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Adventures in Antioxidants: The Story has Just Begun

The general message of antioxidants is evolving and so is the science.

The Promise & Potential of Antioxidants

In order to understand where this market is headed, it makes sense to discuss where this market has been. Herb Woolf, PhD, a spokesperson for BASF, Florham Park, NJ, offered a simple explanation. He said antioxidant supplementation and fortification, in large measure, could be traced back to Nobel Prize winner Dr. Linus Pauling, who suggested that vitamin C prevents, among other things, the common cold.

"The idea for synergistic effects among antioxidant nutrients has more recently developed in part due to the realization that antioxidant nutrients are each u�niquely different in how they perform metabolically," Dr. Woolf said. "Being chemically different, individual antioxidants orient themselves in the body at different sites, albeit subtly, to scavenge free radicals generated either metabolically or by exposure to environmental factors.

"Mimicking nature is now a commercial concept. We experience different antioxidants by consuming whole foods. This concept is now finding its way into products that offer antioxidant combinations and mixtures to consumers," he continued.

Fresh stories have also prompted significant interest in "new antioxidants," according to Hartley Pond, vice president, Technical Sales, FutureCeuticals, Mo�mence, IL. "During the past two years, antioxidants derived from tropical fruits such as a�a�, acerola cherry, mangosteen, camu camu and coffeeberry have received significant attention from consumers and researchers. Grown under intense tropical sunshine, these fruits produce high levels of reactive oxygen species during photosynthesis and they concurrently produce strong antioxidant protection," he said. "I also believe there is an intrinsic romance to fruits from tropical, far off regions, and that consumers enjoy learning about newly available foods and products that offer the promise of nutritional profiles not found in their standard diet."

But the enormous popularity of antioxidants has been both a blessing and a curse. While on one hand the category offers so much diversity and differentiation, it also causes much confusion at both the trade and consumer levels. From a messaging point of view, companies need to approach the category more creatively and efficiently.

Lisa Schinhofen, a market analyst and author of Packaged Facts' most recent report on the antioxidant market, believes antioxidants are nothing more than a buzzword, with few consumers really understanding their function or benefit. With a category wielding so much potential, Ms. Schinhofen suggested that the lack of consumer understanding might be an obstacle for future growth. "I'm surprised that the category is not more dynamic. The category seems to be in a holding pattern right now," she said.

Also holding antioxidants back is FDA's lack of endorsement for the category. "FDA is so reluctant to make associations between antioxidants and health so it's hardly worth doing the research if you're limited in what you can say beyond putting an 'antioxidant' claim on your label," Ms. Schinhofen said. "Research might only pay off in certain instances where companies own a particular segment, as is the case with companies like Heinz, Welch's and POM Wonderful."

One health benefit that has been exploited very well is "protection"-this is where antioxidants seem to have had most success because the message is general and doesn't raise any red flags, yet protection is something consumers are very interested in when it comes to their health.

Welch's is one of the most recent examples. Its latest commercial depicts a little girl no longer scared of monsters because she's put several glasses of grape juice in front of her closet to keep them away. "Don't worry Daddy, the antioxidants will protect me," she says.

Monsters offer Welch's another way to refer to free radicals. Keeping the message simple is key, according to Chris Heye, vice president, Marketing, Welch's, Concord, MA. "If we got too scientific right away, the message might not have broken through," he said. "First and foremost, Welch's is a family brand and we wanted to maintain that essence."

Welch's most recent marketing goal, according to Mr. Heye, is to contemporize the brand. "We had a long running campaign stressing the benefits, taste and heritage of grape juice-and it always featured kids," he said. "This time around we want to focus on the changing needs of today's consumer, specifically 'Gen X' moms and 'Boomer' females."

Although Welch's is a pioneer in the antioxidant segment, Mr. Heye admits that the antioxidant message has been a difficult one to communicate. "I don't think the average consumer understands antioxidants. In fact, I think we are just at the very beginning of telling that story," he said.

