Topics to be covered

• Introduction
• Antioxidants and free radicals
• All About Anti Oxidants
• Synergy of antioxidants
• Recommendations about antioxidant supplements
• Antioxidants and Cancer Prevention
• Staying Young With Antioxidants
• Oxidative damage
• Antioxidant Nutrients
• Studeis on Antioxidants

Oxygen is essential for life on earth. Without its presence, a human would not survive for more than a few minutes. Yet oxygen is a double-edged sword; as its existence gives life, so does it slowly take it away, by a process known as oxidation, the very process by which all things decay, and humans "return to dust". Almost every substance on earth is subject to attack and decay from oxygen. Gold is highly prized because it is essentially impervious to oxygen's attack, although its outer layer does eventually react with oxygen to form a visible brown or black coloration we call tarnish.

In humans, scientists believe that excess oxidative stress plays an important role in the initiation and promotion of atherosclerosis, cancer, cataract, arthritis and other degenerative diseases. Exposure to environmental perils, such as smoking, pollution or irradiation, eventually increases the oxidative stress beyond the ability of the organism's defense system to cope with it.

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Free radicals are atoms or molecules that are highly reactive with other cellular structures because they contain unpaired electrons. Free radicals are natural by-products of ongoing biochemical reactions in the body, including ordinary metabolic processes and immune system responses. Free radical-generating substances can be found in the food we eat, the drugs and medicines we take, the air we breathe, and the water we drink. These substances include fried foods, alcohol, tobacco smoke, pesticides, air pollutants, and many more. Free radicals can cause damage to parts of cells such as proteins, DNA, and cell membranes by stealing their electrons through a process called oxidation. (This is why free radical damage is also called “oxidative damage.”) When free radicals oxidize important components of the cell, those components lose their ability to function normally, and the accumulation of such damage may cause the cell to die. Numerous studies indicate that increased production of free radicals causes or accelerates nerve cell injury and leads to disease.

Antioxidants , also known as “free radical scavengers,” are compounds that either reduce the formation of free radicals or react with and neutralize them. Antioxidants often work by donating an electron to the free radical before it can oxidize other cell components. Once the electrons of the free radical are paired, the free radical is stabilized and becomes non-toxic to cells. Therapy aimed at increasing the availability of antioxidants in cells may be effective in preventing or slowing the course of neurological diseases like HD.

Free radicals are highly reactive forms of oxygen that damage cells throughout the body. As our body creates energy at the cellular level, oxygen is metabolized changing its structure. In this process, the oxygen molecule loses one electron, turning it into a free radical. Free radicals are inherently unstable since they contain “extra energy.  To reduce their energy load, free radicals react with certain cells in the body, interfering with the cells’ ability to function normally.  Free radicals also are created through detoxifying rancid fats and chemicals, such as drugs, food additives and preservatives; and by cigarette smoke, pollutants, sunlight, radiation, and emotional stress. 

Just from oxygen consumption alone, an average 150 pound human utilizes about 3.5 mL oxygen/kg/minute, and if one assumed that about 1% of the oxygen is converted to the superoxide radical, about 1.72 kg or 3.8 pounds of deleterious superoxide radical would be produced per year.  This does not take into account any of the multitude of other methods of producing, or other chemical forms of free radicals in the human body.

According to Richard Passwater, Ph.D., free radicals can result in approximately 80 different age-related diseases. These include cancer, heart attack, stroke, rheumatoid arthritis, cataracts, and Alzheimer's disease. The natural mechanism which protects us from free radicals weakens with age. Therefore, the elderly, smokers and those exposed to environmental hazards, are more susceptible to degenerative diseases.  In today's high-stress "civilized" world, our harried lifestyle, combined with improper diet, over - consumption of fried, processed, and denatured foods, consumption of fats and oils which are themselves oxidized through improper storage and exposure to light and heat, all create damaging free radicals at an ever-earlier age. Exposure to sun, through the weakened ozone layer, also causes free radical destruction which appears as wrinkles, and brown or black spots, sometimes leading to cancers.

You can't escape from free radicals completely because they are a by-product of normal cell metabolism, such as fighting infection or burning glucose for energy. They also help tone the muscles that line the blood vessels, and are important in the production of certain necessary hormones and enzymes.

Free radicals are highly reactive, unstable molecules that have lost one electron and are aggressively looking for a replacement — a process that can result in damage to everything from your DNA to the collagen layer of your skin because these free radicals combine with your body’s cells and tissues to get that electron they need. In this way, excess free radicals can cause damage to blood vessel tissues, and the medical literature has linked these ‘excessive’ free radicals to nearly all health problems.

DNA can be damaged by a free radical and cause it to reproduce incorrectly, too rapidly, or not at all. Free radicals can change DNA to produce potential carcinogens. These effects of free radical attacks are called ‘oxidative damage,’ and an excess of these (or an ineffective natural defense mechanism that would deactivate free radicals) has been implicated as a contributing factor in many diseases. As we age, our bodies become less effective at combating oxidative damage which leads to signs of aging.

Free radicals alter the functioning of the cell. While the cell is somewhat permeable to allow nutrients to enter and wastes to be removed, the free radicals alter this, causing leakage or clogging, and ultimately the death of the cell. Free radicals interfere with the structures inside cells that produce energy, and then leave the cells weak somewhat less defenseless. Free radicals cause LDL (the ‘bad’ cholesterol) to stick to the walls of the arteries.

Free radicals are formed by exposure to such things as tobacco smoke, alcohol, insecticides, radiation, chemicals in the home or at work (chlorine, new carpeting, air fresheners, etc.), even excessive amounts of sunlight. Other causes are a high-fat diet, eating fried foods, or strenuous exercise. It is the free radical production from these sources that we need to be most concerned about, as they cause the excessive and uncontrolled free radicals that can have devastating health effects.

It is now recognized that free radicals are the contributing causes to more than 80 diseases, such as heart disease, cataracts and rheumatoid arthritis. We can help body to ‘scavenge’ or ‘deactivate’ free radicals before they cause harm by avoiding some of these environmental toxins and increasing antioxidant intake. Because antioxidant compounds are effective at very low concentrations, we can gain protection from even moderate dietary changes that increase antioxidant nutrients.

How do free radicals get into our bodies?

     o   From Within - as natural by-products of ongoing
          biochemical reactions occurring in normal metabolic
          functions, in the detoxification processes and in the
          immune system defence.
     o   From Outside - free radicals (better yet! - free radical
          generating substances - Ed) can be found in the food
          we eat, in our water supplies (especially after chemicals
          and pollutants have entered into them), drugs and
          medicine we ingest and the air we breathe.
     o   Our environment contributes immensely to the spread
          of free radicals, as do processes like drugs, radiation,
          pesticides, air pollutants, solvents, fried foods, alcohol,
          tobacco smoke, etc. - All the things most of us are
          exposed to all the time.

What Can We Do?

"Free Radical Scavengers" (anti-oxidants) are key elements in the defence system, which the body uses in order to neutralise the activity of these free radicals.

Vitamin E, Vitamin C, Beta-Carotene and Selenium among other nutritional benefits, have strong anti-oxidant properties. We assume that you are already quite familiar with these important nutrients and take them on a regular basis.

What you probably don't know about and what you need to find out about are the powerful free radical scavengers called proanthocyandins ('Pycnogenols'). As free radical scavengers, these substances are 50 times more powerful than Vitamin E and at least 20 times stronger than Vitamin C (one report we have seen indicates 1000 times stronger).

An even more recent discovery is Curcuminoids which are nature's most powerful and aggressive antioxidants known today, which are about 3 times more powerful than antioxidants from white and maritime pine bark and grape seed OPC extracts.

With the combination of these new discoveries we are now able to combat the effects that free radicals have on our bodies.

Free Radical Scavangers
Standing as the major defender against harmful free radicals is glutathione, our body's own antioxidant, along with the liver - as the primary detoxifier of harmful chemicals both consumed and produced in the body. The livers antioxidant abilities are crucial to human life and well-being. An overburdened liver, with insufficient supply of antioxidants, will result in disease and even death.
There was a time, many decades ago, when a quieter lifestyle, coupled with better quality foods and consumption of more fresh vegetables and fruits, and better quality soil with more nutrients passed to our food supply, helped protect us from free radical damage. In this day and age, supplementation with antioxidants to fight free radicals and prevent age-related diseases is becoming a necessity rather than a choice. In fact, many doctors, including those who do not embrace nutritional supplementation, do take various antioxidant supplements to protect themselves, because they read the ever-increasing studies on their benefits.  They believe that, at the very least, these substances are generally safe and can protect them from oxidative damage. 

Why are antioxidants so important?

As incredible as it might sound, it's true: Antioxidant nutrients can reduce your risk of developing more than eighty diseases, including heart disease, arthritis, and cancer; and can help slow the aging process.

You proba­bly know that people are more likely to develop degenerative diseases as they age. These diseases are caused by, or aggravated by, harmful chemical reactions that take place in the body. The process is inevitable—in fact, these same chemical reactions are what make us age. However, the good news is that these chemical reactions can be slowed, so these diseases are delayed for many, many years. For many people, the effects of these chemical reac­tions can even be reversed, enabling you to feel bet­ter and healthier than you have in years. The mira­cle workers in this process are called antioxidant nutrients, and All About Antioxidants explains howyou can use antioxidant nutrients to feel healthier.Antioxidants can reduce your likelihood of developing a multitude of deadly diseases, such as cancer, heart disease, and premature aging. Antioxidants work by destroying harmful chemi­cals in the body called "free radicals." These free radicals are the culprits in many diseases. Quite simply, antioxidants neutralize them. Knowing how to use specific antioxidants in the right combination can bolster your protection against free radicals.

Among the diseases linked to excess free radicals are:

1. Aging.
2. Cancers.
3. Coronary heart disease.
4. Autoimmune diseases.
5. Rheumatoid arthritis.
6. Alzheimer's disease.
7. Cataracts.
8. Parkinson's disease.

If you are at risk for developing these diseases or have a family history of any one of them antioxi­dant supplementation can give you an edge and help prevent, reduce the severity of, or delay the appearance of these and many other diseases. In fact, one study found that the United States health­care system could save $8.7 billion annually from reduced hospitalizations if Americans consumed optimal levels of antioxidant vitamins C and E, plus beta-carotene. The five-year savings would exceed $45 billion. At a time when the American health­care system is nearly bankrupt, you would think that people would start paying attention.

A single antioxidant alone cannot fully protect you against the many different types of free radicals. However,a balanced combination of antioxidant nutrients very effec­tively helps protect against free-radical damage and thus helps protect you from the different diseases associated with free radicals.

