Whole Foods Magazine

September 2000

Vitamin Connection

 

Antioxidant Recommendations: Part 3 What the studies show

An Interview with Dr. Denham Harman

By Richard A. Passwater, Ph.D.

 

In this series of columns, we are looking at recent recommendations by the Panel of Dietary Antioxidants and Related Compounds for the dietary intake of antioxidant nutrients. In Part 1, we chatted with Panel Chairman Dr. Norman Krinsky and Panel Member Dr. Maret Traber _ about the actual findings of the Panel, rather than the misleading information promulgated in some media reports. In the second installment, we reviewed with Dr. Jeffrey Blumberg some of the complexities and issues of making recommendations for antioxidant nutrient intake. In this column, we will discuss what the studies show with Dr. Denham Harman of the University of Nebraska School of Medicine, who is widely known as the father of the free-radical theory of aging.

I've had the pleasure of knowing and working with many brilliant scientists including four Nobel laureates, but none is more brilliant, nor has done more for human health, nor is a greater pleasure to know and converse with, than Denham Harman. His contributions to the understanding of human health, in my opinion, exceed that of Louis Pasteur. He was the first to appreciate the importance of free radicals in the disease processes.

In fact, I believe that the identification of Dr. Harman's work with the phenomenon of aging actually has prevented him from getting all the credit he deserves. Were he known as the "father of the free radical theory of disease" instead of "aging," I think he certainly would have received his Nobel prize by now. Several theories on aging have been postulated, and none is generally accepted. Meanwhile, as people have focused on Dr. Harman's aging research, they have tended to overlook what his discoveries have taught us about many human diseases. In Table 1, I have listed many of the diseases that have been linked to free radicals. Nevertheless, even this table is now out of date. Most experts agree that there are between 60 and 80 diseases that involve free radicals (the exact number depends on how some of the closely-related diseases are sub-categorized).

Table 1. Diseases and disorders in which free radicals play a role. Free radicals can be the sole cause of a few diseases, but more often are involved in the disease process by predisposing the human body to diseases directly caused by other factors. Free radicals also may worsen the conditions and be antagonistic to the healing process.

 

MULTIORGAN INVOLVEMENT

Aging Disorders of "premature aging"

Immune deficiency of aging

Cancer

Amyloid diseases

Inflammatory-immune injury

Glomerulonephritis (idiopathic, membranous)

Vasculitis (hepatitis B virus, drugs)

Autoimmune diseases

Ischemia-reflow states (reperfusion)

Drug and toxin-induced reactions

Iron overload

Idiopathic hemochromatosis

Dietary iron overload

Thalassemia and other chronic anemias

Nutritional deficiencies

Kwashiorkor

Vitamin E deficiency

Alcohol damage

Radiation injury

 

PRIMARY SINGLE

ORGAN INVOLVEMENT

Erythrocytes

Phenylhydrazine

Primaquine

Lead poisoning

Protoporphyrin photooxidation

Sickle-cell anemia

Malaria

Favism

Fanconi anemia

Lung

Asthma

Cigarette-smoke effects

Emphysema

Hyperoxia

Bronchopulmonary dysplasia

Cystic fibrosis

Oxidant pollutants

Acute respiratory distress syndrome (ARDS)

Mineral dust pneumoconiosis

Bleomycin toxicity

Paraquat toxicity

Heart and cardiovascular system

Atherosclerosis (via oxidation of LDL

Heart attack (acute myocardial infarction via coronary thrombosis via platelet aggregation)

Endothelial injury

Vasospasms

Alcohol cardiomyopathy

Keshan disease (selenium deficiency)

Doxorubicin toxicity

Kidney

Glomenulonephritis (nephrotic antiglomerular basement membrane disease)

Aminoglycoside nephrotoxicity

Heavy metal nephrotoxicity

Renal graft rejection

Gastrointestinal tract and liver

Hepatitis

Endotoxin liver injury

Carbon tetrachloride liver injury

Diabetogenic action of alloxan

Free fatty acid-induced pancreatitis

Nonsteroidal antiinfammatory drug-induced lesions

Joint abnormalities

Rheumatoid arthritis

Brain

Hyperbaric oxygen

Neurotoxins

Senile dementia

Parkinson's disease-MPTP

Alzheimer's

Stroke (thrombosis in cerebral vessels)

