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- Red Wine and Resveratrol –

 

Dreams of Tuscany… And so much more?

 

 

   John W. Grisham

October 10, 2008

 

 

 

So, Here’s the Story

 

 

Red wine and resveratrol –

 

 

What the hype is all about:

People all over the world—from tabloid columnist to connoisseur, from the local Italian farmer to WebMD—are talking about the incredible effects of the newly discovered compound resveratrol, an extract of red wine.  Drinking wine, a culinary, social, and religious tradition dating back thousands of years, is now being heralded as the best thing since the rise of the pill-pushing pharmaceutical industry—except, the phrase “take medication with a meal” holds a slightly different, and perhaps more pleasant connotation.  And, while red wine itself is not actually being marketed in capsule-form, resveratrol has been taken note of in both the scientific community and in popular culture.  Resveratrol in the grape is actually part of the vines immune system, acting as a barrier to harmful bacteria and fungus.  In the human body, it plays a similar role, but this time in the form of what we commonly refer to as an antioxidant.  So, here is the question… Does enjoying a glass of red wine or two each day—with specific regard given to this resveratrol ingredient—have the ability to perpetuate better general health, and to live up to some of the claims made about potential benefits?

 

 

What “they” are saying:

In a society where quick-fixes are in high demand, one as enjoyable as a glass of red wine always holds promise with the public opinion.  WebMD, an increasingly popular online hub for medical Q&A, has called resveratrol “a weapon in battle” (http://www.webmd.com/diet/news/20080617/red-wine-a-weapon-in-battle-of-the-bulge) along with best-selling Fortune Magazine, who published the headline, “Drink wine and live longer” (http://money.cnn.com/magazines/fortune/fortune_archive/2007/02/05/8399158/index.htm).  The story related in Fortune is one about the small start-up pharmaceutical company Sirtris, and their journey towards developing a resveratrol supplement that would have effects on par with similar studies performed on mice.  If successful, the medicines produced would boast the ability to slow down the effects a number of dreaded diseases, from diabetes, to Alzheimer’s, to cancer; this of course, is not to mention the fact that such a drug would likely increase average lifespan as well.  Needless to say, there is a huge monetary incentive behind this industry.  Men’s Health, a well-circulated fitness and nutrition magazine, has haled resveratrol as no less than “legendary” (http://www.menshealth.com/cda/advicedetail.do?site=MensHealth&channel=guy.wisdom&conitem=78bbb666347f5110VgnVCM10000013281eac____&expertId=1c74f5b65fa53010VgnVCM100000cfe793cd____), and Wine Spectator online Magazine suggests the prospect of a new “wine-derived miracle drug” on the horizon (http://www.winespectator.com/Wine/Features/0,1197,3590,00.html).  This discovery is paramount to Christmas Day for a magazine such as The Wine Spectator; the wine industry has no doubt had quite a vested interest in this advertising campaign.  This was clearly evidenced in 1991, when the television show “60 Minutes” aired a segment on the health benefits of red wine.  Just weeks later, according to “askmen.com”, U.S. sales of red wine had increased by 40%, an unprecedented gain in this industry (http://www.askmen.com/sports/health/14_mens_health.html).  A few of the above claims seem a bit brash, while others suggest plausibility.  We will now take a look at the validity behind some of their claims.

 

 

The claims, and what all of this means:

 Claims made by web sites:

§   E-Resveratrol has the power to reverse the aging process, to increase the average lifespan by 30-50 years, and to greatly inhibit the abilities of diseases such as influenza and pneumonia (http://eresveratrol.com/).

§   Bio + Span, a drug produced by “Biotivia”, which includes the compound resveratrol, will help overcome aging on a cellular, physical, and mental level (http://www.biotivia.com/biospanlongevity.html).

§   A glass or two of red wine a day has the ability to reduce the risk of coronary heart disease and perpetuate better general health.  Here are several specific examples:

o   It is a “fat-fighter” (cited from the WebMD article above)

o   It lowers risk of cardiovascular disease

o   It slows development of Alzheimer’s and Parkinson’s

o   It inhibits a variety of cancer lines

o   It may increase longevity of life by a few years

     (examples 2-5 are cited from the Fortune article above)

Mechanisms:

§   Facts:

o   Resveratrol – is a stilbene (i.e. one of several nonflavonoid polyphenolic compounds) found in the skin of grapes as part of their immune system, which acts as and antioxidant in human beings

-   An antioxidant simply refers to a compound that opposes the process of oxidation by counteracting the activity of free radicals within the cell.

