Resveratrol impacts Alzheimer's disease biomarker

Skeletal formula of trans-resveratrol. Image: Wikipedia

The largest nationwide clinical trial to study high-dose resveratrol long-term in people with mild to moderate Alzheimer's disease found that a biomarker that declines when the disease progresses was stabilized in people who took the purified form of resveratrol.

13 sept 2015--Resveratrol is a naturally occurring compound found in foods such as red grapes, raspberries, dark chocolate and some red wines.
The results, published online today in Neurology, "are very interesting," says the study's principal investigator, R. Scott Turner, MD, PhD, director of the Memory Disorders Program at Georgetown University Medical Center. Turner, who treats patients at MedStar Georgetown University Hospital, cautions that the findings cannot be used to recommend resveratrol. "This is a single, small study with findings that call for further research to interpret properly."
The resveratrol clinical trial was a randomized, phase II, placebo-controlled, double blind study in patients with mild to moderate dementia due to Alzheimer's disease. An "investigational new drug" application was required by the U.S. Food and Drug Administration to test the pure synthetic (pharmaceutical-grade) resveratrol in the study. It is not available commercially in this form.
The study enrolled 119 participants. The highest dose of resveratrol tested was one gram by mouth twice daily—equivalent to the amount found in about 1,000 bottles of red wine.
John Bozza, 80, participated in the study. Five years ago, his wife, Diana, began noticing "something wasn't quite right." He was diagnosed with mild cognitive impairment, but only a year later, his condition progressed to mild Alzheimer's.
Diana, whose twin sister died from the same disease, says there are multiple reasons she and John decided to participate in the resveratrol study, and they now know he was assigned to take the active drug.
"I definitely want the medical community to find a cure," she says. "And of course I thought there's always a chance that John could have been helped, and who knows, maybe he was."
Patients, like John, who were treated with increasing doses of resveratrol over 12 months showed little or no change in amyloid-beta40 (Abeta40) levels in blood and cerebrospinal fluid. In contrast, those taking a placebo had a decrease in the levels of Abeta40 compared with their levels at the beginning of the study.
"A decrease in Abeta40 is seen as dementia worsens and Alzheimer's disease progresses; still, we can't conclude from this study that the effects of resveratrol treatment are beneficial," Turner explains. "It does appear that resveratrol was able to penetrate the blood brain barrier, which is an important observation. Resveratrol was measured in both blood and cerebrospinal fluid."
The researchers studied resveratrol because it activates proteins called sirtuins, the same proteins activated by caloric restriction. The biggest risk factor for developing Alzheimer's is aging, and studies with animals found that most age-related diseases—including Alzheimer's—can be prevented or delayed by long-term caloric restriction (consuming two-thirds the normal caloric intake).
Turner says the study also found that resveratrol was safe and well tolerated. The most common side effects experienced by participants were gastrointestinal-related, including nausea and diarrhea. Also, patients taking resveratrol experienced weight loss while those on placebo gained weight.
One outcome in particular was confounding, Turner notes. The researchers obtained brain MRI scans on participants before and after the study, and found that resveratrol-treated patients lost more brain volume than the placebo-treated group.
"We're not sure how to interpret this finding. A similar decrease in brain volume was found with some anti-amyloid immunotherapy trials," Turner adds. A working hypothesis is that the treatments may reduce inflammation (or brain swelling) found with Alzheimer's.
The study, funded by the National Institute on Aging and conducted with the Alzheimer's Disease Cooperative Study, began in 2012 and ended in 2014. GUMC was one of 21 participating medical centers across the U.S.
Further studies, including analysis of frozen blood and cerebrospinal fluid taken from patients, are underway to test possible drug mechanisms.
"Given safety and positive trends toward effectiveness in this phase 2 study, a larger phase 3 study is warranted to test whether resveratrol is effective for individuals with Alzheimer's—or at risk for Alzheimer's," Turner says.
Resveratrol and similar compounds are being tested in many age-related disorders including cancer, diabetes and neurodegenerative disorders. The study Turner led, however, is the largest, longest and highest dose trial of resveratrol in humans to date.


Provided by Georgetown University Medical Center

Diets rich in antioxidant resveratrol fail to reduce deaths, heart disease or cancer

Skeletal formula of trans-resveratrol. Image: Wikipedia

A study of Italians who consume a diet rich in resveratrol—the compound found in red wine, dark chocolate and berries—finds they live no longer than and are just as likely to develop cardiovascular disease or cancer as those who eat or drink smaller amounts of the antioxidant.

