May 13 2014

Resveratrol – Reason for Skepticism

Dr. Oz recommends resveratrol as a supplement to reduce inflammation and protect the heart. On his website you will find:

While resveratrol has been recommended for fighting the physical effects of aging, a brand new study shows it reduced inflammation of the heart in the study’s participants by 26%. Taking one 500 mg capsule of resveratrol daily with food will help you maintain a strong, healthy heart.

How evidence-based is this recommendation? At present we have preliminary in vitro and in vivo studies showing that resveratrol has interesting biological effects that are potentially beneficial, particularly in heart disease. There are some short term human studies as well.

The question is – how predictive are such early promising research results to later long-term clinical studies? I have written many times arguing that the answer is – not very much. There is researcher bias, exploiting degrees of freedom, and publication bias to contend with, all favoring false positive results in the literature.

Further, pre-clinical studies may not predict net clinical effects. There are other factors to consider that could render an interesting effect in the test tube useless in a living person, such as bioavailability. It doesn’t matter what the effect of the supplement is if it does not get absorbed into the body and transported to the relevant site of action.

Also, biology is complex and there may be mechanisms in place that counteract the desired effect or have unforeseen downstream consequences.

So, no matter how promising a new substance seems, we need clinical studies in people with sufficient follow up before we can say what the net clinical effect of supplementation in various populations will be.

Resveratrol is a polyphenol compound found in grape skins, wine, and peanuts. It seems to have anti-inflammatory activity, which can be potentially useful. It also has been shown to reduce platelet aggregation, and therefore can reduce the risk of blood clots, such as those that can cause stroke or heart attacks. It is also an antioxidant, which gives it a certain marketing appeal, but I am not optimistic about the future of exogenous antioxidants in human health. Resveratrol apparently does not lower lipid levels.

All of this may be sufficient for Dr. Oz and other gurus to recommend resveratrol as the next fountain of youth, and for the health food store shelves (actual and virtual) to be full of resveratrol products with astounding health claims. It is not enough, however, to conclude that resveratrol actually works, and there is a metaphorical graveyard full of failed products with similar preliminary results.

A new clinical study sheds further light on the actual effects of resveratrol. From the abstract:

How the Study Was Conducted: The participants (a sample of 783 men and women 65 years or older) were part of the Aging in the Chianti Region study from 1998 to 2009 in two Italian villages. The authors sought to determine if resveratrol levels achieved through diet were associated with inflammation, cancer, cardiovascular disease, and death. Levels were measured using 24 hour urine collections to look for breakdown products of resveratrol.

Results: During nine years of follow-up, 268 participants (34.3 percent) died; of the 639 participants free of cardiovascular disease at enrollment, 174 (27.2 percent) developed cardiovascular disease during the follow-up; and of the 734 participants who were free of cancer at enrollment, 34 (4.6 percent) developed cancer during the follow-up. Urine resveratrol metabolite levels were not associated with death, inflammation, cardiovascular disease or cancer.

This study was not randomized, so that is a weakness. However, it was a fairly large study that followed many relevant clinical outcomes with a 9 year follow up. It also directly measured resveratrol metabolites in the urine, rather than relying on subject reporting.

This one study is not definitive, nor will it be the final word, but it is a solid study with completely negative results. It is, at the very least, reason for serious skepticism about the clinical benefits of resveratrol.

Conclusion

Resveratrol remains an interesting compound, with a great deal of active research that has the potential of yielding useful results.

However, at the present time, clinical claims for health benefits from resveratrol are premature, and now we have clinical evidence that casts serious doubts on such claims.

