Niagen, Nicotinamide Riboside Side Effects vs. NAD+ Benefits
[toc]A whopping $720 million was the price tag for the anti-aging technology developed by Australian biologist David Sinclair. That’s how much GlaxoSmithKline paid for his company, Sirtris Pharmaceuticals, in 2008.
Sinclair’s technology focused on activators of sirtuins. At the time its most famous was SRT-501, a proprietary resveratrol formulation.
Resveratrol and other sirtuin activators are believed to mimic the effects of calorie restriction. Although not entirely proven in humans, for animals – ranging from simple lifeforms like yeast to large mammals like dogs and rhesus monkeys – calorie restriction without malnutrition might be the one known thing which can slow down the aging process.
Rhesus monkeys are thought to be the most similar physiologically to humans, which is why they are so often used in medical studies. These photos are from a study conducted by the University of Wisconsin published in 2009 issue of Science Magazine (1). What makes this study so fascinating is that it’s been on-going since 1989.
On the left is a 27.6 year old normal monkey (average lifespan for species). On the right is a monkey of the same age, but who has been on a calorie restrictive diet since an early age.
Those photos are worth more than a thousand words. While not studied for hair loss or male pattern baldness, it certainly should be!
Some studies have even found it be more effective than exercise at increasing life span. True, exercise protects against problems that reduce lifespan – like diabetes and heart disease – but only calorie restriction has been shown to slow primary aging (2).
The exact reason why is unknown. Researchers believe it may be due to the side effects of less free radicals being produced (and therefore less DNA damage), lower metabolic rates, lower core body temperature, and/or hormesis. Signalling molecules associated with aging including SIRT1, mTOR and PGC-1a are believed to be activated. Some wonder if a similar effect might be possible if we could find a way how to boost NAD levels.
Some compare calorie restriction to hibernation – the body, sensing a shortage of available food, goes into “conservation mode” to prolong life, to ensure it’s still alive for the future when times are better for reproduction.
What happened to resveratrol?
Before we review nicotinamide riboside (which is also sold under the brand name Niagen as a dietary supplement), let’s take a stroll down memory lane. Before the NAD supplement, it was all about resveratrol.
After Sinclair’s charismatic interview on 60 Minutes and the GlaxoSmithKline deal, resveratrol was all the rage during the late 00’s and early 10’s.
Red wine and grape juice – both of which only contain minuscule amounts of resveratrol – were being touted as a superfoods. Shady companies were peddling “one weird trick” to reverse the biological clock of aging. Some went so far as to claim it was the official Dr. Oz approved method (which was a lie, he does not sell or endorse supplements).
In 2013, GlaxoSmithKline gave pink slips to the 60 employees working in the Sirtris division, but continued carrying on some of that R&D under their corporate umbrella.
Here we are now almost a decade later. Nearly a billion dollars paid for sirtuins activators, but no drugs on the market. From excitement to silence.
Will Niagen follow a different path?
So what happened to the resveratrol hype? Activating sirtuins to reverse aging (well, slow it anyway) doesn’t seem to be the debated topic. Rather, it’s that resveratrol and similar synthetic compounds might not be very effective at doing so in humans. Or if they are, they’re an inefficient method for doing so. Is it possible Niagen is more effective?
The fact that resveratrol has faded in popularity is not surprising, considering the suspected high doses needed and the fact that resveratrol (and presumably, similar compounds) are highly sensitive to degradation from light, heat, and air.
It’s one of the reasons we here at Superfoodly are mostly opposed to resveratrol supplements – just the air and light exposure from the manufacturing process alone results in degradation. Given the unscrupulous nature of many supplement marketers, it’s hard telling how much (if any) of the resveratrol powder or capsule is still in its ideal state.
For $5/month they might be worth the gamble, but they cost $50+ per bottle and even that amount may only yield 250 to 500 mg per day – a dosage that might be far too low to have any benefit, if there is any that’s possible. The dosage conversion of resveratrol milligrams per kilogram of body weight in animal models was often exponentially higher than what those resveratrol supplements offer you.
That being said, as per the words of one biotech insider here at Superfoodly, a billion dollars and one decade later with nothing to show is not that unusual in pharma. Will nicotinamide riboside follow the same path as the earlier generation of sirtuin activators and fade away? Or will it along with other future NAD+ supplements be the real deal?
Drugs take many years to develop and when an acquisition is shelved or put on the back burner, it doesn’t necessarily mean the science is lacking. Often times, it has more to do with prioritizing spending for shareholder return and choosing which drug candidates will produce revenue the fastest. Only GlaxoSmithKline truly knows how viable – or not – their portfolio of sirtuins activators might actually be.
In 2013 they claimed they were pursuing their lead candidate SRT2104 (GSK-2245840). There has been some activity, but not a lot.
The graphs pictured above are from research published in 2014 that was conducted under an agreement between GSK, National Institute on Aging (NIA) and the National Institutes of Health (NIH) (3). In other words, it’s unclear how much GSK was bankrolling that study, we’re guessing little to none given this statement on the cover page: This article is a U.S. Government work and is in the public domain in the USA.
Something more recent was published in 2015 with the title; “A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis” (4)
There were 40 patients involved receiving either placebo or escalating doses of SRT2014. In terms of safety, both the drug and placebo groups experienced comparable side effects, which were said to be either mild or moderate.
As far as efficacy, based on skin biopsy analysis, 35% achieved “good or excellent” improvement while placebo was 5%. As you see in the graph, the higher the dosage, the more effective the treatment was.
That may sound great (and it is) but the problem is that even though it was published in 2015, the study was initiated in 2010 and last updated in 2012 (5). It’s not a recent study, they just took forever to publish the results.
What’s going on with resveratrol? The drugs? A look at the FDA’s clinical trials database shows that the last time there was any event for SRT2104 was on February 28, 2013, when they completed their phase 1b trial for ulcerative colitis (6). That has been discontinued/withdrawn, along with SRT2104 for plaque psoriasis, type 2 diabetes, cardiovascular disorders, inflammation, chronic obstructive pulmonary disease (COPD), and muscular atrophy.
Another aging clock – the 20 year lifespan of patents – hints that if the technology made commercial sense, they wouldn’t be dragging their feet, given that the IP protection won’t be good for much longer. Given the positive momentum that Niagen research has had this decade, perhaps GSK later realized that was the train they should have boarded instead.
Nicotinamide riboside vs. resveratrol?
So what has David Sinclair been up to lately? Nicotinamide adenine dinucleotide or NAD+ (because some people ask… it has absolutely nothing to do with the nicotine).
So far the body of evidence for nicotinamide riboside is quite impressive. It does not appear to be an anti-aging supplement scam whatsoever. It is one of the very, very few scientific discoveries in the space that we are excited about.
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 efficient and 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:
Tru Niagen, which is their own brand. 125 mg per capsule with 60 per bottle.
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 Metabolism claims 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).
Two papers from 2014 looked at NR and mitochondrial myopathy (24) (25).
Many look at its effect on broader mitochondrial health and behavior (26) (27).
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 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.
HPN used to sell Niagen powder but they no longer do. Nor does anyone else. Capsules are your only option.
If you want to cut out the middleman and buy from the manufacturer, ChromaDex now sells it under their own label called Tru Niagen. It’s what we use ourselves and you can buy it on Amazon. The reviews for it are excellent.
These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.
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