NATURAL PRODUCTS
Reviving resveratrol Red wine made the compound famous; now one supplement maker hopes ongoing human tests can bring new life to its business
Manufacturers say the prospect of positive outcomes from clinical trials has revived interest in new and improved routes to the chemical. The Swiss biotech firm Evolva has long MELODY M. BOMGARDNER, C&EN WEST COAST been planning for resveratrol’s next moment in the sun. In 2012, it acquired a yeast fermentation process for making resverahealthy diet and regular exercise have long been known trol from sugar from Denmark’s Fluxome to delay or ward off diseases that are more prevalent in Science. That year, the market for resveratrol was estimated to be worth about old age, such as heart disease, diabetes, cancer, and even $50 million annually. cognitive decline. But scientists and consumers have also “At the time, Fluxome was selling some, sought another, less strenuous, way: a pill. but not a lot, of resveratrol,” says Angela Or even better, a glass of wine. In the early tains only 7 mg/L of the compound, whereas Tsetsis, head of Evolva’s resveratrol pro1990s, research suggested that substances in studies showed that positive effects in cells gram. “Evolva took on the technology and red wine might explain the so-called French and animals appeared at a level equivalent really improved upon it to make it more paradox, the observation that wine-loving to 300 mg/L. So suppliers in the supplement cost-effective.” French people have a low incidence of heart industry, many based in ChiIn the years since, howOH problems while also eating foods rich in satna, patented dozens of techever, the buzz around resurated fat, such as butter and cheese. niques for producing large veratrol—and demand for HO While the world cheered the quantities of the molecule. it—has waned. “Like many health-boosting potential of red wine, reIn recent years, a lack of of these compounds that searchers dug deeper into the components progress in testing resverebb and flow, resveratrol has OH of wine in hopes of discovering its chemical atrol’s impact on human been ebbing lately and has Resveratrol secrets. Among wine’s cache of polyphehealth has slowed growth in been slowing down in the nols, they discovered the bioactive moledemand for the compound. But that trend past five or six years,” Tsetsis observes. cule resveratrol. may be about to turn around: A new batch So in addition to improving its fermentaStudies, mostly in cell cultures and in an- of research is now exploring resveratrol’s tion route, Evolva has been working to supimals, showed resveratrol protects against effects on major age-related diseases in port and highlight new clinical trials lookinflammation, oxidative stress, and cancer. humans, including type 2 diabetes, cardioing at how resveratrol might affect blood The compound even seemingly extended vascular disease, cancer, and Alzheimer’s. glucose, metabolic syndrome, and bone the life span of worms, although the same Results from some early Phase II studies health. And last month it gave its resverobservation didn’t hold up for mice. suggest resveratrol influences certain molatrol a brand name, Veri-te, and launched The results were enough to spur demand ecules in the body that are indicators, or a marketing campaign around it aimed at for resveratrol supplements. Red wine conbiomarkers, of disease. supplement makers.
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C&EN | CEN.ACS.ORG | MARCH 6, 2017
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Evolva is working to differentiate its product from the many other sources on the market. For instance, other companies extract resveratrol not from wine or grapes, but from the root of a fast-growing shrub called the Japanese knotweed. But plant extraction presents challenges that Evolva doesn’t have to worry about, Tsetsis explains. For example, the roots of the Japanese knotweed can take in contaminants such as heavy metals from the soil. And extracts can contain another plant chemical, emodin, which is suspected to cause gastrointestinal discomfort and is difficult to remove. Although knotweed roots contain more resveratrol than grapes do, Tsetsis says yield is also lower than what fermentation can achieve. Evolva does, however, compete with the chemical synthesis route to resveratrol developed by the Dutch firm DSM. In 2012, DSM received a patent for a chemical process that uses the petroleum-derived compound 1-(3,5-diacetoxyphenyl)-bromoethane as a starting material. DSM markets its resVida brand resveratrol as “nature identical.” The firm has received approval to market it as a food ingredient in Europe. Another area in which Evolva thinks it has an advantage in the resveratrol supplement market is quality control. The U.S. Food & Drug Administration requires supplement makers to follow good manufacturing practices, but the rules do not apply to ingredient manufacturers. Having to track a complicated supply chain originating in China can be difficult. The industry tries to police itself, Tsetsis says, but there are overarching concerns about quality, purity, and even counterfeiting. Because Evolva makes resveratrol from sugar at its own facility, the supply chain is much shorter. Whether resveratrol comes from fermentation, plants, or petroleum, to be useful in a clinical trial it must be of high purity and known origin, points out Fred Stevens, a professor of pharmaceutical sciences at Oregon State University. An off-the-shelf supplement might be only 50% resveratrol, made with a small amount of grape skin extract with added synthetic resveratrol. Using fully synthetic or fermentation-derived resveratrol instead can provide 98% purity, Stevens says. To be useful in a clinical trial, a large enough dose of resveratrol also has to be administered. Although many supplements offer 100-mg or 250-mg doses of the compound, human studies using these levels tend not to show clinically relevant changes in disease markers. But larger doses of 1 g or greater have had more impact. One reason high doses may be necessary