Since this is an extremely important topic to my point of view, I would like to discuss every aspect of antioxidants and free radicals in this article. While talking about antioxidants the following basic question comes in mind

What exactly are antioxidants?
What are free radicals?
How do free radicals affect our health?

The following topics will provide the answer many of these basic questions. Generally speaking, antioxidants are good for your health, and free radicals are bad. Although antioxidants are abundant in fruits and vegetables, most people do not eat many of these foods and therefore lack sufficient antioxidants. As a consequence, supplementing with antioxidant capsules or tablets becomes very important.

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All About Antioxidants

Q. What is an antioxidant?
A>>An antioxidant is a substance that protects your bodyand other objects from a process called oxidation. The best explanation is to think about why iron turns rusty or butter becomes rancid. Oxygen, which is essential for life, is a very volatile and reac­tive element. It reacts with iron to form rust, and it also reacts with the fats in butter to oxidize them and to make them rancid. A similar process occurs in your body. As you get older, more oxidation occurs—in a sense, it makes your body rusty. Anything that prevents or slows the oxidation process is called an antioxidant. Basically, an antioxidant protects other compounds against oxygen.

Your body produces some antioxidants (called endogenous antioxidants), but you must obtain oth­ers (exogenous antioxidants) from the diet. In fact, some antioxidants, such as vitamins E and C, are absolutely essential for life. The endogenous antioxi­dants are usually enzymes, coenzymes, and sulfur-containing compounds, such as glutathione. The exogenous, or dietary, antioxidants include vitamins such as vitamins C and E, bioflavonoids, carotenoids, and several sulfur-containing compounds.

Q. What is a free radical
A>>A Free radicals can be bad for your health. Quite simply, free radicals are the bad guys that harmyou, and antioxidants are the good guys that pro­tect you.

If you know about atoms these are the basic or smallest building blocks of chemical ele­ments. An atom consists of a nucle­us that contains subatomic particles, such as protons and neutrons. Normally, pairs of electrons orbit the nucleus, kind of like planets around the sun. Molecules consist of groups atoms held together by the actions of these pairs of electrons. Sometimes during chemical reactions, an electron will be pulled away from the rest of the molecule, creating a free radical. Essentially, a free radical is an unpaired elec­tron. Free radicals are highly volatile and reactive, and they seek out another electron to make a new pair. Free radicals cause damage when they pull electrons from normal cells of the body.

Q. What is an antioxidant
A>>A substance that quenches free radicals by donating electrons is called antioxidant and a little bit of the substance must go a long way. In other words, a few molecules of an antioxidant must protect many, many molecules.

Among the antioxidants our bodies make are the enzymes catalase, glutathione peroxidase, and superoxide dismutase (SOD). However, these are not sufficient, and we must obtain others from the diet. Some of the dietary antioxidants include vita­min A and especially the related carotenoid family of compounds, vitamin C, and vitamin E. Minerals are not by themselves antioxidants, but several min­erals can become vital components of antioxidant enzymes made by the body. These minerals include selenium, which is needed to make the glutathione peroxidases; iron, which is needed for catalase; and manganese, copper, and zinc, which are needed for SOD. Sulfur compounds, such as the sulfur-con­taining amino acids cysteine and methionine, help the body produce the most ubiquitous antioxidant within cells, glutathione. Antioxidant coenzymes, such as NADH (nicotinamide adenine dinucleotide), coenzyme Q10, and alphalipoic acid, are made by the body and obtained through the diet.

Q. What is the role of the endogenous antioxidants

A>>The antioxidants your body makes have very specific roles. Many of them are enzymes or coen­zymes, which catalyze reactions in the body. Themost called-upon endogenous antioxidant is glu­tathione, which is the primary antioxidant protector within your body's cells. Glutathione is a small sul­fur-containing compound that teams up with seleni­um-containing enzymes called glutathione peroxi­dases. Other heavy-duty endogenous antioxidants are the superoxide dismutases. One type of SOD con­tains the minerals copper and zinc, while another type contains the mineral manganese. SODs specifi­cally break up a harmful form of oxygen called superoxide into hydrogen peroxide. While hydrogen peroxide can damage cell components, it is not as destructive as superoxide. Another endogenous antioxidant called catalase contains the mineral iron. Catalase breaks down hydrogen peroxide into water. The selenium-containing glutathione peroxidases can also convert hydrogen peroxide into water.

Role of exogenous antioxidants
The exogenous antioxidant nutrients are broad­er in their protective actions. For example, vitamin E resides in fat-containing body components, such as cell membranes and lipoproteins (such as choles­terol), and protects against many different types of oxidants. Vitamin C is the most important antioxidant in the bloodstream. Vitamin E is called a fat-soluble vitamin because it is compatible with fats, whereas vitamin C is called a water-soluble vitamin because it is compatible with water. Any of these individual antioxidants are beneficial to health. But they offer greater benefits when taken as a group.
Benefits of antioxidant nutrients
Vitamin E was once believed to be a vitamin without deficiency symptoms. It was known to be a powerful natural antioxidant, but no one could fig­ure out how it worked in the body. It did not appear to be involved in enzymatic reactions or to be incor­porated into structural components. This vitamin was a mystery that caused many nutritionists to be skeptical that it was indeed essential for humans. Little more was known about it, other than that it was required for the birth of animals. Without vita­min E, laboratory animals would resorb the fetuses before birth.

After researchers discovered the effects of antioxidants on aging and cancer, scientists began looking at many of the nutrients anew in terms of theirantioxidant activities. Studies of antioxidants' effects on the aging process led to the discovery that antioxidant nutrients offered protection against cancer. Some scientists felt that life expectancy was not directly extended, but that it was indirectly extended by preventing or delaying diseases, such as cancer. Later, scientists began studying the incidence of various diseases among groups of people in relation to their intakes of dietary antioxidant nutrients. It was found in studies that the more vitamin E consumed and the longer that those higher amounts were consumed, the more the incidence of heart disease decreased. Gladys Block, Ph.D., of the University of California conducted several studies in which she found that vitamin C and carotenoids were associated with reduced risk of several cancers. In 1993, Harvard researchers published studies showing that vitamin E supple­ments taken for more than two years were associat­ed with reduced incidence of heart disease.

As people began taking more antioxidant sup­plements, they reported improvements in condi­tions ranging from menopause to arthritis. These reports, coupled with the development of plausible theoretical explanations, encouraged more scien­tists to investigate the possible relationships. Eventually, scientists felt sufficiently comfortable to study the relationship of antioxidants and the inci­dence of Alzheimer's disease, cataracts, and other disorders.

Q. Which is the best antioxidant

A>>When people start debating which antioxidant is most important or powerful, they are missing the idea that antioxidants work together in concert. It is like arguing which link in a chain is most impor­tant. The chain is as strong as its weakest link. The same is true with antioxidants. There are reasons for this. Different antioxidants protect against different types of free radicals in different parts of cells and in different places in the body. In addition, antioxi­dants help each other like members of a sports team. This is what I mean by antioxidant synergism—the sum is greater than the parts.

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Synergy of antioxidants

Essentially, antioxidant syner­gism is when the effects of combining antioxidants are greater than you would expect from adding up the effects of all the antioxidants individually. This concept has become important in nutritionto establish the teamwork effects of nutrients in general, but especially of antioxidants. Antioxidants should not be thought of as individual compounds. They should be thought of as complementary play­ers on a team, or in the way that individual instru­ments form an orchestra. Don't you think that a baseball team con­sisting of various infielders, outfielders, pitchers, and catchers would be more effective than another team of nine players, all of which are first-basemen standing around first base?

Dr. Denham Harman of the University of Nebraska had experimented with single compounds to see if they had a protective effect. His first experiments were with sulfur compounds known to be protective against the effects of radiation on the body. In 1968, Dr. Harman demonstrated that a diet consisting of 0.5 percent of vitamin E increased the life spans of mice by about 5 percent. Al Tappel, Ph.D., of the University of California at Davis confirmed the biological synergism of the antioxidant nutrients used in laboratory animal studies. The reason for the synergism is that some antioxidants are more effective against some free radicals, whereas other antioxidants are more effec­tive against other free radicals. Synergism makes every link in the chain strong.

Q. Antioxidants also regenerate or recycle other antioxidants

A>>That's correct. Lester Packer, Ph.D., of the University of California, Berkeley, discovered that some antioxidants can regenerate other antioxi­dants, and this is another reason why they are syn­ergistic. To explain a little more, after an antioxidant neutralizes a free radical, the antioxidant becomes a weak free radical. Another antioxidant can help regenerate this "used up" antioxidant. For example, both alpha-lipoic acid and Pycnogenol can regener­ate used vitamin C, which in turn, can regenerate used vitamin E. This means that alpha-lipoic acid and Pycnogenol extend the usefulness of vitamins C and E.

Q. Foods that contain antioxidant nutrients

A>>A varied diet containing at least five generous servings daily of fruits and vegetables forms the foundation of an antioxidant-rich diet. There are thousands of antioxidant nutrients that occur in whole, unrefined foods that are not available in sup­plements. Unfortunately, many of the antioxidant nutrients are removed during food processing. Vitamin E is stripped from vegetable oils in the refin­ing process and from whole grains during their refinement into white flour. Bioflavonoids taste bit­ter, so they are often removed from refined foods. While a diet rich in fruits and vegetables is the foun­dation, supplements are required to achieve the opti­mal levels of these antioxidant nutrients.

Carotenoids, another family of antioxidants, are found in the yellow, orange, and red fruits and veg­etables, and in some greens. Bioflavonoids are found in most fruits, but particularly the blue and purple ones (such as grapes and blueberries). Vitamin C is found in citrus fruits, and bioflavonoids are found in the rinds (skins) of citrus. Vitamin E is found in whole grains, nuts, and vegetable oils. Selenium is found in whole grains, garlic, and Brazil nuts—if there is enough selenium in the soils inwhich they are grown. So, even eating a diet con­taining the correct foods doesn't guarantee that you will get optimal amounts of selenium.

Q. Free radicals damage the body cells

A>>In 1954, Dr. Denham Harman was the first sci­entist to theorize that the aging process was caused by free radicals. Until then, free radicals were thought to exist only outside the body. The only sci­entists that were familiar with free radicals were organic chemists who utilized the production of free radicals to help synthesize new compounds or make commercial processes for the production of complicated chemicals.

Harman was very familiar with both free radicals and the human body. He was a scientist experi­enced in radiation chemistry while at the Shell Development Company and a physician at the Donner Laboratory of Medical Physics on the Berkeley campus of the University of California. This unique combination gave him the background to have the brilliant insight that free radicals existed in the body and could cause damage.

