Oxidants - the by-products of human metabolism - deliver damaging blows to the cells' DNA. Repair enzymes cut out much of the damage, but eventually time takes its toll. Oxidative attacks on the cells' DNA outpace the ability of enzymes to remove lesions. The cumulative damage is believed to be a major factor in the development of certain cancers and other aging-related illnesses, such as cardiovascular disease.
But in recent years, scientists have pointed to the disease prevention potential of antioxidant properties found in certain nutrients, most notably vitamins C and E and beta carotene. As a result, fruits and vegetables that contain these compounds have taken a prominent place in contemporary recommendations to promote good health and prevent disease.
"This is what mothers have known all along," says Bruce Ames, Ph.D., professor of biochemistry and molecular biology and director of the National Institute of Environmental Health Sciences Center at the University of California, Berkeley.
For more than 20 years, Ames has been an international leader in the field of mutagenesis and genetic toxicology. He was on the board of directors of the National Cancer Institute, is a member of the National Academy of Sciences, and has been elected to the Royal Swedish Academy of Sciences and the Japan Cancer Association. In 1972, he developed a method now used in major drug and chemical companies to detect potential chemical carcinogens with bacterial cultures instead of by lengthy, expensive animal testing.
He has probed the cancer-causing potential of pesticides, pollution, synthetic food additives, and even metabolic rates in animals and humans. During his career, Ames has espoused some controversial viewpoints: Polluted air and water pose very small cancer risks: 99.9% of the toxic chemicals people are exposed to come from natural sources, such as the plants they eat; and pesticides help reduce cancer rates because they cut the cost of fruits and vegetables thereby boosting their consumption.
With controversies on the value of dietary supplements of antioxidants and interpretation of various research results far from resolved, Ames here offers a few thoughts on the role of fruits, vegetables, and antioxidants in disease prevention and how physicians might respond to patients' questions on the subject.
JAMA: You recently were quoted as saying that "the gold" in disease prevention, particularly cancer prevention, is in diet and nutrition. Why is that the case?
Dr. Ames: The beneficial effects of fruit and vegetable consumption are so large when it comes to health. People in the bottom quartile of dietary intake of fruits and vegetables have twice the cancer rate for most types of cancer as people in the top quartile. People in the top quartile were consuming in the range of the two fruits and three vegetables we should be eating every day. We also should be eating less animal fat.
Gladys Block [a Berkeley researcher on cancer and nutrition, formerly with the National Cancer Institute] recently reviewed 172 epidemiologic studies from around the world that had been done on diet and cancer; usually they divide the population up into quartiles. She looked at all of this and it's amazingly consistent, the huge protective effect that fruit and vegetable consumption confers for practically every type of cancer. There is a twofold to threefold difference between the lowest and the highest quartiles of fruit and vegetable intake. For practically every type of cancer, your risk is double if you eat few fruits and vegetables compared with eating lots of them. One of the exceptions is breast cancer - there is a smaller beneficial effect from fruit and vegetable intake.
JAMA: Is diet as important in the prevention of other diseases as it may be in cancer?
Dr. Ames: Absolutely. The rates of heart disease and cataracts are much higher in people not eating enough fruits and vegetables. I think all of the degenerative diseases of aging will be minimized by a good diet. We get our vitamins and micronutrients from fruits and vegetables in a balanced diet. 1 don't think it's the whole story, but it will be a major factor in aging and therefore in all of these degenerative diseases.
JAMA: In the past couple of years antioxidants - vitamins E, C, and beta carotene - have captured public attention as potential cancer preventives. What recommendations should physicians make when patients inquire about their use, including dosages?
Dr. Ames: If you don't get enough antioxidants, it is the equivalent of irradiating yourself. I'm not sold on mega-doses of vitamins, but moderate doses are probably helpful - for example, a pill containing the recommended daily allowance (RDA) of each vitamin. It's inexpensive insurance, and telling people to take a multivitamin is pretty conservative advice.
A little extra vitamin E and C is more likely to help than harm, in my view - perhaps in the range of 400 units of vitamin E and 250 mg of vitamin C, but this is still somewhat controversial. Beta carotene is probably better to get from fruit and vegetables. But for anyone who wants to take an additional small amount, that's probably all right.
JAMA: Some experts/studies suggest that the antioxidant properties of supplements are not as effective as when the nutrient it consumed in foods. Have you found evidence that this is true?
Dr. Ames: At the moment, we haven't identified all of the compounds in foods that have antioxidant properties or which foods may have the highest levels of these compounds. Eventually we will. But that's why some people feel that you shouldn't just be taking vitamins without eating fruits and vegetables.
Eventually we also will determine proper dosages for nutritional supplements, and I suspect it will be useful to take more than we're getting now. Maybe older people or people under oxidative stress especially will need more; smokers need to take a lot more antioxidants than nonsmokers. People who eat more fruits and vegetables get half the lung cancer per given amount of smoking compared with the people who eat less. So there's clearly some big interaction. Plus smoking depletes all your antioxidants. That's known, it's an oxidative stress.
