Table of Contents
The body’s trillion or so cells face formidable threats, from lack of food to infection with a virus. Another constant threat comes from nasty chemicals called free radicals. They are capable of damaging cells and genetic material. The body generates free radicals as the inevitable byproducts of turning food into energy. Others are in the food you eat and the air you breathe. Some are generated by sunlight’s action on the skin and eyes.
Free radicals come in many shapes, sizes, and chemical configurations. What they all share is a voracious appetite for electrons, stealing them from any nearby substances that will yield them. This electron theft can radically alter the “loser’s” structure or function. Free radical damage can change the instructions coded in a strand of DNA. It can make a circulating low-density lipoprotein (LDL, sometimes called bad cholesterol) molecule more likely to get trapped in an artery wall. Or it can alter a cell’s membrane, changing the flow of what enters the cell and what leaves it.
We aren’t defenseless against free radicals. The body, long used to this relentless attack, makes scads of molecules that quench free radicals as surely as water douses fire. We also extract free-radical fighters from food. These defenders are often lumped together as “antioxidants.” They work by generously giving electrons to free radicals without turning into electron-scavenging substances themselves.
There are hundreds, probably thousands, of different substances that can act as antioxidants. The most familiar ones are vitamin C, vitamin E, beta-carotene, and other related carotenoids, along with the minerals selenium and manganese. They’re joined by glutathione, coenzyme Q10, lipoic acid, flavonoids, phenols, polyphenols, phytoestrogens, and many more.
But using the term “antioxidant” to refer to substances is misleading. It is really a chemical property, namely, the ability to act as an electron donor. Some substances that act as antioxidants in one situation may be prooxidants—electron grabbers—in a different chemical milieu. Another big misconception is that antioxidants are interchangeable. They aren’t. Each one has unique chemical behaviors and biological properties. They almost certainly evolved as parts of elaborate networks, with each different substance (or family of substances) playing slightly different roles. This means that no single substance can do the work of the whole crowd.
Antioxidants came to public attention in the 1990s, when scientists began to understand that free radical damage was involved in the early stages of artery-clogging atherosclerosis and may contribute to cancer, vision loss, and a host of other chronic conditions. Some studies showed that people with low intakes of antioxidant-rich fruits and vegetables were at greater risk for developing these chronic conditions than were people who ate plenty of these fruits and vegetables. Clinical trials began testing the impact of single substances, especially beta-carotene and vitamin E, as weapons against heart disease, cancer, and the like.
Even before the results of these trials were in, the media, and the supplement and food industries began to hype the benefits of “antioxidants.” Frozen berries, green tea, and other foods labeled as being rich in antioxidants began popping up in stores. Supplement makers touted the disease-fighting properties of all sorts of antioxidants.
The trials were mixed, but most have not found the hoped-for benefits. Most research teams reported that vitamin E and other antioxidant supplements didn’t protect against heart disease or cancer (18) One study even showed that taking beta-carotene may actually increase the chances of developing lung cancer in smokers. On the other hand, some trials reported benefits; for example, after 18 years of follow-up, the Physicians’ Health Study found that taking beta-carotene was associated with a modest reduction in the rate of cognitive decline. (1)
These mostly disappointing results haven’t stopped food companies and supplement sellers from banking on antioxidants. Indeed, antioxidant supplements represent a $500 million dollar industry that continues to grow. Antioxidants are still added to breakfast cereals, sports bars, energy drinks, and other processed foods, and they are promoted as additives that can prevent heart disease, cancer, cataracts, memory loss, and a host of other conditions.
Often the claims have stretched and distorted the data: While it’s true that the package of antioxidants, minerals, fiber, and other substances found naturally in fruits, vegetables, and whole grains helps prevent a variety of chronic diseases, it is unlikely that high doses of antioxidants can accomplish the same feat.
Randomized, placebo-controlled trials—which, when performed well, provide the strongest evidence—offer little support that taking vitamin C, vitamin E, beta-carotene, or other single antioxidants provides substantial protection against heart disease, cancer, or other chronic conditions. The results of the largest such trials have been mostly negative.
Vitamin E, beta-carotene, and other so-called antioxidants aren’t the silver bullet against heart disease and stroke that researchers were hoping for. Although the final chapter has not been written on vitamin E.