The discovery of biological free radicals and the damage they cause in living systems is worthy of aNobel prize. This discovery has led to many advances in helping people live better longer. By applying the knowledge stemming from Barman's research, we have been able to delay many of the deleterious effects of aging, reduce cancer and heart disease incidence, and relieve much suffering. This fact is often overlooked as the tag given to Harman is "the father of the free-radical theory of aging." Unfortunately, the "aging" focus is too narrow and has obscured the broader implications of Harman's research.

In 1968, Dr. Harman demonstrated that a diet consisting of 0.5 percent of vitamin E increased the life spans of mice by about 5 percent.

Q. How often do free radicals attack body cells

A>>All the time! Bruce Ames, Ph.D., of the University of California at Berkeley estimates that every single one of your body's cells (and you have trillions of them) suffers about 10,000 free-radical "hits" per day. Much of this damage is done to your deoxyribonucleic acid (DNA), or genetic material. One of the consequences is that the mutation rateincreases. Elderly persons have nine times the fre­quency of cell mutations as do infants. These muta­tions increase the risk of cancer. In addition, cell membranes, proteins, and fats are also being dam­aged by free radicals. Over a typical seventy-year life span, the body generates an estimated seven­teen tons of free radicals. Your body needs to have its antioxidant defenses optimized at all times.

A>>Free radicals can damage all types of substances and tissues in the body. The easiest damage, and thus the most frequent, is to body fats. This is because fats are especially prone to oxidation. Scientists use the term "lipid peroxidation" to describe oxidized fats in the body. Lipid peroxidation sets off a chain reaction that will continue throughout the fatty material until stopped by an antioxidant.

Free radicals can damage the nucleic acid bases (adenine, thymine, guanine, and cytosine), which together form DNA. This damage prevents DNA from accurately replicating itself. Damaged, or mutated, DNA leads to the replication of incorrect biological information—such as cancer cells.

Free radicals can also damage proteins, meaningthat some body components may not function effi­ciently. For example, free radicals can damage the collagen proteins in skin, leading to tougher skin. Damaged enzymes (which are proteins) will not work as efficiently to drive biochemical reactions. Nor will the repaired enzymes be able to repair as much free-radical damage, and a downward spiral causes a snowballing effect leading to faster aging and possibly cancer.

Q. How can free radicals cause cancer
A>>There are several ways free radicals can cause cancer. Free radicals can damage DNA, which causes mutations. Mutated cells can develop into cancer.

1. Free radicals can activate so-called cancer genes, also known as oncogenes.
2. Free radicals can suppress the immune system, inactivating the body's defense against

     cancer.

1. Free radicals can activate carcinogens or "precarcinogens" to start the chemical reactions that
   lead to cancer.
2. Free radicals can damage cell membranes and inactivate the sensory mechanisms that limit abnormal cell growth and reproduction.

By quenching free radicals, antioxidant nutrients protect against these undesirable activities.

Q. How do free radicals cause heart disease?

A>> Free radicals damage the particles that carry cholesterol in the blood and, in a sense, turn "good" cholesterol "bad." This damage changes the choles­terol carrier in such a way that it enters into the wall of the arteries and starts the process that results in cholesterol deposits. Free radicals can also turn on blood platelet cells, which can form abnormal clots and set the stage for a heart attack. Free radicals can damage the lining of the arteries, which can lead to cholesterol deposits forming. The process is far more complicated than the old theories about eating too much cholesterol or fats.
Q. Free radicals can cause arthritis
A>>They can certainly aggravate arthritic symp­toms. Arthritis is characterized by inflammation. Inflammation usually involves "superoxide anion"free radical. Arthritis can be treated by reducing inflammation with antioxidants, including SOD. Several studies have shown that dietary antioxi­dants reduce the severity of existing arthritis. One of the promising anti-inflammatory antioxidants is Pycnogenol, found in French Maritime pine bark.
Q. Free radicals can cause cataracts
A>>Cataracts are caused by free radicals reacting with the proteins in the eye lens. The eye lens is nor­mally clear, so light can pass through it. Sunlight also includes ultraviolet rays, which generate free radicals when they react with proteins in the lens. These free radicals, if not quenched by antioxidants, damage the proteins in the eye. The damaged pro­teins are not clear, but cloudy, forming a cataract. Thus, cataracts can be caused by over-exposure to sunlight. High glucose (blood sugar) levels also generate free radicals and can damage the lens. Antioxidants prevent this damage by terminating free radicals. But because there are no blood vessels in the lens, the fluid around it has to contain suffi­cient antioxidants.

Recommendations about antioxidant supplements?
A. Jeffrey Blumberg, Ph.D., chief of the antioxi­dant research laboratory at Tufts University, helped found the Alliance for Aging Research to help dis­seminate exactly this type of information. At a press conference, this nonprofit research group noted that people could live longer and be healthier if they took daily supplements of vitamins C and E andcarotenoids. They recommended that healthy peo­ple should take the following every day:

1. 10OO IU of vitamin E.
2. 17,000-50,000 mg of carotenoids.
3. 250-1,000 milligrams of vitamin C.

Dr. Blumberg reported that "We have the confi­dence that these things really do work." Later in this book, I'll provide more comprehensive recom­mendations for antioxidant supplementation.

Q. Antioxidants for a Healthy Heart

A>>The common heart attack is due to coronary artery disease in which lesions (deposits of cholesterol and other materials) narrow the lumen (opening) of the arteries. The narrowing of arteries by deposits is called atherosclerosis, and when it affects arteries feeding the heart, it's called coronary heart disease. Since there's a lot of cholesterol in these deposits, many doctors assumed that cholesterol-rich foods would dam­age blood-vessel walls. But there's more to the process—levels of free radicals and antioxidants influence your risk of heart disease.

Q. What is a heart attack?

A>>Having narrowed arteries (atherosclerosis), does not cause the common heart attack. Thenarrowed arteries damage blood cells called platelets when the cells are forced to squeeze by. Platelets are the blood cells responsible for clotting, and squeezing and damaging them facilitates the formation of blood clots. The clots can lodge in the narrowed arteries, completely shutting off the flow of blood through that artery. This life-threatening condition is called a coronary thrombosis—a blood clot in a coronary artery.
When a blood clot shuts off the flow of blood in a coronary artery, the region of the heart fed by the artery is starved of oxygen and nutrients. The result is the death of these cells, which is called an infarct. This is the classic heart attack called an acute myocardial (heart) infarction.

Q. What are some other common heart diseases?

A>> Another common form of heart disease is con­gestive heart failure, in which the heart is too weak to pump efficiently. Usually, the heart itself has enlarged as it has tried to compensate for the reduced output. Angina is the pain experienced in the heart when there is not enough blood reaching all parts of the heart during activity. Then there are disorders of the heartbeat rate regularity—too irregular (arrhythmia), too fast (tachycardia), or too slow (bradycardia) for an efficient pumping action. Spasms can clamp an artery shut and cause a heart attack even though there are no significant choles­terol deposits. High blood pressure (hypertension) affects arteries and is a risk factor in various forms of heart disease.

Q. How do cholesterol deposits form?

A>>Cholesterol is a fat and not soluble in blood (which is watery), so it is carried in particles called lipoproteins. Two important lipoproteins are low-density lipoprotein (LDL) and high-density lipoprotein (HDL). The cholesterol carried by LDL is often called the "bad" cholesterol. LDL carries cholesterol to the cells. The cholesterol carried by HDL is often called the "good" cholesterol. HDL carries choles­terol away from cells. Cholesterol deposits seem to form only when LDL becomes damaged by oxida­tion. It's then called oxidized LDL. Oxidized LDL can infiltrate the artery lining and initiate a series of events that trap the cholesterol in the oxidized LDL, attract white blood cells, and form a deposit.

Q. How do antioxidant nutrients protect against cholesterol deposits?

A>>LDL becomes oxidized only when the amount of antioxidants is insufficient to protect the LDL against oxidation. Oxidized LDL is a sign of very low antioxidant levels, because LDL is the medium that transports fat-soluble antioxidants through the body. The prime antioxidant that protects LDL is vitamin E, although other antioxidants help by recycling vitamin E. Other antioxidants can also destroy many of the free radicals before they reach LDL to cause damage. The tendency to form oxi­dized LDL, and hence cholesterol deposits, depends on two factors: the amount of LDL and the balance between antioxidants and free radicals. Both are important, but the antioxidant/free radical balance is the more important of the two.

Q. How do antioxidant nutrients protect against other causes of heart disease?

A>>While a lot of attention has been focused on cholesterol through the years, the strongest dietary association with heart disease is a deficiency of vita­min E. Cholesterol deposits by themselves don'tcause a heart attack. They are a major contributing factor to forming the blood clot (coronary thrombo­sis) that causes the heart attack (acute myocardial infarction). As long as the blood can squeeze by the narrowing caused by the cholesterol deposits in good volume, the heart will receive sufficient oxy­gen and nutrients to keep the heart tissue alive.

A critical factor then is to maintain the proper "slipperiness" of the blood cells and prevent a blood clot from forming in the coronary arteries. Vitamin E, and especially Pycnogenol, have a pro­tective anti-aggregation effect on blood platelets, which are critical factors in the blood clotting process. They are particularly effective against the damage to platelets from stress and smoking.

In addition, the antioxidant nutrient Pycnogenol is a mild hypotensive (an agent that lowers blood pressure), which helps maintain a normal blood pressure. Pycnogenol also acts to maintain ade­quate nitric oxide levels so blood vessels can relax. Recent studies have also linked inflammation to heart disease. Antioxidant nutrients, especially Pycnogenol, reduce inflammation.

Vitamin E is important to the heart and arteries in more ways than protecting LDL from oxidation. As an example, vitamin E is vital to maintaining a healthy lining of the arteries. Tears in the lining of arteries are another way in which deposits can form.Pycnogenol is a secondary factor in every way that vitamin E helps—this is because Pycnogenol regen­erates vitamin C, which in turn, regenerates vitamin E. All of the antioxidants together form one terrific team to prevent heart disease.

Q. Can antioxidant vitamins prevent heart attacks?

A>>Yes, they can—especially vitamin E. A study by cardiologists at Cambridge University found that daily supplements of 400 IU or 800 IU of natural vitamin E reduced heart attacks by 77 percent. This was a large scientific study involving 2,000 people over about five years. In many respects, this single study was the major turning point in making vita­min E acceptable to physicians.

Antioxidant nutrients slow or reverse heart dis­ease. A mixture of the tocotrienol and tocopherol forms of vitamin E reversed the development of cholesterol deposits in people. In another study, researchers reported that vitamin E supplements, 100 IU or more daily, could slow the formation of cholesterol deposits.

