New Expectations for Antioxidants

“Antioxidants have gone through a gradual transition from miracle molecules to marvelous molecules to physiological molecules.”

This is how P.P. Singh and colleagues from the Department of Biochemistry at Era’s Lucknow Medical College and Hospital in India described the progression of antioxidant research over the last several decades.¹ Their statement encompasses the initial enormous potential of antioxidants envisioned by researchers when the free radical theory of aging was proposed, through to the current reality of positive, negative, and inconsistent results seen in clinical trials of numerous health conditions with antioxidant interventions. It further reflects the disappointment of the scientific community when human physiology turned out to be more complex than originally thought and science did not bear out hyped-up antioxidant claims.

In no uncertain terms, endogenous antioxidant defenses and antioxidant intake from exogenous sources (diet and supplements) are critical factors in health and disease. This is a concept that has not changed over the years. What has changed is that the decades of research performed since the free radical theory was first proposed, and the unrealistic expectations of antioxidants as miracle molecules, have been replaced with a better understanding of how these compounds really fit into human physiology. The truth is that the interplay between the effects of antioxidants and the body’s defense systems are both intricate and complex, and ultimately can’t be boiled down to a simple equation stating that antioxidants are “good” and free radicals are “bad.”

Free Radicals, Antioxidants, and Oxidative Stress

Free radical production occurs as a normal byproduct of metabolism within the mitochondria of cells. External factors affecting free radical production include smoking, environmental chemicals, medications, pesticides, and industrial solvents. Maintaining a balance between the production and neutralization of free radicals by antioxidants is critical, as an excessive production of free radicals leads to cellular damage. Estimates suggest that an average human cell is targeted by free radicals 10,000 times each day, with the main targets being cellular proteins, DNA, RNA, sugar, and lipids.²

To deal with this, the body has developed a tremendously efficient endogenous system, which includes two major groups: enzyme-based antioxidants and non-enzyme-based antioxidants. The enzyme-based systems include glutathione peroxidase, catalase, and superoxide dismutase, while endogenous non-enzyme-driven antioxidants consist of vitamin A, coenzyme Q10, uric acid, and glutathione.²

While these systems are remarkably adept at managing free radical production in the body, they certainly do not suffice. This is where dietary antioxidants contribute to maintaining the concentration of free radicals at manageable levels.³ The major natural dietary antioxidants include vitamins C, E, and K; flavonoids; phenolic antioxidants; minerals, including zinc and selenium; and carotenoids such as lycopene, beta-carotene, lutein, and zeaxanthin.² These all participate to bolster the body’s own antioxidant systems.

It is now clear that the originally propagated concept of free radicals being toxic molecules and antioxidants being those compounds that could neutralize the negative effects of the “bad” free radicals is an oversimplification. In reality, free radicals are important participants in human physiology. These compounds are now recognized as being necessary for vital metabolic activities, including cellular signaling, cellular growth and differentiation, the destruction of infected and malignant cells, and the killing of pathogenic organisms.¹ Therefore, it’s likely that striking the right balance of free radical production to antioxidant defenses is critical to optimal health, and that an excess of free radicals, as well as an excess of antioxidants, may have deleterious effects on metabolic function.

Common Antioxidant Misconceptions

Misconceptions regarding the value of antioxidant therapy abound, given the complexities of antioxidant–free radical interactions and the confusing state of the science generated by inconsistent research results, along with the passionate and often extreme views on both sides of the antioxidant debate.

In an attempt to refocus the energy of the research community towards investigating where the real therapeutic potential of antioxidant interventions lies so that good opportunities aren’t missed, Aalt Bast and Guido R.M.M. Haenen from Maastricht University in the Netherlands wrote an opinion piece addressing what they feel are common misconceptions regarding antioxidants.⁴ Let’s address three such considerations, below:

Antioxidants Cure All Disease

The first of these misconceptions is the concept that antioxidants are the cure for all disease conditions. While it’s true that reactive oxygen species and other free radicals play a role in a number of health conditions, antioxidants are unlikely to be the cure for most conditions. Scientists’ initial exuberance based on early (in vitro, animal, preclinical) studies led marketers to make exaggerated and unrealistic claims, which has ultimately resulted in consumer disappointment as well as disillusionment of many researchers in the field.

