Beauty Health for Life

A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models. Whats more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion. Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.

These findings are published in the March 8 issue of Science.

For the last decade, the science of aging has increasingly focused on sirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging. Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin,SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age. By recharging the batteries, SIRT1 can have profound effects on health.

Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.

"In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1," said David Sinclair, Harvard Medical School professor of genetics and senior author on the paper. "Almost all drugs either slow or block them."

In 2006, Sinclairs group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol. (Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company, and remains a scientific advisor. Sirtris currently has a number of sirtuin-activating compounds in clinical trials.)

But while numerous studies, from Sinclairs lab and elsewhere, underscored a direct causal link between resveratrol and SIRT1, some scientists claimed the studies were flawed.

The contention lay in the way SIRT1 was studied in vitro, using a specific chemical group attached to the targets of SIRT1 that fluoresces more brightly as SIRT1 activity increases. This chemical group, however, is synthetic and does not exist in cells or in nature, and without it the experiments did not work. As a response to this, a paper published in 2010 surmised that resveratrols activation of SIRT1 was an experimental artifact, one that existed in the lab, but not in an actual animal. SIRT1 activity in mice was, the paper claimed, at best an indirect result of resveratrol, and perhaps even a sheer coincidence.

As a result, a debate erupted over the particular pathway that resveratrol and similar compounds affected. Does resveratrol directly activate SIRT1 or is the effect indirect? "We had six years of work telling us that this was most definitely not an artifact," said Sinclair. "Still, we needed to figure out precisely how resveratrol works. The answer was extremely elegant."

Sinclair and Basil Hubbard, then a doctoral student in the lab, teamed up with a group of researchers from both the National Institutes of Health and Sirtris Pharmaceuticals to address this question.

First, the team addressed the problem of the fluorescent chemical group. Why was it required for resveratrol to rev up SIRT1 in the test tube? Instead of dismissing the result as an artifact, the researchers surmised that the chemical might be mimicking molecules found naturally in the cell. These turned out to be a specific class of amino acid, the building blocks of proteins. In nature, there are three amino acids that resemble the fluorescent chemical group, one of which is tryptophan, a molecule abundant in turkey and notable for inducing drowsiness. When researchers repeated the experiment, swapping the fluorescing chemical group on the substrate with a tryptophan residue, resveratrol and similar molecules were once again able to activate SIRT1.

"We discovered a signature for activation that is in fact found in the cell and doesnt require these other synthetic groups," said Hubbard, first author of the study. "This was a critical result, which allowed us to bridge the gap between our biochemical and physiological findings.

"Next, we needed to identify precisely how resveratrol presses on SIRT1s accelerator," said Sinclair. The team tested approximately 2,000 mutants of the SIRT1 gene, eventually identifying one mutant that completely blocked resveratrols effect. The particular mutation resulted in the substitution of a single amino acid residue, out of the 747 that make up SIRT1. The researchers also tested hundreds of other molecules from the Sirtris library, many of which are far more powerful than resveratrol, against this mutant SIRT1. All failed to activate it.

The authors propose a model for how resveratrol works: When the molecule binds, a hinge flips, and SIRT1 becomes hyperactive.

Although these experiments occurred in a test tube, once the researchers identified the precise location of the accelerator pedal on SIRT1—and how to break it—they could test their ideas in a cell. They replaced the normal SIRT1 gene in muscle and skin cells with the accelerator-dead mutant. Now they could test precisely whether resveratrol and the drugs in development work by tweaking SIRT1 (in which case they would not work) or one of the thousands of other proteins in a cell (in which they would work). While resveratrol and the drugs tested revved up mitochondria in normal cells (an effect caused activating by SIRT1), the mutant cells were completely immune.

"This was the killer experiment," said Sinclair. "There is no rational alternative explanation other than resveratrol directly activates SIRT1 in cells. Now that we know the exact location on SIRT1 where and how resveratrol works, we can engineer even better molecules that more precisely and effectively trigger the effects of resveratrol."

In older men, a natural antioxidant compound found in red grapes and other plants -- called resveratrol -- blocks many of the cardiovascular benefits of exercise, according to research published today [22 July 2013] in The Journal of Physiology.

Resveratrol has received widespread attention as a possible anti-aging compound and is now widely available as a dietary supplement; much has been made of its role in explaining the cardiovascular health benefits of red wine, and other foods. But now, new research at The University of Copenhagen surprisingly suggests that eating a diet rich in antioxidants may actually counteract many of the health benefits of exercise, including reduced blood pressure and cholesterol.

In contrast to earlier studies in animals in which resveratrol improved the cardiovascular benefits of exercise, this study in humans has provided surprising and strong evidence that in older men, resveratrol has the opposite effect.

What is emerging is a new view that antioxidants are not a fix for everything, and that some degree of oxidant stress may be necessary for the body to work correctly. This pivotal study suggests that reactive oxygen species, generally thought of as causing aging and disease, may be a necessary signal that causes healthy adaptations in response to stresses like exercise. So too much of a good thing (like antioxidants in the diet) may actually be detrimental to our health.

Lasse Gliemann, a PhD student who worked on the study at The University of Copenhagen, explains how they conducted the research, and the results they found: "We studied 27 healthy, physically inactive men around 65 years old for 8 weeks. During the 8 weeks all of the men performed high-intensity exercise training and half of the group received 250 mg of resveratrol daily, whereas the other group received a placebo pill (a pill containing no active ingredient). The study design was double-blinded, thus neither the subjects nor the investigators knew which participant that received either resveratrol or placebo.

"We found that exercise training was highly effective in improving cardiovascular health parameters, but resveratrol supplementation attenuated the positive effects of training on several parameters including blood pressure, plasma lipid concentrations and maximal oxygen uptake."

Ylva Hellsten, the leader of the project, says:"We were surprised to find that resveratrol supplementation in aged men blunts the positive effects of exercise training on cardiovascular health parameters, in part because our results contradict findings in animal studies.

"It should be noted that the quantities of resveratrol given in our research study are much higher than what could be obtained by intake of natural foods."

This research adds to the growing body of evidence questioning the positive effects of antioxidant supplementation in humans.

Michael Joyner, from The Mayo Clinic USA, says how the study has wider implications for research: "In addition to the surprising findings on exercise and resveratrol, this study shows the continuing need for mechanistic studies in humans. Too often human studies focus on large scale outcomes and clinical trials and not on understanding the basic biology of how we adapt."

A chemical found in red wine remains effective at fighting cancer even after the bodys 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 Leicesters Department of Cancer Studies and Molecular Medicine.

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 in clinical 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."