Have antioxidant health claims lost credibility?
In recent years, antioxidants have been added to an array of food, beverages and supplements for their perceived health benefits. From fruit juices to popsicles, breakfast cereals and gummy snacks, and scores of dietary supplements, numerous labels prominently display the word, “antioxidant.” However, advances in the research on antioxidants have made the antioxidant story less straightforward than many think. Ingredients with antioxidant claims, while still scientifically valid in some cases, are due for a makeover.
When antioxidants burst on the scene in the early 2000s, people were excited about them for a number of reasons. Diets rich in fruits and vegetables have known health benefits, reducing the risk of cardiovascular disease, obesity and cancer, and studies pointed to the antioxidant activity of one phytochemical after another. Thus people made the correlation that phytochemical antioxidants must be the reason for the benefits of a healthy diet—and soon assumed it was a cause and effect relationship. Further, the antioxidant tests, most of which pitted the phytochemical of interest against vitamin E, the model antioxidant, showed higher and higher numbers in favor of fruits and vegetables and their components. Together this was the makings of a great story.
And why should anyone have believed otherwise? A cursory review of the vast antioxidant literature would have indicated that scientists also supported the claim “antioxidants = good for you” and that the more antioxidants consumed, the greater the benefit. At that time, the majority of research done had been done outside of the human body.
With the benefit of time, thought and more research, it has become clear that certain compounds act as antioxidants in the body in the classically defined way, but for others, high ORAC (oxygen radical absorbance capacity) numbers otherwise lead to a dead end.
Let’s explore some of the places where the original excitement over antioxidants gets tripped up and why, and then go on to the places where it does have unequivocal benefits. Lastly, we’ll discuss the good news in this story and suggest pathways for the maturing of strategy around antioxidant products.
Early research consisted largely of in vitro test tube and cell studies. In the juggernaut of preclinical antioxidant research, scientists performed “total antioxidant” activity assays like ferric reducing antioxidant power (FRAP) and ORAC on plant extracts and proclaimed them “good for your health” on the basis of their antioxidant power. Today, although some scientists still argue over which assay is most like the conditions in the body, there is a consensus understanding that these assays have limited utility when it comes to showing benefits in humans. This is because how a compound behaves in a test tube does not account for body pH, bioavailability, competitive compounds and other nuances of physiology. In addition, antioxidants are often metabolized in the body to other compounds, so often the body never sees the molecule that was ORAC tested at all. Some antioxidants are even altered in an in vitro environment to be pro-oxidants: in other words, they change to acting like free radicals! In some cases, this is not bad news in the body, and may even explain the observed health benefit—but let’s tell the right story!
Topical applications for cosmetics that tout antioxidants also run into problems. There are few antioxidants that remain stable in formulation and successfully penetrate through the stratum corneum (the outer, dead layer of skin) to affect the living cells deeper down in the epidermis. Since most anti-aging claims are based on the ability of antioxidants to interact with living skin cells, penetration and delivery of intact molecules is critical. (An exception is vitamin C, which does penetrate the skin reasonably well when applied topically and has demonstrated skin benefits.) In addition, most antioxidants are quite difficult to stabilize in formulation (including vitamin C).
There is strong evidence that the “tried and true” vitamins act as antioxidants in the body. One is vitamin E, which is a general term referring to any of the number of tocopherols with the biological activity of d-α-tocopherol. Their role in the body is to prevent the peroxidation of membrane phospholipids, thereby protecting against cell membrane damage. This is a clear example of antioxidant activity in the fatty places of the body (membranes are made of fats). Vitamin C is a water-soluble antioxidant. In humans, it is an electron donor for enzymes that participate in collagen, carnitine, and catecholamine synthesis. It also aids in iron absorption by either chelating iron or maintaining it in reduced form, which is another antioxidant function. The human body synthesizes vitamin A from dietary carotenoids like β-carotene and lycopene. Similar to the way carotenoids quench excess photoradiation in plants, preventing oxidation, β-carotene can treat erythropoietic protoporphyria, a painful photosensitivity condition in humans. Selenium is an integral component of glutathione peroxidase and thyrodoxin reductase, two important endogenous antioxidant enzymes. These selenoenzymes protect cells against the damaging effects of hydrogen peroxide, lipid hydroperoxides, and oxygen radicals.