12 may 2014--"The story of resveratrol turns out to be another case where you get a lot of hype about health benefits that doesn't stand the test of time," says Richard D. Semba, M.D., M.P.H., a professor of ophthalmology at the Johns Hopkins University School of Medicine and leader of the study described May 12 in JAMA Internal Medicine. "The thinking was that certain foods are good for you because they contain resveratrol. We didn't find that at all."

Despite the negative results, Semba says, studies have shown that consumption of red wine, dark chocolate and berries does reduce inflammation in some people and still appears to protect the heart. "It's just that the benefits, if they are there, must come from other polyphenols or substances found in those foodstuffs," he says. "These are complex foods, and all we really know from our study is that the benefits are probably not due to resveratrol."

The new study did not include people taking resveratrol supplements, though few studies thus far have found benefits associated with them.

Semba is part of an international team of researchers that for 15 years has studied the effects of aging in a group of people who live in the Chianti region of Italy. For the current study, the researchers analyzed 24 hours of urine samples from 783 people over the age of 65 for metabolites of resveratrol. After accounting for such factors as age and gender, the people with the highest concentration of resveratrol metabolites were no less likely to have died of any cause than those with no resveratrol found in their urine. The concentration of resveratrol was not associated with inflammatory markers,cardiovascular disease or cancer rates.

Semba and his colleagues used advanced mass spectrometry to analyze the urine samples.

The study participants make up a random group of people living in Tuscany where supplement use is uncommon and consumption of red wine—a specialty of the region—is the norm. The study participants were not on any prescribed diet.

Resveratrol is also found in relatively large amounts in grapes, peanuts and certain Asiatic plant roots. Excitement over its health benefits followed studies documenting anti-inflammatory effects in lower organisms and increased lifespan in mice fed a high-calorie diet rich in the compound.

The so-called "French paradox," in which a low incidence of coronary heart disease occurs in the presence of a high dietary intake of cholesterol and saturated fat in France, has been attributed to the regular consumption of resveratrol and other polyphenols found in red wine.

More information: JAMA Intern Med. Published online May 12, 2014. DOI: 10.1001/jamainternmed.2014.1582

Provided by Johns Hopkins University School of Medicine

Resveratrol remains effective against cancer after the body converts it

A chemical found in red wine remains effective at fighting cancer even after the body's metabolism has converted it into other compounds. This is an important finding in a new paper published in the journal Science Translational Medicine by Cancer Research UK-funded researchers at the University of Leicester's Department of Cancer Studies and Molecular Medicine.

04 oct 2013--The paper reveals that resveratrol – a compound extracted from the skins of red grapes – is not rendered ineffective once it is metabolised by the body.

This is an important development, as resveratrol is metabolised very quickly – and it had previously been thought that levels of the extracted chemical drop too quickly to make it usable inclinical trials.

The new research shows that the chemical can still be taken into cells after it has been metabolised into resveratrol sulfates.

Enzymes within cells are then able to break it down into resveratrol again – meaning that levels of resveratrol in the cells are higher than was previously thought.

In fact, the results appear to show resveratrol may be more effective once it has been generated from resveratrol sulfate than it is if it has never been metabolised because the concentrations achieved are higher.

The team, led by University of Leicester translational cancer research expert Professor Karen Brown, administered resveratrol sulfate to mice models.

They were subsequently able to detect free resveratrol in plasma and a variety of tissues in the mice.

This is the first direct sign that resveratrol can be formed from resveratrol sulfate in live animals, and the researchers think it may help to show how resveratrol is able to have beneficial effects in animals.

The study also showed that resveratrol generated from resveratrol sulfate is able to slow the growth of cancer cells by causing them to digest their own internal constituents and stopping them from dividing.

Professor Karen Brown said: "There is a lot of strong evidence from laboratory models that resveratrol can do a whole host of beneficial things – from protecting against a variety of cancers and heart disease to extending lifespan.

"It has been known for many years that resveratrol is rapidly converted to sulfate and glucuronide metabolites in humans and animals – meaning the plasma concentrations of resveratrol itself quickly become very low after administration.

"It has always been difficult to understand how resveratrol is able to have activity in animal models when the concentrations present are so low, and it has made some people skeptical about whether it might have any effects in humans.

"Researchers have hypothesized for a long time that resveratrol might be regenerated from its major metabolites in whole animals but it has never been proven.

"Our study was the first to show that resveratrol can be regenerated from sulfate metabolites in cells and that this resveratrol can then have biological activity that could be useful in a wide variety of diseases in humans.

"Importantly, we did all our work with clinically achievable concentrations so we are hopeful that our findings will translate to humans.

"Overall, I think our findings are very encouraging for all types of medical research on resveratrol. They help to justify future clinical trials where, previously, it may have been difficult to argue that resveratrol can be useful in humans because of the low detectable concentrations.