is that resveratrol is quickly metabolized in humans. The body absorbs only about 25% of the resveratrol dose, and even less— about 1%—escapes the liver to enter the bloodstream, Stevens points out. “However, it is quite likely that any or all of the metabolites of resveratrol have biological activity in their own right.” Typically, candidate drugs are designed to work on a specific biochemical pathway or receptor, Stevens says. “But who says resveratrol acts on a specific receptor or on a specific pathway?” he asks. Instead, he thinks, the different outcomes that occur with larger doses suggest it affects multiple pathways in the body. Still, researchers can look for mechanistic clues by studying why plants produce resveratrol in the first place. In grapevines and the Japanese knotwood, resveratrol and other polyphenols are known to trigger a biological response in cells that helps them better cope with oxidative stress resulting from chronic inflammation. Chronic inflammation in humans is thought to be linked to aging-related cardiovascular and neurodegenerative diseases. In addition to helping cells cope with the stress of inflammation, Stevens says dietary polyphenols may also inhibit inflammatory pathways more directly. One way the body combats inflammation is by activating a class of enzymes called sirtuins, in particular SIRT1, which regulates proteins and genes involved in inflammation and aging. Animal studies suggest caloric restriction diets can extend life span and prevent cancer by activating the SIRT1 pathway. What really grabs researchers’ attention is that resveratrol, despite some debate about the matter, also appears to activate the same SIRT1 mechanism. That was the lure for R. Scott Turner, director of the Memory Disorders Program at Georgetown University. “I was intrigued by the whole caloric restriction literature,” he says, pointing out that the dietary practice staves off diseases of aging and prevents Alzheimer’s disease in mouse models. Turner received National Institutes of Health funding for a Phase II clinical trial studying the effect of up to 2 g per day of resveratrol on Alzheimer’s biomarkers in patients with mild to moderate versions of the disease. The randomized, placebo-controlled, double-blind study had 119 participants and lasted 52 weeks. The biggest and most interesting result was that resveratrol helped stabilize the quantity of amyloid-β in patients’ cerebrospinal fluid, Turner says (Neurology 2015, DOI: 10.1212/WNL.0000000000002035). Amyloid-β is a peptide that forms plaques in the brain, which scientists suspect cause
Roots of the Japanese knotweed are a common source of resveratrol for supplement makers. or contribute to Alzheimer’s disease. When people have Alzheimer’s, and as the disease progresses, less amyloid-β leaves the brain to enter the spinal fluid. “We think if you can increase the amount of amyloid-β in the spinal fluid, you can decrease the amount in the brain,” Turner says. Turner readily admits that his research does not prove that resveratrol’s effects are tied to sirtuins or that the SIRT1 pathway or caloric restriction affects Alzheimer’s disease. And many more famous drug studies targeting amyloid-β formation have all been failures. He says he hopes to do more studies to show the effect of resveratrol on the brain in people with Alzheimer’s using positron emission tomography scans. But Turner says finding out whether resveratrol slows or delays Alzheimer’s or its cognitive symptoms would require larger Phase III trials that would enroll thousands of patients. Those types of studies are often funded by pharmaceutical companies that have a new, patented molecule that shows promise for treating a disease. Although many firms have patented routes to resveratrol, a molecule that exists in nature cannot be patented. For his part, Stevens says he would like to see more long-term trials that show a dose response for resveratrol, particularly on biomarkers of metabolic syndrome: insulin resistance and blood glucose levels in people with diabetes and the types and amount of fats, or lipids, in the blood. Evolva’s Tsetsis claims that more than 1,500 clinical trials using resveratrol were initiated in 2015. “I hope and expect that awareness and respect for resveratrol will grow in 2017, though it won’t happen overnight.” Still, she says, “I’ve seen some upticks. When I start to get queries from bigger brands and companies, that’s how I know that interest is starting to grow.” ◾ MARCH 6, 2017 | CEN.ACS.ORG | C&EN
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