The Antioxidant Cascade

Wading through the deluge of antioxidant science and products is a daunting but necessary task for retailers

References

It is important to understand the role antioxidants play in nature, protecting living things from certain chemical threats. True to Darwinian Theory, the ability to fend off constant threats is the key to continued survival of the individual and of the species. However marvelous it is, the human immune system is fallible, especially at the hands of free radicals.

These rogue agents are created by numerous biological processes, including metabolism, and are also sometimes the consequences of poor environment and lifestyle, such as exposure to carcinogens and toxins. With an odd number of electrons in their outer shell, free radicals are highly unstable molecules on a quest to steal electrons from their neighbors. This thievery leaves the victims without a vital electron, damaging them and rendering them new free radicals, dubbed reactive oxygen species (ROS)—superoxide, hydrogen peroxide and hydroxyl radical are among the most common. In a cruel twist of fate, the newly-formed ROS becomes the electron criminal, sparking a chain reaction that causes further damage.

At risk of free radical attack are any number of body’s smallest machinery, including DNA and cell membranes. Damage to various body cells has been indicated in the development of some serious diseases and conditions, such as cancer, atherosclerosis and neurological diseases, and it has also been theorized as the catalyst of the process of aging.

Proving nothing is entirely good nor entirely evil, free radicals develop in the body in the presence of molecular oxygen. At times, the body needs the services of free radicals, such as in cell signaling and killing bacteria, and there is even a system in place to control these highly reactive substances and limit the damage they can cause.

The cavalry consists of a group of endogenous enzymes, including glutathione peroxidase (GPx), glutathione reductase, catalase and superoxide dismutase (SOD). GPx is synthesized in the body from the amino acids glycine, cysteine and glutamate, and it is particularly aimed at radical hydrogen peroxide. GPx production declines with age, but this can be limited or even reversed with increased consumption of fruits and vegetables,¹ or via supplementation with the amino acid glutamine.² Production of SOD, which targets superoxide radicals, also declines with age, but supplemental SOD has been hailed an apt rescue. In fact, melonderived SOD (as GliSODin®, from P.L. Thomas) has been shown to promote antioxidant status and blood antioxidant activity, protecting against DNA breaks and lowering isoprostane, a marker of oxidative stress.^3,4 This protective effect has translated to antioxidant benefits against oxidative stress caused by radiation from sun overexposure⁵ and by muscle strain from exercise.⁶

Another boost to endogenous antioxidants is melatonin, which is secreted by the pineal gland during perceived darkness but is also available in supplement form. Synthesized in a lab or sourced from animals, supplemental melatonin has been proven to increase levels of GPx, SOD and catalase, specifically protecting against oxidative damage to DNA and other cells in the brain and liver.^7,8

The mineral selenium is another key ingredient in the production of endogenous antioxidant enzymes, including GPx.⁹ By preserving these enzymes, selenium supplementation has shown a tendency to counter cardiotoxicity,¹⁰ in addition to being linked to decreased risk of various cancers, including prostate, lung and colon.¹¹

On a mitochondrial level, where cellular energy production occurs, the cycle of ATP (adenosine triphosphate) production produces superoxide as a byproduct of its electron transport chain. This superoxide steals from mitochondrial DNA or the cell membrane, causing apoptosis, or cell death. Found in the mitochondrial membrane, coenzyme Q10 (CoQ10) is a vital part of the electron transport chain and has demonstrated antioxidant protection in the mitochondria, especially in heart cells.^12,13 Not only has CoQ10 lowered markers of oxidative stress in atherosclerosis development,¹⁴ but it has also issued cardioprotection by increasing the activity of antioxidant endogenous enzymes.¹⁵

While boosting the body’s own antioxidant defense system is one way supplements can address free radical damage, increasing serum levels of antioxidant micronutrients is another method. More vitamins and minerals in the blood and tissues mean more free radical scavenging all over the body.