"There is considerable commercial interest in developing new forms of resveratrol that can resist or overcome the issue of rapid metabolism. Our results suggest such products may not actually be necessary to deliver biologically active doses of resveratrol to people."

Dr Sarah Williams, Cancer Research UK health information officer, said: "This interesting study supports continued research into resveratrol as a therapeutic molecule, but it's important to note that any benefits from the molecule don't come from drinking red wine. It's well established that drinking any type of alcohol, including red wine, increases the risk of developing cancer."

More information: "Sulfate Metabolites Provide an Intracellular Pool for Resveratrol Generation and Induce Autophagy with Senescence," by K.R. Patel et al. Science Translational Medicine, 2013.

Provided by University of Leicester

Resveratrol in a red wine sauce: Fountain of youth or snake-oil?

Resveratrol is being be touted as the latest wonder drug that will add years to our lives. Credit: Greg Bishop

Resveratrol, a molecule found in red wine (and red grape skin and elsewhere) is back in the headlines after an international team of researchers published a paper in the journal Sciencelate last week. The news made headlines around the world.

17 mar 2013--Researchers believe resveratrol could extend the human life span, and protect people against a wide range of diseases such as cancer, type II diabetes, Alzheimer's, and heart disease.

But is it too good to be true?

Is resveratrol the latest wonder drug that will add years to our lives? Or is this simply the newest science and marketing spiel that will take the rest of our lives to unravel?

And what if resveratrol does not live up to its promise? Who is to blame? The scientists? The media? The marketers? Or the gullible fools who make up the general public?

The health-giving properties of red wine have been advanced as a possible explanation for the French Paradox, the observation that the French have relatively low heart disease despite a high-fat diet. Researchers suggest that the resveratrol in the red wine could be a contributing factor.

The promise of resveratrol has been escalated with research suggesting that it has the capacity to activate a protein called SIRT1 found in mammals. SIRT1 is one of a larger class of proteins called sirtuins that have been shown to extend the life span of yeast, worms, flies and, maybe, mice.

Yes, "maybe mice" because whether it extends a mouse's life is disputed. In fact, the truth seems less clear and more highly valued than a couple of cases of 1950s Grange Hermitage.

Despite doubts about the real value of resveratrol, in 2008 GSK paid $720m for SIRTRIS, a company established by some of the scientists advancing the positive claims for resveratrol.

This may just be the latest attempt at finding the fountain of youth. 

The paper published recently in Science simply reaffirms an earlier claim against contrary evidence. This is science as usual; a scientific shoot-out at the frontier of knowledge in an effort to establish truth.

But some of the claims for resveratrol certainly seem overstated. We are, after all, talking about research that, to this point, has been focused on relatively short-term effects observed on just a few leaves on the phylogenetic tree, in carefully controlled laboratory conditions.

Despite the hype about the connection with red wine, even the researchers admit that the amount of resveratrol in a glass or three of red wine is insignificant relative to the dosing that showed effects in mice. Even so, one of the researchers admits taking resveratrol supplements perhaps to amplify his claims in a style akin to Australian Nobel-laureate Barry Marshall.

So, it may be premature to assume that these findings generalise to humans in the wild.

Add to this the problem of falsification. No, not philosopher of science Karl Popper's notion of falsification as a basis for advancing scientific knowledge, but falsification in terms of made-up data. A number of published studies showing the benefits of resveratrol have been retracted for being fabricated.

All this before the media and marketers get to create a label and write advertising copy to make an appetising and digestible sound-bite (or tipple) for the masses.

The great problem here for seekers of truth is to separate fact from fiction, to separate the infinitely more nuanced reality from vastly simplified human representation.

"Science," said Karl Popper, "may be described as the art of systematic over-simplification." And if scientists are bad, then the media and marketers are probably even worse.

Still, they are all simply selling a story; it appeals because people want to believe it.

The search for the fountain of youth has gone on for millennia. And this search has uncovered just one thing – the spring of human hope flows endlessly. We are hopelessly hopeful.

Our eternal optimism offers value to medicine through the placebo effect, which suggests that people's beliefs can help their own healing. Sadly, this also means that it can take a long time for people to realise that they have been duped.

And anyway, who is to blame when the whole thing is a product of human nature? Do we blame the public for their unbridled optimism and desire for a quick fix? Or the scientific, media and marketing professions for desiring social and financial success?

The flipside to all this is that some of the claimed benefits of resveratrol are available to the public right now. Sirtuins can be activated by exercising a bit more, and eating a bit less.

But that's not a very interesting story; fiction feeds dreams while the facts foster drudgery.

The amount of resveratrol in a glass of red wine is unlikely to have any effect on your health, but if it makes you feel better, raise a glass to the placebo effect. And the proof that science, media, marketers and consumers can together create much value from very little.

