NR clinical trial results iST0CKPH0T0SGETTYIMAGES

Researchers report promising pterostilbene and NR clinical trial results

A clinical trial of an NR and pterostilbene anti-aging supplement appeared to be safe over the short-term as it increased NAD levels in a sustained way. [This article first appeared on the website Author: Brady Hartman. ]

A clinical trial of NR and pterostilbene sustainably increased NAD levels and appeared to be safe over the short-term. Moreover, the study suggests that it increased the mobility of the aging test subjects.

Our NAD levels decline as we age, and as the theory goes, boosting NAD will also increase our energy and keep our bodies in better condition.

The anti-aging elixir used in the trial was identical to a supplement called Basis, distributed by Elysium. Supplement manufacturer Elysium was co-founded by MIT professor Leonard Guarente and features a slate of Nobel-prize-winning scientists on its board.

The clinical trial – concluded in November of last year – consisted of 120 people between the ages 60 to 80. The study participants took either a placebo or a regular or double dose of the NR and pterostilbene capsule daily for eight weeks. The main finding of the study was that the supplement was safe and biologically active, significantly increasing NAD in the bloodstream and wasn’t merely being flushed out. The researchers also observed that those on the double dose experienced increased mobility. The results of the study were published [1] on November 2017 in the open access journal Aging and Mechanisms of Disease, a publication hosted by the respected Nature family of journals.

Beyond showing the supplement was safe over the short-term and increased NAD levels and mobility at the double dose, the study didn’t show much of anything else. Other research shows that increasing NAD levels has remarkable rejuvenating effects in mice.

NR Anti-Aging Elixirs

Scientists and the public alike are excited about the potential of NAD to beat aging in our lifetimes. As we age, the NAD levels in our cells decline. NAD is involved in numerous essential cellular processes. Many longevity scientists – such as Leonard Guarente and Dr. David Sinclair –  say that boosting NAD levels will maintain health and energy levels as we get older.

The Nobel-prize-winning scientists who concocted the anti-aging potion used in the trial are not only trying to boost NAD levels; they are trying to increase the activity of sirtuins as well. Sirtuins are a family of genes that play an essential role in aging and longevity and many different processes in the body.

Clinical Trial of NR and Pterostilbene

This first-of-a-kind human clinical trial demonstrated that nicotinamide riboside (NR) and pterostilbene could increase NAD levels in the blood sustainably and apparently safely.

Until this trial, no other studies had been conducted to show the dose-response and safety of the two supplements in combination. The clinical trial was funded by Elysium Health, the manufacturers of a supplement marketed under the tradename Basis which has the same formula and dosage as the study medication at a single dose. However, to avoid the appearance of skewed results due to funding bias, the trial was conducted by a third party.

The study was a double-blind, randomized, placebo-controlled which found that in participants taking a daily dose of nicotinamide riboside and pterostilbene enjoyed an average 40% increase in NAD levels in the blood when on a daily dose of 250mg nicotinamide riboside and 50mg pterostilbene for the eight-week duration of the trial. Moreover, study participants on the double dose of 500mg/100mg daily experienced improved mobility, while those on the single dose did not.

Nicotinamide Riboside (NR)

Nicotinamide riboside (NR) is the primary active ingredient in this anti-aging potion. NR is a naturally-occurring substance similar to Vitamin B3 (niacin). More importantly, NR is a precursor to nicotinamide adenine dinucleotide (NAD) and stimulates the production of NAD in the body. NAD fuels the sirtuins and helps generate energy in mitochondrial-dense tissues such as the brain, muscle, and liver.

Why Pterostilbene?

Pterostilbene is a derivative of resveratrol that is more potent in some aspects, the most important being that it is more easily absorbed than its predecessor. As the authors of the study put it,

“Despite the reported physiological beneficial effect of resveratrol, its bioavailability in humans is poor. PT [pterostilbene] exhibits greater bioavailability due to the presence of two methoxy groups that allow it to have increased lipophilic and oral absorption, as well as a longer half-life due to reduced oxidation.”

Resveratrol and pterostilbene activate the sirtuins [2], a family of genes that play an essential role in many different physiological functions in the body. Most notably, pterostilbene and resveratrol are potent activators of the sirtuin gene called SIRT1. Resveratrol and its analogs have received considerable attention as anti-aging compounds. [3] Pterostilbene is often referred to as a ‘more potent resveratrol’ and looks promising. However, the natural compound has had significantly less research documenting its benefits than resveratrol.  As the authors of the NR and pterostilbene study put it,

“Based on these considerations, the combination of NR [nicotinamide riboside] and pterostilbene is predicted to synergistically support metabolic health through NR providing NAD+ to all seven sirtuins and pterostilbene providing additional activation of SIRT1.”

Pterostilbene and NR Clinical Trial

The study was double-blinded, in that, neither the participants or the trial investigators knew whether they were getting the placebo or the actual test compound, a blend of NR and pterostilbene.