-   Resveratrol may also have several other effects within the cell, which will be discussed later.

Proposed mechanisms:

o   E-Resveratrol proposes that the taking of large quantities of resveratrol (i.e. 200mg per capsule = roughly 60 times the amount found in one bottle of red wine) will activate to so-called SIRT1 gene.  The activation of this gene will cause the mitochondrial cells to “become more youthful”, thus reversing the aging process (http://eresveratrol.com/).

-   The evidence they cite are primarily trials based on yeast and mice, and have not been proven effective in humans.  Their evidence with regard to validity in humans is a study in which the drug Sirtris SRT501 was shown to lower serum glucose levels and insulin resistance in type II diabetics.  While this was a positive outcome, it by no means validates their much more lofty proposals of anti-aging, etc.

-   The motives here seem a bit underhanded at best.  The way in which the product is so verbosely marketed makes one think twice before trusting in everything that is stated.  One bottle containing 60 caplets costs only $40, which sounds reminiscent of a cheap television infomercial—low cost boasting of huge results.

 

o   Bio + Span proposes that taking 150mg of trans-resveratrol in conjunction with a number of other bioceuticals will activate the “SIRT-longevity genes” and reduce free-radical damage, all adding up for a longer, more healthy life (http://www.biotivia.com/biospanlongevity.html).

-       They actually admit on their webpage to having little or no evidence to back up their stated proposition.  To cite the webpage word for word, “Evidence coming soon”

-       The motives here seem to be mixed.  They seem to be catering to the organic/natural crowd, with a very cheap ($40) option boasting, once again, of monumental results.

 

o   Resveratrol, in the small amount seen in a glass of red wine, has been proposed to have a number of qualities that lend itself to decreasing fat storage in the body and prevention of several well-known diseases.  Each of these works through a different, and fairly complicated biological mechanism, none of which will be explicitly listed here (http://www.webmd.com/diet/news/20080617/red-wine-a-weapon-in-battle-of-the-bulge).

 

 

 

The Caveat:

A majority of the claims made by several of these websites are based entirely off of studies performed on yeast and rats.  In those studies, neither the yeast nor rats experienced adverse affects, but there is no conclusive evidence demonstrating the safety or success of a similar dose of resveratrol in humans.  In fact, the amount of resveratrol used on rats was 100-200 times the amount found in an entire bottle of red wine.  E-Resveratrol does list a few possible reasons not to take their product, specifically stating that “eResveratrol might increase the action of certain blood pressure, cholesterol, and diabetes medications. The dose of these medications may need to be adjusted or eResveratrol may be contra-indicated.” (http://eresveratrol.com/).  It should also be noted here that nearly any study or physician that you might consult would indeed tell you that the benefits of drinking red wine are quite real.  However, all of them would agree that if you do not drink alcohol already, it is not worth the risk to begin drinking red wine now (Vidavalur, 2006).

 

 

 

Here is what the research says:

A great deal of research has been done regarding the efficacy of red wine as it relates to positively affecting health.  As for resveratrol, there are a number of studies that have been performed with conflicting results, and neither side has necessarily gained the upper hand.  The prevailing opinion, of course, is to assume the worst until the extensive use of resveratrol is proven to be safe.

 

History – Resveratrol comes in two conformations, cis and trans.  Trans-resveratrol, the primary conformation found in red wine, was recognized for the first time in 1976.  Researchers Langcake and Pryce found that the leaf tissues on the grape vine synthesized this compound in response to fungal infection or exposure to UV light.  Sixteen years later, in 1992, Siemann and Creasy first took into consideration the presence of resveratrol in wine (Fremont, 2000).

 

 

Trans-Resveratrol

 
The French Paradox – In 1992, Renaud and de Lorgeril coined the phrase “the French paradox.”  This name refers to a peculiar observation they made regarding the dietary habits and health of the French.  They noticed that, while the French have perhaps one of the most awful diets of any developed nation in the world (extremely high consumption of saturated fats, incessant smoking, and little exercise), they seemed to maintain one of the lowest rates for heart disease (Das et al, 2007).  Ever since, there has been a search for an explanation, one of which has been centered around their constant but not unreasonable daily consumption of wine. 