Source: The Conversation

This story is published courtesy of The Conversation (under Creative Commons-Attribution/No derivatives).

Resveratrol falls short in health benefits

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Studying healthy, middle-aged women, researchers found that supplementation with resveratrol, an ingredient in red wine, does not offer the medical benefits previously thought.

Resveratrol, an ingredient in red wine thought to improve insulin sensitivity, reduce risk of heart disease and increase longevity, does not appear to offer these benefits in healthy women, new research at Washington University School of Medicine in St. Louis indicates.

28 oct 2012--The study, reported online Oct. 25 in Cell Metabolism, involved 29 post-menopausal women who did not have type 2 diabetes and who were reasonably healthy. For 12 weeks, half took an over-the-counter resveratrol supplement, and the rest got a placebo, or sugar pill.

"Resveratrol supplements have become popular because studies in cell systems and rodents show that resveratrol can improve metabolic function and prevent or reverse certain health problems like diabetes, heart disease and even cancer," says senior investigator Samuel Klein, MD, director of Washington University's Center for Human Nutrition. "But our data demonstrate that resveratrol supplementation does not have metabolic benefits in relatively healthy, middle-aged women."

The results were somewhat surprising because earlier studies suggested that drinking red wine lowers the risk of health problems.

"Few studies have evaluated the effects of resveratrol in people," Klein explains. "Those studies were conducted in people with diabetes, older adults with impaired glucose tolerance or obese people who had more metabolic problems than the women we studied. So it is possible that resveratrol could have beneficial effects in people who are more metabolically abnormal than the subjects who participated in the study."

Klein, the Danforth Professor of Medicine and Nutritional Science, directs the Division of Geriatrics and Nutritional Science and the Center for Applied Research Sciences. He says many people who have heard about red wine's health benefits want to take resveratrol supplements to get the benefits of red wine without consuming large amounts of alcohol. In recent years, annual U.S. sales of resveratrol supplements have risen to $30 million.

As part of the study, Klein and his colleagues gave 15 post-menopausal women 75 milligrams of resveratrol daily, the same amount they'd get from drinking 8 liters of red wine, and compared their insulin sensitivity to 14 others who took a placebo.

The team measured the women's sensitivity to insulin and the rate of glucose uptake in their muscles, infusing insulin into their bodies and measuring their metabolic response to different doses.

"It's the most sensitive approach we have for evaluating insulin action in people," he says. "And we were unable to detect any effect of resveratrol. In addition, we took small samples of muscle and fat tissue from these women to look for possible effects of resveratrol in the body's cells, and again, we could not find any changes in the signaling pathways involved in metabolism."

But if resveratrol doesn't have a health benefit, then why are red wine drinkers less likely to develop heart disease and diabetes? Klein says there may be something else in red wine that provides the benefit.

"The purpose of our study was not to identify the active ingredient in red wine that improves health but to determine whether supplementation with resveratrol has independent, metabolic effects in relatively healthy people," he says. "We were unable to detect a metabolic benefit of resveratrol supplementation in our study population, but this does not preclude the possibility that resveratrol could have a synergistic effect when combined with other compounds in red wine."

Provided by Washington University School of Medicine

More evidence for longevity pathway

New research reinforces the claim that resveratrol—a compound found in plants and food groups, notably red wine—prolongs lifespan and health-span by boosting the activity of mitochondria, the cell's energy supplier.

03 may 2012--"The results were surprisingly clear," said David Sinclair, a professor of genetics at Harvard Medical School and the study's senior author. "Without the mitochondria-boosting gene SIRT1, resveratrol does not work."
The findings are to be published May 1 in the journal Cell Metabolism.
Over the last decade, Sinclair and colleagues including Leonard Guarente at Massachusetts Institute of Technology have published a body of research describing how resveratrol improves energy production and overall health in cells by activating a class of genes called sirtuins that are integral to mitochondrial function. The cell's power supplier, mitochondria are essential not just for longevity but for overall health.
Sinclair and colleagues had studied sirtuins in a variety of model organisms: yeast, worms, flies and mice. For the first three organisms they were able to thoroughly knock out SIRT1 and show that cells lacking the gene don't respond to resveratrol. But no one had been able to demonstrate the effect in mice, which die at birth without the SIRT1 gene.
In order to solve this obstacle, Nathan Price and Ana Gomes, graduate students in the Sinclair lab, spent three years engineering a new mouse model. These mice, seemingly normal in every way, were designed so that SIRT1 would systemically switch off when the mice were given the drug Tamoxifen.
"This is a drug inducible, whole body deletion of a gene," said Sinclair. "This is something that's rarely been done so efficiently. Moving forward, this mouse model will be valuable to many different labs for other areas of research."
The results were plain: when mice were given low doses of resveratrol after SIRT1 was disabled, the researchers found no discernable improvement in mitochondrial function. In contrast, the mice with normal SIRT1 function given resveratrol showed dramatic increases in energy.
While the tantalizing prospect of increasing healthy lifespan has made resveratrol the subject of intense scientific interest, some researchers have questioned the link to SIRT1. A competing theory holds that resveratrol may work by activating a separate energy pathway called AMPK, which, while also related to mitochondria, does not involve sirtuin genes.
In their new paper, Sinclair and colleagues report that when mice lacking SIRT1 were given low doses of resveratrol, AMPK was unaffected. When doses were significantly increased in these mice, AMPK was activated, but still no benefit to mitochondrial function resulted.
"Resveratrol is a dirty molecule, so when you give very, very high doses, many things could be happening," said Sinclair. "It's standard when you study molecules that you use the lowest dose that gives you an effect because of the risk of hitting other things if you use too much. But for the downstream benefits on energy, you still need SIRT1. Our paper shows that SIRT1 is front and center for any dose of resveratrol."

