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This article was taken from the February issue of Wired UK magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content bysubscribing online
Portentous music blares as a news bulletin-style headline -- "National Medical Report" -- flashes on the computer screen. Against a backdrop of ancient Egyptian mosaics an earnest American voice-over declares: "Six thousand years ago, the ancient Persians offered it as a symbol of peace and friendship. Since then it has been intertwined with the journey of mankind." Cut to the present, and a shot of red wine sloshing into glasses. "Many of today's scientists believe," booms the actor, "that one of [red wine's] key extracts -- resveratrol -- may offer new hope for good health and the prevention of heart disease, cancer and other deadly diseases."
Cue James Betz, "president/founder, Biotivia, Longevity Bioceuticals". Dressed in black, he tells an out-of-shot interviewer, over the image of a blonde lab technician: "A lot of researchers believe right now that resveratrol may be regarded as important a discovery as penicillin." The testimonies follow of a "senior Olympiad [sic]/ resveratrol user", who claims that taking resveratrol supplements cleared up his arthritis, and a cancer survivor who informs us that, having finally "got [his] hands on this product… four months later [he] was playing badminton!" Then comes Betz's money shot. "By health strategies and things like resveratrol," he says, "we can add, say, ten-year increments to our lifespan. And as we add these ten year increments, we're building successive bridges to the ultimate goal, which is essentially infinite lifespan."
The internet seethes with "miracle" pills and cures, pandering to vitamin junkies, the sexually anxious and, that most lucrative of niches, the worried well. Most are easily dismissed as quackery, built on the flimsiest science if any. But resveratrol -- a polyphenol also known as trans-3,5,4'-trihydroxystilbene, found in grape skins, peanuts and berries -- demands closer attention. The compound's advocates talk up an eye-popping ability to stave off a host of age-related diseases including certain cancers, type-2 diabetes, cardiovascular disease and neurological conditions. Its popularity as a dietary supplement -- sold mostly online -- is growing exponentially. It is also the subject of an expanding body of "traditional" clinical research.
Plug "resveratrol" into Google and 4.6 million hits appear. Further data provided by the search engine reveals that the word (including misspellings and combination searches with additional keywords) is searched for, on average, 722,000 times a month, and that interest in the so-called "super compound" has doubled during 2009. Search-traffic data indicating a surge of consumer curiosity about resveratrol has been driven, in part, by media coverage on US TV shows, ranging from Oprah to CBS's 60 Minutes -- viewed more than 470,000 times on YouTube -- and via a blizzard of news stories about how researchers have found that moderate daily consumption of red wine may now be "good for you".
As the scientists toil in their labs, compiling the first flurry of evidence from the earliest clinical trials, the dietary-supplements industry has rushed to fill the void. In the wake of the excitable headlines about resveratrol- inspired breakthroughs, scores of sales sites with names such as megaresveratrol.com, AgeStop.net and ResveratrolMiracle.com now jostle for a slice of a market, which dazzles with cod science.
Gauging the size of the resveratrol business is not easy. No one monitors the industry closely enough. But anecdotal evidence that the market is booming comes from the aforementioned Betz. Tracked down to Spain, the Biotivia boss -- whose business is based in the US and Vienna, but also has a presence across Europe as well as China and India -- says the resveratrol market is still at the "boutique supplement stage", worth about $20 million annually. But with "tons of human trials about to be released -- we're doing a bunch of them ourselves with collaborators", Betz says, a "tipping point" nears. "Then it will go from an early adopter phase to a mass-market product. We think that sales in 2010 will be probably at least five times those of 2009, taking the market to at least $100 million."
When asked to name some of the "tons of human trials" he is referring to, he cites "the first phase of a study on diabetes" at the Albert Einstein College of Medicine (in New York) which "should be published in about three months" and "a study on the effects of resveratrol on the fitness and mitochondria effects of both sedentary and active subjects at Ottawa Hospital". However, Will Steward, professor of oncology at Leicester Royal Infirmary and an expert on diet-derived agents (including resveratrol), tells Wired: "Both of those are good centres, but their studies are very preliminary and we will need to see the data. There are not 'tons of trials'. There are about four [human trials] in cancer at present. We can't derive any information from these yet."
Marketing claims made for resveratrol range from the extravagant to the sci-fi fantastical. One leading UK sales site, AgeStop.net, declares that the compound "activates a longevity gene in certain strains of yeast and extends life expectancy by 70 per cent!"
