In which we learn strange things about these 
powerful antioxidants and how to take them 
If all be true that I do think, 
There are five reasons we should drink; 
Good wine—a friend—or being dry— 
Or lest we should be by and by— 
Or any other reason why.
— Henry Aldrich (1648–1710)

That last line covers it all, but it’s a cinch that Aldrich did not know of at least two good reasons for drinking wine that we now know of—and perhaps it’s just as well, because they don’t roll trippingly off the tongue. One is resveratrol (rez-VEER-a-troll), and the other is quercetin (KWUR-se-tin). Try working those words into a poem! Better yet (and this is easier), just put these natural chemical compounds into your body, because they will probably do you some good.

Resveratrol and quercetin are two examples of antioxidant polyphenols, which are prevalent in such foods as red wine, green tea, apples, berries, pomegranates, and dark chocolate. Many scientists have come to regard polyphenols as being potentially among the most effective natural agents for helping to prevent some of the chronic diseases of aging, including cardiovascular disease and neurodegenerative diseases—and perhaps for helping to slow the aging process itself. We’ll see why shortly.

Supplements Are More Reliable than Food and Drink

First, however, let’s see how you should put resveratrol and quercetin into your body. You could, of course, drink red wine (the best natural source of resveratrol, and a good source of quercetin), and you could eat apples (the skins of which are especially high in quercetin). Both are good for you, but as regards wine, ask your doctor if there is any reason, such as adverse drug interactions, why you should not partake.*

*We advise that you drink no alcohol whatever if it might cause any kind of problem for you or those close to you, and that if you do drink wine or any other alcoholic beverage, you drink responsibly—not more than one or two glasses of wine per day. Any more than that, and the health benefits quickly turn into serious health hazards. (As for apples, no problem—be as irresponsible as you like!)

There is, however, a better way to obtain resveratrol and quercetin on a daily basis, namely, through supplementation—not as tasty, certainly, but more reliable (the resveratrol content of red wines is highly variable, by the way) and less expensive.

Is Resveratrol the Answer to the French Paradox?

Remember “The French Paradox”? That was the 1991 60 Minutes segment suggesting that the high consumption of red wine in France might be related to the low incidence of cardiovascular disease in that country despite the fat-rich diet the French are so fond of. Much scientific evidence in the intervening years has tended to confirm this hypothesis. Epidemiological data support the view that moderate consumption of red wine leads to a significantly reduced risk for heart disease (including heart attack and stroke), and laboratory and animal studies suggest that the credit for this goes to a variety of polyphenolic compounds, of which one in particular stands out: resveratrol.1

Resveratrol is a powerful antioxidant, a factor to which its heart-protective effects are largely attributed. In laboratory studies, it inhibits platelet aggregation (the process by which blood clots are formed) and lipid peroxidation, which is an important factor in the development of atherosclerosis. The lipids in question are those that are carried in the bloodstream by LDL (low-density lipoprotein, or “bad cholesterol”), and their degradation by oxidizing agents such as free radicals facilitates their incorporation into artery-clogging plaque.

But other lipids are important too, notably those, such as phosphatidylcholine (the principal component of lecithin), that constitute the lipid bilayers of which all our cell membranes are made. These lipids are susceptible to peroxidation also; the cell membranes of our brains are especially vulnerable because of the very high levels of oxygen consumption by the human brain and the relatively low levels of antioxidant defense enzymes, such as catalase. Oxidative damage to cell membranes causes gradual deterioration and, eventually, death to the cells.

Resveratrol Has Neuroprotective and Anticancer Effects . . .

Scientists at the University of Missouri have published a review summarizing a great deal of research (much of it done by themselves) on the neuroprotective effects of polyphenols, such as resveratrol.2 One study investigated whether grape polyphenols (of which resveratrol is believed to be the most active) might protect against the ravages of excessive alcohol consumption, which is known to damage or destroy brain cells through oxidative stress. Using rats that were fed diets with and without ethanol (grain alcohol) and with and without grape polyphenols, the researchers found that the latter were highly effective in inhibiting ethanol-induced oxidative stress in the brain. Another study showed that these polyphenols provided some protection for the liver as well.