More information: Cell Metabolism, May, 2012, Vol 15, No 5
Provided by Harvard Medical School

First clinical trial of red wine ingredient shows metabolic shifts

When obese men take a relatively small dose of resveratrol in purified form every day for a month, their metabolisms change for the better. In fact, the effects appear to be as good for us as severe calorie restriction. Resveratrol is a natural compound best known as an ingredient in red wine.

04 nov 2011--"We saw a lot of small effects, but consistently pointing in a good direction of improved metabolic health," said Patrick Schrauwen of Maastricht University in The Netherlands.

The findings in the November issue of the Cell Press journal Cell Metabolism are the first to report the clinical effects of resveratrol.

Earlier studies in animals had shown that resveratrol alleviates insulin resistance and protects against the ill effects of a high-fat diet, among other benefits, he explained. The effects are comparable to what happens when animals or humans significantly restrict the number of calories they consume, a diet plan shown to delay the onset of age-related diseases. Still, no studies had systematically examined the metabolic effects of resveratrol in humans.

To fill that gap, the researchers gave 11 obese but otherwise healthy men a dietary supplement containing 150 milligrams of a 99 percent pure trans-resveratrol (trade name resVida) for 30 days while they measured the amount of energy they expended, the amount of fat they were storing and burning, and more.

The data show that, like calorie restriction, resveratrol supplements lower energy expenditure and improve measures of metabolism and overall health. Those changes include a lower metabolic rate, less fat in the liver, lower blood sugar levels and a drop in blood pressure. Trial participants also experienced changes in the way their muscles burned fat.

"The immediate reduction in sleep metabolic rate was particularly striking," Schrauwen said. Of course, in the case of obesity, it's not entirely clear whether burning fewer calories is a good or a bad thing. It does suggest that participants' cells were operating more efficiently, as they do following calorie restriction.

Those metabolic effects of resveratrol also came with no apparent side effects.

Schrauwen said they chose to study obese individuals given their increased risk for type 2 diabetes. In future studies, he hopes to explore the effects of resveratrol in people who have already progressed to diabetes.

ResVida and other resveratrol supplements are already widely available, but more work is needed to establish whether they indeed have the potential to overcome the metabolic aberrations associated with obesity and aging, according to the researchers.

"I don't see a reason for particular caution, but we do need long-term studies," Schrauwen says.

Provided by Cell Press

Study on effects of resveratrol and quercetin on inflammation and insulin resistance

A study was carried out to examine the extent to which quercetin and trans-resveratrol (RSV) prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-a (TNF-a)—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals.

28 dec 2010--Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-a. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. The authors report that quercetin, and to a lesser extent trans-RSV, attenuated the TNF-a–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1b, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1.

Forum members were concerned about certain aspects of the study, especially the extrapolation of in vitro results to in vivo situations. The in vitro conditions the authors describe are minimally representative of an in vivo condition. In vivo, after consumption of quercetin or resveratrol, these compounds undergo extensive metabolism, leading to glucuronidated, sulphated or methylated compounds. In a previous study, quercetin 3-glucoside was transformed to 3,4-dihydroxyphenylacetic acid, acetate and butyrate in cells from human gut; only 3'-methylquercetin has been detected in human plasma, present at a concentration of 0.1 to 0.2 µM after 3 h. The authors of the current paper are using concentrations up to 60 µM, concentrations which have not been found in vivo.

