The Role of Antioxidants in Exercise and Disease Prevention
Alexandra K. Adams, MD, PhD
THE PHYSICIAN AND SPORTSMEDICINE - VOL 30 - NO. 5 - MAY 2021
In Brief: Excess free-radical formation has been hypothesized to contribute to cancer, atherosclerosis, aging, and exercise-associated muscle damage. Antioxidant supplements such as vitamin C, vitamin E, and beta-carotene have been touted as beneficial for enhancing exercise performance and for preventing certain diseases. Before physicians routinely recommend supplements to prevent exercise-associated damage, more study will be required. Recommendations for the prevention of cardiovascular disease and cancer are more complex. Because study results have been contradictory, individual supplement recommendations must be offered with caution. Physicians must be cognizant of which supplements patients are taking and be prepared to discuss risks and benefits. The most beneficial prescription is probably a daily diet containing five to seven servings of fruits and vegetables.
Many claims have been made for the benefits of antioxidants in enhancing exercise performance, preventing illnesses such as heart disease and cancer, and even mitigating the effects of aging. Patients often take various supplements, sometimes based on confusing and conflicting reports. Physicians need to be aware of what supplements patients are taking and be prepared to discuss the risks and benefits of these treatment strategies with patients interested in health promotion through exercise and supplement use.
Pathophysiology of Oxidation
Tissue damage and disease processes. The adverse effects of excess free-radical formation have been hypothesized to lead to cancer, atherosclerosis, aging, and even exercise-associated oxidative damage. Free radicals are generated from normal oxidative processes in the body and can damage DNA and RNA and inactivate enzymes and other proteins. Free radicals also facilitate oxidation of fatty acids in cell membranes, producing destructive chain reactions that cause cell damage and cell death. Excess levels of free radicals in plasma and the arterial wall increase low-density lipoprotein (LDL) oxidation,1 leading to cytotoxicity and enhanced plaque formation.
Protective mechanisms. Aerobic organisms would not survive without mechanisms that counteract the detrimental effects of free radicals. The system includes the fat-soluble antioxidants such as vitamin E and beta-carotene (a vitamin A precursor); the major water-soluble antioxidant, vitamin C; antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and selenium-dependent glutathione peroxidase (GPX); and low-molecular-weight compounds such as glutathione. These components preserve homeostasis during most normal cell function and mild oxidative stress. When free-radical production is excessive, however, or when the antioxidant system is overwhelmed, such as during nutritional deficiencies or exhaustive exercise, such imbalances may favor an "oxidative stress" environment (figure 1).
Vitamin E. This fat-soluble vitamin is incorporated into lipoproteins and cell membranes and prevents oxidation of polyunsaturated fatty-acids in cell membranes. Vitamin E also inhibits platelet activation and monocyte adhesion1 and is the predominant antioxidant in LDL.2,3 The most active and most common commercial form of vitamin E is alpha-tocopherol.
Vitamin E is found in vegetable and seed oils, wheat germ, and (in lower quantities) meats, fish, fruits, and vegetables. The recommended dietary allowance (RDA) for both men and women is 15 mg/day of alpha-tocopherol.4 Obtaining sufficient vitamin E from the average diet is difficult; supplements can make up the difference. Multivitamins usually contain 30 to 50 IU (30 to 50 mg) of vitamin E.
