Gertsch Group

Institute of Biochemistry and Molecular Medicine, University of Bern, Switzerland

Longevity, red wine and why resveratrol fools even big companies

Longevity, red wine and why resveratrol fools even big companies
Jurg Gertsch - Sat Sep 24, 2011 @ 07:17AM
Comments: 1

Resveratrol is a priviledged chemical structure in the sense that it binds to virtually any protein at a given concentration range. Unfortunately, scientists still work with this molecule in vitro and when they obtain binding (e.g. they find that it inhibits or activates their protein of interest) usually at relatively high concentrations, they deduce that this is interesting. There are hundreds of claims about resveratrol and according to the scientific literature this natural product prevents cancer and makes you live longer. But the story is relatively simple. In vivo, when ingested, this compound will be metabolized quickly in any mammal and disappears rapidly. The concentrations found in vivo are not enough to even nearly trigger the effects found in vitro. And concentration makes the medicine! I just found an interesting story investigated and written by the British science reporter Nicholas Wade (New York Times) about resveratrol. I think it is a very nice story and Wade did a great job.

By Nicholas Wade, New York Times, 21. September 2011

A trans-Atlantic dispute has opened up between two camps of researchers pursuing a gene that could lead to drugs that enhance longevity. British scientists say the longevity gene is “nearing the end of its life,” but the Americans whose work is under attack say the approach remains as promising as ever.

The dispute concerns genes that make sirtuins, proteins involved in controlling cells’ metabolism. Because of their metabolic role, the sirtuins may mediate the 40-percent-longer life enjoyed by laboratory rats and mice put on a very low-calorie diet.

People cannot keep to such a low-fat diet, but drugs that activate sirtuin would in principle be a painless way for humans to add years of lean and healthy life. This idea took wing when resveratrol, a substance found in trace quantities in red wine, was reported to activate sirtuin. In 2008 the pharmaceutical company GlaxoSmithKline paid $720 million for Sirtris, a start-up company trying to develop resveratrol-mimicking drugs that activate sirtuins. (remark Jürg Gertsch: CRACY!)

Since then, several aspects of the sirtuin story have come under scientific challenge, including doubts as to whether resveratrol’s effects are really exercised through sirtuin, and whether the sirtuins are the real or only mediators of the longevity increase linked to a low-calorie diet.

Despite these concerns, the idea that sirtuins promote longevity appeals to scientists because of experiments that were started in yeast and repeated in two other standard laboratory organisms, the roundworm and the fruit fly.

It is these foundation experiments that have now come under attack by David Gems and Linda Partridge, researchers on aging at University College London. In an article published in Nature, they and colleagues have re-examined experiments in which roundworms and flies, genetically manipulated to produce more sirtuin than normal, were reported to live longer.

Both experiments were flawed, they say, because the worms and flies used as a control were not genetically identical to the test organisms. The London researchers report that they have repeated the experiments with proper controls and found that extra sirtuin does not, after all, make the worms or flies live longer.

The genetic study of aging is a relatively new field that has had its fair share of teething problems. In an article in Nature four years ago, Dr. Gems and Dr. Partridge warned of some of the mistakes being commonly made. “The biology of aging is a young field with emerging pitfalls,” they wrote.

The authors of the original worm and fly experiments on the sirtuins fell into one of these traps, the London researchers now write, namely the failure to make sure their test and control animals had the same genetic background in all respects except for the added gene that forced extra production of sirtuins.

In the worm experiment, published by Leonard Guarente of the Massachusetts Institute of Technology in 2001, the strain of worms used had picked up an extra mutation that also had the effect of prolonging life, the London researchers report. When the mutated gene is removed, the worms with extra sirtuin do not live longer, they said.

Dr. Guarente said he did not agree with the thrust of this criticism. The 2001 experiment was done with the best techniques then available, he said. When he heard of the mutated gene two years ago, he redid the experiment, using worms from which the gene had been removed. The worms with extra sirtuin still lived longer, though the effect was less pronounced than before, a finding he also reports in the current Nature article.