Cerebral trauma from stroke (Hypertensive cerebrovascular injury)

Epilepsy

Neuronal ceroid lipfuscinoses

Allergic encephalomyelitis and other demyelinating disease

Ataxia-telangiectasia syndrome

Potentiation of traumatic injury

Aluminum overload

Abetalipoproteinemia

Eye

Cataractogenesis

Macular degeneration

Ocular hemorrhage

Degenerative retinal damage

Retinopathy of prematurity

Photic retinopathy

Skin

Sunburn (solar radiation)

Burn (thermal injury)

Psoriasis

Scleroderma

Porphyria

Contact dermatitis

Photosensitive dyes

Bloom syndrome

Teeth

Periodontitis

Adapted and modified from: Proceedings of the Davis Conference: Oxygen radicals and human disease of Internal Medicine 107: 527 (1987).

 


The antioxidant nutrients that protect us against damage from free radicals not only reduce the risk of developing the diseases listed in Table 1, they decrease our risk of contracting "germ-borne" diseases and genetic diseases as well. Yes, Louis Pasteur discovered that germs are, responsible for many diseases, but germs cause disease only when our immune systems are impaired or overwhelmed. Antioxidant nutrients enhance our immune systems so that germs are less likely to succeed. Later on, we'll look at some of the studies that show this to be true. What is even more exciting, is the fact that antioxidant nutrients help regulate the expression of genes by up-regulation or down-regulation so that genetic diseases may be postponed or completely controlled.

It has been a while since Dr. Harman published his theory in 1956. He is now 84 years old, but usually can be found year round at his office at the University of Nebraska School of Medicine. When he is not there, normally it means that he is presenting new research at a scientific symposium. More details about Dr. Harman and his research can be found in the March 1995 and April 1995 columns.

 

Passwater: Dr. Harman, the media seems to have missed the message about the Panel's report on antioxidant nutrients. What is the message you get from reading this report?

Harman: The overriding message from the Panel is the recommendation that people get more vitamin C and vitamin E in their diets, and that more research be conducted to learn more about the benefits of antioxidant nutrients. The Panel also set safe upper limits fog dietary intake that are far greater than the amounts usually taken by those of us who wish to get effective antioxidant protection.

The Recommended Dietary Allowances (RDA) Committees now appear to be looking beyond classical vitamin deficiency diseases and are beginning to look at improved levels of health. I was pleased to see that this Panel made positive comments about the free radical ;' theory al

though they feel that more studies are required before they can make widespread health recommendations.

Passwater: Yes, the Panel did increase the recommended intakes for vitamin C and vitamin E, but the members didn't believe there is sufficient evidence to make public health recommendations for everyone to get even larger amounts of antioxidants. Since "adequate evidence" is lacking-and we may never have enough evidence about anything to convince some scientists-do you feel that there is "good evidence" on which prudent decisions can be made?

Harman: Yes. Laboratory animal studies-such as those you and I both have conducted many times over-have shown consistently-for about 40 years-that increased levels of antioxidant nutrients improve health as well as longevity. These findings also are supported by epidemiological (population) studies on lifespan, cancer and heart disease as well as in vivo studies.

It has been these studies that have prompted the Antioxidant Panel to be established and have encouraged prudent people to take antioxidant supplements.

Passwater: You bring up an interesting point: we've observed changes in the population that are consistent with antioxidants helping people live better longer. I want to discuss this with you in depth later, but right now I want to follow up on your comment that you were pleased that the Panel's report mentioned the possible benefits of antioxidant nutrients in a number of diseases. What did you find encouraging?

Harman: In discussing cancer, the Panel reported that "a great deal of epidemiological evidence indicates that diets rich in fruits and vegetables are associated with a lower risk. However, these studies provide only limited support for a protective association of individual food components categorized as antioxidants. Data regarding the protection by individual food components against cancer in humans are not yet available." In essence, the Panel recognizes the scientific merits of the possible involvement of free radicals in cancer, but states that there is not sufficient data to evaluate the role of individual antioxidants. Much more research is needed in this area.