Scientists studying zinc have discovered depleted levels of the mineral in prostate cancer patients¹⁸ and have drawn connections between increased lipid peroxidation and low zinc levels in benign prostatic hyperplasia (BPH).¹⁹ Other trials have found zinc counteracts oxidative damage of the endothelium in chronic kidney disease,²⁰ of red blood cells in radiation exposure²¹ and of various eye components in age-related macular degeneration.²²

Fellow antioxidant vitamin C, or ascorbic acid, has exhibited oxidative stress reduction in some of the same body areas, including the brain,³⁰ eyes³¹ and cardiovascular system.³² In fact, both vitamins C and E have been shown to enhance recovery from endurance exercise, lowering various markers of oxidative damage to muscles and tissue, and increasing levels of erythrocyte antioxidant enzymes and plasma antioxidant levels.^33,34,35,36 In tandem, these two vitamins can work on heart disease,³⁷ dementia³⁸ and antioxidant preservation in smokers.³⁹

While supplementing with vitamins E and C has been linked to decreased cancer in smokers,⁴⁰vitamin A supplementation, as beta-carotene, has actually been connected to increased risk of cancer in numerous trials.^41,42,43 However, a Tufts University trial concluded combined administration of beta-carotene, alpha-tocopherol and ascorbic acid was chemopreventive in lung cancer.⁴⁴ Beta-carotene has also been linked to lower incidence of respiratory and airway diseases marked by oxidative damage,⁴⁵ in addition to decreasing risk of prostate cancer,⁴⁶ kidney disease⁴⁷ and oxidative complications of menopause.⁴⁸

At one time, the antioxidant supplement category consisted mostly of certain vitamins and minerals, as well as a few herbs. However, science has caught up to the antioxidant phytochemicals in countless botanicals and plant-based foods.

While the entire class of carotenoids, which are the pigments in various colorful herbs, fruits and vegetables, may counteract free radical activity in the colon,⁴⁹ liver⁵⁰ and the cardiovascular system,⁵¹ non-provitamin A carotenoids lycopene, lutein and zeaxanthin individually possess some potent antioxidant properties. Perhaps the most powerful antioxidant in the bunch, lycopene protects against lipid peroxidation of LDL,⁵² although in vitro tests reveal tomato oleoresin may be more effective than pure lycopene in this antioxidant activity.⁵³ Furthermore, a natural tomato extract (as Lyc-O-Mato®, from LycoRed) increased plasma carotenoids and reduced DNA damage in lymphocytes subjected to oxidation.^54,55

The eye, more specifically the macula, is the main arena for the antioxidant activities of lutein and zeaxanthin, which have a chemical structure that allows them to absorb a wide spectrum of light, including the blue light that causes oxidative damage in the macula and other eye structures. This action underlies the carotenoid pair’s benefit in AMD.

Studies on lutein esters (as Xangold®, from Cognis) revealed lutein accumulates in the macula of both healthy and early-stage AMD patients,⁵⁶ and lutein supplementation increases both plasma and macular levels of the carotenoid.⁵⁷ Additional research found lutein (as FloraGlo®, from Kemin Health) scavenges photo-induced ROS in the eye, while both carotenoids protect against lipid peroxidation that can factor in eye health.⁵⁸

Together, lutein and zeaxanthin—which are found in a handful of vegetables and herbs but are commonly sourced from marigold flowers—also protect the photoreceptor cell layer in the eye from light damage caused by ROS.⁵⁹ Their protection from radiation extends to the skin, limiting the effects of UVB radiation and subsequent acute inflammatory response.^60,61

Joining the antioxidant carotenoid brigade against eye damage is astaxanthin, which is derived from algae and eventually makes it way up to the food chain to various sea animals, giving a red color to krill, lobsters and some crabs. Studies show astaxanthin (as AstaREAL®, from Fuji Health Science) can curb inflammation in the eyes,⁶² as well as improve retinal capillary blood flow.⁶³ Its antioxidant effect on the vascular system also extends to protection against lipid peroxidation of both LDL and HDL cholesterol.⁶⁴ Astaxanthin’s defense against oxidative damage is farreaching, demonstrating benefits against radiation exposure,⁶⁵ exercise-induced ROS injury to the heart and calf muscles,⁶⁶ ischemia in the brain⁶⁷ and microbial-influenced damage in the gut.⁶⁸

Much like the human body, plants manufacture antioxidants for protection against various threats. Among these phytochemicals are isothiocyanates and indoles, found in cruciferous vegetables, and flavonoids, a broad class of polyphenols found in almost every plant.

