From The February 2004 Issue of Functional Foods & Nutraceuticals
Recent research indicates that resveratrol, found in red grapes, extends the life of yeast cells by 70 per cent. Can this result be duplicated in humans? And do supplements work as well as a bottle of red wine?
Man’s pursuit of long life, the so-called fountain of youth, edged closer to fruition with the recent announcement that a dietary component may increase the human lifespan to the point where it would be common to live 125 years. This red-coloured youth potion can be obtained from a bottle of vino, and perhaps as a dietary supplement.
Lead researcher David Sinclair, PhD, assistant professor of pathology at Harvard University Medical School, says the lifespan of all life forms tested so far—yeast cells, fruit flies, worms and mice—has been dramatically lengthened by minute amounts of a red wine extract, resveratrol.
The skin of red wine is the most abundant source of resveratrol, a unique antioxidant that red grapes produce in great amounts as a defence against fungi. The process of winemaking utilises alcohol to extract resveratrol (or 3,4,5-trihydroxystilbene) and then preserves it in an airtight bottle; otherwise it would vanish in days.
Mechanisms of action
Since 1935, researchers have recognised that severe restriction of calories can significantly broaden the lifespan of insects, animals and probably humans.  The mechanism behind calorie restriction appears to be a survival factor that is turned on when living organisms are exposed to harsh conditions. When a living organism is deprived of calories, the sirtuin gene upregulates the activity of an enzyme (histone deacetylase) that prolongs the time cells have in which to repair their damaged genetic material, their strands of DNA. The enzymatic activity also ‘silences’ genes responsible for protein production (ribosomal DNA). Therefore, resveratrol inhibits the over-production of proteins within cells that leads to accelerated ageing. Aged cells typically produce hundreds of thousands of extra copies of ribosomal DNA. The accumulation of these proteins in living cells has been likened to an ageing clock. Slowing down the rate at which proteins are produced slows the rate of ageing itself.
Sinclair began to research the dynamics of this survival mechanism. A family of iron-controlling antioxidant molecules was screened for its ability to increase the activity of the enzyme. From a library of thousands of molecules, 17 activated the human survival/longevity gene. Resveratrol, the extract obtained from red wine, did indeed turn on the survival switch and extend the life of yeast cells by 70 per cent. In human terms, that would be equivalent to 30 to 50 years of added life! Resveratrol was superior to the 16 other molecules tested. 
The uniqueness of resveratrol may be partly explained by the fact it is utilised by cells and orally absorbed by humans better than other antioxidants found in grapes. 
Humans have a similar gene, SIRT1, responsible for activating the same enzyme. The enzyme itself cannot be bottled because to work, it has to be delivered to cells at the right place and time. Cells have machinery to increase enzyme activity on their own. What Sinclair discovered was the dietary switch to turn on this mechanism. What grapes use to turn on this survival mechanism, the calorie restriction mimic, can be transferred to humans in a glass of wine, a cross-species transfer process scientists now call xenohormesis. 
Plants produce resveratrol in response to environmental factors such as ultraviolet radiation (UV-C), fungal infection and temperature changes. 
Editor's Note: (from my bi-monthly HealthQuest Newsletter)
“Phytoalexins are low molecular-weight compounds that accumulate in plants in response to infection, wounding, freezing, UV light exposure, and micro-organism attack. This process, known as Induced Systemic Resistance of plants against pathogens, is a widespread phenomenon, but only recently has the potential health benefits (of these compounds) been recognized.”
Phytoalexins are actually a whole class of phenolic compounds, produced by plants in response to some form of attack. Although this defensive plant mechanism had been studied for nearly 60 years, only recently has the potential health benefits of these compounds been explored in depth.
The most interesting fact about them is that phytoalexins are not usually found in high concentrations in plants that have been grown conventionally... they are (pretty much) unique to organic produce! As it turns out, this is much more important than knowing that your organic carrot has a higher concentration of beta-carotene. What really matters is that your humble organic carrot now contains additional powerful compounds that you just can’t find anywhere else! Even better, research continues to demonstrate that this class of substances provides enhanced antioxidant capabilities, anti-inflammatory properties, anti-aging powers, and significant anti-cancer potential.