Vitamin C. This water-soluble vitamin is the predominant plasma antioxidant that scavenges plasma free radicals and prevents their entry into LDL.3 Vitamin C regenerates oxidized vitamin E and increases cholesterol excretion. Some studies5-7 have demonstrated that vitamin C can improve arterial vasoreactivity. A single dose (2 g) of vitamin C improved vasoreactivity in patients who were chronic smokers,5 had hypercholesterolemia,6 or had cardiovascular disease (CVD).7
Sources of vitamin C include citrus fruits, strawberries, cantaloupe, tomatoes, cabbage, and green leafy vegetables. Cooking can destroy the vitamin, so the best sources are obtained from raw foods or supplements. The RDA is 90 mg/day for men, 75 mg/day for women, with an additional 35 mg/day for smokers.4
Beta-carotene. Carotenoids form a class of more than 600 compounds normally found in fruits and vegetables.8 Beta-carotene is a vitamin A precursor carried in plasma and LDL.9 Both beta-carotene and vitamin A have antioxidant and immunoenhancement properties. Because of previous animal, dietary, and epidemiologic studies, beta-carotene has been the focus of several large chemoprevention clinical trials.8
Carotenoids are found in fruits, yellow-orange vegetables such as carrots, squash, and sweet potatoes, and deep green vegetables such as spinach and broccoli. No RDA has been established.
Selenium. This essential trace element functions through selenoproteins, several of which have antioxidant functions, and includes enzymes such as glutathione peroxidase, a potent free-radical scavenger.
Sources include meat and seafood, and low levels are present in fruits and vegetables. The major forms of dietary selenium are highly bioavailable.4 Selenium levels in plant foods and grains vary with soil content. Certain areas of the world have soils with a low selenium content, and populations in these areas manifest lower plasma levels of the element.10 The RDA is 55 mg/day for both men and women.4
Free-Radical Generation in Exercise
In the past two decades, accumulating evidence has shown that unaccustomed and strenuous exercise induces an imbalance between free-radical production and the body's antioxidant defense systems. However, it remains unknown whether increased free-radical production is an unwanted consequence of exercise that promotes further inflammation and tissue damage, or if the body regulates oxidant production to control inflammation and repair.11 Resistance exercise may also increase free-radical production, although the evidence is less convincing.12
Three main potential pathways exist for increased free-radical generation with exercise. Oxygen consumption increases up to 20 times greater than the resting level, resulting in an elevated flow of oxygen through the mitochondrial electron-transport chain. Superoxide radical may leak from this pathway and be reduced to hydrogen peroxide by mitochondrial SOD. Cytosolic SOD is also available to perform this function. Hydrogen peroxide can then be reduced by CAT and GPX.
Although both enzymes share the primary function of reducing hydrogen peroxide, their substrate specificity and cellular location are different. CAT is found primarily in peroxisomes, organelles involved in nonmitochondrial oxidation of fatty acids and amino acids, and they generate hydrogen peroxide. GPX, a mitochondrial enzyme, uses glutathione, a low-molecular-weight thiol, to reduce hydrogen to water and organic peroxides to alcohol. Thus, GPX plays an important role in inhibiting lipid peroxidation and preventing damage to DNA and RNA.
A second pathway is in organs, such as the liver, kidneys, and gut, that experience a hypoxic environment with blood-flow redistribution to the working muscles. This relative ischemia-reperfusion of the splanchnic region may trigger activation of xanthine oxidase, a membrane-bound enzyme that produces both superoxide and hydrogen peroxide. Finally, neutrophil and macrophage involvement in inflammation and repair may be a potent source of free-radical production.
Antioxidant Supplementation and Exercise
Given that high-intensity exercise can increase free-radical production, antioxidant supplements may offer benefit during prolonged aerobic activity.12-15
Vitamin E. This vitamin is essential for normal cell function during exercise. Animals depleted of vitamin E demonstrate significant free-radical generation, lipid peroxidative damage, and a 40% decline in endurance capacity.16 Endurance performance also decreases in rats fed a vitamin E-deficient diet,16,17 thus implicating vitamin E in protecting against exercise-induced free-radical generation and injury.
At least two animal studies18,19 have shown promising results: Vitamin E supplementation at supraphysiologic doses for a minimum of 5 weeks can decrease lipid peroxide levels with exhaustive exercise. To be effective at all, vitamin E must be given for at least 2 weeks before exercise, and five times the RDA for vitamin E may be necessary to prevent free-radical damage.20 These findings should be balanced against human studies that have not demonstrated convincing evidence for exercise-induced oxidative stress damage. Duthie et al21 found no difference in levels of plasma alpha- or beta-tocopherol in runners following a half marathon. Lovlin et al14 actually noted a decrease in plasma malondialdehyde levels, a marker for lipid peroxidation, in cyclists exercising at 40% to 70% VO2max.