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13 responses so far

13 Responses to “Resveratrol – Reason for Skepticism”

  1. Draalon 13 May 2014 at 10:42 am

    Pfizer published a paper to slam GlaxoKlineSmith’s acquisition of David Sinclair’s company Sirtris.
    http://www.ncbi.nlm.nih.gov/pubmed/20061378

    Turns out that Sinclair’s staff collected bad data
    http://pipeline.corante.com/archives/2010/01/12/the_sirtris_compounds_worthless_really.php

    or even committed fraud
    http://pipeline.corante.com/archives/2012/01/12/a_resveratrol_research_scandal_oh_joy.php

    And now GKS shut it down after paying out >$720 million http://www.xconomy.com/boston/2013/03/12/glaxosmithkline-shuts-down-sirtris-five-years-after-720m-buyout/

  2. Ekkoon 13 May 2014 at 2:43 pm

    It didn’t help that one of the biggest researchers into resveratrol had 20 papers retracted and was found guilty of data fabrication.
    http://en.wikipedia.org/wiki/Dipak_K._Das

    Grape seed extract seems to have some better quality evidence, at least for lowering blood pressure.
    http://www.ncbi.nlm.nih.gov/pubmed/21802563

  3. ccbowerson 14 May 2014 at 10:30 am

    “It is also an antioxidant, which gives it a certain marketing appeal, but I am not optimistic about the future of exogenous antioxidants in human health.”

    I agree, particularly for individual antioxidants as supplements, or even a handful of them as mixed supplements. It is another case of oversimplifying explanations for observations, and over-extrapolating from those ideas from basic science. The media and alt health world gets ahold of these ideas and makes things worse by implying benefits long before the evidence supported those benefits.

    Then science starts to get done that better address the questions, and pulls back the reins. The public then thinks of science as being ‘not being able to make up its mind’ or even fickle/unreliable. This is a common pattern of oversimplification, over-extrapolation and hype, then greater understanding and nuance. The last step is easily overlooked and is not covered nearly as much. There are occasional scientists who themselves don’t due a good enough job tempering the hype, but the way in which science is covered in most of the media make it extremely difficult.

    As a result, the actual progress of science gets misinterpreted as exactly the opposite by the casual observer.

    Obtaining antioxidants from dietary sources may be different, due to having broader, lower concentrations of more antioxidants, or due to other aspects of foods high in antioxidants (may be partially tapping into a correlation of a correlation – diets high in antioxidants may also be healthier for other reasons).

  4. ccbowerson 14 May 2014 at 10:34 am

    This article looks like a pretty good overview of the issue, even if it is a tl;dr paper:

    “Exogenous antioxidants—Double-edged swords in cellular redox state”

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952083/

  5. Ekkoon 14 May 2014 at 12:18 pm

    Actually, on closer inspection, this latest JAMA resveratrol study seems fairly pointless. It just showed that dietary amounts of resveratrol had no benefits, but I thought it was pretty well known that we don’t get much of this compound from our diets anyway.

  6. clgoodon 14 May 2014 at 1:11 pm

    Correction:

    Dr. Oz should henceforth only be referred to as “Kermit the Fraud”.

  7. Teaseron 14 May 2014 at 3:02 pm

    Good examination on the role of polyphenols in the body. He does not recommend supplementing for antioxidants.

    http://wholehealthsource.blogspot.com/2011/02/polyphenols-hormesis-and-disease-part-i.html
    http://wholehealthsource.blogspot.com/2011/02/polyphenols-hormesis-and-disease-part.html

    He reaches the following conclusion:

    “I think that overall, the evidence suggests that polyphenol-rich foods are healthy in moderation, and eating them on a regular basis is generally a good idea. Certain other plant chemicals, such as suforaphane found in cruciferous vegetables, and allicin found in garlic, exhibit similar effects and may also act by hormesis (27). Some of the best-studied polyphenol-rich foods are tea (particularly green tea), blueberries, extra-virgin olive oil, red wine, citrus fruits, hibiscus tea, soy, dark chocolate, coffee, turmeric and other herbs and spices, and a number of traditional medicinal herbs. A good rule of thumb is to “eat the rainbow”, choosing foods with a variety of colors.

    Supplementing with polyphenols and other plant chemicals in amounts that would not be achievable by eating food is probably not a good idea.”