The point of the study was to test to see if the compound was safe and if it raised NAD levels in humans. The researchers also assessed biomarkers such as blood pressure and mobility, such as a six-minute walk and a chair stand test. The researchers also monitored a series of blood factors such as hemoglobin, red blood cell counts, cholesterol, and triglycerides.

Why NAD is Important to Our Health

NAD is a coenzyme found in all living cells and is essential to metabolic health. NAD levels significantly decline as we age, and play a critical role in hundreds of metabolic processes in the cell. More importantly, NAD powers the human longevity genes called sirtuins. While nicotinamide adenine dinucleotide (NAD) plays a role in a multitude of cellular processes, its most notable effects are on the sirtuins, DNA repair, energy levels, and the unfolded protein response (UPR).

Research has shown that healthy cellular communication relies on the coenzyme NAD and a family of proteins called sirtuins. The average human body has trillions of cells. Inside each cell are components called organelles, such as the mitochondria, which communicate with each other to carry out all the processes in our body. This communication consists of nutritional, physical, and chemical processes by which cells convert food to energy, and many other mechanisms necessary to sustain life.

Metabolic Health, NAD, and NR

NAD supports life-sustaining reactions inside the cell and is used as a cofactor in redox reactions. Without NAD, these reactions can’t go forward. For example, we need a NAD molecule to get the molecule ATP – the fuel of our cells – into the cell where it’s needed.

NAD, NR, and Mitochondria

Our mitochondria turn food into energy by generating ATP, a molecule used as the primary source of energy for our cells. Research has shown [4] that NR supplementation raises the levels of NAD in both the mitochondria and nucleus of the cells, and activate some of the sirtuins.

NAD, NR and DNA Damage

Our DNA is regularly exposed to damaging free radicals and radiation, such as UV light. NAD helps our cells function properly, enabling them to correct this DNA damage before it becomes permanent.

NMN Also Boosts NAD

A team of scientists investigating NMN, led by Dr. David Sinclair [5] announced the results of several experiments which showed that the NAD-boosting compound nicotinamide mononucleotide (NMN) restored the vitality and youthfulness of mice. Moreover, it repaired DNA damage caused by radiation exposure or old age. The researchers used NMN – another NAD precursor, that works like NR. In human terms, it was the equivalent of transforming a 60-year-old’s cells and muscles into those of a 20-year-old. In the March 24th, 2017 press release  announcing the finding, Professor Sinclair said

‘The cells of the old mice were indistinguishable from the young mice after just one week of treatment,’

NAD, NR and the Unfolded Protein Response

Since NR stimulates the production of NAD, scientists believe that NR will beneficially stimulate the Unfolded Protein Response (UPR).

NAD is believed to aid in the unfolded protein response, a protective mechanism that guards against mistakes made in the protein manufacturing process. After being translated from messenger RNA to a linked chain of amino acids, proteins are then folded into a three-dimensional shape that suits their function. Messenger RNA (mRNA) is a subtype of RNA that is created during the transcription process and carries, much like a messenger, a portion of the DNA code to other parts of the cell for processing. Proteins that aren’t appropriately folded are destroyed before they leave the cell.

In an experiment conducted in aged mice [6], NR induced the mitochondrial unfolded protein response and stimulated the synthesis of beneficial proteins. The upshot of all this, say the authors of the study, was that the supplement rejuvenated stem cells in the elderly mice.

Sirtuins, NAD and NR

Boosting sirtuins is another goal of the NR and pterostilbene combination.

Sirtuins require NAD to function and are a family of enzymes, proteins, and genes that act as vital regulators in the cell.  Sirtuins affect multiple pathways that increase the lifespan and the overall health of organisms.  Since enzymes are proteins and genes code for proteins, sirtuins are interchangeably referred to by any of those names. Since NR stimulates the production of NAD, scientists believe that NR will beneficially stimulate sirtuins.

As the authors of the NR and pterostilbene trial put it,

 “Sirtuins are known to mediate responses to nutritional and environmental signals including the beneficial health effects of calorie restriction. In addition, NAD+-dependent activation of sirtuins regulates important physiological processes such as circadian rhythm, glucose and fat metabolism, and normal aging.”

Sirtuins were popularized by Harvard University professor David Sinclair, Ph.D., and were initially discovered by a team led by his mentor, Leonard Guarente. Sirtuins turn other genes on and off to control our body’s response to levels of nutrition and stress.

Longevity researchers such as Dr. David Sinclair have linked sirtuins to influencing a wide range of cellular processes such as inflammation, transcription, cellular stress resistance, aging, and apoptosis (cell death).

For example, longevity scientists – called geroscientists -have linked the sirtuin called SIRT1 with cancers;  promoting liver function and regeneration; apoptosis; stem cell differentiation and cell fate determination; delaying replicative senescence in primary fibroblasts;  and neuroprotection against various forms of dementia, such as Parkinson’s and Alzheimer’s disease.