Q. How do antioxidant nutrients protect us from stress?

A>>When your body is under stress, your body increases production of the hormone adrenaline. Unfortunately, adrenaline activates the blood platelets so that they have a greater tendency to clump together and form a blood clot. While Pycnogenol can't make your causes of stress go away, it can help keep your blood "slippery" to reduce the chances of heart attacks and strokes.

Studies conducted in Germany by Peter Rohdewald, Ph.D., and confirmed by Dr. Ronald Watson of the University of Arizona, Tucson, found that Pycnogenol blocks the effect of adrenaline on blood platelets. Pycnogenol is particularly effective against increased platelet aggregation (stickiness and increased clotting tendency) caused by smoking.

Q. Does Pycnogenol work in the same way that aspirin works to prevent heart attacks?

A>>Not exactly. Aspirin is widely prescribed by cardiologists to protect against heart attacks. Thefirst studies showed that aspirin can reduce the inci­dence of a second heart attack in heart patients. Later studies showed that aspirin also reduces the risk of having a first heart attack. So far, this sounds good, but, unfortunately, many people develop serious problems with prolonged aspirin use. They can develop ulcerated linings of the gastrointestinal tract and an increased tendency to bleed. This can cause so much internal bleeding that it can cause death. Some people have been known to develop this condition suddenly and without warning. While aspirin therapy has benefit for many people, check with your doctor before taking aspirin on a long-term basis. In the Pycnogenol studies, the researchers found that 100 mg of Pycnogenol achieved the same desired effect on blood platelets in smokers as 500 mg of aspirin. Furthermore, due to Pycnogenol's effects on the enzyme 5-lipoxyge-nase, rather than on cyclooxygenase—the enzyme that aspirin inhibits—Pycnogenol did not increase bleeding tendency as does aspirin.

Q. How do antioxidant nutrients protect the linings of arteries?

A>> One contributing factor in heart disease is dam­age to the lining (endothelium) of the heart andarteries. This damage can cause clots to form and allow cholesterol carriers to enter the artery walls. Researchers at Loma Linda University, California, studied the protective effect of Pycnogenol using endothelial artery cells. They found that Pycno­genol reduced the damage to the endothelium caused by free radicals. They also noted that Pycnogenol increased the levels of other antioxidants in the cells due to its sparing and regenerative effects. Other studies have shown that vitamins C and E also protect artery linings.

Q. How do antioxidant nutrients relax blood vessels to help prevent high blood pressure?

A>> I'll give you a couple of examples. Pycnogenol has a mild hypotensive (blood pressure lowering) effect that helps prevent high blood pressure. There are two known reasons for this action. One mecha­nism involves the optimization of nitric oxide pro­duction in the blood vessels. Several researchers, including David Fitzpatrick, Ph.D., of the University of South Florida and Lester Packer, Ph.D., of the University of California, Berkeley, have studied this effect.
Nitric oxide has recently aroused much interest among scientists, after having been dismissed for decades as not being an important compound in the body—merely a waste product or inhaled air pollu­tant. Now, we understand that it has far-reaching effects throughout the body. Two enzyme systems control the production of nitric oxide. One enzyme system produces nitric oxide at a constant rate, while the other is activated by stress. Some nitric oxide is always needed, but too much can kill cells. Pycnogenol helps regulate nitric oxide in the body at optimal levels. It helps the body produce ade­quate levels of nitric oxide for necessary functions, while reducing the production of the enzyme that makes nitric oxide when too much nitric oxide is present. Dr. Fitzpatrick tested the effect of Pycnogenol on portions of the aorta and found that it improved the production of nitric oxide in the endothelium, which in turn had a relaxing effect on the aorta.

The other reason for Pycnogenol's hypotensive effect is its effect on dietary fat. In another study, researchers at the University of Maryland found that antioxidants can counteract the deleterious action of a high-fat meal on arteries. A high-fat meal prevents arteries from dilating normally. The ability to widen when needed is critical, especially in per­sons who have heart disease. In this study, healthysubjects ate a 900-calorie fast-food meal of egg, sausage, muffin, and hash browns. The meal con­tained 50-percent saturated fat. The researchers measured the dilation capacity of the brachial artery in one arm of each volunteer before the meal and again two and four hours after the meal. On the next day, the volunteers were given an identical meal, but in addition, they received 1,000 mg of vitamin C and 800 IU of vitamin E. This time, when the dilation capacities were measured, they were near normal, almost as if they had not eaten the high-fat meal.While this vasorelaxation effect is important, Pycnogenol should not be considered a hypotensive drug

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Antioxidants and Cancer Prevention

Cancer is not a single disease, but a group of many similar diseases. There are about 100 different types of cancer, and they all involve an abnormal behavior in some of the body's cells. Most cancers involve tumors. In this chapter, I'll explain what cancer is, how free radicals are involved in cancer, and how antioxidants protect against cancer.

Q. What exactly is cancer?

A>> To understand the nature of cancer, it helps to first understand something about normal cell growth. Typically, the many cells of your body grow and divide in an orderly fashion. Normal cells also eventually die in a process called apoptosis, or cell suicide. When cells lose the ability to control theirgrowth, they can divide quickly without any sense of order. This results in excess tissue, called a tumor.

There are two types of tumors, benign and malig­nant. Benign tumors are not cancerous and do not spread. Only rarely, such as with benign brain tumors, are they likely to kill a person. They can usu­ally be removed through surgery, and they do not usually recur. In contrast, malignant tumors are can­cerous—that is, they can infiltrate and destroy near­by tissues. Malignant cancer cells can also spread through the body and seed new tumors. Cancer cells seem to lose the ability to self-destruct—unless stopped, they just keep reproducing.

Free radicals are involved in cancers in a number of ways. They can mutate DNA, leading to the cre­ation of abnormal cells. Recent research has found that cancerous tumors generate their own free radi­cals and promote still more mutations and abnor­mal cells. This is why some tumors always seem to be a step ahead of the treatment; they are changing rapidly.

Q. How does cancer happen?

A>> Cancer is not the result of one single thing going wrong. A cancer forms through a series of steps. Simply having a mutated cell is not enough tocreate a cancer. The body has many safeguards to protect against aberrant cells. For example, the immune system can come into play and destroy mutated cells before they lead to cancer.

Free radicals seem to encourage the formation of cancers at many different stages. They can mutate, or permanently change, DNA so that it conveys the wrong instructions to cells—telling them to keep growing and not to stop. Normally, cells regulate their proliferation with their ability to sense the pop­ulation of neighboring cells. Free radicals can dam­age cell membranes and inactivate the sensory mechanisms in the membranes that limit cell growth and reproduction. When cell sensors become dam­aged, cell proliferation and growth become uncon­trolled. In addition, free radicals can suppress the immune system, inactivating the body's defense against cancer.

Based on research, antioxidants can stop or slow each of the steps in cancer development. Preliminary evidence suggests that antioxidants can also reduce the chances of metastasis and boost the immune sys­tem. Antioxidants may have a role in apoptosis, which helps eliminate mutated cells from the body. Although antioxidants seem to extend the life of nor­mal cells, they appear to help cancerous cells commit suicide. These findings point to the fundamental reg­ulatory roles of antioxidants.

Q. How do antioxidants protect against cancer?

A>> Antioxidant nutrients protect against cancer in three ways: by destroying cancer-causing free radi­cals, by boosting your body's immune system so it can destroy mutated cells before they become can­cers, and by reducing the tendency of cancer cells to adhere to other organs and glands. In addition, I believe that antioxidants inhibit several tumor pro­moters and the activation of some pre-carcinogens into "true" carcinogens. This effect has been demonstrated with antioxidants called bioflavonoids and explains part of their protective actions against cancers. Dr. David White of the University of Nottingham in England has reported that Pycnogenol inhibits an enzyme (monooxygenase) from converting the prime pre-carcinogen in smoke, benzo[a]pyrene, into its epoxide, which is a true carcinogen.
Don't sweat the details. Population studies have shown that diets rich in fruits and vegetables reduce the incidence of many cancers. Many scien­tists believe that the reason that fruits and vegeta­bles are so protective is that they are rich in antiox­idants, especially vitamin C and bioflavonoids.

Q. How do antioxidant nutrients boost immunity?

A>>Cancerous cells break off from tumors and trav­el through the body via the lymphatic system. They seed new tumors in a process called metastasis. Basically, the cancer cells stick to other tissues and form new tumors. This process requires molecules called cellular adhesion molecules, such as ICAM-1and VCAM-1. Pycnogenol, quercetin, and other antioxidants reduce the activity of these adhesion molecules, preventing the attachment of cancer cells.

Adhesion molecules are also involved in inflam­mation, allergies, and atherosclerosis. By reducing their activity, antioxidants may protect against other diseases and disorders in yet another way. It certainly explains why antioxidants have been reported to ease allergic symptoms.

Q. Is there evidence that antioxidant nutrients actually reduce cancer incidence and death rate?

A>> Yes, there is. Many epidemiological studies show diets rich in fruits and vegetables reduce the incidence of various cancers. Fruits and vegetables are rich in the antioxidant bioflavonoids, carotenoids, and vitamin C. In addition, there are hundreds of laboratory animal studies, including my own, showing that antioxidants reduce the incidence of various cancers. As far as human clinical studies go, there are a few. One joint United States/China study found that supplements of vitamin E, seleni­um, and beta-carotene reduced the risk of many cancers, including lung cancer and stomach cancer,as well as increased life spans. A well-controlled clinical study sponsored by the National Cancer Institute and led by Larry Clark, Ph.D., of the University of Arizona, Tucson, found that taking 200 meg of selenium daily cut cancer incidence and cancer death rate in half, as well as increased life spans. A 1998 Finnish double-blind, placebo-con­trolled clinical study found that vitamin E supple­ments cut prostate cancer incidence by 32 percent. These are just a few of the many studies on the ben­efits of antioxidants.

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Staying Young With Antioxidants

Every living creature or plant grows old. As unpleasant as the thought may be, it's a fact of life. Yet some people age far more gracefully than others and look more youthful. This means that aging occurs at different rates, and research on antioxidants indicates that the rate of aging can be slowed. In this chapter, I explain how free radicals promote the aging process and how antioxidants can retard it.

Q. What happens to people as they age?
A>> Aging is the process that reduces the number of healthy cells in the body. With fewer healthy cells, there is a higher percentage of unhealthy cells. Different organs seem to age at different rates in dif­ferent people. When the percentage of unhealthycells in a particular person grows beyond a certain point, the function of that organ is in jeopardy. In most people, the heart gives out first; in others, it's the immune system or brain.

