Polyphenols - beyond antioxidants

Perhaps the category with the most growth promise, polyphenols such as resveratrol, green tea and cocoa nevertheless suffer from being mischaracterised as antioxidants. David A Mark, PhD, reveals the true nature of these healthful compounds

In 2000, the Institute of Medicine (IOM) defined a dietary antioxidant as follows: "A substance in foods that significantly decreases the adverse effects of reactive species, such as reactive oxygen and nitrogen species, on normal physiological function in humans." Using that definition, IOM included vitamin C, vitamin E and selenium as dietary antioxidants. And stopped there.

Normal cellular processes produce free radicals — primarily reactive oxygen and reactive nitrogen molecules — that unless neutralised by endogenous or exogenous antioxidants will react with lipids, proteins and nucleic acids. Cumulative collateral damage has been theorised as contributing to increased risk for many major diseases: cancer, cardiovascular disease, cataracts, immune senescence, chronic inflammation, age-related macular degeneration, neurodegenerative diseases, diabetes and ageing in general. Animal evidence and observational evidence in humans have been supportive, although some large-scale prospective human trials on vitamin C, vitamin E or selenium have been uneven.1,2,3,4

Outside IOM's official definition, claims are made that polyphenols from fruits and other plant sources are potent antioxidants. The emerging consensus among research leaders, however, is that polyphenols are not functioning as systemic antioxidants. Andrew Waterhouse, professor of enology, UC Davis, concludes simply, "Free-radical trapping is not due to dietary polyphenolics."

Circulating antioxidants such as ascorbic acid, uric acid, tocopherols, carotenoids and glutathione are collectively in excess of 1,000 micromolar while the amounts of polyphenols in the blood are on the order of 10-100 nanomolar — that is, at concentrations thousands of times lower. Even the evidence in support of flavonoids being much more potent antioxidants than classic nutrient antioxidants does not compensate for the lower content and transitory nature of circulating polyphenols in human blood, or whatever reaches target tissues. Helmut Sies, a long-time polyphenols researcher at Heinrich-Heine University in Duesseldorf, Germany, addressed the dilemma in a review. He cautioned against the use of "total antioxidant capacity" in blood plasma as a proxy for functionality.5

What are polyphenols doing?
If not acting directly as antioxidants, what are polyphenols doing? Evidence continues to develop for real-life physiological concentrations having molecular rather than unspecific, direct antioxidant effects. Polyphenol bioactives affect vascular function, signaling and anti-inflammation activity. Increased concentrations of nitric oxide (NO) result in vascular relaxation, measurable by changes to flow-mediated dilation. Improved vascular health may also involve reduced platelet and fibrinogen stickinesss, and lower levels of circulating vascular inflammatory molecules. Complex cell signaling either occurs at the cell surface or the phenol compounds reach the nucleus directly, and either way result in up and down regulation of gene expression.

Roger Corder's group at the William Harvey Research Institute used micro-array studies of human aortic endothelial cells to show that food-derived procyanidins changed the expression of dozens of genes. Production of mRNA for endothelin-1 was decreased and Kruppel-like factor 2 increased — both shifts are associated with lower risk of atherosclerosis.6 Helen Kim has published similar work on changes to mouse brain protein expression to demonstrate down regulation of proteins associated with Alzheimer's disease.7 Anti-inflammation hypotheses involve suppression of NFkB and/or cyclo-oxygenases. Finally, down-regulated gene expression may include decreasing the production of endogenous pro-oxidants such as NADPH oxidase, thus manifesting an indirect increase in antioxidant activity.5

Other-functioning theory frees polyphenols from "The Flavonoid Paradox." J Terao of the University of Tokushima, Japan, uses this term at the Fourth International Polyphenols and Health Conference, 2009, to characterise the problem: numerous epidemiological studies suggest that dietary flavonoids are closely related to the prevention of degenerative diseases such as cardiovascular disease and dementia, yet the bioavailability of these compounds appears extremely low and much of what is absorbed appears to be rapidly converted to inactive conjugated metabolites. In vitro research is often misleading because it uses concentrations and compounds that are not achieved in vivo.8 The Flavonoid Paradox is connected to the French Paradox. It postulates that if red-wine consumption is responsible for the lower than expected incidence of cardiovascular disease in France, it is because of the flavonoid content of the wine — but not because those flavonoids are antioxidants.