In discussing cardiovascular disease, the Panel stated, "[O]f all the chronic disease in which excess oxidative stress has been implicated, cardiovascular disease has the strongest supporting evidence." However, clinical intervention trials have not yet proven the case. Therefore, the Panel concluded, AThus, available data do not adequately substantiate the premise that increasing the intake of vitamin C, vitamin E, or beta-carotene and other carotenoids will reduce the risk of coronary heart disease.@

Passwater: Let me remind our readers that the term "oxidative stress" refers to the imbalance between free radicals and antioxidants. When there are not enough antioxidants to prevent damage to the body, "oxidative stress" is said to occur. Thus, oxidative stress is the condition that allows free radical damage to occur.

Harman: The research indicating involvement of free radicals in cataractogenesis also was discussed in the Panel's report. "Several studies indicate a lowered risk of cataracts associated with either an increased serum level of these dietary components or supplement use. These studies, since observational in nature, do not constitute at this time a sufficient basis for a conclusion that these dietary components can prevent cataracts in humans."

Similarly, with age-related macular degeneration (AMD): "Epidemiological studies find a decreased likelihood of AMD associated with higher intakes of fruits and vegetables, especially those that are rich in the carotenoids lutein and zeaxanthin... The association has also been observed in smokers, who have lower plasma levels of carotenoids and are also at an increased risk of developing AMD. However, all reports are associative in nature and have not established a causal relationship between intake or plasma concentration of lutein and/or zeaxanthin and risk for AMD."

In regard to central neurodegenerative diseases the Panel remarked, "Increasing evidence suggests that a number of common neurodegenerative diseases, such as Alzheimer's, Parkinson's and amyotrophic lateral sclerosis, may reflect adverse responses to oxidative stress. Small intervention trials with either vitamin C or vitamin E have reported symptomatic improvement in those already afflicted with the disease. However, these preliminary findings do not constitute adequate proof of the usefulness of these antioxidants in decreasing the development or delaying the onset of these diseases."

These statements definitely are not negative as the media reports often suggested. These statements recognize that some studies have shown that antioxidants improve the condition of many patients, but that due to the early stage of this area of research, the clinical trials needed to prove the relationship have not been carried out. This is entirely different from saying that clinical trials have been carried out and found no relationship.

The Panel even discussed the possible involvement of free radicals in diabetes mellitus. "Although some evidence suggests diabetes mellitus may be attributable to either an oxidative stress or a stress to reactive carbonyls, much of the research has been inconclusive. In addition, no clinical intervention trial has tested directly whether provision of antioxidants can defer the onset of the complications of diabetes."

Passwater: While scientists do not yet have enough evidence of the type needed to make public health recommendations, there is indeed lots of supporting scientific evidence. There are enough studies to fill a book, but a few will suffice to make this point. This will be hard to do, but could you list just three studies demonstrating that antioxidant nutrients help us live better longer?

Harman: Well, that is a toughie! I would have to include the Harvard epidemiological studies published in the New England Journal of Medicine in 1993 that suggest that vitamin E supplements can reduce the incidence of heart disease in both men and women by about 40%. (1,2) The two studies were published back-to-back in the same journal with the major differences being that one was a study of women and the other of men. So let's count them as a single study giving good evidence that vitamin E reduces the risk of heart disease.

Then there is Dr. Jim Enstrom's epidemiological study that suggests that vitamin C supplements can reduce cancer and heart disease, and extend the average life span of males by about six years. (3)

In another important study, vitamin E and beta-carotene reduced the incidence of prostate cancer. (4) Male smokers, aged 50 to 69, receiving 50 IU of vitamin E daily for six years had a 32% decrease in prostate cancer incidence and a decrease of 41% in prostate cancer deaths.

These are certainly health benefits, and since there is no known adverse risk from taking the supplements at the levels used in the studies, it does seem prudent to take antioxidant supplements.

Passwater: I'll share my list with our readers shortly, but let me follow up on your list. Can the effects reported in these studies be obtained by good diet alone?