The most striking factor in the aging process is the body's loss of youthful "reserve" because of the decreasing number of healthy cells in each organ. For example, fasting blood glucose (blood sugar) levels remain fairly constant throughout life, but the glucose tolerance measurement shows a less effec­tive response with aging. Glucose tolerance tests measure the reserve capacity of the endocrine sys­tem to respond to the stress of an increased glucose load. This same diminishment holds true for the recovery mechanisms of other systems. Simply stat­ed, the aging process is the body's loss of ability to respond to challenges or stresses. The mass of healthy active cells in each organ declines as a per­son ages, diminishing the organ's ability to function normally.

Q. What causes this loss of reserve?
A>> By this point, you probably know the answer yourself: free radicals. The cumulative effect of tril­lions of free-radical reactions is the loss of cells. This damage occurs in a number of ways. For example,free-radical damage to the cell membranes can impair the cells' ability to transport nutrients into the cell and waste products out. As a result, the cell will die.

Free radicals also damage the cell's DNA, so that instead of replicating a healthy cell, it produces a mutant cell that does not function completely nor­mally. Some of these cells may become cancerous, but most simply become less efficient with time. This cellular inefficiency is a hallmark of aging.

The result of these and many other types of free-radical reactions is that the number of healthy, active cells in the body decreases. This is analogous to the light bulbs in an old theater marquee that burn out one by one. For a while, the message can still be read, but as the number of burned-out bulbs increases, eventually the message is not discernible. In the body, the cells in each organ decline, but the organ still functions—up to a point.

Q. Can antioxidants help me live longer?

A>>The answer is yes—but the real idea is to live better as well as longer. We should not want to just add years to our lives, but also to add life to our years.In the laboratory animal experiments that I con­ducted, my antioxidant-supplemented animals lived longer—about 30-percent longer average life spans and 10-percent longer maximum life spans. Furthermore, they weren't just a bunch of old decrepit animals. They were healthier, looked younger, were more active, and had less disease. The question then became, "Will antioxidant nutrients do the same for humans?"

Unfortunately, we don't have double-blind, placebo-controlled clinical trials performed over the entire life span of thousands of humans to prove this—and we never will see such studies carried out. The expense would be astronomical. We do, however, have other evidence.

As the popularity of taking antioxidant supple­ments has increased, we have witnessed a decline in chronic disability, heart disease death rate, and, at long last, cancer. At the same time, the average life span has increased. Although this evidence is indi­rect, it does support the idea that there has been a positive effect on millions of people taking antioxi­dant supplements. Basically, if antioxidants reduce your risk of cancer and heart disease, they will inevitably extend your life expectancy.

There have been many other studies, in addition to those I described earlier. A number of years ago, I participated in a study with Linus Pauling, Ph.D.,and Jim Enstrom, Ph.D., that examined mortality among health-conscious elderly Californians. This study found that the death rate was lower for sup­plement users. Male supplement users had a 22-percent lower risk of death and women had a 46-percent lower risk of death. Later, Enstrom and his colleagues reported that vitamin C supplements that provided over 250 mg per day reduced the mortality rate in men by 35 percent, which translat­ed to a six-year increase in life expectancy.

One recent study, reported in the Journal of the American Geriatrics Society, found that centenari­ans—people aged 100 years or older—had substan­tially higher levels of antioxidants and lower levels of free radicals in their blood, compared with peo­ple between the ages of 70 and 99. They also ate rel­atively large quantities of antioxidant-rich fruits and vegetables.

Q. Can antioxidant nutrients help prevent cataracts?

A>>Yes, they can. Cataracts, clouding of the lens of the eye, are associated with aging, with exposure to sunlight, and with diabetes. They are caused by free radicals oxidizing the protein that forms lenses. A number of studies have found correlations betweenhigh antioxidant intake and reduced risk of cataracts. One recent study reported that women who took vitamin C supplements—at least 400IU daily for ten or more years—were less likely to develop cataracts. Several antioxidants are of particular benefit to the eyes. Vitamin C, of course, and also vitamin E have been associated with a lower risk of cataracts. Lutein, related to beta-carotene, may also reduce the risk of cataracts. Lutein is the only carotenoid found near the lens. In addition, the lens is bathed in a fluid rich in glutathione. You can increase your body's production of glutathione by taking vitamin C, alpha-lipoic acid, and N-acetylcysteine —all very good and important antioxidants

Q. Can antioxidants really create more youthful looking skin?

A>>They can help preserve your skin, reduce the aging of skin, and maybe even reverse some dam­age. People with very weathered or wrinkled skin likely either smoked for much of their lives or spent a lot of time outdoors. Smoking is a major generator of free radicals throughout the body—that's why it has been linked to so many types of cancer. Its most visible effects, however, are probably on the skin. Similarly, exposure to sunlight's ultraviolet rays generates large numbers of free radicals in the skin.

To demonstrate the effect of free radicals, exam­ine the skin on the back of your hand by pulling it away from the hand. Let it go and count the num­ber of seconds it takes for the skin to spring back to place. Do the same test with people of different ages. In general, younger people will have more elastic skin that quickly rebounds compared with older people. Now, do the same test with skin from a part of your body that has not been as exposed to sunlight. See the difference? The skin is of the same age all over your body, but it has aged more where exposed more to sunlight.

To minimize free radical damage to the skin, minimize your exposure to the sun and don't smoke. To counter damage, take an antioxidant for­mula and consider applying an antioxidant cream or lotion to your skin. Antioxidants are absorbed and retained by the skin. Lester Packer, Ph.D., at the University of California, Berkeley, has conducted a number of experiments showing that skin antioxi­dants are quickly used up under oxidative stress. Vitamins E and C and beta-carotene reduce free-radical damage to the skin. Packer has also demon­strated that antioxidants in the skin work synergistically, which shouldn't be all that surprising because they work together every place else in the body.

Q. Can antioxidant nutrients help protect against sunburn?
A>> To a certain extent they can. Sunburn is inflam­mation caused by free radicals, whose production was triggered by ultraviolet rays in sunlight. While antioxidants are not a sunscreen or sunblock, per se, they do increase the skin's resistance to free radicals and inflammation—and the skin's ability to repair damage. In a number of studies, European research­ers found that supplementation with beta-carotene and the use of a topical sunscreen was far more effective in reducing sunburn than the use of a sun­screen alone. Other beneficial antioxidants include vitamins E and C and flavonoids, particularly Pycnogenol. Taking antioxidants internally, and applying them topically, can give you inside-out protection against sunburn.
It's not too late to take antioxidants—inside and outside—after a sunburn either. They will help restore normal levels of antioxidants in the skin, and they should reduce inflammation and speed healing. Remember that excessive exposure to sun­light increases the risk of skin cancer, particularly among fair-skinned people. It makes no sense to tempt fate.

Q. Can antioxidant nutrients improve fertility?

A>>Yes, vitamin E, vitamin C, selenium, alpha-lipoic acid, and ferulic acid (an antioxidant found in Pycnogenol) have each been shown to improve fer­tility. Horse breeders swear by Pycnogenol and vitamin C. Antioxidants in general improve sperm motility—that is, their ability to swim. Many urolo­gists recommend that their infertile male patients take antioxidants, as well as stop smoking. A num­ber of studies in men have found that antioxidant supplementation normalizes the appearance of sperm and increases the likelihood of fertilizing their partner's eggs. In one study, 1,000 mg of vita­min C daily improved the sperm of men who smoked. Ami Amit, M.D., reported in the journal Fertility and Sterility that he gave 200 IU of vitamin E daily for three months to men with normal sperm counts but low fertilization rates. The men's fertil­ization rate improved by 30 percent.

Q. Can antioxidants improve arthritis?
A>>Rheumatoid arthritis is an inflammatory dis­ease. By now, you understand that free radicals promote inflammation. While antioxidants are not a cure for arthritis, they can reduce the inflammation, swelling, and pain associated with this condition. Vitamin E and selenium have individually and in combination reduced pain and swelling in arthritis patients. In Israel, a study found that 600IU of vita­min E reduced the pain of arthritis in half of the patients, compared with only 4 percent of the patients receiving a placebo.

Arthritis may also be aggravated by low levels of vitamin C. When people do not obtain enough vita­min C, their blood vessels are more likely to leak. Some of these blood cells can leak into joints, where they stimulate an inflammatory reaction. Recently, French researchers described two patients with scurvy (a severe deficiency of vitamin C) whose symptoms included rheumatism. When they were given high doses of vitamin C, their symptoms went away.

Q. Can antioxidants protect against Alzheimer's disease?
A>>Yes, they can. Free radicals are involved in Alzheimer's disease, and antioxidants have been shown to help. In a major study, published in the New England Journal of Medicine, researchers foundthat late-stage Alzheimer's disease patients who took 2,000 IU of vitamin E daily for just two years were able to delay for six to seven months key symptoms of the disease. It has not been proven, but I suspect that taking more modest doses of vita­min E (400 IU daily) much earlier in life will prevent or delay the onset of Alzheimer's disease. Ishwarlal Jialal, M.D., of the University of Texas Southwestern Medical Center said, "Anyone with a family history of Alzheimer's disease or heart disease would be foolish not to take daily vitamin E supplements.

One of the characteristics of Alzheimer's disease is the accumulation of beta-amyloid protein, which literally chokes brain cells to death. In laboratory experiments, researchers at the Salk Institute of Biological Sciences, San Diego, have found that Pycnogenol prevented beta-amyloid from accumu­lating in brain cells. I'm convinced that the best approach is taking a broad selection of antioxidants. I'll describe such a program in the next chapter.

Q. How to Use Antioxidants

A>>So far we have discussed antioxidant nutrients and what they do. We have put special emphasis on heart disease, cancer, and aging. This should be adequate to understand that antioxidants can indeed improve your health and help you live better longer. Now, let's put what we know to practical use.

Q. Why should I take vitamin E?
A>>Vitamin E is the body's principal fat-soluble antioxidant. It's also an essential nutrient. No other antioxidant can really fit its shoes, so it is one of the most important antioxidants you can take. It's par­ticularly important because of the huge amount of fats (particularly the polyunsaturated vegetable oils) people consume today in the form of fried foods. Such fats are very prone to oxidation, and they increase a person's requirements for vitamin E to prevent oxidation.

Of all the antioxidants, the evidence supporting the use of vitamin E is by far the most extensive. A recent study found that almost half of cardiologists were taking it. It comes close to being a "magic bul­let"—a label given to it that was once criticized.