The Good News
Clinical and epidemiological evidence continues to support cardiovascular benefits in humans. Clinical trials presented at Experimental Biology 2010 added blueberries and strawberries to the list of flavanol foods such as dark chocolate and Concord grape juice with blood pressure-lowering activity.9 Years ago, all of the cognitive evidence was from animal models, plus a bit of epidemiology for red wine reducing risk of dementia.10 Now, human evidence for cognitive benefits begins to accrue. Krikorian reported a small study with older adults drinking Concord grape juice seeing improvements in list learning and trends for other memory improvements.8 Spencer reported similar benefits in humans for blueberries. Spencer postulated changes to protein and lipid kinase signaling cascades and improved vascular function as two possible mechanisms.8

For cancer, a 2009 epidemiological meta-analysis by Tang reported a 24 per cent reduction in risk of lung cancer with high dietary flavonoid intake.11

For weight management, a 2010 meta-analysis by Phung confirmed that green tea catechins have a useful, albeit modest, effect on weight loss — on the order of 3 pounds over 12 weeks.12 This aligns with earlier observations of increased energy expenditure with EGCG consumption. Evidence from recent conferences suggests that some phenols, including resveratrol, will increase the number of mitochondria in adipose and muscle cells. This would support the apparently paradoxical reported decreases in fat mass and increases in muscle mass occurring at the same time.

Cranberry evidence continues to accrue. The proanthocyanidins (PACs) in cranberries are primarily linked by A-type bonds vs B-type for other proanthocyanidin-rich foods. A-linked PACs appear to be more effective in blocking bacterial adherence. The cranberry beverage and supplement clinical evidence is consistent for reducing the risk of urinary tract infections, and promising for oral bacteria as well as other bacteria.

Are polyphenols safe?
A 2005 review by LI Mennen evaluated the risks and safety of polyphenol consumption. Animal models evaluating high concentrations of specific polyphenols have demonstrated carcinogenicity, genotoxicity, thyroid toxicity, estrogenic effects (by isoflavones), antinutritional effects such as interference with protein and iron absorption, and interactions with pharmaceuticals. While the authors go on to state: "It has not been proven that these effects also happen in humans," they caution against the development and marketing of polyphenol supplements without adequate safety assessment. Supplements can be designed to deliver higher polyphenol content than can be reached by polyphenol-rich foods, and hence need greater scrutiny.15

Specific safety studies have been conducted with various polyphenols. For example, one study of pomegranate capsules providing as much as 1,420mg/day containing 870mg of gallic acid equivalents found no serious adverse events in any of the 64 overweight individuals.16

ORAC abides
In vitro testing of antioxidant capacity, for which the Oxygen Radical Absorbance Capacity (ORAC) assay is most widely recognised, has become marketing shorthand for claiming 'superfruit' status or a role as an "Antioxidant Superpower." Analytical results are available for a wide list of foods.17 Problems with using ORAC for marketing and comparative marketing purposes start with the revised ORAC fluorescein method giving about double the ORAC value of the old phycoerythins method used in the earlier literature.

Comparisons are also unfair when, based on a "per gram" basis, as this favours spices and dried fruit over fresh fruit and fruit juices. For example, dried Tibetan goji berries (Chinese wolfberries) are claimed as having 10 times the antioxidant content of fresh blueberries.

Some companies are making distinctions between hydrophilic, lipophilic or combined ORAC without there being any physiological basis for the nuances. Finally, starting in 2009, Brunswick Laboratories introduced Total ORAC FN as a patented measurement of antioxidant activity against five free radicals: hydroxyl, peroxyl, peroxynitrite, singlet oxygen and superoxide anion.18 Any claims for "My ORAC is Bigger than Your ORAC" will need to take into account exactly what ORAC methods were used for the products being compared.