The company provides a phone number for "live help" on its website. A scrupulously polite, and almost certainly outsourced, operator tells me resveratrol is "a very good product to stop the progression of cancer growth…". It becomes immediately apparent that she's reading from the company's website, as she informs me, haltingly: "It also increases the level of… quinone reductase." What's that? A long pause. She isn't sure. "The liver uses these enzymes to detoxify the carcinogens. [Resveratrol] also acts as a beneficial phytoestrogen," she adds mysteriously.
She fills the ensuing gap by saying: "It also reduces all the cholesterol in your body." And what about claims that resveratrol extends life -- what's that based upon? "You know it actually protects against prostate cancer," she says. "It will give you extended life [sic]. It acts in a protective role against the formation of colon cancer. [Yes, she's reading again.] So that's the reason, you know, you'll get an extended life with [resveratrol]."
If, anything, my conversation with another supplements site -- myprotein.co.uk, "the UK's leading online manufacturer and supplier of sports and nutritional supplements" -- proves even more bizarre. Among the plethora of "sports supplements and nutrition" it offers is "super-strength" Trans-resveratrol at £12.95 for 90 tablets (250mg). "This wonderful antioxidant," it claims, "has been shown to have a number of positive health effects, including: cancer prevention, anti-viral, control of type-2 diabetes, anti-ageing, anti-inflammatory and life-prolonging properties."
Its phone number is a little harder to locate than AgeStop's, but when I dial it I'm put through to an in-house "nutritionist", who sounds like a teenager with a Saturday job. "Obviously no one's got the cure for cancer at the moment," he points out when asked about resveratrol's claimed "cancer prevention" properties. "But [resveratrol] has been known to help the immune system fight off cells of that sort." Just in case there's any confusion, he adds: "But obviously it's not full, 100 percent cancer prevention." And then: "It's also been known and proven for anti-ageing within skin cells and muscle cells."
Leicester Royal Infirmary is a sprawl of municipal-style buildings. The hospital is home to one of Europe's largest cancer-prevention research groups, where Will Steward jointly oversees laboratory and human trials concerning the role "diet-derived agents", including resveratrol, play in reducing cancer risk and progression.
Extracts from Wired's conversations with dietary-supplements companies -- including claims that resveratrol supplements "reduce the causes of cancer", elicit a weary sigh from Steward. "It's twaddle," he says. "Isn't it an example of how awful the field of supplementary medicine can be? There is zero clinical evidence that it prevents cancer at the moment, simply because the trials haven't been done. I treat hundreds of people with cancer every year and they are incredibly vulnerable. They and their families waste a fortune on these 'treatments', potentially adding to [the patient's] toxicity."
Similarly, he gives short shrift to the claim that resveratrol's discovery may be as important as that of penicillin. "You just can't say that. Penicillin's saved millions of lives; even if we treat a few cancers, we will not save anything like as many lives -- so that's complete twaddle too."
Yet Steward has great hopes for resveratrol. Six years ago, he and his team began working with researchers at the University of Michigan on the "first ever" trials with resveratrol and its role in cancer prevention. Funded by the US's National Cancer Institute, and now also by Cancer Research UK, a series of three trials -- involving a total of 80 people -- began looking first at healthy volunteers and then at people with colon cancer, who were given increasing doses of resveratrol as tablets, initially to gauge safety, then dosage. Repeat tissue biopsies of participants were taken to look for any indication that resveratrol might have a cancer-treatment or -prevention effect. At the time of going to press, the results from the final trial had just been submitted for publication.
All Steward will tell Wired for now is: "Resveratrol, up to five grammes daily, was well tolerated and safe, and blood markers of biological effect looked promising, showing that [resveratrol] could have effects on cells which would be valuable in preventing cancer."
In contrast to the screeching claims of marketers, Steward is guarded about resveratrol's prospects. "The bottom line is that diet and its effect on cancer and disease are very difficult to determine," he says. "And a lot of promising things come to nothing in the end. So one can say about resveratrol only that, at this stage, it looks promising. It's got good science behind it. We've shown in the laboratory that it does a lot of impressive things to cells: it causes cells to die when there's something abnormal in the cell; it blocks blood-vessel formation, which is very valuable as a potential to treat cancer; and it has an effect on more than 100 different pathways in cells which have been implicated in cancer development or the survival of cancer cells once they're formed. What we've now got to decide is how much is sensible to give people to have that effect and translate that into an effect in a good clinical trial to prove it."