Q. Is natural vitamin E better than synthetic?
A>>It certainly is. Vitamin E activity is shared by eight different compounds—four of which are mem­bers of the tocopherol family (alpha-, beta-, gamma-, and delta-tocopherol) and four of which are mem­bers of the tocotrienol family (alpha-, beta-, gamma-, and delta-tocotrienol). The most common form of vitamin E found in American foods is gamma-toco-pherol, but this is because most of the oils Americans consume are highly refined. Biologically, the human body selects for the natural d-alpha tocopherol form of vitamin E over all others, though other natural forms do play important roles in health.

Synthetic vitamin E, which is identified by the term "dl-alpha" is not assimilated or retained as well as the natural form. For many years, naturalvitamin E was rated about 36-percent more effec­tive, on an equal-weight basis, than synthetic vita­min E. Two recent studies have found that it is actu­ally twice as potent.

The manufacturers of vitamin E supplements prefer to use the esterified forms of alpha-toco-pherol, which are much more stable than the unes-terified form. The stable esterified forms are the alpha-tocopheryl acetate and alpha-tocopheryl suc-cinate. Esterified forms can be found in both natural and synthetic vitamin E supplements.

Q. Can you explain a little more about tocotrienols?
A>>Tocotrienols are a family of four compounds that have weak vitamin E activity. However, they may produce health benefits independent of their vitamin E activity. For example, preliminary studies suggest that tocotrienols can lower blood choles­terol and significantly reduce the size of existing cholesterol deposits.
Q. How much vitamin E do I need?
A>>You certainly need more than the meager 8 IU or so found typically in daily American diets. The current RDA is 15 IU daily, and this is also far below the amount needed to reduce the risk of heart dis­ease. The Harvard studies found that at least 200 IU daily for at least two years is needed to reduce the risk of heart disease. Based on various studies, the optimal amount seems to be 400 IU daily, though many people will benefit from still higher dosages.
Q. What are the benefits of taking vitamin C?
A>>Vitamin C has many health benefits, but recent research has shown that large numbers of middle-class Americans do not obtain enough of it. The late Nobel laureate Linus Pauling, Ph.D., recommended vitamin C to reduce symptoms of the common cold. In analyzing almost two dozen studies on vitamin C and colds, Harri Hemila, Ph.D., of the University of Helsinki, Finland, found that 2 to 6 g daily reduced cold symptoms by about one-third.

Pauling also recommended that cancer patients take large amounts of vitamin C—10 g or more daily. Abram Hoffer, M.D., Ph.D., found that vita­min C decreased pain and increased life expectancyin cancer patients — but that a broader vitamin/ mineral program worked even better.

In a study, Mark Levine, M.D., Ph.D., of the National Institutes of Health, found that the first symptoms of vitamin C deprivation were fatigue and irritability. In clinical practice, Hugh Riordan, M.D., of Wichita, Kansas, has consistently found that large amounts of vitamin C supplements relieve fatigue in patients.

Most animals produce their own vitamin C. Humans and a handful of other animals do not. But biochemically, they still seem to need large amounts of it. For example, gorillas in the wild eat foods con­taining about 4.5 g of vitamin C daily. Pauling thought that people need at least 1 gram (1,000 mg) of vitamin C daily — he took 18 g daily and lived to age 93. 1 think there are compelling reasons to take several grams of vitamin C daily.

Q. What are carotenoids, and are they good antioxidants?

A>>Carotenoids are antioxidants that do double duty as plant pigments. For example, beta-carotene makes carrots orange, and lycopenes give tomatoes their red color. Their colors enable them to absorbspecific frequencies of sunlight and prevent the for­mation of light-induced free radicals.

About forty to fifty carotenoids are found in the American diet, though only fourteen are absorbed into the bloodstream. There are actually two classes of carotenoids: the carotenes and the xanthophylls. Carotenes are hydrocarbons, meaning that they con­tain only atoms of carbon and hydrogen, while the xanthophylls also contain oxygen.

Beta-carotene has been the star of the carotenoid family. The body can split a molecule of beta-carotene in half to form two molecules of vitamin A. Since this is done only on an "as-needed" basis, beta-carotene is considered a safe source of vitamin A. Then it was discovered that beta-carotene was a very effective antioxidant, especially in protecting against the reactive oxygen species called "singlet oxygen." It also is vital to a healthy immune system.

In recent years, other carotenoids have gained sci­entific respectability. Among these are lutein and lycopene. If you eat a diet with varied fruits and veg­etables, you probably get plenty of carotenoids. People at risk of certain conditions may benefit from extra amounts of some. I'll discuss this shortly.

Q. If I get a lot of carotenoids, do I need vitamin A too?

A>>Many people have been taught that vegetables, such as carrots, are good sources of vitamin A. This is not completely true. There is no vitamin A in car­rots or any other vegetable. Fruits and vegetables can contain lots of carotenoids, which our bodies can convert to vitamin A, but "preformed" vitamin A is found only in animals. Therefore, if you are a strict vegetarian, you may have trouble getting opti­mal amounts of vitamin A.

Many people will do better with preformed vita­min A in their diets. Vitamin A, of course, is an essential nutrient. Older persons and diabetics may have lower efficiencies in converting carotenoids into vitamin A. Therefore, it is a good practice to get some vitamin A in the diet, as well as ample carote­noids.

Q. What is lycopene?

A>>Lycopene is one of the more important dietary carotenoids. The richest source of it is tomato sauces (more so than raw tomatoes); there is also some in watermelon and guava. One study found that men who ate ten or more lycopene-rich tomato meals weekly had a 45-percent reduced risk of developing prostate cancer. Diets rich in lycopene are also associated with a reduced risk of pancreatic and cervical cancers. Recently, a European-based study reported that diets high in lycopene have been associated with a 48-percent reduction in heart attacks com­pared with diets low in lycopene.

Q. What are lutein and zeaxanthin?

A>>Like lycopene and beta-carotene, lutein is a very important carotenoid, and zeaxanthin, another carotenoid, is often associated with it. Lutein is found in many leafy green vegetables, alfalfa, marigold petals, and egg yolks. Zeaxanthin is found in corn. The body may be able to convert some lutein into zeaxanthin.

Lutein and zeaxanthin are essential for vision. They form the macula lutea, which, because of its yellow color, filters out harmful blue light. People with macular degeneration are often deficient in lutein and zeaxanthin and have only a thin, ineffec­tive deposit of lutein and zeaxanthin in the eye. Because the macula is responsible for both "fine" and "central" vision, macular degeneration can lead to serious visual impairment and blindness.

Recent research indicates that lutein might also protect against heart disease and cancer. Because lutein is fat soluble, it is transported by the low-density lipoprotein (LDL) form of cholesterol. At least one study indicates that lutein protects vita­min E from oxidation in LDL. It may also contribute to the health of the immune system.

Q. What are bioflavonoids?

A>>The term bioflavonoids, or flavonoids, covers thousands of nutritional substances that have a common basic structure. Nearly all are found in plants, which means they are also common in fruits and vegetables. The structure of flavonoid com­pounds makes them easy to donate electrons to other molecules, and thus they are usually excellent antioxidants. Although flavonoids have many simi­larities, they have differences, which lead to their varied biochemical activities.

Like carotenoids, flavonoids serve as plant pig­ments that filter out harmful wavelengths of light. Some common bioflavonoids include quercetin, rutin, hesperidin, genistein, diadzein, and those found in many herbs. Herbalists have been success­fully using bioflavonoid-rich plant extracts for cen­turies to treat various illnesses. Flavonoids were discovered in 1936 by Nobel laureate Albert Szent-Gyorgyi, M.D., Ph.D. He found that flavonoids pre­vented capillary permeability, or fragility, whichresulted in easy bruising and edema. Szent-Gyorgyi initially called flavonoids "vitamin P" (for the per­meability factor). Later, most scientists dropped the vitamin P name, though flavonoids do have vitaminlike functions.

Q. What is Pycnogenol?

A>>Pycnogenol is derived from the bark of French Maritime pine trees, and much of the product con­sists of a subgroup of antioxidant flavonoids called proanthocyanidins. Pycnogenol also consists of sub­stances chemists call "organic acids," which are also powerful antioxidants. All together, Pycnogenol con­sists of about forty or so compounds. It is a good example of synergistic antioxidants. Lester Packer, Ph.D., has found that the key flavonoids in Pycnogenol are not as powerful individually as the total sum of antioxidants naturally found in Pycnogenol.

Q. What is coenzyme Q10?

A>>Coenzyme Q10, or CoQ10, is a vitamin-like sub­stance made by the body and also found in foods, such as organ meats. Its primary function is in helping to convert food to energy. Secondary to this, it is a powerful antioxidant. These two functions do overlap. It is beneficial to people with various types of heart failure. CoQ10 increases the energy output of hearts, making them stronger. Unlike drugs, it does this naturally. Some cardiologists recommend as much as 300 to 400 mg of CoQ10 daily to treat heart failure, though most people do not need this much. Some recent research indicates that it may also help prevent the recurrence of breast cancer.

You've mentioned alpha-lipoic acid — can you explain more about it?

Like CoQ10, alpha-lipoic acid plays key roles in converting food to energy. German physicians have used it for years to treat diabetic polyneuropathy, a severe nerve disorder. It can also lower and stabilize blood sugar levels, making it important for diabet­ics and people prone to diabetes.

Alpha-lipoic acid is also a very powerful antiox­idant. The body converts some alpha-lipoic acid into dihydrolipoic acid, an even more powerful antioxidant (which, unlike alpha-lipoic acid, is not sold as a supplement). In addition, alpha-lipoic acid can help regenerate numerous other antioxidants, including vitamin C, vitamin E, and glutathione.

High blood sugar levels generate large numbers of free radicals. These free radicals account, in part, for the complications of diabetes. Alpha-lipoic helps in two ways, by lowering blood sugar levels a little and by quenching free radicals.

What is NADH?

NADH stands for nicotinamide adenine dinu-cleotide. This is a complex compound built around vitamin B3 (niacinamide, nicotinamide). Like CoQ10 and alpha-lipoic acid, NADH plays a key role in converting food to energy. (These substances are not interchangeable—they function in different places during energy-producing chemical reactions.) Similar to CoQ10 and alpha-lipoic acid, NADH is also a powerful antioxidant.

Jorg Birkmayer, M.D., Ph.D., director of the Birkmayer Institute for Parkinson's Therapy, Vienna, has been a leader in the clinical use of NADH. He has found it helpful in many patients with Parkinson's disease, Alzheimer's disease, depression, and chronic fatigue. In one small study of Alzheimer's disease patients, Birkmayer found that 10 mg of NADH daily before breakfast for eight to twelve weeks resulted in striking improve­ments. The Alzheimer's disease patients' averagescores on cognitive and function tests improved by 50 percent.