For the future, Mr. Heye says he's excited at the prospect of Welch's being able to communicate the specific benefits of grape juice in relation to blood pressure, heart health and skin care.

Speaking of specific health benefits, Paul Dijkstra, CEO, InterHealth Nutraceuticals, Benicia, CA, says while consumers are interested in antioxidants, they are looking for antioxidants that are connected to certain health issues. "An ingredient that is marketed as a 'powerful antioxidant' will be too vague and will get lost among the many other 'powerful antioxidants' on the market," he said. "Antioxidants are more effectively marketed when positioned for a particular use, which requires scientific substantiation and a focused marketing message."

Reaching the Right Audience

As companies continue to sharpen their marketing messages on the general theme of antioxidants, many are refining their messages to capture a more targeted audience.

Charlene Lee, executive vice president and general manager, Cyvex, Irvine, CA, says her company constantly surveys the market to make sure it creates products for the right consumers. Consequently, Ms. Lee believes the antioxidant market will be a key area of growth due to demographic, social and cultural forces. "Specifically, the aging Baby Boomer generation's impact will continue to drive this market, as disease prevention and anti-aging are key interest areas for this growing segment," she said.

Doug Klaiber, COO, Decas Botanical Synergies, Carver, MA, also talked about targeting Baby Boomers, as well as moms. "I think antioxidants apply to such a wide spectrum of consumers. Baby Boomers in particular represent a pretty obvious consumer target, but so do moms between the ages of 35 and 50, who buy groceries that contain antioxidants to give their families the health protection they need."

To Steve Siegel, vice president, Ecuadorian Rainforest, Belleville, NJ, the message of antioxidants applies to all consumers. "The faces of antioxidant consumers are rapidly changing and becoming indistinguishable. In the past, lines were clearly drawn separating products targeted spe�cifically to women and those targeted to men. Today, it is quite another story, with both men and women concerned about maintaining a healthy and youthful appearance-this has greatly changed the antioxidant consumer basis," he said. "In today's marketplace, the antioxidant consumer is male, female, young and old-it is everyone."

BASF's Mr. Woolf believes "antioxidant" consumers have not yet set themselves apart from the traditional pattern of the typical dietary supplement or fortified food consumer. "This consumer cannot determine the added value of consuming more antioxidants in their diet," he said. "Following the USDA's Food Guide Pyramid, the average American should consume three vegetable and two fruit servings a day-the traditional source for dietary antioxidants. However, about 80% of the population is not meeting this guideline on a daily basis."

Mr. Woolf added, "When half the U.S. population is overweight, a category in which most individuals are in oxidative stress, under-consumption of fruits and vegetables as the primary source of antioxidants can only heighten the need for supplemental antioxidants."

Antoine Dauby, marketing manager, Naturex, Avignon, France, believes consumers have been overexposed to the term antioxidant. As a result, he thinks they are showing renewed interest in antioxidants for their specific benefits. "Today consumers understand that antioxidants offer wide but targeted benefits. For example, everyone is aware that lutein is beneficial for eye health and lycopene is recommended for prostate health," he said. "As consumers become more educated and selective, more end producers will have to communicate the targeted benefits, the active compound content and the proven efficacy, instead of simply labeling the products 'antioxidants.'"

While the move to condition-specific is clear, Scott Rosenbush, business manager, Botanicals, PL Thomas, Morristown, NJ, makes a distinction between food and supplements. "The food industry is limited in the claims they can make. They are generally not using clinically supported doses of ingredients due to claim limiations and cost considerations," he said. "When it comes to supplements, however, companies are definitely interested in being able to make claims. They are no longer looking for general antioxidants-the focus has turned very specifically to clinically supported ingredients where there is a defined, proven health benefitand claim that the manufacturer can communicate to the consumer."

Scientifically speaking, according to Brien Quirk, director of R&D, Draco Natural Products, San Jose, CA, it makes sense to create more condition-specific antioxidant formulas since it is known that some types of free radicals play a more specific role in certain diseases due to the nature of the unique free radicals created. For example, he said, neurodegenerative diseases are related more to nitric oxide-inflammation generated free radicals.