In further studies using just resveratrol, the Missouri researchers (and others) found evidence of its neuroprotective effects against cell death mediated by or caused by oxidative stress. In addition, they described evidence for anti-inflammatory effects and for anticancer effects. The latter were first reported in a seminal study published in 1997 establishing that, in cell cultures, resveratrol has an inhibitory effect on all three of the major steps in carcinogenesis: initiation, promotion, and progression.3 That study spawned a torrent of scientific papers elucidating the cellular and biochemical mechanisms of action of this remarkable compound, which has demonstrated activity against many forms of cancer.4

. . . In Laboratory and Animal Studies

It must be noted, however, that almost all the resveratrol studies have been conducted in vitro (“in glass,” i.e., using cell cultures in the laboratory) or in animals—in the latter case with doses usually far greater (on a body-weight basis) than the amounts used for dietary supplementation in humans.

Although the few human clinical trials with resveratrol have yielded disappointing results compared with the glowing promise of the laboratory experiments, there is reason for some optimism based on a few rat studies that have shown resveratrol to have significant anticarcinogenicity (and at remarkably low blood levels) when administered orally or by injection.4 These results must be viewed with caution, however, because it turns out that rats and humans metabolize resveratrol very differently; thus the studies may or may not be relevant to human concerns.5

(For information on a mystery associated with resveratrol metabolism, see the sidebar “A Bioavailability Conundrum.” And for information regarding a novel way of taking resveratrol, and why it may or may not be a better way, see the sidebar “A Better Way to Take Resveratrol?”.)


A Bioavailability Conundrum

… while Mother 
Nature knows all.
For a nutrient to be beneficial, it must be bioavailable, i.e., it must be readily absorbed from your digestive tract into your bloodstream, and there it must survive long enough to get to the tissues or organs that need it, and be utilized. Nutrients that are demonstrably beneficial are, by definition, bioavailable to at least some degree (but the degree varies widely among nutrients)—otherwise how could they be effective?

Scientists believe that resveratrol may be an extraordinarily effective chemopreventive and anticarcinogenic agent, based on laboratory and animal studies. But resveratrol poses an extraordinary problem: although it’s well absorbed (at least 70%) by the gut, its bioavailability is almost zero, owing to its rapid and extensive metabolism to two types of chemical derivatives: sulfates and glucuronides.1-4 It appears that most of the conversion of resveratrol to these metabolites occurs in the gut (the metabolites are readily absorbed into the bloodstream, however), and the process is completed by the liver within about half an hour. The result is that unmetabolized resveratrol is virtually undetectable in the blood.

That being true, some researchers have suggested that the large body of laboratory research on which the therapeutic reputation of resveratrol largely rests may be irrelevant, because the agent used may have been the wrong agent, namely, resveratrol rather than its metabolites.1,3-5 We simply don’t know yet whether these metabolites would produce similar beneficial effects. Some evidence from nutritional physiology suggests that they would, while other evidence suggests that they would not. Only hard experimental facts will tell, and experts in this field are suggesting that the research focus be shifted from resveratrol to its metabolites.

Another possibility is that resveratrol may depend for its bioavailability on the presence of the myriad other compounds (including many other polyphenolics) with which it coexists in nature, i.e., in the grapes and in red wine, because these compounds may inhibit its metabolism to sulfates and glucuronides in our bodies.3 In fact, one of the other dominant polyphenolics in red wine is the flavonoid quercetin, which, in laboratory cell cultures, does inhibit the action of some of the enzymes responsible for converting resveratrol to these metabolites; not surprisingly, perhaps, red wine does the same.6-8

This, then, could be one of those cases in which our efforts to “improve” on Mother Nature, by focusing on resveratrol alone, have fallen short. We will have to wait and see what further research tells us on this intriguing subject. Meanwhile, see the other sidebar for a new way of taking resveratrol (and quercetin and other supplements as well).


