Dietary supplement shows promise for reversing cardiovascular aging

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Scientists have long known that restricting calories can fend off physiological signs of aging, with studies in fruit flies, roundworms, rodents and even people showing that chronically slashing intake by about a third can reap myriad health benefits and, in some cases, extend lifespan.

From a public health perspective, that advice would be impractical for many and dangerous for some.

What is nicotinamide riboside?

nicotinamide riboside moleculeIn 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).

 

effect of NAD boosting on cell activity

 

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:

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.

Side effects

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:

syringe viles in cup

  • 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.

Hearing loss

how NR benefits hearing lossA 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).

NR results in diabetic mice
(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

NAD+ levels in brain, muscle, liverWhile 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.

Asthma

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.

Alzheimer's Disease charts

(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:

Science Magazine cover

Vol 352, Issue 6292,
June 17, 2016

“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.

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A new University of Colorado Boulder study published today indicates that when people consume a natural dietary supplement called nicotinamide riboside (NR) daily, it mimics caloric restriction, aka “CR,” kick-starting the same key chemical pathways responsible for its health benefits.

Supplementation also tends to improve blood pressure and arterial health, particularly in those with mild hypertension, the study found.

“This was the first ever study to give this novel compound to humans over a period of time,” said senior author Doug Seals, a professor and researcher in the Department of Integrative Physiology.

“We found that it is well tolerated and appears to activate some of the same key biological pathways that calorie restriction does.”

For the study, published in the journal Nature Communications, Seals and lead author Chris Martens, then a postdoctoral fellow at CU Boulder, included 24 lean and healthy men and women ages 55 to 79 from the Boulder area.

Half were given a placebo for six weeks, then took a 500 mg twice-daily dose of nicotinamide riboside (NR) chloride (NIAGEN). The other half took NR for the first six weeks, followed by placebo.

The researchers took blood samples and other physiological measurements at the end of each treatment period.

Participants reported no serious adverse effects.

The researchers found that 1,000 mg daily of NR boosted levels of another compound called nicotinamide adenine dinucleotide (NAD+) by 60 percent.

NAD+ is required for activation of enzymes called sirtuins, which are largely credited with the beneficial effects of calorie restriction.

It’s involved in a host of metabolic actions throughout the body, but it tends to decline with age.

Research suggests that as an evolutionary survival mechanism, the body conserves NAD+ when subjected to calorie restriction.

But only recently have scientists begun to explore the idea of supplementing with so-called “NAD+-precursors” like NR to promote healthy aging.

“The idea is that by supplementing older adults with NR, we are not only restoring something that is lost with aging (NAD+), but we could potentially be ramping up the activity of enzymes responsible for helping protect our bodies from stress,” Martens said.

The new study also found that in 13 participants with elevated blood pressure or stage 1 hypertension (120-139/80-89 mmHg), systolic blood pressure was about 10 points lower after supplementation. A drop of that magnitude could translate to a 25 percent reduction in heart attack risk.

“If this magnitude of systolic blood pressure reduction with NR supplementation is confirmed in a larger clinical trial, such an effect could have broad biomedical implications,” the authors note.

Ultimately, the authors say, such CR-mimicking compounds could provide an additional option — alongside the dietary changes and exercise currently recommended — for people whose blood pressure is not yet high enough to warrant medication but who are still at risk for a heart attack.

They stress that the study was small and “pilot in nature.”

“We are not able to make any definitive claims that this compound is safe or going to be effective for specific segments of the population,” said Martens, now an assistant professor at the University of Delaware.

“What this paper provides us with is a really good stepping stone for future work.”

Martens and Seals have applied for a grant to conduct a larger clinical trial looking specifically at the impact of NR supplementation on blood pressure and arterial health.

Martens is also launching a separate trial looking at the impact NR has on older adults with mild cognitive impairment, a precursor to Alzheimer’s disease.

The study was partially funded by grants from the National Institutes of Health and the American Federation for Aging Research. ChromaDex, the maker of NIAGEN provided supplements and some financial support.

Story Source:

Materials provided by University of Colorado at Boulder. Original written by Lisa Marshall. Note: Content may be edited for style and length.


Journal Reference:

  1. Christopher R. Martens, Blair A. Denman, Melissa R. Mazzo, Michael L. Armstrong, Nichole Reisdorph, Matthew B. Mcqueen, Michel Chonchol, Douglas R. Seals. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD in healthy middle-aged and older adultsNature Communications, 2018; DOI: 10.1038/s41467-018-03421-7

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