Positioning an antioxidant as having a benefit a consumer can feel or measure has always been a very complicated issue for this nutraceutical category. This is partly because one can't necessarily feel the relief of oxidative stress when they consume antioxidants-unless, of course, you happen to be an athlete. Jeremy Appleton, ND, CNS, technical marketing manager, Nutrition, EMD Chemicals, Gibbstown, NJ, explained, "Most people can benefit from antioxidants, but you can't feel an antioxidant preventing the oxidation of LDL cholesterol. Many other benefits, such as disease prevention, also cannot be immediately felt."

However, Mr. Appleton continued, "Of late, antioxidants are particularly popular in sports nutrition because that is one arena where their effects are immediately perceived. Athletes can feel the difference it makes in endurance and muscle soreness during and after a workout. But in general people are less likely to spend the money and remember to swallow the pills if the benefit isn't tangible."

Ingredient Trends

The antioxidant market, particularly in the area of superfruits, is ripe for growth. Mr. Dauby of Naturex, like many other experts, sees continued growth and expansion in this category. "The market for superfruits is one of the biggest successes over the past few years," he said. "The beverages containing superfruits like pomegranate or a�a� offer the attractive combination of health benefits and exotic tastes. Supplements incorporating botanicals like pomegranate, cranberry and red grapes are performing very well too. Unfortunately, vitamin C and E face challenges in the marketplace with slow to declining growth and price erosion."

Catering to the superfruit trend, Cyvex has launched VitaTropic tropical fruit blend. "Superfruit antioxidants are the talk of the industry and the buzz among health-conscious consumers. And for good reason, since a�a�, mangosteen, pomegranate and noni contain potent antioxidants," Ms. Lee stated. "VitaTropic contains polyphenols, xanthones and el�lagic acid standardized to 6000 ORAC."

Ms. Lee also pointed out that commoditized antioxidant materials like vitamin C and vitamin E are flat, if not declining.

Mr. Pond of Futureceuticals says antioxidants like vitamin E have been underperforming for the last several years. "Antioxidants or vitamins, such as vitamin E, which have received inconclusive or potentially negative research reports have been hit hard, probably too hard, in the market," he said. "As a result, there have been declines in popularity, particularly in larger dose formulations."

That said, Sharrann Simmons, senior marketing manager, Cognis Nutrition & Health, La Grange, IL is hopeful about vitamin E's future. "Perhaps one day soon we'll regard vitamin E as the comeback kid. We are seeing a slower but steady climb back for this powerful antioxidant that was blindsided in recent years by a controversial meta-analysis," she said. "Research has emerged recently that helps put the conflicting findings in context. Some suggest the dose was the cause as others question the type of vitamin E used and, most important, the overall health of the subjects. A new study just published in JAMA strongly suggests that 'vitamin E is important to physical health as you age.'"

Draco's Mr. Quirk feels if the antioxidant is both functional in adding some value to a food or drink and has more specific health benefits, then there is more value attached to that ingredient. He cited blueberries and pomegranates as examples. "Blueberry antioxidant polyphenols are valuable for their ability to reduce cognitive decline with aging, while pomegranate polyphenols may help decrease the clogging of the arteries and increase vasodilation," he explained.

Mr. Quirk added that plant-based polyphenols are growing much faster than isolated carotenoids because they are found naturally in functional foods, such as green tea, chocolate and red wine. Botanical extracts derived from fruits and vegetables, he says, will help supplant growth in food-derived antioxidants as vitamin-based antioxidants stagnate.

"Fruits-based antioxidants have been shown to confer some of the best multipurpose antioxidant effects and work better in unison with more than one type of fruit, according to Cornell research. In fact, the secondary effects of fruit antioxidants for arthritis, anti-aging, heart disease and cancer prevention go beyond just reducing free radicals," Mr. Quirk said. "Some of the food-based antioxidants upregulate the body's own production of antioxidants to much higher levels. This has been shown with broccoli compounds, which can increase the body's antioxidant response element (ARE)."