Sulfurophane, an isothiocyanate in broccoli, up-regulates certain detoxification enzymes that protect DNA from damage by carcinogens and ROS,⁶⁹ and also helps reduce intracellular oxidative stress.⁷⁰ Broccoli is also home to indole-3-carbinol, which has been shown as anticarcinogenic, possibly due to suppression of free radical production.^71,72

Fellow crucifer garlic has been shown to not only scavenge free radicals, but also increase SOD, GPx, catalase and glutathione levels, in addition to inhibiting lipid peroxidation and inflammatory prostaglandins.⁷³ Aged garlic extract has proven particularly beneficial in heart health, curbing peroxidation of erythrocytes and LDL cholesterol,⁷⁴ translating to antioxidant benefits to hypertensive patients.⁷⁵ Garlic also confers antioxidant benefits to the bladder mucosa and the degenerative brain^76,77 while also inhibiting free radical formation in diabetes pathology.⁷⁸

However, the bulk of phytochemical antioxidant action is attributed to flavonoids found in fruits and assorted botanicals. Supporting advice to consume more richly-colored produce, the vibrantly pigmented anthocyanins found in numerous fruits protect against many health problems marked by oxidative stress. Anthocyanin-rich strawberries, which also contain tons of other phytonutrients, can decrease toxins and limit oxidative damage to DNA,⁷⁹ manifesting as antioxidant protection against neurodegeneration and cancer.^80,81 Similarly, blueberries can safeguard neurons from oxidative damage,⁸² reducing the development of various age-related brain diseases.⁸³ Likewise, bilberries protect against AMD;⁸⁴blackberries impede tumor formation in the oral cavity;⁸⁵ and cranberries address numerous free radical-driven health problems, including liver cancer, kidney stones, gum disease and urinary tract infection.^86,87,88,89 Evidence is mounting suggesting a combination of multiple berries delivers an even more powerful antioxidant punch than do the individual berries. An extract of seven berries (as OptiBerry®, from InterHealth Nutraceuticals) provided total body antioxidant protection from oxidative stress, with particular benefit to the liver and lungs.⁹⁰ This anthocyanin-rich extract also has demonstrated preventive actions against cancer and hypercholesterolemia.⁹¹

Anthocyanins, along with proanthocyanidins and resveratrol, are abundant in grape seed extract (GSE), which has been found to enhance antioxidant status and decrease free radical-induced lipid peroxidation in the cardiovascular and central nervous systems.^92,93 As a result, GSE is not only of benefit to hypertensive and hypercholesterolemic patients,^94,95 but it also attenuates inflammation indicated in various skin conditions.⁹⁶ GSE may be a more powerful antioxidant than red wine,⁹⁷ which can increase plasma antioxidant levels,⁹⁸ offering notable protection from oxidative stress in the brain and kidneys.⁹⁹

Antioxidant fruits have taken the market by storm, especially pomegranate and noni, both of which contain a vast array of phytonutrients. Flavonoids, ellagic acids, tannins and punicalagin round out pomegranate’s antioxidant polyphenolic roster.¹⁰⁰ This exotic fruit delivers numerous heart health benefits possibly due to antioxidant properties,¹⁰¹ with specific modulation of oxidative stress in macrophage cells¹⁰² and coronary endothelial cells.¹⁰³

Although its robust polyphenolic content is still being determined, noni (as Tahitian Noni Juice®, from Tahitian Noni International) has exhibited antioxidant protection of DNA in cancer pathology, showing exceptional action against lipid hydroperoxide (LPO) and superoxide anion radical (SAR).¹⁰⁴ Other research has shown noni juice also counters plasma LPO and SAR in smokers, helping to prevent cancer, pulmonary and cardiovascular disease development by scavenging free radicals and limiting lipid peroxidation.¹⁰⁵

