The War on Radicals

By Sarah Richardson|Friday, July 01, 1994
RELATED TAGS: AGING, SUBATOMIC PARTICLES
Free radicals are bad: flies live longer without them. But smokers live longer without vitamin pills. Broccoli remains a good idea.

One of the central ironies of our lives has to do with our metabolism: we need oxygen to extract energy from food, yet oxygen kills us in the end. At least that is what some biologists have suspected for more than 40 years now. As an accident of oxygen respiration, the theory goes, we produce aggressively reactive molecules called free radicals, which then proceed to attack our DNA, our proteins, and the fatty membranes of our cells. The mounting cellular damage weakens and withers us as we age. It also makes us more susceptible to cancer and heart disease.

This venerable theory of aging has lately been the subject of conflicting news. On the one hand, after all these years the theory has passed its first direct test, done by biologists at Southern Methodist University. Working with fruit flies, they proved that boosting levels of free-radical-fighting enzymes through genetic engineering can slow down aging and lengthen life span. On the other hand, the implication of the theory that matters most to human beings--that it is possible to fight free radicals by taking plenty of vitamins--has recently taken a knock. A study of 29,000 smokers in Finland found that their risk of contracting lung cancer actually increased substantially when they took supplements of beta- carotene, a precursor of vitamin A.

Even in the flap that followed the announcement of the Finnish results, however, no one was questioning the potential of free radicals to do damage. Free radicals are damaging because they are reactive, and they are reactive because they are molecules with an extra unpaired electron. Radiation, cigarette smoke, and pollution can all convert various molecules into free radicals. But the most common one in the human body is the oxyradical. It’s produced whether we like it or not, says SMU biologist William Orr, because we breathe oxygen.

The oxyradical is formed in the mitochondria, the cellular engines that ultimately turn a meal into a walk around the park. Within the mitochondria, high-energy electrons are harvested from carbohydrates and other food. They are then shuffled through a cascade of reactions that extract energy from the electrons and use it to make ATP, the molecule that fuels most cellular work. Oxygen’s job is to catch the electrons at the end of the cascade. The problem, says Orr, is that as much as 3 percent of the time, an oxygen molecule catches one electron too many.

That makes for some bad chemistry. Instead of being hungry for electrons, like normal oxygen, an oxyradical is desperate to hook up with any molecule that will solve the problem of its extra electron. It can latch onto the cell’s DNA, for example, and thereby alter or even break the fragile double helix. It can yank a positively charged proton off a lipid molecule in the cell membrane--and the lipid may then steal a proton from its neighbor, and so on down the line until there is a trail of deformation in the membrane. If the damage spreads to one of the many proteins that form channels through the membrane, it can block traffic in and out of the cell.

As damage accumulates, cells falter. Sometimes they die. Cells that do not reproduce, such as those in muscle tissue, the brain, and the lens of the eye, may be particularly vulnerable. Damage to these cells may explain why we get weak, become senile, and acquire cataracts as we age. The loss of normal function may also disrupt the cell’s defenses against cancerous growth.

Humans and fruit flies fight back, says Orr, with antioxidants: enzymes and vitamins that mop up free radicals before they do harm. An enzyme called superoxide dismutase, for instance, disarms the oxyradical by converting it to hydrogen peroxide. But if too much hydrogen peroxide builds up, it can produce more free radicals. So another enzyme, catalase, splits hydrogen peroxide into water and oxygen. The two enzymes work together.

To see how well they work, and to directly test the free-radical theory of aging, Orr and his colleague Rajindar Sohal first created two kinds of mutant flies--one with an extra copy of the gene for superoxide dismutase, the other with an extra gene for catalase. Then they watched to see if the extra enzyme produced by the added gene would allow the flies to live longer. We observed very minor effects, says Orr. More flies lived to be older than normal, but none outlived the longest normal life span, which is 71 days.

But when he and Sohal crossed the two mutants and produced offspring that carried extra copies of both genes, they got a very different result. The souped-up flies not only lived nearly one-third longer--up to 91 days--but were spry enough to match the pace of younger flies crawling up the side of a glass beaker. We think the flies are happier, says Orr. And since the two enzymes have no known function other than to disable free radicals, the results offer direct support for the theory that free radicals promote aging, at least in fruit flies.