Regardless of method, the limitations of in vitro measurement of antioxidant activity does not address limited bioavailability for many of the larger polyphenols, nor the fact that smaller molecules are metabolized so quickly that no trace of the unaltered molecule can be found in the blood, only sulfated, methylated or glucoronidated metabolites.

Claims for relevant biomarkers also have problems. Reporting a higher plasma antioxidant capacity after feeding an antioxidant food or supplement does support the idea that compounds are bioavailable and retain at least some of the purported chemical activity. However, without any connection to a clinically relevant outcome, this is not sufficient to support a health claim.5 The ex vivo assay demonstrating increased resistance of low-density lipoprotein to oxidation is in the same boat.

Are DRIs next?
Are we ready for a Dietary Reference Intake for dietary polyphenols? Not yet. Bioavailability, functionality of specific subsets, dose/response relationships and safety need more research.5 Given that academic researchers continue to shift their focus to beyond simple antioxidant mechanisms, it is time, however, for the major industry marketers of fruit juices, teas, dark chocolates, and polyphenol supplements to support the paradigm shift. This can be accomplished via changed marketing language plus combined support for a conference or series of conferences intended to standardise new terms of measuring content, clinically relevant biomarkers and clinically relevant outcomes.

David A Mark, PhD, is president of dmark consulting LLC, a Boston-area science consulting firm. His 25+ years of industry R&D experience includes functional foods, dietary supplements and medical nutrition products. www.dmarknutrition.com.

Disclosure: Dr Mark has as clients dietary supplement companies which market polyphenol-containing products, but not resveratrol-containing products.

The phenol phlood
Being a polyphenol-rich food with health benefits used to mean being part of an elite list buttressed with good epidemiological evidence or multiple clinical trials: red wine, Concord grape juice, tea, dark chocolate, cranberries and tree nuts. Clinical trial results suggest that weeks to months of two to three servings per day, containing 400 to 800 mg total polyphenols of which 100 to 200 mg are from the flavanol subset, can have beneficial effects. This intake range represents a doubling to tripling of intake from all dietary sources for the U.S. diet.13,14

At the 2007 meeting of the Institute of Food Technologists it was apparent that a 'phlood' of foods and supplement ingredients were applying to be members of the family of polyphenol-rich sources. These include additional fruits often identified as superfruits: açai, blackberries, blueberries, bilberries, elderberries, dried plums, mangosteen, noni, sea buckthorn, tart cherries, and Chinese wolfberry (goji), plus newer entries such as amaranth, coffee fruit, Jamaica flower, mashua, papaya, sorghum, white tea and many spices. Subsequent conferences have added to the list: strawberries, Indian gooseberry (alias amla fruit, amalaki or amalaka), maqui, hazelnut skins and schisandra, to name just a few.8,9



How to play nice with resveratrol
You've heard the health report about this promising polyphenol. Bill Sardi instructs how to best formulate with the raw material once it enters your facility

Resveratrol is a molecule that resists a neat description. It is both a drug and a dietary supplement. It is an antioxidant and a pro-oxidant. It inhibits new blood-vessel formation that promotes the growth of tumours and destroys vision at the back of the eyes, yet it accelerates new blood-vessel growth in the heart to aid healing following a heart attack.

Resveratrol is a light-sensitive molecule. Exposed to ultraviolet radiation, resveratrol can isomerise, or transform into a different molecular configuration, from trans-resveratrol to cis-resveratrol. If kept in total darkness, it may revert to trans-resveratrol.