Harman: No. In the vitamin E and heart health study, the protective effect was not observed below 100 IU/day The individuals who benefited from vitamin C in Dr. Enstrom's study averaged about 300 mg/day. Men in the prostate study took 50 IU/day.

Passwater: Is it safe to take megavitamin quantities of vitamin C and vitamin E, as commonly advocated?

Harman: Yes. Vitamin C intake commonly advocated in megavitamin usage is from about 200 mg to around 2,000 mg. I am not aware of any adverse effects in this range. Vitamin E intake advocated is often around 200 to 1,000 IU/day. Again, I am not aware of any adverse effects in this range.

Passwater: Does the Panel's report change any of your recommendations for antioxidant supplementation.

Harman: No.

Passwater: I knew that was a silly question, but I wanted your answer on the record.

You listed studies that support the body of evidence that antioxidant nutrients reduce the risk of human heart disease and cancer, while increasing lifespan. This is what we have learned over 30 years beginning with our animal experiments. There are other human studies that can be named that add to this line of evidence. I also choose to pick studies that show the health benefits of antioxidant nutrients against heart disease and cancer and improve lifespan.

My favorite is Dr. Larry Clark's study showing that taking supplements of 200 mcg a clay of selenium cuts the cancer death rate in half. (5) 1 have been preaching since 1972 about the importance of selenium in protecting against cancer. This was the basis for one of my patents. (6) In the future, I hope to be able to present evidence that certain selenium compounds of the triselenide family destroy cancer.

I'm with you on the Harvard studies: I agree that there is no better choice for showing that vitamin E reduces heart disease risk. The data are strong, and when you add in the prestige of the journal and the Harvard research group, you have a compelling story. I also have fun in pointing out that these two studies confirm my 1976 epidemiological study. (7)

I, too, like to point to Enstrom's study that indicates that vitamin C increases the lifespan of men because it is an extension of a study in which I participated with Dr. Linus Pauling and Dr. Enstrom. (8) By the way, as this interview is going to press, a supporting article has just appeared in the July American Journal of Clinical Nutrition (AJCN). (9) Researchers from the National Heart, Lung and Blood Institute, Johns Hopkins University and Tulane University examined blood levels of vitamin C in a nationally representative sample of U.S. adults. Using government data from nutritional surveys and death records, they concluded, "These data suggest that men with low serum ascorbate (vitamin C) concentrations may have an increased risk of mortality, probably because of an increased risk of dying from cancer."

My fondness for these studies aside, my first choice now is the research conducted by Dr. K.G. Losonczy and colleagues at the National Institute of Aging. In their study of 11,178 persons aged 67-105 years, they found that vitamin E supplements alone and vitamin E plus vitamin C supplements synergistically together reduced total mortality (all-cause mortality) and coronary diseases. The study was published in the AJCN in 1996 as "Vitamin E and Vitamin C Supplement Use and Risk of All-cause and Coronary Heart Disease Mortality in Older Persons." (10)

In this study, vitamin E alone reduced the risk of (lying (all-cause mortality or total mortality) by 34% and reduced the risk of dying from coronary disease by 47%. More striking is that vitamin E alone reduced the risk from dying of coronary heart disease by 63% and the risk of dying from cancer by 59/.

Vitamin E and vitamin C taken together reduced the risk of dying by 42% and reduced the risk of dying from coronary disease by 53%. The researchers concluded, "These findings suggest protective effects of vitamin E supplements in the elderly."

As an aside and not to count as one of my three selections: this year, Dr. Losonczy and colleagues reported that "vitamin E and vitamin C supplements may protect against vascular dementia and may improve cognitive function in late life." (11) In this study, vitamin E and vitamin C reduced the risk of developing vascular dementia by 88% and mixed or other demen6as by 69%. This addresses the quality of life as well as the length of life.

Also, it brings me back to the point you made earlier: people are living better longer and taking antioxidant supplements is part of the reason. You recently published your observations on this subject in the journal of the American Aging Association. (12) What are some of your observations on the effects of antioxidant supplements on disease and aging in the United States population?