JAMA: What about research from Finland published last year that showed male smokers who took beta carotene supplements had more lung cancer than men taking placebo, and that vitamin E had no beneficial effect?
Dr. Ames: In the Finnish study, the participants had been smoking for 30 years. Most of the damage already had been done, and then [the researchers] gave them very small amounts of vitamin E. I don't think it was that definitive an experiment. Plus, they didn't give them any extra vitamin C. Finns don't eat a lot of fruit and vegetables, and C and E are needed together. It was a well done experiment, but I just don't feel it is the last word.
JAMA: What do you think is on the horizon concerning diagnostic tests to measure levels in the body of so-called scavenger enzymes, such as superoxide dismutase (SOD), that inactivate cell-damaging free radicals released during oxidation?
Dr. Ames: That's measuring genetic differences in individuals. It's worth working on, but I don't see that coming into regular clinical use. Measuring SOD or other antioxidant enzymes in individuals is very expensive and not likely to be very useful, at least at the present time.
What would be extremely useful is for physicians to routinely assay levels of vitamins or other biochemical markers, such as the homocysteine level, that indicate food imbalance. It would also be useful to measure the amount of smoking and ethanol consumption by appropriate assay; you could measure acetaldehyde from drinking and nicotine from smoking. That's where we could really make progress. Instead, physicians ask patients about their risk factors for disease and depend on the accuracy of their answers. With these assays, physicians quickly could determine whether patients have sufficient level of folic acid, ascorbate, vitamin E, and other beneficial nutrients. That is the future of preventive medicine.
These types of tests represent a more serious attempt at disease prevention. No one is doing this kind of testing now, but if physicians really are going to be involved with prevention, they will have to look at patients' biochemical parameters. These tests also will tell you how much oxidative stress there is. Patients who are smokers are using up folate and vitamins C and E, and they need more. Assays should be available soon, and they shouldn't be expensive. This is going to have a big impact.
JAMA: If such diagnostic tests are reliable, what are the implications for potential therapeutic approaches?
Dr. Ames: With assays to measure biochemical markers in blood, physical examinations would include monitoring of the patient's metabolism as well as more standard indicators of health, such as heart rate. The physician then might tell the patient, "You have less than 4 ng/mL of folate in your blood. That is the level that causes chromosome breaks and increases your risk for cancer."
We've just developed an assay to measure aldehydes coming out of lipid peroxidation, and there will be many others on the market. Equipment is being developed to analyze all of these assays inexpensively, the way it's done now with automated biochemical panels. The trick will be in deciding which tests are the most critical. Antioxidants and folate are important; maybe we also should measure some end-products of oxidation.
Routine testing is important because we have huge numbers of people at risk for chromosome breakage because of folate deficiencies. Currently, 15% of the population and about half of poor African Americans in the United States are folate deficient. And, if they don't get enough ascorbate, it's the same as stepping unprotected in front of an x-ray machine. These are important things for preventive medicine.
Of course, physicians can just ask about health behaviors, such as diet and smoking, but that's not as reliable as actually measuring levels of biochemicals. Psychologically, I think it's more effective when a printed report shows a patient if he or she is in the bottom 10% or 20% of folate levels where there is chromosomal damage.
JAMA: Patients would like to believe there is a "magic bullet" that can delay or prevent disease and aging, and some news accounts give the impression that antioxidants may be that magic bullet. Please explain the limitations of antioxidants in disease prevention.
Dr. Ames: There are three magic bullets: Don't smoke, eat a good diet, and exercise.
JAMA: Where do environmental factors, such as diet, exercise, or smoking, leave off and individual genetic factors begin?
Dr. Ames: Genetics obviously plays a role. We're learning that with heart disease and the people who have a genetic constitution that makes them more susceptible. We need to learn more about people who are at risk because of their genetic makeup and what happens in different interactions with the environment. But I think right now we know what to do. We have three big killers out there - smoking, bad diet, and to a lesser extent, sedentary lifestyles. We need to be constantly pushing patients to improve in these areas.
JAMA: Only 9% of Americans eat the recommended two servings of fruit and three of vegetables per day. How can the medical community help improve that statistic?
Dr. Ames: Physicians have so much clout with patients. When physicians can give patients a copy of tests that show, because of nutritional deficiencies, their chromosomes are being injured and they are increasing their risk of cancer - that's going to have a big impact.
Actually, the United States isn't quite as bad as that 9% statistic. Many Americans may not follow the RDA's religiously, but they eat three fruits and two vegetables a day, and that's pretty good. It's the 25% of Americans who aren't eating enough fruits and vegetables - zero, one, or two servings per day, particularly if they are smoking - who are in trouble. But unfortunately, the arrival of these new methods in preventive medicine is slow in coming. People haven't realized yet that this is the way it has to go.