Mr. Quirk considers the following to be some of the top antioxidants based on popularity, amount of research, total antioxidant levels and positive secondary effects: blueberry, pomegranate, broccoli, wolfberry, mangosteen, milk thistle flavonoids, cocoa catechins, green tea polyphenols and black currant.

One ingredient not mentioned by Mr. Quirk but highlighted by many other experts is cranberry. The latest Agricultural Research Service Report from USDA, containing the results of the most comprehensive analysis of antioxidants in foods, showed that cranberries score among the highest of all common fruits on the ORAC antioxidant scale.

Known for their antioxidant activity, flavonoids, the largest subgroup of phytonutrients, are beneficial compounds found in plant-based foods, including cranberries. Specifically, cranberries contain a subclass of flavonoids called anthocyanins, which are known for their role as antioxidants. Additionally, cranberries contain a subclass called proanthocyanidins (PACs), known for helping to inhibit E.coli-the bacteria responsible for 80-90% of urinary tract infections-and helping to maintain a healthy urinary tract.

Mr. Klaiber of Decas also says cranberry is the only fruit in the world to have a health claim. Indeed, on December 3, 2004, the French Food Authority (AFSSA) approved a health claim for North American Cranberry PACs. The claim states that any product containing North American Cranberry PACs can "help reduce the adhesion of certain E. coli bacteria to the urinary tract walls."

Highlighting other antioxidant standouts, EMD's Mr. Appleton discussed CoQ10 and vitamin D. "CoQ10, despite its expense, has emerged as a winner in the antioxidant category. And it is deserving of this success, as it boasts an impressive resume of clinical validation. Although CoQ10 itself isn't 'emerging,' new uses for it are. It's not just used for heart health anymore, but is finding its way into sports nutrition and functional foods," he offered. "Vitamin D has also gotten a makeover in the last couple of years. Evidence continues to emerge showing new applications for this old vitamin. Many people don't even know that vitamin D is an antioxidant. People who think it's just for bone health are usually surprised by all the emerging research on cancer, multiple sclerosis, autoimmune disease and diabetes."

Jeff Wuagneux, president and CEO, RFI, Blauvelt, NY, described the advantage of using chocolate extracts in antioxidant formulations, "Chocolate extracts combine natural antioxidants with compounds for cognitive health and energy, without the fat and sugar from chocolate itself," he said. "RFI's Chocamine is an example of such a chocolate extract with strong cognitive health and energy properties. Its versatility allows it to be used in both food and supplement products."

Also on Mr. Wuagneux's radar are mushroom extracts. "Recent advances in analytical chemistry have discovered that L-ergothioneine, a unique and powerful naturally-occurring antioxidant compound, is found in very high levels in mushrooms," he said. "Shiitake, oyster, king oyster and maitake mushrooms contain the highest amounts of ergothioneine-40 times that found in wheat germ, one of the few other dietary sources of L-ergothioneine."

Mr. Wuagneux went on to explain that L-ergothioneine is an intracellular antioxidant, similar to glutathione, which has some unusual physico-chemical properties that make it unique amongst other natural antioxidants. "RFI is introducing a line of mushroom extracts, including an antioxidant mushroom blend rich in L-ergothio�neine," he said.

Lastly, Mr. Wuagneux touched on the resurgence in yerba mat�. He said while this herb is mainly known for its energy components (xanthene alkaloids like caffeine), it is also rich in antioxidant polyphenols. "Yerba mat� beverage manufacturers are beginning to tout this aspect of the plant as well as its energy properties," he said. "RFI manufacturers a yerba mat� extract-conventional and organic-standardized to polyphenols for use in antioxidant blends."

Greg Ris, vice president of sales, Indena USA, Seattle, WA, offered his picks for emerging antioxidants. "Over the past year, the antioxidants that have performed well include various berry and fruit products, including mangosteen, pomegranate and goji berry. The growth of these products will continue and we'll see other berry and superfruit products enter the mix," he said, adding, "The success of these products signals the consumer's desire for antioxidant supplements that are more like foods. I also expect olive fruit polyphenols to gain acceptance in 2008."