Harman: The percentage of the population that takes antioxidant supplements has grown since the mid-1950s from probably less than a fraction of 1% to 40% or 50% today. According to accepted figures, it appears that most people who take antioxidant supplements take them on an irregular basis. Around 4% of Americans take vitamin E daily (usually 100 IU or more) and 8% take vitamin C (frequently 500 mg). Antioxidant supplement advocates often also take coenzyme Q-10, polyphenols such as Pycnogenol, lipoic acid and melatonin supplements.

Passwater: Has the balance between food antioxidants and supplement antioxidants changed during this period?

Harman: In comparison, food antioxidant consumption, such as fruits and vegetables, has remained relatively constant over this period, so the ratio has changed dramatically towards supplement antioxidants.

Passwater: We always advocate that a diet rich in fruits and vegetables is the foremost requirement for good health, but there is a limit to how many fruits and vegetables one (,,in eat.

Harman: Yes, there are many reasons to eat a varied diet containing lots of fruits and vegetables. However, to significantly increase the antioxidants in the body to counteract free radicals, one needs more than is easily provided by the food alone. Remember that the Harvard vitamin E studies found that the protection against heart disease was apparent only in those taking supplements. Also, in the selenium study by Dr. Clark-the one you mentioned in which the cancer death rate was cut in half-the result was obtained with supplements at a level that would be difficult, if not impossible, to obtain on American diets alone.

Here's another example: a person would have to eat about six cups of peanuts-with all the calories and fat they contained-in order to obtain the amount of vitamin E in one 400 IU capsule.

Passwater: You are saying that the intake of antioxidant supplements has increased since the 1960s. So, in the real world, does that mean we are we living better longer?

Harman: The average life expectancy at birth (ALE-B) increased from 69.7 years in 1960 to 75.4 years in 1990 and 76.1 years in 1996. The 65 years and older age group increased by 86.7% and the 85-plus years age group grew by 225.2%. There are many factors contributing to this improvement, but the important point is that the results are in agreement with the premise. This is a first requirement. If lifespan were decreasing, that would not be supportive.

Passwater: Well, my next question is this: if we are living longer, are we living better longer? That's the important thing.

Harman: Yes. The good news is that the number of chronically disabled individuals aged 65 and over is not increasing at its former rate. In fact, the rates are significantly lower than forecast by the official government 1982 and 1984 Long Term Care surveys. In 1994, there were 33.7 million people aged 65 and over in the United States. The number of chronically disabled people in that group was 7.1 million. That is 1.2 million people fewer than had been predicted just 10 years before. That's 17%nearly one in five-fewer disabled persons. Again, we can't say that all of the improvement is due to antioxidant supplements, but the data once again support the premise that they help people live better longer.

Passwater: Presently, the scientific community has great interest in the Genome project and identifying genes that increase the risk of disease. Many people are under the false impression that cancer is hardwired into our genes. Our genes account for only 20% to 40% of cancers, and even this contribution is largely regulated be antioxidants that can help determine whether the gene is expressed or suppressed. Diet and environmental factors, both of which affect the antioxidant-free radical balance (oxidative stress), are the overwhelming contributing factors in cancer. Cancer is a disease that usually takes a decade or two to develop. Have there been enough people taking meaningful dosages of antioxidant nutrients to produce a noticeable effect on cancer rate?

Harman: The total cancer incidence and total cancer mortality rates have been decreasing since 1991. This has been the first decrease since the record keeping was instituted in the 1930s. As you mentioned, because of the mechanisms involved for free radicals and oxidative stress to initiate the cancer process, it would take a long lead time for the cancer death rate to be altered by taking antioxidant supplements because we have to be concerned with a combination of both dosage and time. If the cancer death rate had fallen earlier, it would not be supportive of the premise that antioxidant involvement makes a difference. Again, there may be other contributing factors that help explain the decrease in cancer death rate, but the data once again support the premise that antioxidant supplements help us live better longer.

Passwater: The biggest killer has been heart disease. There are several proposed mechanisms by which antioxidant nutrients protect us against heart disease. What do the data show?

