Resveratrol or Quercetin: What's the Difference

Resveratrol became famous as the "molecule of red wine" and a possible "longevity activator"; quercetin as the flavonoid of onion and apples with an anti-inflammatory reputation. Both are plant polyphenols, both are sold as antioxidants, and both share a similar problem with bioavailability. Yet in chemistry, mechanisms and evidence they differ substantially.

Two classes of polyphenols

Resveratrol belongs to the stilbenes — a small group of polyphenols in which two aromatic rings are connected by a double bond. It exists in two forms, trans and cis, of which trans-resveratrol is considered the more biologically active and stable. It is its content that is usually stated on supplement labels.

Quercetin is a flavonol, one of the most widespread flavonoids in the plant world. Its molecule has the three rings typical of flavonoids and several hydroxyl groups that determine its pronounced antioxidant properties in vitro. In plants, quercetin is predominantly bound to sugars in the form of glycosides, for example rutin or isoquercitrin.

For plants both substances are means of defense. Resveratrol is a phytoalexin; its synthesis increases in response to fungal infection, ultraviolet light or damage. Quercetin performs functions of protection against ultraviolet light and oxidative stress and takes part in pigmentation.

In humans, neither of these molecules is essential: there is no "resveratrol deficiency" or "quercetin deficiency". Talking about them is therefore a conversation about the pharmacological action of bioactive compounds, not about filling a shortage, as in the case of vitamins and minerals.

Where we get them from

Resveratrol occurs in the diet in small amounts: in the skin of red grapes, red wine, peanuts and blueberries. Even a substantial amount of wine provides very little resveratrol compared with the doses used in research. Industrially, for supplements it is most often obtained from the root of Japanese knotweed (Polygonum cuspidatum) or synthesized.

Quercetin is represented in the diet far more widely. There is plenty of it in onions (especially red), capers, apples with the skin, berries, broccoli, green and black tea. Average dietary intake in Western countries is estimated at tens of milligrams per day, whereas with resveratrol it is a matter of fractions of a milligram or single milligrams.

For quercetin the form in food matters: onion glucosides are absorbed noticeably better than rutin from other sources, since they are hydrolyzed already in the small intestine. Rutin, on the other hand, requires the participation of the large-intestine microflora, which slows and reduces absorption.

So already at the level of sources there is a fundamental difference: quercetin is an ordinary component of a healthy diet, while resveratrol in the doses used in research can be obtained only from supplements.

Bioavailability: the main shared problem

The classic study by Walle and colleagues (2004) showed the resveratrol paradox: it is absorbed well, but the bioavailability of the free molecule is very low. The reason is rapid and massive metabolism in the intestine and liver, where resveratrol is converted into glucuronides and sulfates. It is these conjugates that predominantly circulate in plasma.

Quercetin faces a similar problem. After absorption it is also intensively conjugated, and the concentration of the free aglycone is very small. Studies show that quercetin conjugates can accumulate in plasma with regular intake, but their own activity is less well studied.

Manufacturers offer various solutions: micronized resveratrol, liposomal forms, complexes of quercetin with phospholipids (phytosomes), enzymatically modified isoquercitrin. Some of them do indeed raise the plasma concentration in pharmacokinetic studies, but this does not yet mean a proven clinical effect.

This shared problem casts doubt on transferring results from the test tube to humans. The concentrations at which the substances act in cell cultures are often orders of magnitude higher than those achievable in the blood after taking supplements.

Mechanisms of action

Resveratrol became famous after works that linked it to activation of the sirtuin SIRT1 — an enzyme associated with the mechanisms of caloric restriction. The study by Baur and colleagues (2006) showed that resveratrol improves the health and survival of mice on a high-calorie diet. It later turned out that the direct activation of SIRT1 depended largely on the experimental conditions, and the mechanism remains a subject of debate.

Other described targets of resveratrol are activation of AMPK, an effect on mitochondrial biogenesis, and an anti-inflammatory action via NF-κB. In laboratory studies quercetin is credited with inhibition of inflammatory enzymes, stabilization of mast cell membranes (hence the interest in allergy), an antioxidant action and an effect on mitochondrial biogenesis in animal muscle.

• Resveratrol:sirtuins and AMPK, mitochondria, vascular function, inflammation.
• Quercetin:inflammation and mast cells, antioxidant defense, vascular tone, inhibition of some liver enzymes.
• In common:low bioavailability and a large gap between test-tube data and clinical results.

Quercetin is also known as a senolytic in combination with dasatinib — a substance that in experiments selectively eliminates senescent cells. This is an active research topic, but no conclusions for everyday supplement use can yet be drawn from it.

Quercetin inhibits the enzyme CYP3A4 and the transporter protein P-glycoprotein, which creates the potential for interactions with drugs. For resveratrol too an effect on cytochromes P450 has been described, so people who take medications continuously should take this into account.

Human evidence and the athletic context

A review of clinical studies of resveratrol (Smoliga et al., 2011) attested that results in humans are far more modest and contradictory than in animals. Individual works showed an effect on insulin sensitivity or vascular function, others no changes. There are no large long-term studies with clinical endpoints.

For athletes the study by Gliemann and colleagues (2013) is telling: in older men resveratrol not only failed to enhance but even weakened the positive changes in cardiovascular measures from training. This is consistent with a broader concept: high doses of antioxidants can blunt the signals through which the body adapts to load.

For quercetin the meta-analysis by Kressler and colleagues (2011) showed a small statistically significant effect on endurance which, in the authors' assessment, has little practical significance for trained athletes. Quercetin was also studied as a means of reducing respiratory infections after intense exercise, with ambiguous results.

The safety of both substances in ordinary supplement doses in short-term studies is generally acceptable. At doses in grams, gastrointestinal disturbances have been described for resveratrol. For quercetin the main caveat concerns interactions with drugs and intake by people with kidney diseases.

Editorial conclusions

Resveratrol and quercetin are representatives of different classes of polyphenols: stilbenes and flavonols. Quercetin is an ordinary component of the diet; resveratrol in significant amounts comes only from supplements.

Both have low bioavailability of the free form, and both show far more impressive results in the test tube and in animals than in clinical studies in humans.

In the athletic context quercetin has a small signal for endurance, and resveratrol even has data on a possible weakening of adaptations to training. This is an important argument against taking high doses of antioxidants "for recovery".

The editorial team examines the practical choice in the article "Resveratrol vs Quercetin: What to Choose and for Whom". We also recommend our pieces on antioxidants and adaptation to training and on NAD+ precursors.

References

1. Walle T, Hsieh F, DeLegge MH, et al. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32(12):1377–1382.
2. Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444(7117):337–342.
3. Smoliga JM, Baur JA, Hausenblas HA. Resveratrol and health — a comprehensive review of human clinical trials. Mol Nutr Food Res. 2011;55(8):1129–1141.
4. Gliemann L, Schmidt JF, Olesen J, et al. Resveratrol blunts the positive effects of exercise training on cardiovascular health in aged men. J Physiol. 2013;591(20):5047–5059.
5. Kressler J, Millard-Stafford M, Warren GL. Quercetin and endurance exercise capacity: a systematic review and meta-analysis. Med Sci Sports Exerc. 2011;43(12):2396–2404.
6. Li Y, Yao J, Han C, et al. Quercetin, inflammation and immunity. Nutrients. 2016;8(3):167.
7. Merry TL, Ristow M. Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol. 2016;594(18):5135–5147.