The Rocky Road of Research

As revealed through several years of debating antioxidant test methods, there is no one-size-fits-all solution to assessing the antioxidant potential of a particular substance or finished product.

The Oxygen Radical Absorbance Capacity, or ORAC, method has gained significant momentum over the years, but many experts point to it being only a small piece of an enormously complex puzzle. According to Ginny Bank, president, Full Spectrum Consulting, Boulder, CO, who spoke at a recent webinar on antioxidants for Nutraceuticals World, "Every test you do is all part of this puzzle and you need to examine the picture in its entirety in order to assess antioxidant potential."

Ms. Bank says following a 2005 conference, Dr. Ronald Prior of the USDA published a paper in the Journal of Agriculture & Food Chemistry in which he reviewed the advantages and disadvantages of a range of antioxidant test methods. Three tests emerged and were subsequently recommended for standardization: ORAC, TEAC (Trolox Equivalent Antioxidant Capacity) and F-C (Folin-Cointreau).

Ms. Bank notes that although the authors made a really good case for standardization, they also made some disclaimers about using these tests to assess total antioxidant potential. F-C, for example, is a good test but it only looks at phenols-what about catechins? TEAC never really gained that much momentum.

ORAC, on the other hand, has become quite visible, according to Ms. Bank, who used Google to chart its rising popularity. She said in the beginning of 2004 there were 3880 Google hits for "antioxidants and ORAC." In May 2005, that number jumped to 16,400 and in May 2007 it skyrocketed to 115,000. These hits not only included products, but also links to health articles, education sites and food commissions.

"We as an industry need to temper our enthusiasm for ORAC and use it for what is most appropriate because there is massive confusion and misuse of ORAC re�sults in product marketing," Ms. Bank said. "ORAC is a valuable method for quality control because it establishes consistency between batches/lots of products. It also works well when comparing one antioxidant to another, as long as the same solvent is used in both comparisons. But on other measures of antioxidant activity, it doesn't perform as well. For example, it doesn't provide a picture of how the antioxidant works in biological systems."

Dr. Prior, the creator of ORAC, admits that he never expected it to rise to the level of prominence it has today. "Back in 1999 during a review of our research projects, as required by USDA, an outside reviewer said ORAC would become a mainstay method in the U.S., as TEAC would in Europe," he said. "It went well beyond my expectations."

As far as the confusion surrounding ORAC is concerned, Dr. Prior commented, "At some point there needs to be a simplified message that consumers can understand. However, when you look at the science behind antioxidants it is clear we need to move beyond generalities. Some of these compounds are having health effects that may not be the result of an antioxidant mechanism."

"Marketing in most cases has gone way beyond the science," Dr. Prior added. "There are groups of companies that have utilized the message of antioxidants to promote a commodity. They have been successful and have had enough science to back themselves up. The problem occurs when companies focus on having the biggest number-this is where things have gotten out of hand."

EMD's Mr. Appleton elaborated on the ORAC issue. "A supplement with a high ORAC value may be useless internally, so you have to look at other evidence. Understanding oxidative stress and oxidation/reduction activity in the body is not a simple matter," he said. "Each antioxidant must be considered for much more than its ORAC value-how does it affect biological processes and tissues? How does it make you feel when you take it? Does it interact with other nutrients? Does it have any demonstrable clinical effects?"

There is a new assay on the block called the cellular antioxidant activity (CAA) assay, which evaluates an antioxidant's potential at the cellular level. It was developed by Rui Hai Liu, PhD, a scientist in the Cornell University Department of Food Science. Last year he used the assay to determine the antioxidant activity of wild blueberries, which were found to perform better in cells compared to cranberries, apples, red and green grapes.