 

 

Just Red Wine? – As the question surrounding the French Paradox first began to turn out answers, wine was the first suspect.  But was it wine, or any alcoholic beverage?  And if it was wine, was it just red wine, or was it any product of the grape?  In one case-control study, The Copenhagen Heart Study, researchers looked for the association between alcohol and an endpoint such as atherosclerosis or myocardial infarction (MI).  They performed a prospective follow-up of 13,000 individuals, and found that there was the expected inverse relationship between the amount of wine consumed and the risk of coronary heart disease.  This same correlation was not found for consumers of beer and spirits (Vidavalur et al, 2006).  A number of results from similar studies evidenced the same conclusion.  Lucie Fremont, in her review of resveratrol, cites several recent studies which all demonstrated that no appreciable cardio-protective effects were observed with wines other than red wine (Fremont, 2000).  And while the effect is never as large as that associated with red wine, a number of other studies have disagreed with Fremont and Vidavalur, arguing that there is indeed some benefit which comes solely from the moderate consumption of ethanol (Das et al, 2007).

 

So, What Sets Red Wine Apart? – Resveratrol is found in the skin of the grapes from which wines is made.  In white wine, the skin is removed before the wine is allowed to age, and thus some of the effects seen in red wine are perhaps absent in whites.  For this same reason, red wine appears to maintain a few more added benefits than its wheat-derived beer and spirit counterparts.  One researcher, Thomas Walle, reported performing a study in which volunteers drank half a bottle of red wine, and no resveratrol could be detected.  He concluded that resveratrol is simply inactive in humans because it lacks the necessary biological context to perform (Gerstel, 2006).  The scientific evidence, however, is stacked greatly against Professor Walle.  A whole host of studies would suggest otherwise.  One such study, conducted on rats by E. Bertelli, showed a substantial absorption of resveratrol into the blood.  Each day for 15 days, 13ug of resveratrol (equivalent to a rodent-size glass of wine) was administered to the rats.  It was observed that the compound quickly entered the blood stream and could be detected in significant concentrations in several organs.  In another study, E. Bertelli demonstrated that, “at modest dosages, resveratrol [is] pharmacologically active both in vitro and in vivo.  The authors [suggest] that an average drinker of wine can, particularly in the long term,  absorb a sufficient quantity of resveratrol to explain the beneficial effect of red wine on human health (Fremont, 2000, page 667).

 

 

Epidemiological Studies and A Possible Confounding Variable – Two researchers, Klatsky and Armstrong, performed a study comparing the consumption of alcohol with Coronary Heart Disease (CHD) mortality rates in France and Finland.  Their study took into account 13,000 questionnaires administered between 1978 and 1985.  The strongest inverse correlates were with consumption of alcohol (r = -0.43) and even more so with wine (r = -0.67).  The people with the lowest risk of contracting CHD were the group who preferred wine to other alcoholic beverages and drank in moderation.  They also bring to the table a very important possible confounding variable—that is, that people who drink wine are societally more inclined to health consciousness than are people who prefer other alcoholic beverages (Goldberg et al, 1995).  So, while there seems to be conclusive evidence that the resveratrol of red wine does indeed reduce CHD mortality rates, this variable must be accounted for and kept in mind.

 

 

Resveratrol As An Antioxidant – Arteriosclerosis accounts for nearly half of all the deaths in the United States.  This process of atherogenesis is greatly accelerated by the oxidation of low-density lipoproteins (LDL), which are often referred to as the “bad cholesterol.”  Resveratrol, however, retards this process, reducing LDL sensitivity to peroxidation.  And aside from these specialized functions, resveratrol acts simply as a run-of-the-mill antioxidant, hunting down free radicals, which are potentially harmful to the body if found in high concentrations (Das et al, 2007).


 

Resveratrol As A Promoter of HDL – Resveratrol also promotes the increased presence of high-density lipoproteins (HDL), which are commonly known as “good cholesterol.”  These molecules are necessary for the transport of cholesterol from the arteries back to the liver for metabolism and excretion.  Because it effectively removes this potential build-up of arteriole plaque, resveratrol’s promotion of HDL’s can be seen as healthy and protective against arteriosclerosis (Das et al, 2007).

 

 

Resveratrol As An Anti-Cancer Agent – The anti-cancer capabilities of resveratrol were first discovered in an experiment performed in Japan using the extract of Yucca schidigera.  Direct evidence of the chemopreventative activity of resveratrol was observed through a number of different processes.  It acted as an antimutagen, it induced the detoxification of carcinogens, and once again, we see it perform as an antioxidant (Fremont, 2000).

 

Resveratrol As An Attenuator of Platelet Aggregation – Blood clotting is no doubt an important skill for the body to maintain.  However, when such clotting begins to build up on the inside surfaces of blood vessels, one begins to worry about the risk of coronary heart disease.   In one human study, subjects drank 375mL of red wine each day for several weeks, and experienced a marked decrease in ADP-induced platelet aggregation.  This is yet one more health benefit exemplified by resveratrol (Das et al, 2007).

