blueberry plant

Pterostilbene Supplement Benefits: Longevity Miracle or Hoax

[toc]If you have been following longevity research and nutrition news for any amount of time, then you are all too familiar with “the next big thing” that often times, just ends up being a big dud.

Supplement manufacturers and the media will hype something, convincing you to spend your hard earned money on it. Years later, in retrospect, you realize that it was a complete scam.

Maybe not an intentional hoax, but in the sense that the people involved with it got carried away in their excitement and enthusiasm, before there was research to back up the suspected health claims.

That brings us to what today is being hailed as the next big thing… pterostilbene. They say it’s stronger and better than resveratrol (whatever happened to that, you will learn in a minute). But does the current research actually warrant you buying “the other resveratrol” or should you remain tightfisted for now?

What is pterostilbene?

The pronunciation is terro-still-bean (the “p” is silent). It is a sirtuin activating compound as well as an antioxidant. It can be found in blueberries, grapes, almonds, peanuts, and other plant-based food sources. The bark of Pterocarpus marsupium (Indian kino tree) and some other non-food sources also contain trace amounts. Chemically related to resveratrol, it demonstrates many of the same health benefits and in some instances, appears to offer even more profound results.

pint of blueberriesLike resveratrol, the foods containing pterostilbene contain only miniscule amounts. For example, how much pterostilbene there is in blueberries – which is one of the richest sources – has been detected as being between 99 ng to 520 ng per gram of fruit (the Vaccinium ashei species was measured) (1).

To put that number in perspective, your average blueberry package – the deeper sized clamshell – is one dry pint and should weigh around 12 ounces. That’s 340 grams. If you ate the entire package, the total amount of pterostilbene in the blueberries you would get is only 0.03 to 0.18 mg.

The studies demonstrating or suggesting benefits for heart disease, cognitive decline, diabetes, and caloric restriction effects involve dosages which are several hundred or even thousands of times higher than that (or the equivalent in animal models, based on their body weight). For that reason, dietary sources are considered inadequate and researchers almost always use supplements in their studies.

Pterostilbene vs. resveratrol

The resveratrol compound was first mentioned in a Japanese scientific publication in 1939 by Michio Takaoka, but it took over half a century until researchers began discovering its biological effects (2). In a similar manner, the now defunct German life sciences journal Experientia addressed when pterostilbene was discovered, in 1977 (3). But like resveratrol, it took decades until researchers began to understand the potential health benefits of pterostilbene.

Resveratrol gained great fanfare in 2008 when a publicly traded biotech company who was pioneering medicines around the compound was acquired for over $700 million by GlaxoSmithKline. In the nearly decade since, the dietary supplements containing the ingredient continue to be hot sellers, but there has hardly been a peep from GSK as to the medical developments (or lack thereof) involving natural or synthetic sirtuin activators.

pterostilbene and resveratrol chemical structures
Both have very similar structures, however pterostilbene has two methoxy groups and that increases bioavailability compared to resveratrol.

The first thing that comes to your mind as to why that is probably involves the science and it not being up to par. In some regards, that’s a correct assumption to make.

However the reasoning for it being subpar, at least based on outside research in academia (because no one knows GSK’s internal findings) seems to have more to do with the many drawbacks of resveratrol.

It’s poorly absorbed, has an extremely short half-life, is destroyed easily by light, and oxidizes quickly when exposed to air. For these reasons, extremely high dosages are needed and even then, they’re fragility makes them a big gamble in the precise confines of pharmaceutical dosings.

In short, the consensus among researchers doesn’t seem to be the doubt of SIRT activators and the suspected advantage when they can be expressed, but rather, what and how are the best ways to turn them on.

On the other hand, compare resveratrol versus the stability and bioavailability seen with pterostilbene:

  • 80% bioavailability versus 20% for resveratrol (4). That means it has 4x the rate of absorption.
  • What is the half-life of pterostilbene? 105 minutes. Compare that to resveratrol, which is just 14 minutes (5).
  • Less oxidation from air
  • Less sensitive to light

Perhaps most noticeable is the half-life of nearly 2 hours, which is over 7x that of resveratrol. Despite its 15 14 minutes of fame, research has suggested that its effect continues after it is broken down in the body. In other words, it has “turned on” things which do not immediately turn off.

Regardless, the very short time makes it far from ideal for pharmaceutical uses, where it’s hard to get patients to take a pill more than once a day. Perhaps that is one of the reasons GSK has shelved that family of compounds.