  1. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailability, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomark Prev 2003;12:953-7.
  2. Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos2004;32:1377-82.
  3. Wenzel E, Somoza V. Metabolism and bioavailability of trans-resveratrol. Mol Nutr Food Res 2005;49:472-81.
  4. Wenzel E, Soldo T, Erbersdobler H, Somoza V. Bioactivity and metabolism of trans-resveratrol orally administered to Wistar rats. Mol Nutr Food Res2005;49:482-94.
  5. Yu CW, Shin YG, Chow A, Li YM, et al. Human, rat, and mouse metabolism of resveratrol. Pharm Res 2002;19:1907-14.
  6. De Santi C, Pietrabissa A, Spisni R, Mosca F, Pacifici GM. Sulfation of resveratrol, a natural product present in wine, and its inhibition by natural flavonoids. Xenobiotica 2000;30:857-66.
  7. De Santi C, Pietrabissa A, Mosca F, Pacifici GM. Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver. Xenobiotica2000;30:1047-54.
  8. Pacifici GM. Inhibition of human liver and duodenum sulfotransferases by drugs and dietary chemicals: a review of the literature. Int J Clin Pharmacol Therapeut2004;42:488-95.



 A Better Way to Take Resveratrol?

Because resveratrol is so extensively metabolized in the gut before it even has a chance to reach the bloodstream (see the other sidebar), it’s tempting to think that one might improve its bioavailability by bypassing the digestive tract in favor of a more direct route to the blood. Indeed, such a route is available through the use of PEGylated liposomes, which are manmade cells that encapsulate drugs or nutritional supplements so that they can be delivered to the blood without interference from agents that might alter them. Formulated as a liquid suspension, the liposomes can easily be absorbed through the mucous membranes of the mouth. (For a discussion of the advantages of delivering nutrients in this novel way, see “Better Supplementation with PEGylated Liposomes” on page 4 of this issue.)

Because this technique promises good delivery of free (unmetabolized) resveratrol to the blood, it can produce higher blood levels of resveratrol—briefly. The problem here, though, is that the liver will still rapidly metabolize the resveratrol as soon as it’s released by the liposomes, as indicated by a study that compared oral and intravenous delivery of resveratrol to human subjects.1 With oral delivery, no free resveratrol was detectable in the blood at any time (its metabolites were readily detectable, however); with IV delivery, there were measurable levels initially, but they dropped quickly and were gone after half an hour.

It seems that, for whatever reasons, nature may not want free resveratrol to be in our blood, despite its potentially outstanding health benefits. Only time and further research will indicate the best course of action for capitalizing on this potential.

Meanwhile, however, it’s intriguing to consider the results of a resveratrol study at the Medical University of South Carolina, using cultures of a human intestinal cell line called Caco-2.2 The researchers found that unmetabolized resveratrol molecules accumulated in these cells (which are called enterocytes) while the metabolites were transported out. They concluded that “… the finding of an almost 40-fold accumulation of resveratrol in the Caco-2 cells in comparison with the incubation buffer is remarkable and emphasizes that the enterocytes could be a major biological target site for this dietary preventive compound.”

In other words, it could be that resveratrol’s benefits will be found largely in the intestines, which are reached via oral ingestion of the supplement (as is true, of course, with wine), and the authors report, in a subsequent paper, that a number of resveratrol studies are now focusing on colon cancer.1 They speculate that resveratrol’s benefits might also be found in the initial stage of the compound’s course through the body—in the epithelial cells of the mouth, throat, and esophagus, which they call the “aerodigestive tract.”


  1. Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos2004;32:1377-82.
  2. Kaldas MI, Walle UK, Walle T. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J Pharm Pharmacol 2003;55:307-12.