Joseph Bellanti, M.D., director of Georgetown University's International Immunology Center, Washington, D.C., recently reported that nineteen of twenty-six patients with chronic fatigue syn­drome improved after taking NADH supplements. Eight of the patients benefited from significant relief of symptoms.

What is glutathione?

Glutathione is the antioxidant workhorse with­in the body's cells. This powerful antioxidant is a sulfur-containing tripeptide formed in the body from three amino acids: cysteine (a sulfur-contain­ing amino acid), glutamic acid, and glycine. Glutathione assists in keeping the immune system healthy, neutralizing intracellular free radicals, and detoxifying many harmful chemicals. Glutathione serves as a substrate, or chemical foundation, for many enzymes, such as the selenium-containing glutathione peroxidases that reduce free radical reactions.

Glutathione plays a key position in the antioxi­dant cycle, as it can regenerate most other antioxidants, but not NADH. Glutathione levels can beincreased with several nutritional supplements, including selenium, N-acetyl cysteine, cysteine, and alpha-lipoic acid.

What is NAC?

NAC, technically known as N-acetylcysteine, is another important antioxidant. It works chiefly by increasing the body's production of glutathione. A study by Italian researchers found that NAC sup­plements greatly reduced symptoms of the flu. Other researchers are investigating NAC as a can­cer-preventing compound. It is similar to the sulfur-containing amino acid cysteine, but better absorbed and more efficient.

What would be a basic antioxidant protection plan?

Fruits and vegetables are the richest sources of antioxidants. Therefore, the foundation of any antioxidant-boosting dietary plan would be to eat a variety of fruits and vegetables—a total of five to nine servings daily. Next, I would recommend a good multivitamin/multimineral support for basic nutrition. To this foundation, add the following:

• 200-400 IU of natural vitamin E.
• 250-1,000 mg of vitamin C.
• 50-100 mcg of selenium.

If your multivitamin/multimineral supplement contains these amounts, you're off to a great start.

What is a more comprehensive antioxidant program?

Again, start with a diet containing five to nine servings of fruits and vegetables and a good multi­vitamin/multimineral supplement. To this, add the following antioxidants. You may be able to find most of these in a high-potency multivitamin or antioxidant formula. Strive for the dosages listed below, but a little less or a little more would be fine.

• 400-800 IU of vitamin E.
• 500-4,000 mg of vitamin C.
• 100-200 mcg of selenium.
• 15-25 mg of mixed carotenoids.
• 8,000-12,000 IU of vitamin A.
• 30-120 mg of CoQ10.
• 25-100 mg of Pycnogenol.
• 25-100 mg of alpha-lipoic acid.

On top of that, if you're inclined and can afford it, consider the following optional antioxidants:

• 5-10 mg of NADH.
• 300-600 mg NAC.
• 5 mg of lycopene.
• 5 mg of lutein (along with some zeaxanthin).
• 50-100 mg of grape seed extract.

Q. Are all of these antioxidant nutrients safe?
A>>Yes, they are. All of these substances are found in traditional diets, though many are removed, through food processing, from the modern Western diet.

Bear in mind that everything can be toxic at some level—including oxygen and water. The amounts discussed as being optimal are far below the levels that could cause adverse effects. However, it must be pointed out that selenium and vitamin A do have toxic limits that you should be aware of. Here are some upper limits.

• Selenium—Do not exceed 600 mcg daily.
• Vitamin A—Do not exceed 25,000 IU daily.
• Vitamin C—25 g and above may cause loose stools.
• Carotenoids—Take no more than 25 mg daily, if you are a heavy smoker or heavy drinker.

You may exceed these upper limits for short peri­ods of time under the direction of your physician.

Q. What's the future of antioxidant research?

A>>Thousands of articles on antioxidants now appear each year in scientific and medical journals. This is in stark contrast to twenty or thirty years ago, when very little research was being conducted on free radicals and antioxidants. Researchers are cur­rently focusing on the most basic details of how they work—that is, molecular biology. This is about as "hard" as science gets. The evidence so far is that free radicals damage genes and activate "bad" genes, whereas antioxidants protect genes and activate "good" genes. Because genes contain the biological instructions for how our bodies work, this research demonstrates that free radicals and antioxidants function at the core of our existence. All trends point to future research being positive and confirming the many health benefits of antioxidants.

Conclusion

Free radicals and antioxidants are among the most important discoveries of the past 100 years. One can hurt you, and the other can protect you.

In the years since Dr. Denham Harman first pro­posed that free radicals fuel the aging process, researchers have documented their role in more than eighty diseases. All of the major diseases con­fronting people today—heart disease, cancer, Alzheimer's disease, and arthritis—are caused by or aggravated by free radicals.

The beauty of natural antioxidants is that they neutralize free radicals. In doing so, they can slow down and often reverse free radical damage—and reduce your risk of disease. And while many indi­vidual antioxidants, such as vitamins E and C, can have remarkable and rapid benefits, antioxidants generally work best as a group. This is because they are clearly synergistic.

As we move into the twenty-first century, antioxidant research is on the upswing. Thousands of studies on antioxidants are published in scientific and medical journals each year. Antioxidant sup­plements, which concentrate many of the antioxi­dants found in foods, are safe and relatively inex­pensive, compared to the pain and cost of treating disease. It only makes sense to eat an antioxidant-rich diet and to fortify your diet with additional antioxidants.

The take-home message of this book is simple: Antioxidants can help you live better, longer—to add life to your years, as well as years to your life.

Oxidative damage

Oxidative damage to cells is thought to be a causative factor in disease and aging. The culprits are free radicals or reactive species of oxygen, nitrogen or chlorine. Superoxide, hydroxyl ions, hydrogen peroxide, and nitric oxide are examples of free radicals. These are atoms or molecules with an unpaired electron. Free radicals are naturally occurring and an important part of biological functions such as immunity, inflammation, growth and repair. Free radicals can have negative effects when they damage proteins, lipids and nucleic acids. They are normally held in balance in biological systems by antioxidant defense mechanisms. Environmental insults, infections, smoking, radiation and sunlight can also cause the formation of free radicals.
Antioxidant defenses act in concert in cell differentiation and growth, immune responses, cell membrane integrity, and normal DNA repair. Oxidative stress occurs when there are more free radicals than can be dealt with due to environmental insult, disease or malnutrition. Even exercise, because of an increase in oxygen demand and utilization, increases the formation of free radicals. However, regular exercise builds up body defense systems and protects against damage. An improper balance between formation and destruction of free radicals may play a role in degenerative disease and aging. Antioxidants in the diet may prevent disease and deficiencies may be deleterious to fetal and childhood development.

Antioxidant micronutrients must be supplied in the diet. Fruits, vegetables and whole grains are better sources of antioxidants than pill forms, but, in general, supplementation is beneficial. A balanced diet including several servings per day of fruits and vegetables is recommended.

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Antioxidant Nutrients

Vitamin C

Vitamin C is a water soluble antioxidant found in fruits and vegetables that directly scavenges some free radicals and recycles vitamin E. It is also known as ascorbic acid and is used in various foodstuffs to prevent rancidity, in meat curing, and to prevent fruit discoloration. It is unstable to heat and oxidation but survives freezing.
Most animals can make this vitamin, with the exception of primates, guinea pigs and some bats. The deficiency disease is called scurvy and manifests by numerous defects in connective and epithelial tissue maintenance and repair. Scurvy takes 3-4 months to develop because it takes that long for bodily vitamin C stores to be depleted. The RDA is 60 mg/day but higher doses are well tolerated up to about 1800 mg/day; even if there is no evidence that mega doses are beneficial. Vitamin C has been suggested to be protective against coronary heart disease, presumably because it prevents LDL oxidation.

Beta carotene

Beta carotene is a water soluble precursor to Vitamin A, but is an antioxidant in itself. Beta carotene gives vegetables such as corn, squash and carrots their rich yellow color. It is found in many other pigmented fruits and veggies, egg yolk, butter, and milk as well.

Vitamin E

Vitamin E comes in six naturally occurring forms (found in whole grains, fish oils, nuts and seeds) but alpha tocopherol is the most potent as a vitamin and is widely distributed in food. Vitamin E is the most potent and least toxic fat soluble antioxidant and is important in protecting cell membranes from oxidative damage. It is absorbed in the small intestine, delivered to the liver, and packaged into lipoproteins for delivery to the tissues. Tissues or structures exposed to the highest amounts of oxygen, such as erythrocytes, mitochondria, and cells of the respiratory tree, seem to accumulate more vitamin E than other structures or tissues. The RDA is 10 IU for men and 8 IU for women and normal blood levels are in the range of 0.5-0.7 mg/dL. Deficiency has not been seen in otherwise healthy children or adults, but experimentally the symptoms include muscular weakness and fragile erythrocytes.

Flavanoids

Flavanoids are antioxidant molecules found in plant sources such as fruit, flowers, roots, stems, tea, wine, grains and vegetables. They are often responsible for the beautiful coloring of plant structures. Indeed, a general rule of nutrition is the relationship of the vibrancy or depth of color to the nutritional content of the fruit or vegetable. More pigment is usually associated with greater nutritional value.

Flavanoids have been shown to have antiviral, antiallergic , anti-inflammatory, antithrombogenic and anticarcinogenic effects in vitro. Flavanoids act as antioxidants by directly scavenging free radicals, chelating reactive elements such as iron, or by inhibiting oxidative enzymes. Many of the other actions are mediated by their inhibitory action on prostaglandin synthesis and mediators of inflammation. Flavanoids also inhibit tyrosine kinases, many of which are involved in cell growth and proliferation.

Some 4000 flavanoids have been found. There are four main groups of flavanoids; 1) flavones, 2) flavanones, 3) catechins, and 4) anthocyanins. It is the flavones and catechins that appear to be important flavanoids in oxidation defenses.

Perhaps the most important flavone is quercetin found in apples, onions, broccoli and berries. The flavanones are found primarily in citrus fruits and peels. Catechins are found in teas and red wine. Anthocyanins are present in cherries, berries, wine, grapes and tea. No daily requirement for flavanoids has been established, but a balanced diet containing fresh fruits and vegetables, tea, and moderate amounts of red wine is recommended.

Selenium

Selenium is an essential trace element in the diet that is distributed in the earth's crust at 0.09 ppm. The RDA for selenium is 70 ug/day for adults. Selenium toxicity has been seen at higher levels. Glutathion peroxidase is a free radical scavenging enzyme that contains selenium. It acts to destroy peroxides and thus protects lipid membranes as does Vitamin E. Indeed, these two antioxidant defense mechanisms work in concert and spare one another.