Pterostilbene health benefits

Like resveratrol, the medical research for pterostilbene is quite new. In fact, the bulk of it has taken place just this decade. As of the time of writing, out of the 283 pieces of medical research on PubMed, over two-thirds of them (202) were published within the last 5 years.

This means the findings and benefits suggested by research are preliminary at this point and are not proven or conclusive. Keep this in mind when reading product reviews.

There have been 3 completed clinical trials and those are perhaps the most compelling pieces of research to date. In addition to those, here’s a review of the current body of research.

May reduce blood pressure

blood pressure meterCompleted and published in 2014, a randomized, double-blind, and placebo controlled human trial was conducted at The University of Mississippi School of Pharmacy (6) (7). A total of 80 patients were involved with the following characteristics:

  • both males and females were used
  • average age of 54 (ranging from 45 to 64 years old)
  • average weight of 195 lbs
  • average BMI of 30
  • none were smokers
  • total cholesterol ≥200 mg/dL and/or LDL ≥ 100 mg/dL

The patients were divided into the following four groups:

  • Group 1 (HD): 125 mg twice daily of a pterostilbene supplement
  • Group 2 (LD): 50 mg twice daily of the same supplement
  • Group 3 (LD + grape): 50 mg twice daily + 100 mg of grape seed extract twice daily
  • Group 4 (placebo): twice daily

The daily supplementation went on for up to 8 weeks in each group. The models and their results were adjusted for age, gender, and race.

The results?

blood pressure results of pterostilbene and placebo

The chart on the left shows systolic blood pressure and on the right, diastolic blood pressure.

At a dose of 250 mg per day (the “HD” pink line), it was concluded that pterostilbene reduces blood pressure in adults.

There was an adverse side effect seen, which was a minor increase of LDL or “bad” cholesterol when used by itself, however the group taking grape seed extract in combination with it did not appear to experience the same level of LDL increase.

Weight loss support

The same aforementioned clinical trial also found that some patients appeared to lose weight as a result of the supplement.

Among the patients who took supplements of pterostilbene, those who were not on cholesterol lowering medication exhibited minor weight loss.

table measuring weight loss benefits*Compared to placebo
**Bold indicates significance
BMI: body mass index (kg/m2); TC: total cholesterol (mg/dL); LDL: low-density lipoprotein (mg/dL); TG:triglycerides (mg/dL); LD: low dose; LD + GE: low dose + grape combination; HD: high dose.

Here’s a quote from a 2017 rat study where pterostilbene was 0.5% of their diet (36):

“…markedly suppressed the abdominal white adipose tissue (WAT) accumulation in obese rats.”

While this would definitely be a nice side effect, it’s very premature for anyone to claim pterostilbene benefits for weight loss. More human studies need to be done.

May delay diabetic retinopathy

chart of in vitro diabetic retinopathy testsEndothelial are a type of cell which lines the surface of blood vessels and lymphatic vessels. In a high glucose environment (i.e. diabetes) they experience increased damage, especially those within the eyes which can lead to blindness. In fact, it is the leading cause of blindness among working-age adults in America.

An in vitro study evaluated the effect of pterostilbene on human retinal endothelial cells and found that it “may delay DR [diabetic retinopathy] through alleviating inflammation and antioxidation to suppress hRECs over proliferation.” (9)

While not specific to diabetes bur rather eye health in general, another study published in 2016 found that it helped protect corneal epithelial cells from inflammation and oxidative damage (10). No research has been published to evaluate if it might help with other common eye diseases such as Age Related Macular Degeneration.

May slow age-related cognitive decline

reperfusion injury
While not from either study, this photo shows the side effects 24 hours after a right middle cerebral artery stroke in a human. The resulting faulty blood brain barrier has let contrast enter the brain, which is a bad thing. Photo credit: OHSU Dept. of Neurology

Protecting the brain from oxidative stress is a unique challenge, because many antioxidants are unable to cross through the blood-brain barrier.

Just like alpha lipoic acid, pterostilbene has been found to cross the blood brain barrier, which means it might offer protective assistance for neurodegenerative diseases like Alzheimer’s disease and cognitive decline from other oxidative stress contributors (11).

Acute cerebral ischemia-reperfusion injury is damage to the brain caused when blood supply returns to the tissue after it has been deprived of oxygen (ischemia). A number of traumatic events can cause it, including stroke. When it occurs, mitochondrial oxidative stress can damage the brain.