There is some debate whether resveratrol is stable or not. The very existence of cis-resveratrol is evidence that it is not stable when exposed to ultraviolet (UV) light because this is the only way cis-resveratrol can be produced. Left in solar light for about an hour, about 80-90 per cent converts from trans- to cis-resveratrol.1 Even under milder fluorescent lighting, about 80 per cent of resveratrol in solution isomerised to the cis- form after 30 days.2

Resveratrol is also subject to degradation at high temperatures. After 18 minutes of exposure to 190°C (374°F) heat, between 17 and 46 per cent of the resveratrol had degraded in the various species of berries.3 At 104°F resveratrol was shown to degrade by 10 per cent after 600 hours.4 If temperature during extraction from botanical sources such as giant knotweed or grape skin exceeds 125°C (257°F), significant degradation will occur.5

The instability of resveratrol places some restriction on its inclusion in foods and beverages. Light and heat are the primary culprits. Part of the reason why wine is a good dietary source of resveratrol may be its packaging — dark bottles in cool storage.

Efforts have been made to stabilise resveratrol in dietary supplements. Freeze-drying does not appear to preserve resveratrol.6 Liposomal encapsulation has been successfully demonstrated to preserve trans-resveratrol.7 Microencapsulation (enfolding in plant starches and dextrins) has also been successfully employed to preserve and improve absorption of trans-resveratrol in dietary supplements.8 Micronisation — a process of reducing the average diameter of a solid material's particles — is also employed by some resveratrol manufacturers to improve absorption.

The provision of resveratrol as a liquid improves the speed but not the extent of oral absorption.9 One study mistakenly claimed buccal delivery (as a melting lozenge in the mouth) elevates blood levels better than absorption in the digestive tract.10 However, resveratrol lozenges would provide only a momentary advantage. This study was based upon data in the first few minutes after absorption, before resveratrol is fully metabolised in the liver. About 70 per cent of resveratrol is absorbed in the digestive tract and it is then shuttled through the liver where it is metabolised — conjugated (attached) to detoxification molecules sulphur and glucuronate.11 If there is no liver metabolism, resveratrol would have a short half-life, estimated at about 14 minutes. But once sulphated and glucuronidated, it will last for up to nine hours in the blood circulation.12

Resveratrol is going to continue to impress researchers and be the subject of future research and commercialisation initiatives. It serves as an example of herbal-derived small molecules that will stack up against the best synthetic molecules pharmacology can engineer.

Bill Sardi, managing partner of Resveratrol Partners dba Longevinex, has applied for numerous patents regarding resveratrol-based technologies. Email: [email protected].


Select suppliers: Polyphenols come in all shapes and sizes
AM Todd
Apple PE (Malus pumila) has 75% polyphenols; oolong tea leaf PE is 15% polyphenols; and resveratrol is available 20%, 50%, 95% and 99%.

Amax Nutrasource
Grape seed has 95% proanthocyanidins; grape skin has either 20% or 30% polyphenols. Resveratrol is available at 20% or 50%.

Barry Callebaut
Cocoa kings like to point out that cocoa contains four times the polyphenol content as tea and twice as much as red wine.

Biogin Biochemicals
OleaLife olive-juice powder is 10-90% polyphenols.

Blue California
Apple (Malus pumila) polyphenols are 10% and 40% polyphenols; grape skin (Vitis vinifera) are 25% polyphenols; green tea is 30%, 60%, 90% or 95% polyphenols; and resveratrol is 8%, 20%, 85% trans-resveratrol.

Cactus Botanics
Mangosteen extract has 30% polyphenols.

Charles Bowman
Vinoserae is the brand name for its wine polyphenol powder. Resveravine is the grape vine oligostillbenes brand, and Frutologic is a polyphenolic nitric-oxide potentiator.

BioVin is a full-spectrum grape extract,;PomActiv is a pomegranate extract standardised to 70% ellagic acid.

Evesse brand apple polyphenols is available as a powder and granule; it has a neutral taste and odour for ease in formulation.

DNP International
Resveratrol derived from Polygonum cuspidatum is soluble in alcohol, acetone and ethyl ether.