In Spain, researchers have developed a method to intentionally expose red grapes to artificial ultraviolet radiation (UV-C) after harvest in order to enhance reservatrol content.  In general, the concentration of resveratrol in red wine is up to 10 times greater than in white wine.  But even among red wines, the concentration of resveratrol can vary by a factor of 20.  Wine processing that utilises macerated red grapes, for example, yields more resveratrol.
Because moisture and humidity foster fungal growth, and resveratrol is produced in greater quantity in response to infectious agents, the resveratrol concentration in red wine grapes is greater in northern latitudes than southern. So, wines from New York or Canada provide more resveratrol than wines produced in California, France or Italy.  Among the varieties of red wine, numerous studies confirm that pinot noir provides the highest amounts of resveratrol.  However, growing and harvesting conditions as well as winemaking practices greatly influence the resveratrol content in bottled wine.
While plants may contain resveratrol, this protective antioxidant must be extracted from its source to be bioavailable to humans. The winemaking process utilises the fermentation process to produce an alcohol extract of resveratrol. Alcohol extracts resveratrol from grapes better than water, glycerine or stomach acids. Red wine is just an alcohol extract as a beverage.
Another abundant natural source of resveratrol is the giant knotweed plant (Polygonum sachalinense, P. cuspidatum), also known as fo-ti or he-shou-wu in China. It is grown commercially in China for production of resveratrol in dietary supplements. In Japan a variety of knotweed plant is used to make Itadori tea, a non-alcohol source of resveratrol. 
Supplements fall short
Dietary supplements providing resveratrol from red wine or knotweed are available. Surprisingly, tests conducted at Harvard University by Sinclair have failed to find any significant biological activity in resveratrol dietary supplements in tablets, capsules or as liquid herbal extracts.  Leroy Creasy, PhD, a professor of plant science at Cornell University in Ithaca, New York, reported that resveratrol supplements failed to exhibit much biological activity—evidenced by the ability to activate an enzyme that promotes DNA repair and lengthen the life of yeast cells—compared to wine, but apparently his report went unnoticed by manufacturers. Creasy claims it would take thousands of capsules of resveratrol to provide the equivalent amount of resveratrol found in a glass of red pinot noir wine.  Encapsulation fails to duplicate the airtight environment found in a wine bottle, which preserves the resveratrol.
Although studies are lacking that show resveratrol in pills work, resveratrol appears to work in wine, and also under laboratory conditions as a pure 100 per cent molecule, produced under nitrogen and preserved in part by refrigeration.
However, a relatively new technology called Licaps, developed by Capsugel specifically for liquid ingredients, fills gelatin capsules in a nitrogen rather than an oxygen environment and seals dietary supplements ingredients in an airtight pill. A nitrogen bubble inside the capsule also retards any spoilage. Licaps technology is being utilised to produce the first stabilised red wine extract, which has demonstrated biological activity, showcasing the need for special measures that should be undertaken in the manufacture of resveratrol supplements.
Small amounts work
How much resveratrol is needed to produce healthy ageing? A small amount of resveratrol was found to increase the survival of yeast cells by three-fold even when the cells were exposed to ionising radiation.  Mega doses of resveratrol do not produce greater longevity and in fact may work in an opposite manner and become problematic to genes. Three five-ounce glasses of red wine per day, which provide about 3mg resveratrol, would be sufficient for humans to achieve enzyme activity levels equivalent to those achieved in the laboratory. However, much higher amounts of resveratrol have been used successfully in animal tests for treating cancer. 
Bill Sardi is a health journalist writing from San Dimas, California. His new book, The Anti-Aging Pill, is available at www.hereandnowbooks.com Bill Sardi has a commercial interest in a resveratrol company.
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