Two different studies involving mice and mice brain cultures suggest that this stilbene compound might help to reduce damage:

“…decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury.” (12)

“….increased the cell viability and decreased the lactate dehydrogenase (LDH) leakage and apoptotic ratio in vitro. ZnPP and HO-1 siRNA both blocked PTE-mediated cerebral protection by inhibiting HO-1 signaling and further inhibited two HO-1 signaling-related antioxidant molecules…” (13)

Other research focused on possible benefits for age-related cognitive decline is only just beginning (14). It’s far too early to know if that or Alzheimer’s might be helped by this compound.

Antioxidant properties

The Oxygen Radical Absorbance Capacity or ORAC value has not been measured for pure pterostilbene powder, however a fair amount of research has been done which has looked at its antioxidant properties. To date, there has been research involving animal models, in vivo (in a body, either animal or human), and in vitro (using test tube measurements).

We’re not just talking about generic antioxidant effects. There have been several dozen papers published and here is a sampling of the more interesting and unusual findings.

Testicular injuries

In rats with testicular ischemia/reperfusion injuries, it was found to help with oxidative stress and the study concluded that it “may be a promising therapy for testicular I/R injury” (8).

Arthritis relief

You may have came across some supplement marketing and over-hyped alternative medicine articles which claim that pterostilbene helps arthritis. The truth is that only one study has been done for this topic back in 2010. Therefore, only weak evidence – at best – exists to suggest it might be beneficial. That being said, this study did paint a promising picture.

rat arthritis study chartIn this study, arthritis was induced in rats (16). A portion of those received pterostilbene supplements at a daily dose of 30 mg per kilogram of body weight. It was said “the treatment significantly lowered the number of neutrophils in blood on days 14 and 21 without significant down-regulation of neutrophil oxidative burst.”

In plain English, neutrophils are an immune system response which are important for destroying pathogens, but their dark side is an overproduction of them in inflammatory diseases – like rheumatoid arthritis – which can cause further tissue damage and greater inflammation.

In 2017, research out of China claimed that it fights inflammation by activating the Nrf2 pathway. (35)

Minimizing liver damage

A study used acetaminophen, which is the active ingredient in Tylenol, and gave an overdose to rats in order to induce hepatoxicity (chemically induced liver damage).

In combination with silymarin (milk thistle seed extract), the pterostilbene at a dosage of 50 mg per kilogram of body weight was given for 15 days leading up to when the acetaminophen was used. It was found to have protective properties which were attributed to its “antioxidant, anti-inflammatory, and antiapoptotic actions” (15).

Increasing muscle mass

male bodybuilder working shoulder musclesChromaDex is one of if not the largest supplier for the synthesized version of this nutrient. They have licensed several patents in the field, including the “anti-obesity effect of pterostilbene” which is jointly owned by the USDA and an university (18).

One patent in particular ChromaDex has been focusing on involves combining this nutrient with caffeine (19).

It’s among one of the three three clinical trials for this nutrient (20). The results of the human clinical trial were published in June 2016 (21).

The goal was to find out if there were ATP gains achieved through a supplementation which contained it, among other ingredients.

Adenosine triphosphate (ATP) is the biochemical process in which our muscles store and use energy. It is a complicated process to explain but in short, the benefits of ATP efficiency are important for bodybuilding, endurance athletes, and others who undergo strenuous physical activities.

In the study, 21 resistance-trained athletes, with an average age of 27 years, were given pterostilbene caffeine cocrystal supplements 45 minutes prior to training. On rest days, they also received the supplement.

  • Group 1: received a 150 mg daily dose of ancient peat and apple extracts, 180 mg blend of caffeine anhydrous and pterostilbene-bound caffeine, and 38 mg of B vitamins
  • Group 2: received a placebo of equal volume

The conclusion?

“Athletes who benefit from increased muscle mass but not fat mass, such as bodybuilders and skill-position football players, as well as recreational athletes seeking improved body composition may benefit from the use of the present supplement combination.”

This was based on muscle thickness increases of +0.49 cm compared to placebo at only +0.04 cm. The rectus femoris (thigh muscle) was +1.07 cm2 versus placebo at −0.08 cm2. Creatinine remained unchanged at +0.00 mg/dL versus +0.15 mg/dL for placebo. The estimated glomerular filtration rate (a level of kidney function) was −0.70 mL/min/1.73 versus placebo at −14.6 mL/min/1.73.

Slowing atherosclerosis progression

This is one of the most common diseases seen in aging, where plaque builds up inside the artery walls over time. It can begin at a very early age and due to the fact that it tends to only worsen and not get better, it becomes especially problematic for seniors.

Vascular endothelial cell (VEC) apoptosis is considered to be a primary event which occurs during the formation of atherosclerosis.