No one has done the human equivalent of Orr’s enzyme-boosting experiment. But people around the world are experimenting every day with boosting the body’s second line of defense against free radicals: vitamins like folic acid, A, C, and E. These vitamins attack free radicals in a different way from enzymes; they absorb the extra electron without becoming free radicals themselves, and thus they stop the destructive chain reaction. But unlike enzymes, they aren’t made in the body. They have to be extracted from food or taken in supplements.

There is no hard evidence yet that antioxidant vitamins retard aging per se, but a few epidemiological studies have linked a higher intake of vitamins with a lower risk of heart disease, and around 200 such studies have found a reduced risk of cancer. While in most of these studies the source of vitamins was food, in others it was vitamin pills. Just last fall researchers working in China reported the results of a large clinical trial of vitamin supplements. They found a significantly decreased risk of cancer among 30,000 people who took a combination of beta-carotene (which the body converts to vitamin A), vitamin E, and selenium every day for over five years.

It was against this backdrop of near consensus that the results of the Finnish study, reported this spring in the New England Journal of Medicine, were so disturbing. The six-year clinical trial had one clear advantage over the Chinese study: many of the Chinese subjects suffered from nutritional deficiencies, which inevitably left doubt as to whether the benefits of vitamin supplements would prove as great in a well- nourished population. The 29,000 men in the Finnish study were all well fed. On the other hand, they were also all smokers over the age of 50. The researchers chose that population because they were specifically looking for evidence that vitamin supplements could reduce the risk of lung cancer. A statistically significant reduction was more likely to show up, they figured, in a population that could expect more cases of lung cancer to begin with.

As it turned out, the researchers did not have to worry about whether they had seen a significant reduction in lung cancer risk--because they saw no reduction at all. For six years the Finnish men were given one of four treatments, to which they were randomly assigned: 20 milligrams of beta-carotene a day, 50 milligrams of vitamin E, both the beta-carotene and the vitamin E, or a placebo. The results were not all bad, at least as far as vitamin E was concerned. It provided no protection against lung cancer and even led to a moderately increased risk of hemorrhagic stroke (bleeding in the brain). But the men who took it, either alone or with beta-carotene, had a 34 percent lower risk of prostate cancer and a 16 percent lower risk of colorectal cancer than the control group. The most startling finding, however, concerned the subjects receiving beta-carotene. They had an 18 percent higher risk of lung cancer than the control group.

The results may simply be a statistical fluke. One clinical trial, everyone agrees, proves nothing. The first large study of the effects of aspirin on heart attack survivors, for instance, suggested that it actually increased their risk of a second attack--but after many more trials, aspirin is now routinely given to such patients. We have to wait and see what other tests demonstrate, says Demetrius Albanes, a researcher at the National Cancer Institute and a leader of the Finnish study.

But if the Finnish results are real, no one has a good explanation for them yet. That vitamin E might increase the risk of hemorrhagic stroke makes a kind of sense, according to Albanes, because vitamin E is thought to reduce the stickiness of blood platelets and thus to promote bleeding. The idea that beta-carotene might promote rather than discourage lung cancer, though, caught everyone by surprise. Maybe, some researchers have suggested, beta-carotene has a different effect on smokers than on nonsmokers. Or maybe it is possible to lose too many free radicals; our own immune cells, after all, are thought to use them as weapons against disease.

Or maybe we will never understand the antioxidant effects of vitamins until we understand how they work in concert. We just don’t know that much about all the things that are going on in the second line of defense, says Orr. If you add so much of one vitamin, you might lower the effect of another. And overall you might be actually reducing the antioxidative defenses.

In the end, and especially after Orr’s experiments with fruit flies, most researchers would probably agree that free radicals contribute to aging and disease, and no one much doubts that eating a lot of vitamin- rich fruits and vegetables is a good idea. Interestingly enough, the Finnish study confirmed this conventional wisdom even as it was casting doubt on the value of beta-carotene supplements: among the placebo takers in the study, those who had the highest levels of vitamin E and beta- carotene in their blood at the start of the study--as a result of the food they ate--had a 20 to 30 percent lower risk of lung cancer than placebo takers who ate few or no vegetables. It may be, says Albanes, that you need to take the whole spectrum of nutrients in the form of a food in order to get the benefits.

Ours is only one study, but it gives a very surprising result, he says, referring to the negative effect of beta-carotene. It should probably throw an element of caution into the frenzy that has taken place over the past few years about claims that these vitamins can prevent just about everything.
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