“We agree there is a glitch in one of the worm strains used in the 2001 paper,” Dr. Guarente said in an interview. “We absolutely do not agree that there is a serious question about whether sir2 extends life span in worms,” he said, using the name for the worm’s version of the sirtuin protein.

“I think the whole thing is a tempest in a teapot,” he said.

Stephen Helfand of Brown University is the author of the fly experiments. Like Dr. Guarente, Dr. Helfand criticized the London researchers for focusing on an old experiment of his and ignoring a subsequent one that reached the same conclusion with a much-improved technique.

In the more recent experiment, published in 2009, he was able to arrange that genes for extra sirtuin were switched on only when the flies were given a drug. The test and control flies were genetically identical, and differed only in whether they got the drug. Those with the drug lived longer, he reported.

Dr. Gems said at first that he had not cited Dr. Helfand’s 2009 experiment because it was “redundant,” and then he said that Nature had limited the number of papers he could cite.

All scientists agree that it is important to correct flawed experiments, but there are differences of opinion as to how this should be done. The London group believes the aging field is full of sloppy experiments done by people new to the field and more interested in publicity than in excluding the factors that confound this difficult subject. The American sirtuin researchers under criticism believe the London group has gone beyond simple correction into “gotcha” science that is not collegial. Usually, they say, if a scientist cannot repeat another’s experiment, he will call up first to find out why instead of putting his objections into print first.

Scientists not involved in the dispute say that sirtuins remain a field of vast interest, even if their relationship to longevity now seems considerably more complex than originally suggested. The theory that resveratrol activates sirtuins, which then prolong life span, is popular because of the notion that drinking red wine can make people live longer, but it “should have been abandoned five years ago,” said Richard A. Miller, who studies aging in mice at the University of Michigan. “But sirtuins are very important proteins which probably have a lot to do with how diseases are controlled.”

Dr. Miller suggested that Nature had given too much attention to resveratrol and sirtuin reports in the past. “Maybe they are trying to make amends by giving equal time to people who have been more careful,” he said.

Gertsch: This story reminds me of a report in which resveratrol was shown to bind at low nM concentrations to the cannabinoid CB1 receptor and acted as an inverse agonsit like rimonabant, the drug that makes you loos weight. Everything looked very nice only that we and other could not reproduce it. Finally, the corresponding author of that work (who is a great scientist and should be awarded a medal for this) did the experiments himself and was not able to reproduce the data of his student - he retracted the paper (click here) - personally, I feel that more than half of all publications on resveratrol are artifacts.

 

LOOKING BACK AT THE BEGINNING OF THE "DISCOVERY"

New York Times Date: 24 August 2003

Biologists have found a class of chemicals that they hope will make people live longer by activating an ancient survival reflex. One of the chemicals, a natural substance known as resveratrol, is found in red wines, particularly those made in cooler climates like that of New York. The finding could help explain the so-called French paradox, the fact that the French live as long as anyone else despite consuming fatty foods deemed threatening to the heart.

Besides the wine connection, the finding has the attraction of stemming from fundamental research in the biology of aging. However, the new chemicals have not yet been tested even in mice, let alone people, and even if they worked in humans, it would be many years before any drug based on the new findings became available.

The possible benefits could be significant. The chemicals are designed to mimic the effect of a very low-calorie diet, which is known to lengthen the life span of rodents. Scientists involved in the research say that human life spans could be extended by 30 percent if humans respond to the chemicals in the same way as rats and mice do to low calories. Even someone who started at age 50 to take one of the new chemicals could expect to gain an extra 10 years of life, said Dr. Leonard Guarente of the Massachusetts Institute of Technology, one of the pioneers of the new research.