In the Women’s Health Study, 39,876 initially healthy women took 600 IU of natural source vitamin E or a placebo every other day for 10 years. At the study’s end, the rates of major cardiovascular events and cancer were no lower among those taking vitamin E than they were among those taking the placebo. However, the trial did observe a significant 24 percent reduction in total cardiovascular mortality. Although this was not a primary endpoint for the trial, it nevertheless represents an extremely important outcome. (2)
Earlier large vitamin E trials, conducted among individuals with previously diagnosed coronary disease or at high risk for it, generally showed no benefit. In the Heart Outcomes Prevention Evaluation (HOPE) trial, the rates of major cardiovascular events were essentially the same in the vitamin E (21.5 percent) and placebo (20.6 percent) groups, although participants taking vitamin E had higher risks of heart failure and hospitalization for heart failure. (3) In the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI) trial, the results were mixed but mostly showed no preventive effects after more than three years of treatment with vitamin E among 11,000 heart attack survivors.(4) However, some studies suggest potential benefits among certain subgroups. A recent trial of vitamin E in Israel, for example, showed a marked reduction in coronary heart disease among people with type 2 diabetes who have a common genetic predisposition for greater oxidative stress. (5)
A 2014 study from the Journal of Respiratory Research found that different isoforms of vitamin E (called tocopherols) had opposing effects on lung function (20)
- The study analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort and measured serum levels of alpha and gamma tocopherol in 4,526 adults
- Lung function was tested using spirometric parameters- Higher parameters are indicative of increased lung function, lower parameters are indicative of decreased lung function
- The study found that higher serum levels of alpha tocopherol were associated with higher spirometric parameters and that high serum levels of gamma tocopherol were associated with lower spirometric parameters.
- Though the study is observational in nature it confirmed the mechanistic pathway of alpha and gamma tocopherol in mice studies (21)
Beta-carotene, meanwhile, did not provide any protection against heart disease or stroke, as demonstrated by the Physicians’ Health Study. (6)
What about combinations? The findings are complicated and not entirely clear. In the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) study, 13,017 French men and women took a single daily capsule that contained 120 milligrams of vitamin C, 30 milligrams of vitamin E, 6 milligrams of beta-carotene, 100 micrograms of selenium, and 20 milligrams of zinc, or a placebo, for seven and a half years. The vitamins had no effect on overall rates of cardiovascular disease. (7)
In the Women’s Antioxidant Cardiovascular Study, vitamin E, vitamin C, and/or beta-carotene had much the same effect as a placebo on myocardial infarction, stroke, coronary revascularization, or cardiovascular death, although there was a modest and significant benefit for vitamin E among women with existing cardiovascular disease. (8)
When it comes to cancer prevention, the picture remains inconclusive for some antioxidant supplements. Few trials have gone on long enough to provide an adequate test for cancer. In the long-term Physicians’ Health Study, cancer rates were similar among men taking beta-carotene and among those taking a placebo. (6) Other trials have also largely showed no effect, including HOPE. (3) The SU.VI.MAX trial (7) showed a reduction in cancer risk and all-cause mortality among men taking an antioxidant cocktail but no apparent effect in women, possibly because men tended to have low blood levels of beta-carotene and other vitamins at the beginning of the study. A randomized trial of selenium in people with skin cancer demonstrated significant reductions in cancer and cancer mortality at various sites, including colon, lung, and prostate. (9) The effects were strongest among those with low selenium levels at baseline.