  8. Mlemaon 14 May 2014 at 4:47 pm

    We continue to discover phytonutrients in plants which we subsequently learn are vital to human health. Plants manufacture hundreds, and even thousands of secondary metabolites But we don’t necessarily know the effect of consuming these compounds in isolation. Since we may continue to learn what the synergistic value of the compounds in plants might be, I think (personally) it’s a good idea to eat them as part of the whole food. Likewise, I think it’s something to consider in plant breeding. As we breed for caloric yield, taste and other factors, we often lose health benefits (except the health of having enough food to keep one alive of course)

    http://www.nytimes.com/2013/05/26/opinion/sunday/breeding-the-nutrition-out-of-our-food.html?pagewanted=1&_r=0

    http://www.nytimes.com/interactive/2013/05/26/sunday-review/26corn-ch.html?ref=sunday

  9. ccbowerson 14 May 2014 at 7:07 pm

    Mlema-

    I was with you until the very end. The problem is much more about diets that do not include a good balance of fruits and vegetables, rather than worrying about various wild species we should be eating from 10,000 years ago. Crabapples, for example, are generally extremely sour, sometimes woody and often bitter – many are borderline inedible yet may look good on a chart of ‘phytonutrients.’ The healthier plant is the one actually eaten.

    It is interesting, however, to look at such varieties to see if there is a way of incorporating some of their perceived advantages in a way that is acceptable to the average consumer. It appears to be a trend currently, and I think there are certainly positives to expanding the types of fruits and vegetables available to the average consumer (from a U.S. persepctive, anyways).

  10. Bill Openthalton 14 May 2014 at 7:29 pm

    ccbowers –

    Or we could take a leaf out of my Grandma’s book, who firmly believed that the worse it tasted, the better it was for your health. Cue in cod liver oil.

  11. ccbowerson 14 May 2014 at 9:09 pm

    Bill O-
    That reminds me of this product called “Father John’s Medicine,” available in the US and marketed for cough. The box has a look out of the early 1900s, and with cod liver oil and licorice as the primary flavorings- it’s something that would have impressed your grandmother.

  12. Mlemaon 14 May 2014 at 9:57 pm

    Bill O., ccbowers,

    I didn’t mean to imply that we should eat food that doesn’t taste good, or go “backwards” in breeding. I think we just need to be cognizant in going forward. As we learn more about these various phytonutrients, we may find that many more compounds that we’d like to retain may be worth assessing in new cultivars. It’s a trade off for our type of agriculture and meat production (feed crops).

    From the NY Times article:

    “Throughout the ages, our farming ancestors have chosen the least bitter plants to grow in their gardens. It is now known that many of the most beneficial phytonutrients have a bitter, sour or astringent taste. Second, early farmers favored plants that were relatively low in fiber and high in sugar, starch and oil. These energy-dense plants were pleasurable to eat and provided the calories needed to fuel a strenuous lifestyle.”

    I definitely think it would be a mistake to try to reduce calories in plants. THAT would be going backwards. But as for myself, I tend to enjoy a number of flavors that I know a lot of people don’t like. I sometimes just crave a lemon slice, and I eat the whole thing, skin and all. But it’s gotta be one of those good lemons with the thick pith. :)

  13. Mlemaon 14 May 2014 at 10:11 pm

    Bill O.

    my Grandma had us go down into the spring-fed creek behind the house (she couldn’t walk due to polio at age 3) to get watercress. She also dug dandelions in the spring. She ALSO would let me have (just one) of these every once in a while, just for the fun of chloroform I guess :)

    http://kozmicdreams.com/images/Home%20and%20Collections/ephemera/health%20and%20beauty/parke%20davis%20throat%20drops%20front.jpg

    (can’t believe there was actually a picture of this online :)

    She lived to age 94.

    I’m sure I’m romanticizing the past because I really enjoyed it. You can’t go backwards, but why not try to retain what’s good to add to what we’ve made even better? I can still dig dandelions. People can still get mushrooms in lots of places, and even sell some at farmer’s markets. Anyway, I’m just yammering on now because I love food and I think I’m a little bit hungry :)

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