One recent development, however, gave Steward and others in the field a huge boost. In April 2008, GlaxoSmithKline paid $720 million for Sirtris Pharmaceuticals, a company founded by Harvard professor David Sinclair which develops drugs with the same effects as resveratrol. "The fact that a massive company like Glaxo has been prepared to put an awful lot of money into buying a company which, essentially, just makes resveratrol and similar agents has got to mean they also feel optimistic about it, after doing due diligence," says Steward. "Companies like that don't do things lightly."
In 2006, Sinclair collaborated with Dr Rafael de Cabo of the National Institute on Aging (part of the US National Institutes of Health) in what is now viewed as one of the game-changing studies on resveratrol. The international team was able to demonstrate that overweight, aged male mice, fed on a high-calorie diet supplemented by a high dose of resveratrol, were healthier and lived longer than the group not given the compound. The findings, published in Nature that November, were the first to prove that resveratrol had an impact on the well-being and survival rates of mammals. Earlier trials had successfully extended the lifespans of yeast, worms, flies and fish.
Today, Spanish-born de Cabo is conducting resveratrol trials with rhesus monkeys, the results of which are due to be published "very soon". From his government laboratory in Baltimore he tells Wired that, so far, the latest trials -- in that well worn, scientist-beloved phrase -- "looks promising". However, when I ask whether evidence exists from published data to support claims that resveratrol can extend human life and inhibit diseases, including certain cancers and cardiovascular disease, he says it doesn't. "For humans, [we know] nothing. All that we have right now from data published on humans is a couple of short-term studies; the rest of it is all anecdotal. There is no strong scientific evidence of anything that you can claim right now in terms of any potential beneficial clinical effect of resveratrol in humans." Although significant strides have now been made in trials on mice and rats, and there have been "myriad positive responses to resveratrol" in "slower organisms" including yeast, flies, worms and fish, de Cabo is blunt about the supposed benefits of resveratrol in humans: "The problem is that there is very little data that says, for example, if you take100mgof resveratrol a day for three weeks your cholesterol will go down. We just don't know that. It's almost like we're in diapers in terms of our understanding of what the biological potency in humans is for resveratrol."
De Cabo is similarly scornful of the resveratrol supplements trade. "As scientists we need to follow established good practice of scientific and clinical behaviour -- we have to go through all the steps," he says. "The companies making those unproven claims are making a business out of preliminary data in animal models. One good thing, so far, is that no one has died." Right at the end of our conversation he adds: "In part, this boom in resveratrol has been our fault -- it's been our papers that have raised expectations. I'd love to claim all the glory for a compound that's going to fix everything," he laughs, "but right now we just don't have the data."
Biotivia managing director James Betz is willing to try to back up the more outlandish claims in his resveratrol infomercial video. But first there's the issue of the PhD he places after his name in the "management team" section of his corporate website. The PhD is in cell biology from the University of Vienna. Yet he later concedes: "The degree of doctor in Austria may not in all cases be considered as a PhD -- in the US, for example." He says he first came across resveratrol in 1994 and, after perusing "some remarkable papers", he concluded it was potentially "a really remarkable compound". Fast-forward a decade and the supplements-company boss says that with "a couple of hundred, very good, mostly peer-reviewed papers, some of which had been published in some pretty prestigious journals, most of which were coming out of China, Japan or India", he decided that "this thing really had some potential".
Using a Chinese supply line of Polygonum cuspidatum, also known as Japanese knotweed (a good source of resveratrol), he set about "designing a product". Today, he claims, his business acquires "about 60 per cent of all the polygonum extract being produced in China right now".
When asked to name some of these "remarkable papers" he'd read in 1994, Betz first refers Wired to Google Scholar. "If you search for resveratrol you will see many of the studies I referred to," he emails. But when pressed for "a couple of standout examples", he writes back: "I am having a bit of trouble finding the early 1990s studies, but I have noted a few for you." He then proceeds to list "two early studies by Bharat B. Aggarwal, an Indian researcher who is still one of the top two or three scientists deeply involved in resveratrol research." He attaches The Handbook of Antioxidants, a book which contains chapters by Aggarwal and a January 2008 study entitled "Targeting Inflammatory Pathways for Prevention and Therapy of Cancer: Short-Term Friend, Long-Term Foe". Curiously its abstract, or introductory summary makes no mention of resveratrol.