Draco Natural Products
Standardized Full-Spectrum Extract blueberry-fruit extract is loaded with polyphenols and anthocyanins. Grape seed has 95% polyphenolic value. Green tea is available in a range of polyphenol content and also in caffeinated or decaffeinated versions.

resVida is 99% trans-resveratrol, suitable for tablets, capsules, solfgels, powdered beverages, nutrition bars, yoghurts and more. resVida TB is a tablet-grade formulation for higher doses.

Resveratrol is available at varying purity specifications.

CocoaVia boasts high polyphenol content. It uses Mars' proprietary Cocoapro technology with more than 15 years of research on cocoa flavonols.

Oligonol lychee-fruit polyphenols is suitable for supplements, and is also GRAS for food products.

NP Nutra
Açai extract is at a high-potency 10% polyphenol extract.

Orgen-GT is an organic and decaffeinated green tea extract with 90% polyphenols. Orgen-P pomegranate is an organic 50% polyphenol extract with high ORAC value.

Pacific Rainbow
Grape seed is 95% polyphenols, while resveratrol from giant knotweed is a minimum of 50%.

The flagship MegaNatural line includes MegaNatural BP, MegaNatural Gold Grape Seed extract and MegaNatural GSKE Grape Pomace Extract. These are GRAS for beverages, soluble in water, and synergistic with vitamins C and E.

Resvenox is a 95% resveratrol standardised extract of Polygonum cuspidatun. The company also offers a standardised extract of grape seed at 95% proanthocyanidins.

TSI Health Sciences
Opteava green tea extract with the most active polyphenol catechin EGCG is manufacturerd in a GMP-certified botanical extraction facility specially designed to produce various extract grades. TSI also offers 25% resveratrol.


1. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Institute of Medicine. Dietary Reference Intakes: Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: National Academy Press, 2000. pp. 35-57, 186-283.
2. Vivekananthan DP, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 2003;361:2017-23.
3. Coulter ID, et al. Antioxidants vitamin C and vitamin E for the prevention and treatment of cancer. J Gen Intern Med 2006;21:735-744.
4. Lippman SM, et al. Effect of selenium and vitamin E on risk of prostate cancer and other cancers. JAMA 2009;301:39-51.
5. Sies H. Polyphenols and health: update and perspectives. Arch Biochem Biophys 2010 (in press).
6. Caton PW, et al. Regulation of vascular endothelial function by procyanidin-rich foods and beverages. J Agric Food Chem 2010;58:4008-13.
7. Deshane J, et al. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem 2004;52:7872-83.
8. 4th International Conference on Polyphenols and Health, December 7-11, 2009, Harrowgate, UK.
9. Experimental Biology, April 24-28, 2010. Anaheim, CA, USA.
10. Mark DA, Shukkit-Hale B, Joseph JA. Blueberries and the aging brain. The Food Industry (Japan) 2006;49:50-55.
11. Tang NP, Zhou B, et al. Flavonoids intake and risk of lung cancer: a meta-analysis. Japan J Clin Oncol 2009;39:352-359.
12. Phung OJ, Baker WL, et al. Effect of green tea catechins with or without caffeine on anthropometric measures: a systemic review and meta-analysis. Am J Clin Nutr 2010;91:73-81.
13. Manach C, et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr 2004;79:727-747.
14. Brat P, et al. Daily polyphenol intake in France from fruit and vegetables. J Nutr 2006;136:2368-73.
15. Mennen LI, et al. Risks and safety of polyphenol consumption. Am J Clin Nutr 2005;81(suppl):326S-329S.
16. Heber D, et al. Safety and antioxidant activity of a pomegranate ellagitannin-enriched polyphenol dietary supplement in overweight individuals with increased waist size. J Agric Food Chem 2007;55:10050-54.
17. Wu X, et al. Lipophilic and hydrophilic antioxidant capacities of common foods in the United States. J Agric Food Chem 2004;52:4026-37.
18. "Brunswick Labs introduces next generation total ORAC for food and nutrition" Press release, April 20, 2009. www.brunswicklabs.com.

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