The Good News
As human research sought to answer deeper questions about how antioxidants act in the body, the story became at once simpler and more complex. Compounds that are antioxidants in vitro fall into three categories when examined in the body:
1) those that have an effect due to their antioxidant properties
2) those that have not shown an effect
3) those that have an effect, but not due to their antioxidant properties
There are some antioxidants that have come onto the scene that, when tested, do have effects that stem from their antioxidant properties. One example is punicalagin, an ellagitannin found in pomegranate and responsible for its heart health benefits. Research has shown it prevents LDL oxidation, which is an antioxidant function. Several other compounds have shown this effect on LDL oxidation in humans, such as cocoa polyphenols, CoQ10, and astaxanthin. In addition, the carotenoids lutein and zeaxanthin accumulate in the human eye and help protect against macular degeneration by neutralizing free radicals caused by UV exposure.
But there is also much research that has sought antioxidant effects and found none. Many antioxidants that claim effects have never been tested in humans at all, or have only shown ambiguous results. The “antioxidant paradox” is a term used to describe the puzzling observation that large doses of antioxidants fail to prevent or treat diseases caused by oxidative damage, even when presumed pharmacological levels are observed in the blood. Scientists believe this occurs for two primary reasons. First, while oxidative damage may play a role in neurodegenerative diseases, cancer, and cardiovascular disease, there are many other complex factors involved that would not respond to antioxidant therapy. Second, the body’s endogenous antioxidant defense system is sophisticated and highly regulated. Dietary antioxidants, even in high doses, may have little effect on the overall antioxidant capacity of the body.
On the other hand, much new research on the mechanisms of purported antioxidant compounds has come to show that their effects are real, but are driven by actions other than antioxidant ones. A case in point is many flavonoids. Green tea catechins (often marketed as antioxidants) have effects on cardiovascular disease, metabolic syndrome, and photoaging that are driven by mechanisms such as reducing inflammation, modulation of cell signaling pathways, and regulation of DNA methylation. Proanthocyanadins have long been recognized for their potent antioxidant power, yet scientists now believe their health benefits stem from their ability to influence the metabolism and composition of gut bacteria. In addition, cocoa flavanols are technically antioxidants, but their main action as an enhancer of circulation is due to effects on nitric oxide levels that are independent of antioxidant mechanisms. Recent clinical trials have shown that curcumin’s effects on osteoarthritis are due to reduced collagen and cartilage degradation. The mechanism appears to be unrelated to antioxidant capacity. Carnitine, although technically an antioxidant, has as its main function to shuttle fatty acids into the mitochondria and remove toxic fatty acyl-CoA metabolites. Complex mechanisms of these types are arguably the most interesting new research in the field.
The time is drawing near that companies selling products for their antioxidant abilities should be thinking about new strategies for the future. For most ingredients, the term antioxidant is only getting weaker from a science point of view. Its regulatory status for ingredients without daily values is shaky and has even been challenged in a few high profile court cases. But the good news is, many compounds billed as antioxidants have documented health benefits in humans that are driven by other mechanisms. These should be developed further or sought out in new research, and turned into the dominant marketing messages for these products. In the end it is more differentiating and the customer will be better served. We all know that new science, claims, and strategies take time, making this message all the more cogent. So go out there and build the future! NIE
Dr. Risa Schulman is a dietary supplement and functional food expert, focusing on sound science, claims and strategy. Drawing on 18 years of experience, she is currently the president of New Jersey-based Tap~Root consulting firm. Schulman and her team assist ingredient suppliers, manufacturers, start-ups, biotechs, pharma, law firms and investment bankers. Dr. Barbara Schmidt has a BS in horticulture from The Pennsylvania State University and a MS in Plant Biology from Arizona State University. Her PhD is from the University of Illinois, Urbana-Champaign (UIUC) where she studied phytochemistry with a focus on anticancer and antioxidant compounds from berries. As a Postdoctoral Associate at Rutgers University, Schmidt worked on numerous projects investigating therapeutic properties of natural products. She has been working in the natural products industry on product development for nine years.