As well, researchers have linked sirtuins to energy efficiency and alertness during the low-calorie situations that occur during periods of intermittent fasting and calorie restriction, although the relationship is controversial. Sirtuins can also control circadian clocks and affect the creation of new mitochondria.

Pterostilbene and NR Clinical Trial Design

The investigators divided 120 healthy participants between the ages of 60 and 80 into three groups.  Forty participants in the single dose group received a dose of 250 milligrams of NR daily.  Forty participants in the double-dose group received a dose of 500 milligrams of NR daily, which they took at breakfast for eight weeks. The control group did not receive the treatment and consisted of 40 participants. The control and test subjects were matched for various lifestyle factors, such as ethnicity, sex, smoking status, alcohol consumption and so forth.

Clinical Trial Results

The blood tests showed that the single dose groups enjoyed a forty percent increase in NAD levels. The trial investigators just took blood samples on day zero, day 30, and day 60. The results were statistically significant.

A Curious Homeostasis Effect

The results suggest that homeostasis mechanisms regulate the blood levels of NAD. The double dose group enjoyed an initial 90% increase in NAD levels. Unfortunately, this gain was not sustained for the 60-day trial period. Instead, the blood levels of the double dose group rose and then eventually decreased to 55%, a level above those in the single dose group.

This result demonstrates the phenomenon of homeostasis, a natural process in which the body tries to maintain balance. Those of us who have attempted to lose weight and failed, have seen homeostasis in action. Homeostasis adds to the difficulty of addressing the metabolic changes that occur in aging.

Improved Mobility With Double Dose NR

Mobility increased significantly with the double daily dose of the NR and pterostilbene mixture, in both the chair-stand and the six-minute walk test. The higher dose seems to improve mobility but not the single daily dose. The researchers speculate that the double dose of NR and the resveratrol derivative used in this part of the trial might improve muscle health. However, the clinical trial investigators also note that a more extensive study needs to be performed to confirm this conclusion.

An Aversion to Adverse Events

There were some adverse events in both the test and control groups. 13 participants in the placebo group reported 18 adverse events (AE).  15 participants in the first test group reported 25 AE, and 17 participants reported 23 AE. The adverse effects included fatigue, diarrhea, and headache. Because the adverse effects are divided relatively equally among the test and control groups, the authors of the NR and pterostilbene study reported

“There were no significant differences in the incidence of AEs among groups.”

Bottom Line

The main finding of the study was that the NR and pterostilbene supplement was safe and increased NAD levels in the bloodstream and wasn’t merely being flushed out. A secondary observation was that those at the double dose seemed to experience increased mobility.

NR seems to be the main active ingredient that provides the health benefits of this combination. Pterostilbene appears to be the lesser of the two components in the concoction, regarding efficacy.

Those on 250mg/50mg of NR and pterostilbene enjoyed a 40% increase in NAD levels.  Those on 500mg/100mg experienced a more substantial rise in NAD levels but lost many of their gains, eventually leveling out to a 55% sustained increase.

Research has shown that increasing NAD levels produces remarkable rejuvenating effects in mice. Moreover, the evidence from other animal experiments is very compelling. However, beyond showing the supplement was safe over the short-term and increased NAD levels, the NR and pterostilbene study didn’t show much of anything else. What works well in mice, often doesn’t work well in humans. While boosting NAD levels is very promising, it will require further studies to see if it has the same effect in humans.

References and Additional Reading

[1] Ryan W. Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente & Eric Marcotulli. “Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, double-blind, placebo-controlled study.” Link to the research article in Nature.

[2] Hartman, B. “Genes Rule Over Our Aging Bodies – Dr. David Sinclair on Sirtuins.” November 14, 2017. Web. Retrieved Jan 30, 2018. Link to Dr. David Sinclair article on sirtuins.

[3] Hartman, B. “Old Human Cells Rejuvenated with ‘Breakthrough’ Anti-Aging Discovery.” November 9, 2017. Web. Retrieved Jan 30, 2018. Link to resveratrol article.

[4] Srivastava, Sarika. “Emerging Therapeutic Roles for NAD+ Metabolism in Mitochondrial and Age-Related Disorders.” Clinical and Translational Medicine 5 (2016): 25. PMC. Web. 30 Jan. 2018. Link to the research article.

[5] Hartman, B. “Dr. David Sinclair, Discoverer of Anti-aging NAD Fad, Speaks About Human Trials of NMN.” September 30, 2017. Web. Retrieved Jan 30, 2018. Link to the article on clinical trials of NMN.

[6] Zhang, H. et al. “NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice.” Science 352, 1436–1443 (2016). Link to the article in Science. 

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Cover photo credit: Solidcolours via iST0CKPH0T0SGETTYIMAGES. (Getty Images).


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