According to Dr. Liu, the CAA assay takes antioxidant measurement to a new level, moving beyond test tube assays to bioactivity inside cells. "We've taken the next step toward understanding antioxidant activity by examining how antioxidants react within cells," he said. "This new approach is more biologically relevant as it accounts for uptake, metabolism, distribution and activity of antioxidant compounds in cells versus solely looking at antioxidant value."

Dr. Prior also views the CAA assay as an advancement. "The CAA assay provides information regarding cellular levels of antioxidants, which is important to our understanding in this area of antioxidant research," he commented. "How useful the assay will be in predicting in vivo uptake and availability of dietary antioxidants remains to be determined with further research."

Ms. Bank also believes tests measuring cellular uptake can be very useful and relatively inexpensive. One problem with the CAA test is that the results don't correlate with other tests, such as ORAC and TEAC.

Further, she says the test uses human liver tumor cell lines, which is not a good biological substrate because the cells can produce reactive oxygen species as part of their normal behavior. In fact, she claims liver tumor cell lines typically have more cells undergoing apoptosis, which generates reactive oxygen species.

Lastly, the CAA test uses quercetin as the standard against which antioxidant activity is measured. But quercetin needs DMSO (another potent antioxidant) to get into the cell, so in the end the results of antioxidant capacity might wind up being inflated.

Another test that might resolve issues posed by the CAA assay is the CAP-e test. It uses red blood cells, which have no mitochondria and therefore do not produce reactive oxygen species on their own. Further, this test doesn't use a solvent (DMSO) to force compounds into the cell. It also uses gallic acid as the standard.

In creating a complete antioxidant picture, human clinical trials are frequently missing from the equation, but this is starting to change.

"Last year, USDA's Dr. Prior conducted a study showing the effect of plasma antioxidant activity after consumption of different fruits and berries," Ms. Bank said. "ORAC levels in the plasma were assessed before and after meals (postprandial). The study found that the timing of the consumption of antioxidants is key to easing oxidative stress after a meal. There definitely needs to be more studies like these to examine the biological relevance of antioxidants."

Dr. Prior expanded on these study results. "The most significant finding of that study is that the consumption of a meal that's high in carbs/lipids and not antioxidants is putting the body in an oxidative stress situation," he explained. "Now, a single meal may not be a big deal, but over time those types of meals will have a cumulative effect, with the potential to lead to cardiovascular disease or cancer. So theoretically, consuming an antioxidant with every meal may reduce that oxidative stress."

Dr. Prior says he's become more convinced over the years that oxidative stress plays more of a role in disease processes than previously thought. "What re�searchers are trying to figure out now is if disease causes oxidative stress or oxidative stress causes disease," he said.

The ultimate goal for Dr. Prior is finding out how antioxidant foods relate to health outcomes. "In our lab we're interested in insulin sensitivity and metabolic syndrome. We're looking at anthocyanins and procyanidins-compounds from berries that may facilitate insulin's action. We're also doing studies with anthocyanins and obesity."

"Antioxidant effectiveness" is still an unresolved issue, according to BASF's Mr. Woof, who also discussed the importance of evaluating oxidative stress. "Long-term intervention studies have not shown the expected beneficial results in decreased incidence of disease or an increase in longevity," he said. "What is obviously lacking is a validated biomarker to benchmark oxidative stress.

"DNA damage is emerging as a biomarker since there are many indications that individuals with elevated amounts of DNA damage have a higher incidence of chronic disease later in life," Mr. Woolf continued. "Foods rich in antioxidants, as well as individual antioxidants in dietary supplement form, have been shown to reduce DNA damage levels and bring them within normal, self-repairable levels. In vitro chemical analyses are useful for comparative purposes, however DNA damage is emerging as a reliable, in vivo marker for oxidative stress."

As Ms. Bank summed up her views on antioxidants, she said, "The layperson is just beginning to understand the basic message, which is that there are these compounds called antioxidants and they fight free radicals and free radicals are bad. This simple message has taken several years to permeate the public's consciousness. In the end, it may be a question of 'what comes first'-does educating the public on condition-specific antioxidants drive the market for such products or does the introduction of such products drive the consumer's education?"