Vitamin C. Less convincing is the evidence for vitamin C supplement-mediated protection against exercise-induced oxidative damage. One study22 demonstrated that ascorbate is an effective antioxidant in human plasma. Improved musculoskeletal healing has been reported in patients who took 500 to 1,000 mg of ascorbic acid two to four times a day.23 A recent review24 notes that although large doses of vitamin C are claimed to reduce fatigue and muscle damage, none of the studies examined specific oxidative stress markers, and therefore such large-dose strategies must be interpreted with some caution. Furthermore, high doses of vitamin C in the presence of iron can have pro-oxidant effects.25 High-dose vitamin C (>2 g/day) can cause diarrhea, bloating, and false-negative occult blood tests but does not increase levels of urinary oxalic acid.26
Coenzyme Q10. Supplementation with coenzyme Q10 (CoQ10) has also been suggested to be beneficial for endurance athletes. Rats given CoQ10 had reduced creatinine kinase and lactate dehydrogenase enzyme activities after downhill running,27 but similar effects were not seen in human subjects after cycling to exhaustion.28 Finally, one study29 in unsupplemented rats showed that SOD attenuated lipid peroxidative damage from acute bouts of exercise.
Enzymes, exercise, and training. No evidence shows that long-term physical activity leads to any permanent detrimental effects on skeletal muscle (table 1). This observation suggests that regular exercise might enhance the enzymatic defense systems against free-radical activity. For example, mitochondrial enzymes GPX and manganese-dependent SOD play a major role in free-radical production and are consistently upregulated with chronic exercise training (see table 1).30,31 In addition, some animal studies32,33 demonstrate that acute exercise stimulates antioxidant enzyme activity in skeletal muscle and to a lesser extent in cardiac tissue and the liver. The degree of change depends on both the training status and the muscle fiber type studied.
Antioxidants and eccentric muscle damage. Investigators have speculated that free radicals may play a role in muscle damage associated with eccentric muscle activity.11,34 Recent studies35,36 in animal models have provided some evidence to support the assertion that vitamin E deficiency is associated with certain types of muscular dystrophy.37 Because of the possible link between eccentric muscle activity and oxidative stress damage, some studies36,38,39 have examined the effects of antioxidant vitamin supplementation or depletion. The results, however, are conflicting and make it difficult to make an unequivocal antioxidant recommendation to prevent such damage.
Antioxidants and Disease Prevention
Before the interest in antioxidants and intensive exercise arose, many epidemiologic studies showed that diets high in antioxidants were associated with a decreased risk of chronic disease, especially CVD and cancer.40-49 In addition, a number of important clinical trials have been conducted (table 2).
European and US studies revealed that the risks of CVD and cancer were inversely correlated with fruit and vegetable consumption.50-54 Plasma levels of vitamins E, C, beta-carotene, and selenium are inversely correlated with cross-cultural CVD mortality.50,51,55,56 However, epidemiologic studies cannot prove causality for a number of reasons, including selection bias. In addition, other food components such as flavonoids may be responsible for the beneficial health effects seen.
Cardiovascular disease. Many prospective cohort studies have shown a relationship between intakes of vitamins E, beta-carotene, and vitamin C and CVD. The Health Professionals Study57 (41,910 male physicians) noted a 40% risk reduction for coronary heart disease (CHD) among individuals in the upper quintile of vitamin E intake (about 400 IU/day) compared with men in the lowest quintile (6 IU/day). After adjustment for other additional factors and other vitamins, physicians in the highest quintile of beta-carotene intake (19,034 IU/day) had a 29% CHD risk reduction compared with those in the lowest quintile (3,969 IU/day), with the benefit only for smokers. The study noted no vitamin C benefits.