Why Resveratrol Is Attractive

In any case, the results described by the Missouri researchers are in accord with those of many other studies demonstrating the ability of various polyphenols (not just resveratrol) to combat the effects of oxidative stress—which is believed to be a major factor in the aging process—and to help protect against cancer, heart disease, vision disorders, allergies, viral infections, and more. In a recently published paper on the conundrum posed by resveratrol’s low bioavailability, two British scientists wrote:4

Diet-derived polyphenols, such as resveratrol, with interesting cancer chemopreventive properties in experimental models, remain attractive as clinical candidates. One reason for their attractiveness is the fact that the long-proven use of their dietary sources suggests low potential for unwanted side effects, although this notion may not hold if they are administered at high doses as single agents.

Quercetin Is Attractive Too

If “quercetin” were substituted for “resveratrol” in that quote, it would probably be just as valid. Like resveratrol, quercetin has been the subject of many in vitro and animal studies (but few human studies) demonstrating a broad spectrum of therapeutic activities, which are attributed primarily to its strong antioxidant effects.* Although quercetin, unlike resveratrol, is poorly absorbed (about 25%) by the gut, its metabolic fate is similar: it’s so extensively metabolized to sulfates and glucuronides that free (unmetabolized) quercetin has never been detected in human plasma.6

*Quercetin (but not resveratrol) belongs to the class of polyphenolic compounds called flavonoids, which are plant pigments that give colors to flowers, fruits, vegetables, and herbs. Quercetin is the most abundant flavonoid in fruits, vegetables, and wine.

 With quercetin too, the questions regarding the biological activity of the compound itself versus that of its metabolites are still largely unanswered. Epidemiological evidence, however, has long suggested that a substantial dietary intake of quercetin and similar antioxidant flavonoids confers protection against cardiovascular disease, and perhaps cerebrovascular and neurodegenerative diseases as well.

Liposomal Quercetin Works Better in the Brain

When considering the effects of any substance on the brain, a key question is: will it cross the blood-brain barrier (BBB)? This brain-defense system is notoriously fussy about which molecules it will admit to the inner sanctum—some molecules are readily admitted while other, very similar ones, are excluded, often for no apparent reason. Quercetin and similar flavonoids are among the many classes of compounds with a poor ability to cross the BBB.

A recently published paper by scientists in Uruguay, however, cites research of theirs showing that this ability is improved if the quercetin molecules are delivered in the form of liposomes.7 This underscores the importance of the manner in which drugs or nutritional supplements are administered. The research in question demonstrated quercetin’s neuroprotective action against the effects of experimentally induced cerebral ischemia (impaired blood supply to the brain) in rats.

The study illustrates the value of flavonoids’ neuroprotective as well as antioxidant effects in helping to prevent the brain damage associated with some diseases. The authors stated that the benefits of such compounds are also seen in the blood vessels supplying the brain, which means that they’re active on both sides of the blood-brain barrier. 


  1. Hendler SS, Rorvik D, eds. PDR for Nutritional Supplements. Medical Economics Company, Montvale, NJ, 2001, pp 397-401.
  2. Sun AY, Simonyi A, Sun GY. The “French paradox” and beyond: neuroprotective effects of polyphenols. Free Rad Biol Med 2002;32(4):314-8.
  3. Jang MS, Cai L, Udeani GO, et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275:218-20.
  4. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailability, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomark Prev 2003;12:953-7.
  5. Kaldas MI, Walle UK, Walle T. Resveratrol transport and metabolism by human intestinal Caco-2 cells. J Pharm Pharmacol 2003;55:307-12.
  6. Mochizuki M, Kajiya K, Terao J, Kaji K, Kumazawa S, Nakayama T, Shimoi K. Effect of quercetin conjugates on vascular permeability and expression of adhesion molecules. BioFactors 2004;22:201-4.
  7. Dajas F, Rivera-Megret F, Blasina F, et al. Neuroprotection by flavonoids. Braz J Med Biol Res 2003;36:1613-20.