Harvard School of Public Health
IntroductionThe 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.
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. 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.
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.
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.
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. 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. 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.
Beta-carotene, meanwhile, did not provide any protection against heart disease or stroke, as demonstrated by the Physicians' Health Study.
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.
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.
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.
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.