Although asked for just a couple of examples, Betz sends links to five studies, also listing scientists and institutions in China "publishing studies on resveratrol since the early 1990s", adding: "Most of these studies are only in the Chinese language." Later, he forwards a batch of studies "cited by Dr Joseph Maroon, neurosurgeon and good friend". A Google search reveals Maroon, author of The Longevity Factor: How Resveratrol and Red Wine Activate Genes for a Longer and Healthier Life, has an alleged vested interest. He is an adviser to Vinomis Labs, a company which aims to become "the leading manufacturer and supplier of nutraceutical products based upon resveratrol". Indeed, he even appears on its home page.
So how does Betz justify his assertion that "by health strategies and things like resveratrol… we're building successive bridges to the ultimate goal, infinite lifespan"? At three and-a-half minutes, his answer is elusive -- and only fleetingly mentions resveratrol. He starts by citing the progress that science is making in gerontology, how "we double our total base of [scientific] knowledge about every ten years" and that "a lot of medicine is dependent on our computing capacity, so as computing capacity increases we're able to solve problems we couldn't solve before."
So far, so speculative. Betz continues: "There are a number of things coming together -- stem-cell research, new pharmaceuticals, new medical technologies, ability to grow organs. All of these things are converging on a point which I would say is in five to ten years, at which time we will be able to easily give someone who can afford it another 20 years," he claims. "During those 20 years we will see another enormous expansion. So that's why I feel that if you take advantage of what's available now – good diet, exercise and things like resveratrol -- you can easily add ten years. And in ten years we'll achieve breakthroughs that we have no ability to comprehend presently."
And on resveratrol's potential, he goes even further: "Resveratrol will be more influential than penicillin." He explains: "Resveratrol has been shown to be effective in an incredibly wide range of diseases. If you look at its applicability for cancer, diabetes and inflammatory disease; its neuroprotective properties; and the fact it's going to be more refined and developed from this stage on, I think that's a fair statement."
But is it a fair statement, given that two prominent scientists in this field have dismissed it? "There is still a paucity of whole clinical human-trial data. Most of the results are from in-vitro human and animal studies." Betz cites three "completed human clinical trials", none of which appears to bolster his case: a 2008 "Phase 1" trial by the University of Arizona, "studying the side-effects of resveratrol and to see how it works in healthy adult participants"; phase 1 of the Leicester Royal Infirmary/University of Michigan 2004 trial; and an ongoing "pilot" study by the University of Wisconsin "to determine the effects of resveratrol extract…on cognitive and global functioning on patients with mild to moderate Alzheimer's disease on standard therapy".
Betz -- and yet more flamboyant salesmen in the supplements trade -- may soon have to revise the promotional material for resveratrol, in Europe at least. From 2010, all health claims for foods (including dietary supplements) have to be assessed by European Food Safety Authority (EFSA) scientists. The authority declined to comment on claims made about products featured in this article, but it did say that an investigation into claims that resveratrol "contributes to cell protection from the damage caused by free radicals and helps to fight against skin ageing" will report at an unconfirmed date.
Cancer Research UK is more forthright in condemning those who hype resveratrol for its cancer- inhibiting properties. "Many vitamin and mineral supplements were believed to be potent cancer fighters until trials and large studies showed they are usually ineffective and can even increase the risk of cancer in some cases," says the charity's Yinka Ebo. "Resveratrol has a few anticancer properties when tested in animals or cells grown in a lab. But, to date, there is no strong evidence that resveratrol supplements can prevent cancer in people."
Unproven claims about so-called "miracle supplements" abound, driven by a largely unregulated industry employing the toolkit of the marketing trade. Yet resveratrol is different. Lost in the clamour is a growing body of evidence that the compound shows "promise" in a range of clinical applications. But data takes time to gather. Until a series of full clinical trials is completed, peer reviewed and published in reputable journals, resveratrol's story will remain one in which hype drowns out science.
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This article was taken from the February issue of Wired UK magazine. Be the first to read Wired's articles in print before they're posted online, and get your hands on loads of additional content bysubscribing online
This article was originally published by WIRED UK