 

 

What Research Says About the Website Claims:

1)  E-resveratrol makes the claim that through the activation of the SirT1 gene, the mitochondrial cells will begin to “become more youthful”, thus reversing the aging process.  The notion of slowing the aging process is not entirely fallacious, but it does not take place via mitochondrial cells becoming “more youthful”.  It is, in fact, due to the inhibition of the insulin-signaling pathway in the body.  And, while the slowing of this process is plausible and even possible, it is fantastical to think that aging can be reversed.  In a study performed by J. Zhang, it is demonstrated that it is not the alleged SirT1 proteins that inhibit the insulin-signaling pathway, but the Sir2 family histone deacetylases, which mediate this process (Zhang, 2006). 

2)  The Bio + Span product, who also claimed the miraculous nature of the SirT1 gene, is also seen to be a fraud.  Is this to say, however, that taking resveratrol in pill form would not have a positive impact on one’s health?  It very well may.  But, we can say with certainty, that the claims that they have made have been scientifically disproven.

 

 

And as for the final word on resveratrol and red wine…


       The amount of resveratrol found in red wine is quite small.  So, while the benefits found in such a compound are many, their relative impact is not terribly large.  However, as Fremont was seen to allege in the above analysis, the impact of even such a small quantity of resveratrol can indeed by discerned.  We can probably count on the fact that we will never see the reversal of the aging process.  And we can be certain that there will never be a red wine naturally endowed with enough resveratrol to sufficiently inhibit the insulin-signaling pathway and effectively slow the process of aging.  However, as asserted by Barger et al, with a much larger dose of this compound, we may actually see the development of product that would indeed slow aging.  But as for now, we will settle for improving the quality of life through resveratrol’s uncanny ability to retard some of the ailments that effectively lead to premature aging and death (Barger et al, 2008).

The principle concern and hesitation at this point in time is rooted in the fear of testing the drug on human subjects.  A great deal of success has been seen in trials performed on yeast, house flies, and mice, but Professor Richard Weindruch of the University of Wisconsin warns, “I think one needs to be very cautious about making dramatic leaps from the yeast model into mammals” (Hall, 2003, page 1165).  Trials performed on mice may give us a general idea of how the human body would react to certain stimuli, but there is really no way to know for sure.  

Cristoph Westphal, the CEO of one small pharmaceutical corporation said recently, “Part of my job is to calm people down," he says. "You have to remember, most things in biotech don't work."  And while resveratrol cannot yet be called the elixir of life or the fountain of youth, we cannot help but look to the future with eyes wide with anticipation, at that which is to come.  It seems now to be only a matter of time.  So, by all means, continue to drink and be merry.  Enjoy life whilst all the while reaping the fruits of good health!


 

 

 

 

 

“God in his goodness sent the grapes, to cheer both great and small; little fools drink too much, and great fools not at all” – Anonymous

 

 

 

 

 

 

References:

 

Barger JL, Kayo T, Vann JM, Arias EB, Wang J, et al. (2008). A low dose of dietary resveratrol partially mimics caloric restriction and retards aging parameters in mice. PLoS ONE 3(6), e2264.

 

Das, Samarjit, Santani, Dev D., & Dhalla, Naranjan S. (2007). Experimental evidence for the cardioprotective effects of red wine. Experimental Clinical Cardiology. 12, 5-10.

 

Fremont, Lucie (2000).Biological effects of resveratrol. Life Sciences. 66, 663-673.

 

Gerstel, Judy (2006, Nov 10). Ready to drink 60 bottles of wine every day?; Agent in wine helps fat mice but effects not tested on humans. Toronto Star, p. E.4.

 

Goldberg, David M., Hahn, Susan E., & Parkes, Joel G. (1995). Beyond alcohol: Beverage consumption and cardiovascular mortality. Elsevier Science. 155-187.

 

Hall, Stephen S. (2003).Longevity research: In vino vitalis? Compounds activate life-extending genes. Science Magazine. 301, 1165.

 

Vidavalur, Ramesh, Otanji, Hajime, Singal, Pawan K., & Maulik, Nilanjana (2006). Significance of wine and resveratrol in cardiovascular disease: French paradox revisited. Experimental Clinical Cardiology, 11, 217-225.

 

Zhang, Jiandi (2006). Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochemistry Journal. 397, 519-527.

 

 

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