Harman: Heart disease has been declining since the 1950s as some of the risk factors were brought under control and considerable life-saving progress has been made in first-aid CPR, medicines and surgeries. However, there has been a significant improvement in the rate of decline of heart disease that began in 1965. As your 1976 study and the 1993 Harvard studies show, vitamin E supplements are associated with a 40% or more decrease in risk of heart disease.

Passwater: OK. The real life and real people data support the premise. And I would like to suggest that older age groups today look and act much younger than comparable age groups in previous generations.

We have already presented our lists of the top three studies that indicate antioxidant supplements help us live longer. Now let's look at more of the studies. While there are a few studies that have

not found an association between antioxidant supplements and decreased illness, the body of the scientific literature-and as you have just shown, the observed results with real people-does support the premise that antioxidant supplements help us live better longer. In science, we give much more weight to positive results than to negative results because there are many factors that bury the true effect and keep it from being distinguished from the background information. Inappropriate measurements, insufficient time allowed for the effect to be observed, and insufficient numbers of people enrolled in the studies are often the reason that real effects are not observed in studies. What is important is the entire body of the scientific evidence-including mechanistic and laboratory animal studies, as well as epidemiological and clinical studies.

In conclusion, let's look in more detail at heart disease, just to illustrate more of the depth of the body of science. There are several mechanisms by which vitamin E and some other antioxidants can prevent heart attacks. The most widely discussed is the fact that vitamin E and other antioxidants prevent oxidation of the cholesterol carriers in the blood called low density lipoproteins (LDL). Normal LDL does not form cholesterol deposits in the arteries. It is only the oxidized LDL (Ox-LDL) that invades the arteries and begins the plaque-building process that leads to narrowed arteries and the disease called atherosclerosis. But even after cholesterol deposits form, antioxidants such as vitamin E and Pycnogenol reduce the risk of having a blood clot form in the narrowed arteries by their action on blood platelets. These antioxidants keep the blood "slippery" rather than "sticky" and tending to clot. If a blood clot forms, it shuts off blood flow and can result in a coronary thrombosis and myocardial infarction (heart attack) or stroke. These antioxidants, and possibly others, keep the platelets and red blood cells from sticking together, and, just as important, sticking to the artery walls where they can narrow and inflame them. Another way in which vitamin I? protects against heart and artery disease is via its protection of the lining of the artery (endothelium) which helps keep injury-related plaque from forming. There are other mechanisms, too, by which antioxidants, especially vitamin E, work to reduce the risk of death from heart disease.

We already have mentioned the Harvard studies showing that supplementation with more than 100 IU of vitamin E for more than two years decreases heart disease by 40%. Now I would like to add the study by Fred Gey that found that the greatest risk factor for heart disease was vitamin E deficiency. This one risk factor was more significant than blood cholesterol, blood pressure and tobacco smoking combined. This relationship held true in all of the 12 countries studied. (13, 14) The study found that heart disease was inversely correlated to blood levels of vitamin E, whereas there was poor association between heart disease and blood cholesterol levels.

Harman: It's difficult to talk about the body of scientific evidence on vitamin E and heart disease without mentioning the Cambridge University study referred to as the

CHAOS study. (15) CHAOS is an acronym for Cambridge Heart Antioxidant Study. This was an intervention trial in which 2002 heart patients were divided randomly into one of three groups and given either a placebo or 400 IU or 800 IU per day of vitamin E. After 200 days, both vitamin E groups had a 77% decrease in nonfatal myocardial infarction (common heart attack) and a 47% reduction in combined cardiovascular disease death and non-fatal myocardial infarction. The huge reduction in heart attacks was statistically significant (p=0.005, 95%Cl= =89 to -53) .

Critics of this study pointed out that there wasn't a statistically significant reduction in myocardial infarction death in spite of the great reduction in non-fatal heart attacks. However, the researchers provided more information in a later report that is important. (16, 17) An analysis of the heart attack deaths shows that there were six heart attack deaths in the patients who were compliant with taking the vitamin E supplement, 21 heart attack deaths in the "non-compliant group" and 32 in the placebo group. Some patients were originally assigned to take vitamin E supplements, but for one reason o- another decided not to. They are called "non-compliant." Blood levels of vitamin E and pill counts distinguish compliant patients from non-compliant patients. Only six of 59 heart attack deaths were in the group that took vitamin E supplements.