The new result was announced last week at a scientific conference in Arolla, a small village in the Swiss alps, by Dr. David A. Sinclair of the Harvard Medical School.

The new development has roused the enthusiasm of many biologists who study aging, because caloric restriction, the process supposedly mimicked by the chemicals, is the one intervention known for sure to increase longevity in laboratory animals.

A calorically restricted diet includes all necessary nutrients but has some 30 percent fewer calories than usual. The diet extends the life span of rodents by 30 to 50 percent, and even if it is started later has a benefit proportionate to the remaining life span. Scientists hope, but do not yet know, that the same will be true in people. A similar mechanism exists in simpler forms of life, making biologists believe that they are looking at an ancient strategy, formed early in evolution and built into all animals. The strategy allows an organism, when food is scarce, to live longer, postpone reproduction and start breeding when conditions improve.

Two experiments to see if caloric restriction extends life span in monkeys are about at their halfway point — rhesus monkeys live some 25 years in captivity — and the signs so far are promising, though not yet statistically significant. But even if caloric restriction did extend people's life spans, the current epidemic of obesity suggests how hard it would be for most people to stick with a diet containing 30 percent fewer calories than generally recommended.

Biologists have therefore been hoping to find some chemical or drug that would mimic caloric restriction in people by tripping the same genetic circuitry as a reduced-calorie diet does and give the gain without the pain.

Dr. Sinclair and his chief co-author, Dr. Konrad T. Howitz, of Biomol Research Laboratories in Plymouth Meeting, Pa., say they have succeeded in finding a class of drugs that mimic caloric restriction in two standard laboratory organisms — yeast and fruit flies. Both mice and humans have counterpart genes that are assumed to work in a similar way, though that remains to be proved.

Independently, Elixir Pharmaceuticals, a company in Cambridge, Mass., found a different set of chemicals that mimic caloric restriction, Ed Cannon, the chief executive, said. "We can do the same things he can do," Dr. Cannon said of Dr. Sinclair's findings. Because of testing and regulatory requirements, "we are 8 to 10 years away from having an approved drug," Dr. Cannon added.

In an interview from Arolla, Switzerland, where he presented his findings, Dr. Sinclair said, "I've been waiting for this all my life," adding, "I like to be cautious, but even as a scientist, it is looking extremely promising."

So far, Dr. Sinclair and his colleagues have shown that resveratrol prolongs life span only in yeast, a fungus, by 70 percent. But a colleague, Dr. Mark Tatar of Brown University, has shown in a report yet to be published that the compound has similar effects in fruit flies. The National Institute of Aging, which sponsored Dr. Sinclair's research, plans to start a mouse study later in the year.

Despite the years of testing ahead to prove that resveratrol has any effect in people, many of the scientists involved in the research have already started drinking red wine.

"One glass of red wine a day is a good recommendation. That's what I do now," Dr. Sinclair said, adding he hoped the finding would not lead people to drink in excess. "One glass of wine is enough," he said. However, resveratrol is unstable on exposure to the air and "goes off within a day of popping the cork," he said.

Dr. Tatar, asked if he had changed his drinking habits, said, "No, I have always preferred red wine to white."

The new finding is so novel that health authorities have not yet had time to make a detailed evaluation of the research. Dr. David Finkelstein, the project officer at the National Institute of Aging, which financed the study, said that he would not advise anyone to start drinking red wine. "At this point, we have no indication that there will be a benefit in people," he said, adding that the calories in a glass of wine would lead to weight gain.

Dr. Toren Finkel, the head of cardiovascular research at the National Heart, Lung and Blood Institute, said that "I would be cautious in sending out the message that one glass of wine a day will make you live 10 years longer." "The concentration of resveratrol in different wine differs," he said. "As a drug, it is not ready for prime time." But he acknowledged that the concept of a drug that mimicked caloric restriction "is a great idea.".