There were also concerns with the work on cell uptake of quercetin and resveratrol. Primary adipocytes were incubated with the polyphenols, but it is not clear whether or not the concentrations used were subtoxic. Our current knowledge is limited about local concentration of the molecules we are studying in subcellular compartments, their interaction with alternative targets, and eventually their transformation into products that could be more or less active on a given specific pathway. The real difficult and important issue is the identification of a reasonable convergence -- if not agreement -- between data originating from extremely distant approaches. In this case, the notion that metabolic diseases are related to a homeostatic imbalance in adipose tissue, linked to a different redox status, linked to activation of specific pathways, and that different redox sensitive polyphenols do have a protective effect, encompasses the evidence produced by extremely distant approaches.

From a clinical point of view, the role of phytochemicals acting as antioxidants and anti-inflammatory agents could be extremely important in inflammation-associated chronic conditions such as cardiovascular disease, diabetes, and cancer. Quercetin and resveratrol may indeed play an important role in this regard, and need to be investigated further to establish the clinical importance of natural dietary compounds in the prevention of chronic degenerative conditions.

Provided by Boston University Medical Center

'Sip red wine' for health

16 june 2009--Scientists have said that people should sip their wine to get its “cancer-busting antioxidant working”, the Daily Express reported. It said that the mouth absorbs 100 times more resveratrol, a compound in red wine, than the stomach. The newspaper said that resveratrol attacks cancer cells and can protect the heart and brain from damage.

This news story is based on a review of recent research on the effects of resveratrol on health, disease and longevity. The newspaper reports the authors as saying that the mouth absorbs 100 times more resveratrol than the stomach, but even so the human-equivalent doses of those demonstrating benefit in animal experiments “are well above those achievable... through a normal diet”. For instance, to get an equivalent dose to that which achieved a 50% extension in the lifespan of fish, a person would need to consume around 60 litres of red wine a day. Resveratrol has health improvement potential, but clearly more research in humans is needed.

Where did the story come from?

The research was carried out by Dr Lindsay Brown and colleagues from the University of Queensland in Brisbane, the University of Connecticut School of Medicine in the US, the University of Debrecen in Hungary and the University Hospital of Heidelberg at Manheim in Germany. The study was funded by the National Institutes of Health and the Dietmar Hopp Foundation. It was published in the medical journal Alcoholism: Clinical and Experimental Research.

What kind of scientific study was this?

This is a narrative review of recently published research on the potentially beneficial ingredients in red wine. The authors discuss how these ingredients, particularly polyphenols (chemical substances which include resveratrol), could work in the human body and their potential therapeutic uses.

Resveratrol is a type of compound known as a small polyphenol. It has been studied extensively in animals and insects and has been shown to extend the life of some yeasts, roundworms, fruit flies and obese mice given a high calorie diet. It is thought to have similar effects to a low calorie diet and to slow the aging process.

The authors discuss recent evidence of the effects of resveratrol and put forward some theories for how it might have these effects. In particular, they discuss the apparent contradiction that while low doses improve the survival of some cells, providing a cardioprotective or neuroprotective effect, it kills cancer cells when given in high doses.

They discuss research into the potential benefits of resveratrol on cancer, inflammation, gastrointestinal diseases, neuroprotection, diabetes, heart health, blood pressure, blood vessels and cellular health, structure and function.

The researchers also discuss what is known about how the ingredients in red wine may benefit the body. They talk about the “bioavailability” of resveratrol and other polyphenols, a property of a drug that describes how much of it enters the circulation and becomes “available” for the body to use.

What were the results of the study?

There are a number of different aspects to the researchers’ discussion into resveratrol. Some of the news reports of this research summarise them all, concluding that resveratrol has therapeutic potential, while the Daily Express focussed on the bioavailability of the compound.

What interpretations did the researchers draw from these results?

The researchers say that further research is needed to understand the role of resveratrol and other polyphenols, and how low to moderate amounts of red wine provide benefit compared to white wine, beer or spirits.

They say that the known harms associated with alcohol consumption have prevented a fully controlled clinical trial of the effects of moderate consumption of red wine on cardiovascular disease risk.

This narrative review discussed research on how resveratrol and other components of red wine may benefit health and how this might occur. Some news reports have focussed on one aspect of the review: the bioavailability of resveratrol. It is not clear where the Daily Express sourced the information that the mouth absorbs 100 times more resveratrol than the stomach.

The researchers note that, so far, the positive observations in research have been made with doses of resveratrol “that are well above those achievable in humans through a normal diet”. They say that red wine is almost the only source of resveratrol in the human diet. To achieve an equivalent dose to the one that apparently extended the lifespan of fish by 50%, a person would need to consume around 60 litres of red wine a day, which is certainly not feasible (or recommended!).