Passwater: Another study of interest is the GISSI study. (18) Here GISSI is an Italian acronym for a phrase meaning prevention of heart attacks. It is often reported as being a negative study, but when the details are closely examined, there are positive findings. This study of 11,324 heart patients was conducted in Italy and compared the effects of fish oil and vitamin E supplements on death and heart attacks. The summary found that there was a positive benefit from the fish oil (1,000 mg/day) and that when 300 IU of vitamin E was added, there was no additional benefit. Thus, it was incorrectly concluded that there was no benefit from taking the vitamin E. However, a subgroup analysis of heart disease deaths showed a decreased risk for individual components (ranging from a 20% lower risk for all cardiovascular deaths to a 35% lower risk of sudden death) in the vitamin E group.

Harman: I also find the study from the University of Maryland by Dr. Gary Plotnick and his colleagues to be very informative. Antioxidants even provide a short-term, more immediate protective effect against heart attacks. High-fat meals cause the arteries to constrict for up to four hours after a high-fat meal. However, vitamin C and vitamin E supplements taken before the high-fat meals prevent this constriction of the arteries. (19)

Passwater: That reminds me of the studies in which cholesterol deposits were reversed. The authors of both studies have discussed their research in this column. In the August 1992 column, we discussed Dr. Anthony Verlangieri's research. In a 1992 report in the journal of the American College of Nutrition, Dr. Verlangieri and a colleague revealed that vitamin E not only reduced the rate of cholesterol deposit formation in primates, but also regressed existing deposits. (20)

More recently, in the February 1998 column, we spoke with Drs. Marvin Bierenbaum and Tom Watkins about their research showing that a mixture of natural vitamin E vitamers, primarily tocotrienols but with some tocopherols, reversed the cholesterol deposits in carotid arteries in the neck. (21) Yes, these studies showed a reversal of heart and artery disease.

Harman: Those studies remind me of the DeMaio study in which 100 patients who had undergone coronary angioplasty were given either 1,200 ICJ of vitamin E daily or a placebo. After four months, restenosis (re-narrowing of the arteries

due to plaque build-up) occurred in half of those receiving the placebo and only a third (34.6%) of those receiving vitamin E supplements. (22)

Passwater: There are many more heart disease studies that we could cite, and we also could discuss Dr. Jeffrey Blumberg's team of scientists who have shown that vitamin E enhances immunity against germ diseases, but we'll discuss his research directly with him in an upcoming column. We could go on and on, but I think we've made our point for prudent people. Antioxidant supplements do help us live better longer. Thank you Dr. Harman for helping us to keep our readers informed about the dangers of free radicals and the benefits of antioxidant nutrients. Next month, we will continue looking at the implications of the Antioxidant Panel's report and chat with Dr. Balz Frei, director of the Linus Pauling Institute, concerning some of the "junk" reports about vitamin C that have made recent news. WF

References:

1. Vitamin E Consumption and the Risk of Coronary Heart Disease in Women, Stampfer, MT; Hennekens, C. H.; Manson, J.E.; Colditz, GA; Rosner, B. and Willett, W.C. New Engl. J. Med. 328:1444-1449 (1993)

2. Vitamin E Consumption and the Risk of Coronary Heart Disease in Men, Rimm, E.B.; Stampfer, MJ.; Ascherio, A.; Giovannucci, E.; Colditz, G.A. and Willett, WC. New Engl. J. Med. 328:1450-1456 (1993)

3. Counter viewpoint: Vitamin C and Mortality, Enstrom, J.E. Nutrition Today 28 (May-June) :3942 (1993)

4. Prostate Cancer and Supplementation with Alpha-tocopherol and Beta-carotene: Incidence and mortality, Heinonen, O.P et al. J. Natl. Cancer lnst. 90:440-446 (1998)

5. Effects of Selenium Supplementation for Cancer Prevention in Patients with Carcinoma of the Skin: A randomized controlled trial, Clark, L.C.; Combs, G.F, Jr; Turnbull, B.W et al. J. Amen Med. Assoc. 276:1957-1963 (Dec. 25, 1996)