Using in vitro and in vivo measurements in mice, it was concluded that pterostilbene may protect the human umbilical vein vascular endothelial cells (the type used in the study) against oxidized low-density lipoprotein (a cause of plaque) “by downregulating LOX-1-mediated activation through a pathway involving oxidative stress, p53, mitochondria, cytochrome c and caspase protease.” (17)

Anti-cancer properties

cancer headline in newspaper with magnifying glassIt’s always dangerous to claim any type of nutrient or compound can help prevent cancer or reduce side effects from treatment. Cancer is a very complex disease with virtually countless causes and pathways for expression. We certainly do not want to give the impression that pterostilbene cancer research is anything other than preliminary and unproven.

With that caveat said, out of the 283 research documents on PubMed related to this compound, nearly half (122 of them) contain the word cancer (22). Cancer may very well be the most studied topic related to this compound.

While pterostilbene offers antioxidant advantages to healthy cells, a good amount of research suggests it might actually decrease the antioxidant defenses of unhealthy cells; aggressive cancer cells (23). For example, below are the in vivo results of mice with melanoma pterostilbene treatment. The markers measured were:

(A) corticosterone
(B) adrenocorticotropin hormone (ACTH)
(C) corticotropin-releasing hormone (CRH)
(D) noradrenaline (NORA)

in vivo mice skin cancer study results

In addition to melanoma, it is believed other types might be effected in the same way.

Colon cancer

15 papers or roughly 5% of the total are related to colon tumors. A Polish study cultured human colorectal cancer cells and it was found to decrease the proliferation rate in a dose and time dependent manner (27). 72 hours after treatment, this chart displays the results which suggest that higher pterostilbene dosages might offer greater anti-cancer benefits.

pterostilbene effect on colorectal cancer cells

Breast cancer

There have been 29 papers published on this topic, which represents nearly 10% of all papers written about pterostilbene. A broad range of pathways have been studied, from targeting cancer stem cells (24) to suppressing tumor growth by Src/Fak signaling (25). Triple-negative breast cancer (TNBC), which is one of the most deadly forms, was studied because it was theorized that some cases might be preventable through diet (26).

Lung cancer

There are 9 papers related to lung and as similar to the breast cancer research, they are not looking at the same things. Some propose that the molecule might inhibit lung cancer through induction of apoptosis (28), the Notch1 signaling pathway (29), the EGRR-mediated pathways (30), as well as other theories. In short, it’s believed to possibly be beneficial in multiple ways.

Prostate cancer

Metastasis-associated protein 1 (MTA1) has been linked to an aggressive form of prostate cancer in humans. It has been proposed that dietary pterostilbene is a novel MTA-1 inhibitor. In a study involving mice, it was said that the substance “significantly inhibits MTA1-dependent cell proliferation and angiogenesis and induces MTA1-targeted apoptosis” (31).

effect on MTA1 in mice

There are several other pieces of research which have looked at other ways it may assist in treating or preventing prostate cancer.

Ovarian cancer

Only one paper has been published which has specifically addressed ovarian. That was published in 2016 and it looked at whether or not this stilbene would cause apoptosis (cell death) by activating caspase in ovarian cancer cells. The conclusion was “The study demonstrates for the first time the cytotoxic potential of pterostilbene against ovarian cancer cells.” (33)

Pancreatic cancer

Five papers have been published (3 of which have an overlapping author) which looked at the anti-proliferative effects for cancer of the pancreas in vitro and in vivo using animal models.

It was concluded that the substance alters gene expression and increases antiproliferative markers cytochrome C, Smac/DIABLO, and MnSOD/antioxidant activity. In vivo, it was said to decrease pancreatic tumor growth in mice (32).

Pterostilbene side effects

Pteropure supplement facts label
pTeroPure is the proprietary synthesized form owned by ChromaDex. They do not sell the product to consumers but rather, they sell the ingredient to supplement manufacturers.

If you’ve ever taken pure resveratrol powder or high dosage capsules of 500 mg and above, then you already know about some of the horrendous digestive side effects which can result. That’s due to where most dietary supplements derive their resveratrol; Japanese Knotweed (Polygonum cuspidatum).

Diarrhea and stomach cramps are extremely common with that P. cuspidatum. The good news is that the natural food sources of pterostilbene, such as blueberries, do not have those side effects. The synthesized version (used in supplements) doesn’t have them either. So if you’ve had a bad experience taking resveratrol in the past, you shouldn’t cast aside this compound for those same nasty reasons.

The preliminary research and suspected benefits may sound impressive, but is pterostilbene safe?