Flavonoids in various other botanical products have displayed similar antioxidant benefits. Proanthocyanidins, catechins and other flavonoids in pine bark extract (as Pycnogenol®, from Natural Health Science) can restrict oxidative damage while raising antioxidant enzyme levels in the retina,¹⁰⁶ kidneys and liver,¹⁰⁷ in addition to controlling oxidation and related damage to plasma LDL and DNA.¹⁰⁸ This extract also addresses oxidative stress related to radiation exposure, indicating a benefit to skin health.¹⁰⁹

Catechins and theaflavins have been crowned the antioxidant champions in green and black tea, consumption of which has been linked to lower risk of cancer.¹¹⁰ Research has suggested tea might scavenge free radicals before cancer-causing damage can occur.¹¹¹ This antioxidant protection is also extended to the cardiovascular system,¹¹² as well as the brain,¹¹³ kidneys,¹¹⁴ liver¹¹⁵ and prostate.¹¹⁶

Catechin and other flavanols also figure prominently in the antioxidant benefits of cocoa. Epicatechins and their metabolites have been singled out as keys to cocoa’s nitric oxide-related vasodilation,¹¹⁷ which may explain its benefits on lipid peroxidation, thrombosis formation and hypertension.^118,119,120

In a similar vein, flavanones, common to citrus fruits, have also exhibited antioxidant actions in heart health, including hypertriglyceridemia, hypertension and hypercholesterolemia.^121,122,123 Among the individual citrus bioflavonoids, hesperidin (lemons and oranges) has protected cells from damage caused by toxins and hydrogen peroxide,¹²⁴ naringenin (grapefruit and oranges) inhibited amyloid-beta-induced ROS in the brain,¹²⁵ and limonene (lemons) limits the pulmonary devastation of the pro-oxidant ozone.¹²⁶ Commonly found in the peels of the fruits, polymethoxylated flavones, including tangretin and nobiletin, (as Sytrinol®, from SourceOne Global and KGK Synergize) can improve various parameters of atherosclerosis,¹²⁷ in addition to modulating inflammation parameters central to the immune response.¹²⁸

With no shortage of antioxidant ingredients and products to choose from, retailers are faced with a daunting challenge of stocking their shelves with the highest quality and most effective products. Adding to the quandary, for any given antioxidant subcategory, there are numerous different product versions. What differentiates one product from another, and how do they all compare on antioxidant potency?

“Retailers and consumers are challenged by the concept of relative power and efficacy of antioxidants—it is a new and poorly understood area,” said Kenneth Israel, director of marketing for Soft Gel Technologies (SGTI). He and other industry members noted the ORAC (Oxygen Radical Absorptive Capacity) assay is an emerging standard used in marketing antioxidants, but its usefulness is limited. “It is poorly understood and often misrepresented,” he added.

ORAC is an in vitro (test tube) measurement of antioxidant potential of a substance relative to specific oxygen free radicals at a given point in time. While this is somewhat useful as a starting point, it does not address activity in vivo (in the body), which is more dependent upon bioavailability. “An antioxidant’s measure, once it has been ingested, will vary, so [ORAC] is not a ‘gold’ standard by any means,” advised James Roza, vice president business development, technology & science of SourceOne Global.

Eric Anderson, brands manager of P.L. Thomas & Co., said ORAC’s benefit is extremely limited and has a potentially huge downside. “It is a stretch to extrapolate what happens in the test tube to human benefits,” he reasoned. “Does a larger ORAC number guarantee a consumer is going to realize the promised benefits? The answer to this question is never given, because there is no proven correlation.” He said for now, ORAC is strictly a marketing device.

Shon Whitney, vice president of marketing communications of Tahitian Noni, agreed. “Some companies are engineering products to achieve high ORAC scores purely from a marketing perspective, but most have not been tested in clinical trials or in the body,” he said. “It’s difficult to rely just on that score.”