There is a growing body of evidence, largely from animal studies, that resveratrol can have a positive effect on health. Importantly, the researchers emphasise that red wine contains only a small amount of resveratrol and a human would need to drink an unrealistically large amount to have the same levels as those demonstrated in animal studies. Excessive alcohol consumption is associated with serious health risks and recommendations to drink in moderation should be taken seriously. If sipping wine prevents excessive alcohol intake then it should be encouraged, but human studies are needed to investigate the real health effects of red wine before it can be recommended for health reasons.

Links to the headlines

Red wine is good for you, if you let it linger. Daily Express, June 14 2009

Red wine ingredient is a 'wonderdrug'. The Daily Telegraph, June 11 2009

Links to the science

Brown L, Kroon PA, Das DK, et al. The Biological Responses to Resveratrol and Other Polyphenols From Alcoholic Beverages. Alcoholism: Clinical and Experimental Research: Published online: 10 Jun 2009

Anti-aging pathway enhances cell stress response

People everywhere are feeling the stress of a worldwide recession. Our cells, too, are under continual assault from stress.

20 feb 2009--Hidden from sight, our cells battle challenges such as their environment, bacteria, viruses, too much or too little oxygen, and physiological stressors. Molecular systems protect cells under assault, but those systems can break down, especially with age.

To better understand how cells are protected from stress and damage, a team led by Northwestern University researchers studied the effect of resveratrol, a beneficial chemical found in red wine, on human cells in tissue culture.

The findings may help explain what happens in neurodegenerative diseases, which are age-related, when cell protection fails, proteins misfold, lots of damage accumulates and the system falls apart.

The researchers discovered a new molecular relationship critical to keeping cells healthy across a long span of time: a protein called SIRT1, important for caloric restriction and lifespan and activated by resveratrol, regulates heat shock factor 1 (HSF1), keeping it active. HSF1 in turn senses the presence of damaged proteins in the cell and elevates the expression of molecular chaperones to keep a cell's proteins in a folded, functional state. Regulation of this pathway has a direct beneficial effect to cells, the research shows.

This role of SIRT1 -- a protein already of great interest to pharmaceutical companies -- was not previously known. The results will be published in the Feb. 20 issue of the journal Science.

"When SIRT1 levels are high, you are in a high-protection mode," said Richard I. Morimoto, Bill and Gayle Cook Professor of Biochemistry, Molecular Biology and Cell Biology in Northwestern's Weinberg College of Arts and Sciences. He led the research team.

"Ironically, triggering the stress response and perhaps maintaining the cell in a protective state over a long period of time can keep cells healthy," said Morimoto. "The cell is protected against an accumulation of damage when HSF1 is more active."

SIRT1 levels decrease as humans age, Morimoto explains. Cells can't respond to stress as well. This decrease in SIRT1 may help explain why protein misfolding diseases, such as Alzheimer's, Parkinson's, Huntington's and adult-onset diabetes, are diseases of aging.

"We now have a powerful way to think about addressing neurodegenerative diseases," said Morimoto. "We have identified a pathway that can be manipulated to alter lifespan. Discovering this new basis for therapeutics is very exciting."

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In addition to Morimoto, other authors of the Science paper, titled "Stress-Inducible Regulation of Heat Shock Factor 1 by the Deacetylase SIRT1," are Sandy D. Westerheide, from Northwestern; Julius Anckar and Lea Sistonen, from Åbo Akademi University in Turku, Finland; and Stanley M. Stevens Jr., from the University of Florida.

Scientists Find Clues to Aging in a Red Wine Ingredient’s Role in Activating a Protein