This is the one bright spot for antioxidant vitamins. A six-year trial, the Age-Related Eye Disease Study (AREDS), found that a combination of vitamin C, vitamin E, beta-carotene, and zinc offered some protection against the development of advanced age-related macular degeneration, but not cataract, in people who were at high risk of the disease. (10, 11) Lutein, a naturally occurring carotenoid found in green, leafy vegetables such as spinach and kale, may also protect vision. However, relatively short trials of lutein supplementation for age-related macular degeneration have yielded conflicting findings. (12, 13) A new trial of the AREDS supplement regimen plus lutein, zeaxanthin, and fish oil is underway. This trial could yield more definitive information about antioxidants and macular degeneration. (14)
If antioxidants were harmless, it wouldn’t much matter if you took them “just in case.” A few studies, though, have raised the possibility that taking antioxidant supplements, either single agents or combinations, could interfere with health. The first inkling came in a large trial of beta-carotene conducted among men in Finland who were heavy smokers, and therefore at high risk for developing lung cancer. The trial was stopped early when researchers saw a significant increase in lung cancer among those taking the supplement compared to those taking the placebo. (15) In another trial among heavy smokers and people exposed to asbestos, beta-carotene was combined with vitamin A. Again an increase in lung cancer was seen in the supplement group. (16) Not all trials of beta-carotene show this harmful effect, however. In the Physicians’ Health Study, which included few active smokers, no increase in lung cancer or any other adverse affect was seen even after 18 years of follow-up. (6)
Another possible red flag: In the SU.VI.MAX trial, rates of skin cancer were higher in women who were assigned to take vitamin C, vitamin E, beta-carotene, selenium, and zinc. (17)
Free radicals contribute to chronic diseases from cancer to heart disease and Alzheimer’s disease to vision loss. This doesn’t automatically mean that substances with antioxidant properties will fix the problem, especially not when they are taken out of their natural context. The studies so far are inconclusive, but generally don’t provide strong evidence that antioxidant supplements have a substantial impact on disease. But keep in mind that most of the trials conducted up to now have had fundamental limitations due to their relatively short duration and having been conducted in persons with existing disease. That a benefit of beta-carotene on cognitive function was seen in the Physicians’ Health Follow-up Study only after 18 years of follow-up is sobering, since no other trial has continued for so long. At the same time, abundant evidence suggests that eating whole fruits, vegetables, and whole grains—all rich in networks of antioxidants and their helper molecules—provides protection against many of these scourges of aging.
1. Grodstein F, Kang JH, Glynn RJ, Cook NR, Gaziano JM. A randomized trial of beta-carotene supplementation and cognitive function in men: the Physicians’ Health Study II. Arch Intern Med. 2007; 167:2184–90.
2. Lee IM, Cook NR, Gaziano JM, et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women’s Health Study: a randomized controlled trial. JAMA. 2005; 294:56–65.
3. Lonn E, Bosch J, Yusuf S, et al. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA. 2005; 293:1338–47.
4. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. 1999; 354:447–55.
5. Milman U, Blum S, Shapira C, et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype. A prospective double-blinded clinical trial. Arterioscler Thromb Vasc Biol. 2007:ATVBAHA.107.153965.
6. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996; 334:1145–49.
7. Hercberg S, Galan P, Preziosi P, et al. The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med. 2004; 164:2335–42.
8. Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta-carotene in the secondary prevention of cardiovascular events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern Med. 2007; 167:1610–18.
9. Duffield-Lillico AJ, Reid ME, Turnbull BW, et al. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: A summary report of the nutritional prevention of cancer trial. Cancer Epidemiol Biomarkers Prev. 2002; 11:630–39.
10. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001; 119:1417-36.
11. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta-carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001; 119:1439-52.
12. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004; 75:216-30.
13. Bartlett HE, Eperjesi F. Effect of lutein and antioxidant dietary supplementation on contrast sensitivity in age-related macular disease: a randomized controlled trial. Eur J Clin Nutr. 2007; 61:1121-27.
14. Age Related Eye Disease Study 2 (AREDS2). National Eye Institute.
15. Albanes D, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst. 1996; 88:1560-70.
16. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996; 334:1150-55.
17. Hercberg S, Ezzedine K, Guinot C, et al. Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr. 2007; 137:2098-105.
18. Semba RD, Ferrucci L, Bartali B, Urpi-Sarda M, Zamora-Ross R, Sun K, Cherubini A, Bandinelli S, Andres-Lacueva C. Resveratol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med. 174(7):1077-84
19. Dysken MW, Sano M, Asthana S, et al. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial. JAMA. 2014;311(1):33-44.
20. Marchese ME, Kumar R,Colangelo LA, Avila PC, Jacobs DR Jr, Gross M, Sood A, Lui K, Cook-Mills JM. The vitamin E isoforms α-tocopherol and γ-tocopherol have opposite associations with spirometric parameters: the CARDIA study. Respiratory Research 182(7):4395-405.
21. Berdnikovs S, Abdala-Valencia H, McCary C, Somand M, Cole R, Garcia A, Bryce P, Cook Mills JM. Isoforms of vitamin E have opposing immunoregulatory functions during inflammation by reducing leukocyte recruitment. J Immunol. 182(7):4395-405
The aim of the Harvard T.H. Chan of Public Health Nutrition Source is to provide timely information on diet and nutrition for clinicians, allied health professionals, and the public. The contents of this Web site are not intended to offer personal medical advice. You should seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this Web site. The information does not mention brand names, nor does it endorse any particular products.