6. Method and Composition to Reduce Cancer Incidence, Passwater, R.A. and Olson, D.M. U. S. Patent 6,090,414

7. Vitamin E Usage and Heart Disease Incidence, Passwater, R.A. Prevention 28(1) 6371 (1976)

8. Mortality among health-conscious elderly Californians, Enstrom, I.E. and Pauling, L. Proceed. Natl. Acad. Sci. 79:6023 - 6027 (Oct 1982)

9. Vitamin C Status and Mortality in U. S. Adults, Loria, C.M.; Klag, Mj.; Caulfield, L.E. and Whelton, PK.

10. Vitamin E and Vitamin C Supplement Use and Risk of All-cause and Coronary Heart Disease Mortality in Older Persons, Losonczy, K.G.; Harris, TB. and Havlik, R.J. Amer. J. Clin. Nutr 64(2):190-196 (Aug 1996)

11. Association of Vitamin C and C Supplement Use with Cognitive Function and Dementia in Elderly Men, Masaki, K.H.; Losonczy, K.G.; Izmirlian, G.; Foley, D.J.; Ross, G.W.; Petrovitch, H.; Havlik, R. and White, L.R. Neurology 54(6):1265 -1272 (Mar 28, 2000)

12. Antioxidant Supplements: Effects on disease and aging in the United States Population, Harman, D. J. Amer Aging Assoc. 23:25-31 (2000)

13. Inverse Correlation Between Plasma Vitamin E and Mortality from Ischemic Heart Disease in Cross-Cultural Epidemiology, Gey, K.E; Puska, P; Jordan, P and Moyer, U.K. Amen J. Clin. Nutr 53:3265-334S (1991)

14. Plasma Vitamin E and A Inversely Correlated to Mortality from Ischemic Heart Disease in Cross-Cultural epidemiology, Gey, K.F. and Puska, P Ann. N. Y. Acad. Sci. 570:268282 (1989)

15. Randomised Controlled Trial of Vitamin E in Patients with Coronary Disease: Cambridge Heart Antioxidant Study (CHAOS), Stephens, N.G.; Parsons, A.; Schofield, PM.; Kelly, E; Cheeseman, K.; Mitchinson, M.J. and Brown, M J. Lancet 349:781- 786 (1996)

16. Mortality in the CHAOS Trial, Mitchinson, MJ.; Stephens, N.G.; Parsons, A.; Bligh, E.; Schofield, P.M. and Brown, M.J. Lancet 353 (9150):381- 382 (Jan 30, 1999)

17. Long-term Alpha-tocopherol May Yet Prolong Your Life, Mitchinson, M. Brit. Med. J. 316(7127):308 (Jan 24, 1998)

18. Dietary Supplementation with n-3 Polyunsaturated Fatty Acids and Vitamin E after Myocardial Infarction: Results of the GISSI-Prevenione Trial GISSI-Prevenione Investigators. Lancet 354:447-455 (1999)

19. Effect of Antioxidant Vitamins on the Transient Impairment of Endothelium-dependent Brachial Artery Vasoreactivity following a Single High Fat Meal, Plotnick, G.D.; Corretti, M.C. and Vogel, R.A. J. Amer. Med. Assoc. 278:1682-1686 (1997)

20. Effects of d-alpha-tocopherol supplementation on experimentally-induced primate atherosclerosis, Verlangieri, A.J. and Bush, M.J. I Amen Coll. Nutr. 11:130 -137 (1992)

21. Antioxidant-induced regression of carotid stenosis over three years, Kooyenga, D.K.; Geller , M.; Watkins, T.R. and Bierenbaum, M.L. Proceedings of the 16th International Congress of Nutrition, Montreal (July 29, 1997).

22. Vitamin E Supplementation, Plasma Lipids and Incidence of Restenosis After Percutaneous transluminal coronary angioplasty (PTCA), DeMaio, S.J.; King, S.B.; Lembo, NJ et al. J. Amer. Coll. Nutr 11:68-73 (1992)

2000 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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