In a study58 of supplement use in 11,178 elderly people, vitamin E consumption reduced the risk of all-cause mortality by 34% and CHD by 47%. Vitamins E and C together caused a reduction in total mortality by 42% and coronary mortality by 53%. Vitamin E supplements averaged greater than 100 IU/day. The Scottish Heart Health study59 (10,349 participants) found lower CHD risk among patients in the highest quintile of dietary vitamin E intake, but not significantly so for those with CHD.
In a study60 of more than 121,000 female nurses between the ages of 30 and 55, women in the highest quintile of vitamin E intake (>100 IU/day) had a 31% lower CHD risk compared with women in the lowest quintile. No effects were found with multivitamins, vitamin C, or beta-carotene. The National Health and Nutrition Examination Survey-1 cohort study61 revealed an inverse relationship between those with the highest vitamin C intake (diet and supplements) and CHD risk among 11,349 US men and women between the ages of 25 and 74 in a 10-year study. Selenium levels were inversely correlated to CHD mortality in one study,62 but others provide conflicting data.3 Ubiquinone, a reduced form of CoQ10, has been reported to decrease LDL oxidation and improve ejection fraction.63-65 However, two small randomized controlled trials66,67 evaluated the effects of CoQ10 on patients with class 3 and 4 heart failure and found no significant benefit.
Cancer. Recent reviews of the existing epidemiologic studies have found a strong effect of fruit and vegetable consumption to lower all types of cancer risks.52,54 Persons in the lowest quartiles of fruit and vegetable consumption have 1.5 to 2 times the risk of cancer compared with people who have higher intakes.52
For vitamin A, more than 100 case-control and cohort studies have examined the relationship between carotenoid-containing fruits and vegetables and cancer risk.68 The relationship between carotenoid intake and lowered risk of lung and stomach cancers has been the most consistent, with risk reductions of 10% to 90% seen in people with the highest dietary intakes.68 For lung cancer, risk reduction was primarily seen after controlling for smoking.
Many studies have also shown an inverse relationship between lung cancer risk and vitamin C intake. Dietary vitamin C has also been shown to lower the risk of breast cancer (8 studies), colon cancer (10 studies), stomach cancer (9 studies), and oral and esophageal cancers (5 studies).52
Studies of the relationship between selenium intake or plasma selenium levels and cancer have been less conclusive. Ten prospective studies have shown an inverse relationship of plasma selenium levels and cancer risk, but in only 6 was the relationship statistically significant.52 Observational studies of vitamin E intake showed lower risks of stomach cancer (3 studies), lung cancer (2 studies), breast cancer (5 studies), and colon cancer (2 studies).52
Mortality and Antioxidant Supplementation
Although many epidemiologic studies have implicated consumption of fruits, vegetables, and antioxidant supplements in preventing disease, these studies cannot prove causality. To date, there have been five large, randomized, controlled trials looking at the effects of vitamin supplementation on mortality due to CVD and cancer (see table 2).58-68
CVD and cancer. Many studies present conflicting results about vitamin E for primary and secondary CVD prevention. The Cambridge Heart Antioxidant Study (CHAOS),46 a double-blind, placebo-controlled trial, was designed to test whether high-dose vitamin E (400 IU or 800 IU) would reduce risk in CVD patients. Vitamin E significantly reduced overall fatal and nonfatal CVD events by 47%, and nonfatal MI by 77%, but it did not produce a significant effect on overall mortality (relative risk, 1.18). These results strongly support evidence that vitamin E at doses greater than 100 IU/day reduces CVD events.
Two more recent trials47,48 do not support these results. In patients who had a recent myocardial infarction (MI), fish oil or vitamin E (300 IU/day) was given to assess secondary outcomes of MI, stroke, and cardiovascular (CV) death. Vitamin E supplementation offered no benefit.47 The Heart Outcomes Prevention Evaluation (HOPE) trial48 evaluated the effect of 4.5 years of supplemental vitamin E (400 IU/day) against a placebo and either the angiotensin-converting enzyme inhibitor ramipril or matching placebo in patients at high risk for CV events. Primary outcomes of MI, stroke, and death from CV causes showed no significant benefit of vitamin E compared with placebo. Both trials are ongoing to assess longer-term effects on cancer.