Expectations for these compounds as a cure-all were set too high as results from initial laboratory studies were extrapolated to potential results in the human body. These results often don’t translate directly for a number of reasons-a primary one being that the bioavailability of certain compounds (polyphenols, for example) appears to be extremely low.

Species-specific differences in research were also often inadequately accounted for. For example, it seems that mice may be more sensitive to the effects of antioxidant compounds than humans are, so extrapolating results from animal studies to humans has proven difficult. Thus, while antioxidant interventions are relevant for a number of health conditions, it turns out they aren’t the panacea they were once expected to be.

The More, The Better

Another trend in antioxidant research has been using increasingly higher doses to achieve a desired effect. This has given rise to the misconception of “the more, the better.”

Antioxidant dosing is something that should be evaluated based on available safety and efficacy data per compound; it can’t be assumed that higher doses will give more benefit across the board. Also, higher doses may yield toxic effects, potentially leading to adverse outcomes.

Furthermore, a greater targeted antioxidant effect may lead to an over-suppression of free radical formation-a certain level of which is necessary for metabolism. Thus, applying the concept of “the more, the better” is not appropriate, and serious research consideration needs to be given to identify the dose conferring the best benefit-to-risk ratio.

Any Antioxidant Will Do

The term antioxidant is a general descriptive term that doesn’t account for the diverse mechanism and sites of action of the distinct chemical compounds falling under this category. For example, certain antioxidants can be hydrophilic, while others act better in a lipid environment. Similarly, these compounds often target distinct free radical species.

These different sites of action and biological activities give each compound a unique biochemical profile, which is an important consideration when selecting the right antioxidant combination for a specific indication. Another aspect for consideration in this regard is that selection of an incorrect antioxidant may imbalance endogenous protective mechanisms, especially when these compounds are administered at high doses. This makes selecting the right set of compounds at the correct doses even more critical in order for consumers to realize their therapeutic benefit.

Indeed, given these misconceptions and extreme positions on both sides of the antioxidant debate, recalibrating expectations and aligning them on the basis of well-conducted research studies is critical in enhancing our understanding of the true role these compounds play in health and disease. Numerous studies in cells, animals, and humans point to the beneficial effects of antioxidants.² This research should be reconciled in a manner which leads to continuous refinement of research directions to understand how best to apply these findings in clinical situations and confer maximum potential benefit. Furthermore, understanding conditions in which oxidative stress is at levels higher than “normal” through the development of standardized assessment tools may yield greater insight into specific conditions and individuals that will ultimately benefit from antioxidant supplements.⁵

Clearly, ongoing research in many significant areas attests to the usefulness of antioxidant therapy in health and disease. Some of these include cardiovascular health and neurodegenerative conditions. Furthermore, recent studies continue to yield interesting findings regarding the benefits of antioxidant consumption.

Lutein and Lycopene for Atherosclerosis

Lutein is a carotenoid compound in the class known as xanthophylls and is best known for its significant benefits to eye health. Lycopene is a carotenoid best known for its potential benefits to prostate health. Both carotenoids also confer significant antioxidant protection. Research is now examining the potential benefits of both compounds in the realm of cardiovascular health.

Zhi-Yong Zou and colleagues from the School of Public Health at Peking University in Beijing, China, evaluated the impact of lutein or lycopene supplementation in individuals with subclinical atherosclerosis.⁶ The investigators included 144 subjects between the ages of 45 and 68 with subclinical atherosclerosis in the trial. They looked at the effect of supplementation on carotid intima-media thickness (thickness of the inner walls of the carotid artery) to assess the progression of atherosclerosis. Participants were assigned to receive 20 mg of lutein, 20 mg of lutein plus 20 mg of lycopene, or a placebo supplement daily for 12 months.

Using Doppler ultrasound at baseline and after 12 months of supplementation, the researchers found statistically significant decreases in carotid intima-media thickness in both the lutein and the lutein-plus-lycopene groups, while no significant change was seen in the placebo group. The combination group saw more than twice the decrease in arterial intima thickness than the group supplemented with lutein alone, suggesting a synergistic benefit of the two antioxidants in reducing atherosclerotic progression.

Antioxidants for Male Fertility

Estimates suggest that one in 20 men will be affected by decreased fertility due to the impact of oxidative stress on sperm function. Sperm are particularly susceptible to damage as a result of oxidative stress, as their cell membranes are rich in fatty acids, which are readily affected by lipid peroxidation. This leads to damage of the sperm membrane, impacting sperm motility and the ability of sperm to penetrate the female egg cell membrane, as well as alterations to the sperm DNA. Decreased fertility is a significant factor impacting the ability of couples to conceive.