Dr. Sinclair said that he and Dr. Howitz were working on chemical modifications of resveratrol that would be more stable. Ownership of the patent will be split 50:50 between their parent institutions, the Harvard Medical School and Biomol.

Resveratrol is synthesized by plants in response to stress, like a lack of nutrients or contracting a fungal infection. It exists in the skin of both red and white grapes but is found in amounts 10 times higher in red wine because of differences in the manufacturing processes.

According to the Oxford Companion to Wine, Pinot Noir tends to have high levels of the chemical, while Cabernet Sauvignon has lower levels. "Wines produced in cooler regions or areas with greater disease pressure, such as Burgundy and New York, often have more resveratrol," the book says, whereas wines from drier climates like California or Australia have less.

Besides resveratrol, another class of chemical found to mimic caloric restriction is that of the flavones, found abundantly in olive oil, Dr. Howitz said.

The enthusiasm scientists are showing for the new discovery, despite its preliminary nature, stems in part from a train of fundamental discoveries stretching back a decade. In 1991, Dr. Guarente decided to study the basis of aging, then considered an unpromising field of research. He spent four years searching for strains of yeast, a common laboratory organism, that lived longer than others. By 1997, he and Dr. Sinclair, who worked in his laboratory at the time, had discovered the reason for the new strains' longevity. It centered on a gene called sir2, for silent information regulator.

Dr. Guarente next found that when yeast live longer because of starvation, sir2 is the gene that mediates the response. His research then started to fuse with longstanding work on caloric restriction as he and others showed that starvation is sensed by sir2, which triggers the cellular changes that lead to increased life span.

What Dr. Sinclair and Dr. Howitz did was to take the human version of sirtuin, the enzyme produced by the sir2 gene, and devise a test to tell when the enzyme was activated. They then screened a large batch of likely chemicals to see if any made the enzyme more active. Their screen produced two active chemicals, both of a similar chemical structure and known as polyphenols. That led them to expand the search to more polyphenols. The most active compound in the second screen was resveratrol. Dr. Sinclair said he was amazed "that in an unbiased screen we pulled out something already associated with health benefits."

Much attention has been paid to resveratrol in the last few years because it is a candidate for explaining the apparent innocuousness of the French diet despite its artery-weakening ingredients. Epidemiological studies point to red wine as containing some beneficial antidote, but it is not yet certain whether alcohol, or resveratrol, or both, are the active ingredients.

Why should chemicals like resveratrol play a role both in the French paradox and in caloric restriction? Dr. Sinclair believes the chemicals are produced by plants in response to stresses like starvation and that browsing animals may have evolved to make use of the chemicals as a signal of hard times ahead. Other scientists said this idea was possible but not particularly plausible.

Dr. Guarente, his former mentor, founded Elixir Pharmaceuticals to pursue the same goal of developing drugs that mimic caloric restriction. Dr. Guarente said Dr. Sinclair's results were plausible and exciting. He said diet-mimicking drugs might add a decade of life to someone starting them at age 50, based on the calculation that the 30 or so years of life expected at that age could be increased by one third, and assuming that humans would benefit from caloric restrictions to the same degree as mice.

Dr. Cynthia Kenyon, of the University of California, San Francisco, an expert on aging in roundworms and a cofounder of Elixir, said from Arolla that Dr. Sinclair's work was "really remarkable."

Elixir uses the same screen for sirtuin activity as Dr. Sinclair did, one provided by Biomol. It is not yet clear if the efforts by Dr. Sinclair and Elixir will be competitive or collaborative, Dr. Howitz said.

In either case, considerable testing lies ahead to see if the promise of the new research can be fulfilled.

Comments: 1

Comments

1. Jonathan Wells   |   Wed Feb 08, 2012 @ 08:49AM

Interesting blog - there are numerous resveratrol food supplements on the market with health promises. I always wondered about side effects but now see that the substance is not bioavailable. Do you know whether natural resveratrol (e.g. as found in red wine extracts) is better taken up?

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