts into NAD—may slow aging in the animals, mimicking the effects of calorie restriction. “We get the same effects as exercise or dieting,” he says. “The mice are leaner, have more energy. They can run further on a treadmill.” That research continues, and is poised to be tested in humans: the first stage of the trials of NMN that he was preparing to begin in August at a Harvard-affiliated hospital will test for NAD increases in the blood; after that, he plans to study NMN’s efficacy in treating diseases. Sinclair has been taking the compound himself for about a year. He’s reticent about that, to avoid sounding like a “kook,” but claims his lipid profile has improved dramatically and he feels generally less fatigued—though he admits this is not scientific.
There is a cautionary note to sound, says Jeffrey Flier, Walker professor of medicine and former dean of Harvard Medical School (HMS). The NAD precursor already on the market as a dietary supplement, nicotinamide riboside (NR), is sold by New York-based Elysium Health, founded by MIT biologist Leonard Guarente, Ph.D. ’79, who played a central role in establishing the link between sirtuins and aging, and was Sinclair’s doctoral adviser. The company doesn’t make any specific claims about aging prevention (legally, it can’t); instead, it promotes its product as “the one daily supplement your cells need.” Flier has criticized the company for using the names of the highly credentialed scientists on its advisory board (featured prominently on its website) to market an unproven product: “Elysium is selling pills [without] evidence that they actually work in humans at all,” he says, echoing the strongly worded Boston Globe op-ed he wrote earlier this year condemning the company’s marketing scheme.
Sinclair, who co-directs the Glenn Center for the Biology of Aging at HMS, is not linked to Elysium—his clinical trials go squarely down the traditional medical route, rather than through the loosely regulated supplement industry. “That’s the contrast,” he says. “I’m taking a pharmaceutical approach, FDA approval.” Still, whatever animal research portends about the potential of NAD (and however alluring the promise of a cure for aging), the history of pharmaceutical development suggests it’s much too soon to expect any benefits for humans. Often “molecules may be helpful to animals in a limited set of studies, but then are not shown to be helpful in humans,” Flier warns. “There are many, many, many examples of that.”