Antioxidant supplements such as coenzyme Q10, vitamin C, n-acetylcysteine, and L-carnitine have shown promise in reversing the effects of oxidative stress in sperm and improving chances of conception in couples.

A recent Cochrane Review assessed studies in which subfertile male partners of couples seeking fertility assistance were supplemented with antioxidants.⁷ In three trials, the partners of men taking oral antioxidant supplements experienced a statistically significant increase in live birth rate compared to partners of men in the control group, with an odds ratio of 4.85. An analysis of a further 15 trials including 964 couples found that antioxidant supplementation significantly increased pregnancy rate (odds ratio of 4.18). These positive findings suggest substantial benefits in fertility associated with antioxidant supplementation in male partners of couples undergoing assisted fertility techniques.

Oral Glutathione Supplements in Humans

Glutathione is the major endogenous antioxidant compound in the body and is often referred to as the “master antioxidant” because of its crucial role in detoxification processes and as a protector against the development of disease. Given its importance in the body as a regulator of the endogenous antioxidant system, research interest has been high regarding the potential of a glutathione supplement to raise endogenous glutathione levels.

Studies in certain animal models have shown that oral glutathione supplements can be absorbed and can then raise plasma and tissue levels of glutathione. However, whether such supplements behave similarly in humans has been a matter of debate. A recent study published by John Richie and colleagues from Penn State University College of Medicine may provide some of the first direct evidence that glutathione from oral supplements is capable of increasing plasma glutathione levels as well as tissue stores.⁸

The study was conducted as a six-month, randomized, placebo-controlled trial in 54 adults aged 30–79. Subjects received either 250 mg or 1000 mg of Setria glutathione (from ingredient supplier Kyowa Hakko USA; New York City) or a placebo daily.

Glutathione levels in blood, plasma, red blood cells, white blood cells, and buccal mucosal cells were assessed at baseline and at 1, 3, and 6 months. At six months, glutathione concentrations significantly increased in all tissues in the high-dose group, while significant increases were also noted in the low-dose group in blood and red blood cell glutathione stores.

The researchers further noted a reduction in levels of oxidative stress as measured by a decrease in the ratio of oxidized glutathione to reduced glutathione after six months in both supplemental groups. This study is significant in that it showed for the first time that oral glutathione supplements increase blood and tissue levels in humans and are subsequently associated with a reduction in oxidative stress.

Managing Expectations

Antioxidant consumption through diet and supplementary means continues to hold significant therapeutic potential. Given a greater understanding of the endogenous antioxidant defense system, it is hopeful that researchers on both sides of the antioxidant debate can cut through the hyperbole and focus on the true therapeutic potential of antioxidant compounds and how they should be administered.

Managing expectations by focusing on sound research, and not hyping these critical nutritional compounds as cure-alls or panaceas, will allow clinicians and individuals to use antioxidant supplements wisely as a part of a comprehensive health regimen.

References

1. Singh PP et al., “Reconvene and reconnect the antioxidant hypothesis in human health and disease,” Indian Journal of Clinical Biochemistry, vol. 25, no. 3 (July 2010): 225–243.
2. Carocho M et al., “A review on antioxidants, prooxidants and related controversy: natural and synthetic compounds, screening and analysis methodologies and future perspectives,” Food and Chemical Toxicology, vol. 51 (January 2013): 15–25.
3. Pietta PG, “Flavonoids as antioxidants.” Journal of Natural Products, vol. 63 (2000): 1035–1042.
4. Bast A et al., “Ten misconceptions about antioxidants,” Trends in Pharmacological Sciences, vol. 34, no. 8 (August 2013): 430–436.
5. Poljsak B., “Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants,” Oxidative Medicine and Cellular Longevity, (2013) 956792.
6. Zou ZY et al., “Effects of lutein and lycopene on carotid intima-media thickness in Chinese subjects with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial,” British Journal of Nutrition, vol. 111, no. 3 (February 2014): 474–480.
7. Showell MG et al., Cochrane Database of Systematic Reviews, (2011) CD007411.
8. Richie JP et al., “Randomized controlled trial of oral glutathione supplementation on body stores of glutathione,” European Journal of Nutrition (2014). Published online ahead of print May 5, 2014.  

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