In mice, a whopping daily dosage of 3,000 mg per kilogram of body weight was given, which is around 500x higher than what humans typically consume. Even at that dosage, it did not cause death during the experiment and failed to show any clinically significant toxicity (34).

But of course humans are not mice. In 1 of the 3 human clinical trials, the first one mentioned regarding blood pressure, the participants were given up to 250 mg per day (125 mg dose twice daily) and the side effects were comparable to placebo.

However there was one potentially dangerous side effect seen and that was, as previously mentioned, an increase in LDL “bad” cholesterol. Though when taken in combination with grape seed extract, that side effect was much less pronounced.

scrambled eggs, sausage, bacon
While not being dismissive of the potential side effect, there may be much bigger cholesterol concerns from diet. Only non-animal sourced foods (vegan) are 100% cholesterol-free.

Obviously attention should be paid to this safety concern, however it is worth remembering that the participants weren’t exactly shining examples of a healthy lifestyle. They were all obese given that their average BMI was 30 and none had low cholesterol to begin with.

In the clinical trial evaluating fitness benefits in healthy people, the changes were:

  • total cholesterol was 161.2 before and 164.2 after
  • HDL “good” cholesterol was 50.1 before and 48.5 after
  • LDL “bad” cholesterol was 94.1 before and 99.7 after
  • triglycerides were 65.9 before and 69.3 after
  • systolic blood pressure was nearly the same pre and post trial (127.6 before, 128.0 after)
  • diastolic blood pressure followed a similar trend (76.6 before, 78.2 after)
  • heart rate increased (58.9 before, 64.9 after)

In short, it’s tough to tell whether the changes are statistically significant given that they were exercising throughout the trial heavily, so it’s not a good comparison to your average Joe or Jane who sits at a desk all day. Also their average age was only 27.

There is no RDA or RDI for it. The pterostilbene recommended dosage according to most of the supplements on the market is serving size of 1 capsule containing 50 mg. This typical amount is substantially lower than the dosages seen in these human clinical trials.

However on the same token, the best results seen from studies – whether those were human studies, in vitro, or in vivo animal models – involved dosages which would translate into significantly higher amounts, when converted to the equivalent average human body weight.

Whatever the case, you should speak with your doctor before taking a pterostilbene supplement or any other dietary supplement for that matter. Safety should not be assumed just because something is sold over the counter.

Miracle or hoax?

This compound is definitely not a scam or hoax. The question is not whether it has benefits, but rather, it seems to be the question of what exactly those are when will they be proven? To date, the research is too preliminary to draw firm conclusions about it.

So far we have reviewed the medical research, but perhaps equally or even more intriguing is the possible sirtuin activation and what that might offer. Is pterostilbene better than resveratrol? The research suggests it is, given that its half-life is 7x longer and it has substantially better bioavailability and stability.

The reason resveratrol has generated so much hype is because as a SIRT1 activator, many prominent scientists believe it may mimic the effects of a calorie restrictive diet. That’s the process of basically starving one’s self, but without malnutrition.

Running a multi-decade study in humans following such a disciplined diet is near impossible, but carefully controlled studies using animals, including rhesus monkeys which are believed to be the genetically closest to humans, have shown that a calorie restrictive diet actually slows down the aging process in the animals. It may turn out to be the only way to slow the clock.

NAD+ effects on young vs. old monkeys
Will sirtuin activation be the key to increasing longevity in humans or not?

The photos you see on the right are from a study the University of Wisconsin has been running since 1989 and those photos were taken in 2009.

Those are two monkeys which are both 27.6 years of age, which is the end point of their average life span.

That’s obvious when you see the monkey on the left, which looks every bit its old age. However the monkey on the right has been on a calorie restricted diet since an early age. It looks and acts like a much younger monkey.

It’s remarkable to think they are both the same age and diet alone has done that.

If – and we emphasize the if part – pterostilbene is proven in the future to be an effective SIRT1 activator in humans, it might very well change our approach to anti aging and longevity. Even though the research to date suggests it is, that is not undeniable or conclusive proof.

Best supplements?

Unlike most other vitamins and minerals, where the quality can differ dramatically among brands, the decision here is fairly straightforward. Pterostilbene for sale, regardless of which brand you’re referencing, is almost certainly getting their active ingredient from the same supplier.

Since the manufacturing process is patented, it only leaves one game in town for supplement companies to source this product from.

Of course you should still buy from respected brands, because you want to make sure the company is legitimate and not cutting corners in what they provide you. Though among the brands, your decision should largely be based on who has good pricing. Here are a few respected names on the market you can compare:

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.