By NICHOLAS WADE
27 nov 2008--A new insight into the reason for aging has been gained by scientists trying to understand how resveratrol, a minor ingredient of red wine, improves the health and lifespan of laboratory mice. They believe that the integrity of chromosomes is compromised as people age, and that resveratrol works by activating a protein known as sirtuin that restores the chromosomes to health.
The finding, published online Wednesday in the journal Cell, is from a group led by David Sinclair of the Harvard Medical School. It is part of a growing effort by biologists to understand the sirtuins and other powerful agents that control the settings on the living cell’s metabolism, like its handling of fats and response to insulin.
Researchers are just beginning to figure out how these agents work and how to manipulate them, hoping that they can develop drugs to enhance resistance to disease and to retard aging.
Sirtris, a company Dr. Sinclair helped found, has developed a number of chemicals that mimic resveratrol and are potentially more suitable as drugs since they activate sirtuin at much lower doses than resveratrol. This month, one of these chemicals was reported in the journal Cell Metabolism to protect mice on fatty diets from getting obese and to enhance their endurance in treadmills, just as resveratrol does.
Though the sirtuin field holds considerable promise, the dust has far from settled. Resveratrol is a powerful agent with many different effects, only some of which are exerted through sirtuin. So drugs that activate sirtuin may not be as splendid a tonic for people as resveratrol certainly seems to be for mice.
The new finding concerns maintenance of the chromosomes, the giant molecules of DNA that make up the genome.
Each cell has six feet of DNA packed into its nucleus, carrying the 20,000 or so genetic instructions needed to operate the human body. Each cell must provide instant access to the handful of these genes needed by its cell type, but also keep the rest firmly switched off to avoid chaos.
Sirtuin’s normal role is to help gag all the genes that a cell needs to keep suppressed. It does so by keeping the chromatin, the stuff that wraps around the DNA, packed so tightly that the cell cannot get access to the underlying genes.
But sirtuin has another critical role, one that is triggered by emergencies like a break in both DNA strands of a chromosome. After a double strand break, sirtuin rushes to the site to help knit the two parts of the chromosome back together. But in this salvage operation, it leaves its post, and the genes it was repressing are liable to come back into action, causing mayhem.
This, Dr. Sinclair and his colleagues suggest, may be a fundamental cause of aging in mice and probably people, too.
The gene-gagging role of sirtuin was discovered in the 1980s by biologists studying yeast, a standard laboratory organism. Dr. Sinclair and Leonard Guarente of the Massachusetts Institute of Technology found in 1997 that sirtuin could also repair a certain kind of genomic damage in yeast, and in doing so extended the yeast cell’s lifespan. But this particular kind of damage does not occur in mammalian cells, raising the puzzle of why extra sirtuin should be good for them.
Dr. Sinclair’s new report, if verified, resolves this problem by showing that sirtuin has retained its genomic repair role in higher organisms but that the repair is focused on a different kind of genomic damage — that of breaks in a chromosome.
These experiments “elegantly demonstrate” that sirtuin works in much the same way in mammals as in yeast, Dr. Jan Vijg of the Albert Einstein College of Medicine wrote in a commentary in Cell. The question now is whether sirtuin is a pro-longevity factor in mammals, he said in an e-mail message.
Ronald Evans, a biologist at the Salk Institute, said the new report was provocative but did not prove the case that the relocation of sirtuin was a cause of aging. Tests with mice genetically engineered to lack the sirtuin gene could show if the mice suffered from premature aging, as Dr. Sinclair’s idea would predict.
Dr. Sinclair said he agreed that the case for sirtuin’s role in aging had not been proved. “We are careful not to say this is the cause of aging, but based on everything we know it’s not a bad hypothesis,” he said.
It would be nice to test aging in mice that lack the sirtuin gene, as Dr. Evans proposed, but they die too young, Dr. Sinclair said.
Dr. Sinclair has been taking large daily doses of resveratrol since he and others discovered five years ago that it activated sirtuin. “I’m still taking it, and I feel great,” he said, “but it’s too early to say if I’m young for my age.”

Researchers identify cancer preventive properties in common vitamin supplement

PHILADELPHIA, 8 july 2008 – Early laboratory research has shown that resveratrol, a common dietary supplement, suppresses the abnormal cell formation that leads to most types of breast cancer, suggesting a potential role for the agent in breast cancer prevention. Resveratrol is a natural substance found in red wine and red grapes. It is sold in extract form as a dietary supplement at most major drug stores.
"Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts. We believe that this could stop the whole progression that leads to breast cancer down the road," said Eleanor G. Rogan, Ph.D., a professor in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center.
Rogan was the lead author of the report that was published in the July 2008 issue of Cancer Prevention Research, a journal of the American Association for Cancer Research.
For the current study, Rogan and colleagues measured the effect of resveratrol on cellular functions known to contribute to breast cancer.
The formation of breast cancer is a multi-step process which differs depending on type of disease, a patient's genetic makeup and other factors. However, scientists know that many breast cancers are fueled by increased estrogen, which collects and reacts with DNA molecules to form adducts. Rogan and colleagues found that resveratrol was able to suppress the formation of these DNA adducts.
"This is dramatic because it was able to be done with fairly low concentrations of resveratrol to stop the formation of these DNA adducts in the cells we studied," said Rogan. Although researchers experimented with up to 100 µmol/L of resveratrol, the suppression of DNA adducts was seen with 10 µmol/L. A glass of red wine contains between 9 and 28 µmol/L of resveratrol.
The researchers also found that resveratrol suppressed the expression of CYP1B1 and the formation of 2,3,7,8-Tetrachlorodibenzo-p-dioxin, two known risk factors for breast cancer.
Rogan said resveratrol works by inducing an enzyme called quinone reductase, which reduces the estrogen metabolite back to inactive form. By making estrogen inactive, resveratrol decreases the associated risk.
The current study was conducted in laboratory cultures, and will need to be confirmed in larger human trials, Rogan said.