In the Women's Health Study,49 an ongoing trial of antioxidant supplements and prevention of cancer and CVD, 50 mg of beta-carotene given on alternate days had no effect on cancer, CVD, or overall mortality in healthy women age 45 or older. Results of supplementation with vitamin E (600 IU on alternate days) are pending.
A recent small 3-year study69 examined the effects of simvastatin with or without niacin and a combination of antioxidants (Vitamins E, C, selenium, and beta-carotene) or placebos on CVD protection in 160 patients with CVD. No clinical or angiographically measurable benefit from antioxidants was found. Other primary and secondary prevention trials have considered the combined outcomes of CVD, cancer, and mortality (see table 2). Many other supplementation trials are ongoing, and the results should be available soon.
Cancer studies. Many clinical trials of antioxidants for cancer prevention have been done, and most have focused on vitamin A and its derivatives. Supplemental beta-carotene has failed to reduce cancer risk in randomized trials and showed increased risk of lung cancer in the Alpha Tocopherol Beta Carotene (ATBC) trial42 (see table 2). However, a lower incidence of prostate cancer was found with vitamin E supplementation. Three double-blind, randomized, controlled trials assessed the effect of beta-carotene and/or vitamin E and C supplements on the recurrence of colon adenomas in patients who had resected adenomas; supplementation showed no significant effect.8 In a randomized controlled trial70 among patients receiving bacillus Calmette-Guerin immunotherapy, bladder tumor recurrence decreased from 80% to 40% in patients who took megadoses of vitamins A, B6, C, E, and zinc.
Selenium supplementation in patients with a history of basal cell or squamous cell skin cancer was examined in a large randomized, controlled trial; mean follow-up was 6.4 years.71,72 Recurrence rate of skin cancer did not change, but total cancer incidence and mortality, as well as incidences of lung, colorectal, and prostate cancers were significantly reduced in patients who received selenium. Several ongoing research trials may shed light on the effectiveness of combinations of antioxidant vitamins on cancer prevention.52,53
Lingering Questions and Preliminary Answers
Antioxidants are vital dietary requirements that play a major role in protecting us from our environment, and they probably play a role in preventing CVD and cancer. Available evidence points to the benefits of food-derived antioxidants, but more evidence is needed before antioxidant or enzyme supplementation can be routinely recommended for people engaging in prolonged exercise. Because of conflicting study results of antioxidants in preventing CVD and cancer, more conclusive studies will be required. In general, routine antioxidant supplementation for preventing exercise-induced oxidative stress damage is still questionable, because the inflammation and associated oxidative stress damage may be important in healing.
Future studies should focus on assessing the value of antioxidant supplementation for attenuating postexercise tissue damage. Recommendations of individual nutrients to patients must be done with caution, but a diet that contains five to seven servings of fruits and vegetable daily is probably the most beneficial prescription. A daily multiple vitamin may also be needed to meet nutritional needs since the benefit outweighs any possible harm.73,74 Combinations of supplements may prove to be more beneficial than individual nutrients, especially in preventing cancer.
Dr Adams is an assistant professor in the department of family medicine, and Dr Best is an assistant professor in the departments of family medicine and orthopedic surgery at the University of Wisconsin at Madison. Dr Best is an editorial board member of The Physician and Sportsmedicine. Address correspondence to Thomas M. Best, MD, PhD, Depts of Family Medicine and Orthopedic Surgery, UW Medical School, 621 Science Dr, Madison, WI 53711; e-mail to [email protected].
Disclosure information: Dr Best discloses no significant relationship with any manufacturer of any commercial product mentioned in this article. No drug is mentioned in this article for an unlabeled use.