Given the limited scope and controversy of ORAC scores manufacturers are turning to other tests and science for evidence of antioxidant capabilities. “Even though our PomElla pomegranate product is high-ORAC, we emphasize research on the in vivo bioactivity of antioxidants,” said Blake Ebersole, marketing coordinator of Geni Herbs. Anderson agreed: “It is incumbent upon industry to substantiate an antioxidant’s benefits in human research and thus fulfill the marketing promise made to the consumer.” Addressing possible confusion retailers might have on this issue, Roza suggested retailers interested in learning more should read the NNFA (National Nutritional Foods Association) backgrounder on ORAC, which can be found on its Web site (www.nnfa.org).

Beyond the questions of antioxidant potency comparisons, retailers deciding on inventory must also consider the wide range of antioxidant delivery forms and the abundance of both single and multi-ingredient formulas. Some see demand for both general antioxidant blends and targeted antioxidant formulas. “Consumers want the most for their money—antioxidant blends deliver more, and ‘broad-spectrum antioxidants’ deliver more protection than stand alone antioxidants,” reasoned Larry Logsdon, founder of Tahiti Trader.

Israel countered, ”Real growth and market focus has been on targeted products. Consumers are demanding products that have demonstrated measurable benefits in humans, preferably against specific disease conditions or stress environments.”

Allen Luke, owner of Fruit Essentials, noted some “single” ingredient supplements offer a broad range of different actions. “Cranberry seed oil not only contains numerous antioxidants—such as beta-carotene and all 8 isomers of tocopherols and tocotrienols— but it also contains plant sterols, oleic acid and omega-3 fatty acids,” he said. “This synergistic nutrient profile allows multiple delivery options within functional foods and supplement products.”

Frank Schonlau, Ph.D., director of scientific communications for Natural Health Science (NHS), added it is important to take into consideration ongoing research and articles highlighting the virtues of antioxidant combinations, such as Pycnogenol and CoQ10. “The idea of combination products for certain health problems is relevant and accepted around the world,” he confirmed. Ebersole seconded the idea of science-based support, adding research showing both increased general antioxidant activity and specific benefits to targeted health problems and free radicals can offer a one-two punch.

While most experts agree consumers strive to get antioxidants from foods first, the average lifestyle prohibits such, leaving many people open to supplementation. Whether single or multiple, general or targeted, antioxidant products come in a variety of delivery forms, including tablets, capsules and liquids, as well as functional foods and beverages. “For bioavailability, a liquid is favored over a solid, as it is more readily available and absorbable in the digestive tract, and it generates a quicker response,” explained Jarakae Jensen, managing director of noni research, product development and process research/quality control of Tahitian Noni. “On the flip side, capsules might give more extended response, and deliver a longer lasting benefit.”

Kimberly Austin, director of sales at NHS, suggested the decision on antioxidant delivery form may well boil down to personal consumer preference, including nods to lifestyle, age, product availability and convenience. “I’ve witnessed a greater number of people looking to fill their diet with antioxidant rich fruits and also take a dietary supplement,” she said. “The combination of food and supplement enables people to consume the right amount of antioxidants on a daily basis.”

As science whittles down foods and plants into their finest components, more antioxidant substances emerge. As a result, antioxidant supplements of every imaginable form and concoction flood the market. As easy as it may be to get lost in this vast universe of never-ending antioxidants, a basic awareness of antioxidant science, including research findings on specific ingredients or formulas on specific health concerns become a crucial tool. “When assessing an antioxidant product, it’s always helpful to know what form and levels of the nutrient were used in the clinical study,” Roza advised.

Experts agree retailers should seek out products differentiated from the pack by human clinical support vs. marketing devices. “Newness often initially trumps the actual reality of how effective an ingredient is,” Israel noted. “However, the market is generally efficient at eliminating inefficient or ineffective products.” He and others recommended retailers demand substantiation on claims and safety as a way of building credibility with consumers.

Ebersole punctuated this concept: “From a retailer’s perspective, if something really works in the body, the chances are greater for repeat sales, as well as stronger customer relationships.”

References

June 2006 Health Supplement Retailer
"Antioxidant Cascade" References

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