Superoxide dismutase

Superoxide dismutase is an enzyme that, in concert with the enzyme catalase, can disarm and destroy free radicals, particularly superoxide. Claims that taking supplements is beneficial to forestall or reduce the effects of aging have not been proven. In fact, superoxide dismutase taken orally (even sublingually) is destroyed in the digestive system. Copper and zinc are required in the functioning of cytosolic superoxide dismutase and manganese is required for the mitochondrial version.

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Studies on Antioxidants

Antioxidant Foods

Fruits and vegetables supply antioxidants other than those you can get from pills, say researchers at the USDA’s Jean Mayer Human Nutrition Research Center on Aging at Tufts University in Boston.
Ron Prior and co-workers fed 36 men and women aged 20 to 40 or 60 to 80 a diet containing ten servings of fruits and vegetables a day. Then they measured the “antioxidant capacity” of the participants’ blood samples by seeing how well the blood deactivated damaging oxidized free radicals in a test tube.
 
After two weeks, the antioxidant capacity of the participants’ blood rose in both groups, though more consistently in the older people.
 
“Based on this and other studies, it appears that compounds other than vitamins C and E and carotenoids contribute a major portion of the increase in antioxidant capacity,” says Prior. Among the foods with the highest antioxidant capacity were oranges, cauliflower, and peas.

In a separate study from the Johns Hopkins Medical Institutions in Baltimore, researchers found a higher antioxidant capacity in 83 people who ate eight to ten servings of fruits and vegetables a day than in 40 others who ate fewer servings. —Bonnie Liebman

Antioxidant Vitamins and Zinc Reduce Risk of
Vision Loss from Age-Related Macular Degeneration

Same Nutrients Have No Effect on the Development of Cataract

High levels of antioxidants and zinc significantly reduce the risk of advanced age-related macular degeneration (AMD) and its associated vision loss. These same nutrients had no significant effect on the development or progression of cataract. These findings from a nationwide clinical trial are reported in the October 2001 issue of Archives of Ophthalmology.

Scientists found that people at high risk of developing advanced stages of AMD, a leading cause of vision loss, lowered their risk by about 25 percent when treated with a high-dose combination of vitamin C, vitamin E, beta-carotene, and zinc. In the same high risk group — which includes people with intermediate AMD, or advanced AMD in one eye but not the other eye — the nutrients reduced the risk of vision loss caused by advanced AMD by about 19 percent. For those study participants who had either no AMD or early AMD, the nutrients did not provide an apparent benefit. The clinical trial — called the Age-Related Eye Disease Study (AREDS) — was sponsored by the National Eye Institute (NEI), one of the Federal government's National Institutes of Health.

"This is an exciting discovery because, for people at high risk for developing advanced AMD, these nutrients are the first effective treatment to slow the progression of the disease," said Paul A. Sieving, M.D., Ph.D., director of the NEI. "AMD is a leading cause of visual impairment and blindness in Americans 65 years of age and older. Currently, treatment for advanced AMD is quite limited. These nutrients will delay the progression to advanced AMD in people who are at high risk — those with intermediate AMD in one or both eyes, or those with advanced AMD in one eye already.

"The nutrients are not a cure for AMD, nor will they restore vision already lost from the disease," Dr. Sieving said. "But they will play a key role in helping people at high risk for developing advanced AMD keep their vision."

A common feature of AMD is the presence of drusen, which are yellow deposits under the retina. Often found in people over age 60, drusen can be seen by an eye care professional during an eye exam in which the pupils are dilated. Drusen by themselves do not usually cause vision loss, but an increase in their size and/or number increases a person's risk of developing advanced AMD, which can cause serious vision loss.
The three stages of AMD analyzed in this study are:

1. Early AMD. People with early AMD have, in one or both eyes, either several small drusen or a few medium-sized drusen; these people do not have vision loss from AMD.
2. Intermediate AMD. People with intermediate AMD have, in one or both eyes, either many medium-sized drusen or one or more large drusen; in these people, there is usually little or no vision loss.
3. Advanced AMD. In addition to drusen, people with advanced AMD have, in one or both eyes, either:

• A breakdown of light-sensitive cells and supporting tissue in the central retinal area (advanced dry form); or
• Abnormal and fragile blood vessels under the retina that can leak fluid or bleed (wet form).

These two forms of advanced AMD can cause serious vision loss. Scientists are unsure about how or why an increase in the size and/or number of drusen can sometimes lead to advanced AMD, which affects the sharp, central vision required for the 'straight ahead' activities in our daily routine, such as reading, driving, and recognizing faces of friends. One observation is that the larger and more numerous the drusen, the higher the risk of developing either form of advanced AMD. People who have advanced AMD in one eye are at especially high risk of developing advanced AMD in the other eye. The formulation used in the study contained several antioxidant vitamins, which are nutrients that can help maintain healthy cells and tissues. They also contained zinc, which is an important mineral incorporated into many body tissues.

The nutrients evaluated by the AREDS researchers contained 500 milligrams of vitamin C; 400 international units of vitamin E; 15 milligrams of beta-carotene; 80 milligrams of zinc as zinc oxide; and two milligrams of copper as cupric oxide (Copper was added to the AREDS formulations containing zinc to prevent copper deficiency, which may be associated with high levels of zinc supplementation). In this trial, the NEI collaborated with Bausch & Lomb, an eye care company that provided the formulation evaluated by the AREDS researchers and financially supported the laboratory testing and distribution of study medications.

"Previous studies have suggested that people who have diets rich in green, leafy vegetables have a lower risk of developing AMD," said Frederick Ferris, MD, director of clinical research at the NEI and chairman of the AREDS. "However, the high levels of nutrients that were evaluated in the AREDS are very difficult to achieve from diet alone.

"Almost two-thirds of AREDS participants chose to take a daily multivitamin in addition to their assigned study treatment," Dr. Ferris said. "The AREDS also showed that, even with a daily multivitamin, people at high risk for developing advanced AMD can lower the risk of vision loss by adding a formulation with the same high levels of antioxidants and zinc used in the study."

The Age-Related Eye Disease Study involved 4,757 participants, 55-80 years of age, in 11 clinical centers nationwide. Participants in the study were given one of four treatments: 1) zinc alone; 2) antioxidants alone; 3) a combination of antioxidants and zinc; or 4) a placebo, a harmless substance that has no medical effect. The benefits of the nutrients were seen only in people who began the study at high risk for developing advanced AMD — those with intermediate AMD, and those with advanced AMD in one eye only. In this group, those taking "antioxidants plus zinc" had the lowest risk of developing advanced stages of AMD and its accompanying visual loss. Those in the "zinc alone" or "antioxidant alone" groups also reduced their risk of developing advanced AMD, but at more moderate rates compared to the "antioxidants plus zinc" group. Those in the placebo group had the highest risk of developing advanced AMD.

Dr. Ferris said some people with intermediate AMD may not wish to take large doses of antioxidant vitamins or zinc because of medical reasons. "For example, beta-carotene has been shown to increase the risk of lung cancer among smokers," he said. "These people may want to discuss with their primary care doctor the best combination of nutrients for them. With the use of the high levels of zinc, it is important to add appropriate amounts of copper to the diet to prevent copper deficiency."

In the cataract portion of the study, researchers discovered that the same nutrients had no significant effect on the development or progression of age-related cataract. A cataract is a clouding of the eye's lens that blocks some light from reaching the retina and interferes with vision. "Participants taking the 'zinc alone' treatment, the 'antioxidants alone' treatment, or the combination of zinc and antioxidants were all about as likely to develop a cataract as those taking a placebo," Dr. Ferris said.

"At the time the study was planned, laboratory and animal research had suggested that antioxidants might be of benefit in treating or preventing cataract," he said. "Also at that time, limited epidemiologic and clinical trial data suggested that antioxidants might affect the development of cataract. However, our analyses did not find any connection between the antioxidant vitamins used in the AREDS and cataract development."
Despite the evidence that these nutrients did not lower the risk of cataract development over the seven-year period of the study, Dr. Ferris noted that an effect over a longer period of time, or with different doses of these or other antioxidants, cannot be ruled out.

The AREDS participants reported minor side effects from the treatments. About 7.5 percent of participants assigned to the zinc treatments — compared with five percent who did not have zinc in their assigned treatment — had urinary tract problems that required hospitalization. Participants in the two groups that took zinc also reported anemia at a slightly higher rate; however, testing of all patients for this disorder showed no difference among treatment groups. Yellowing of the skin, a well-known side effect of large doses of beta-carotene, was reported slightly more often by participants taking antioxidants.

"The AREDS formula is the first demonstrated treatment for people at high risk for developing advanced AMD," he said. "Slowing the progression of AMD to its advanced stage will save the vision of many who would otherwise have had serious vision impairment."

Antioxidant Supplements: Can They Slow Mental Decline?
Source: Tufts University

June 5, 2003
There has been much ballyhoo in recent years over the potential health benefits of antioxidant nutrients, such as vitamins E and C. They are thought to counteract the harmful effects of so-called "free radicals" - molecules that can damage cells in the body and thereby increase the risk for chronic diseases, such as heart disease and cancer. Free radicals might also affect mental functioning and may contribute to the mental decline that is associated with aging. A recent study suggests that taking antioxidant supplements may help stave off age-related mental decline. The results are published in the American Journal of Clinical Nutrition.
Studying aging female nurses

Researchers studied almost 15,000 female nurses participating in the Nurses' Health Study. Beginning in 1980, they collected data on several of the nurses' lifestyle factors, including the use of vitamin E and vitamin C supplements. From 1995-2000 they then administered, by phone, cognitive function examinations - tests of mental performance - to the women who were 70-79 years of age at that time.
The researchers performed statistical analyses to determine if prior and/or current use of vitamin supplements had any association with mental function. In doing so, they allowed for other factors that could potentially influence the outcome, such as education level, smoking, high blood pressure, and cardiovascular disease.
Long-term use of vitamins E plus C shows the most benefit

Women who were currently taking supplements of both vitamin E and vitamin C and had done so for several years performed better on the cognitive function test compared with women who had never taken vitamin E or C supplements. Longer duration of supplement use was associated greater benefit. The benefit of supplement use was strongest among women who had low amounts of vitamin E in their diets, and was less pronounced among women taking just vitamin E with no vitamin C. There was no benefit observed among women taking just vitamin C.

How antioxidants might work
The exact mechanisms by which antioxidants may improve mental function have yet to be fully explained. There are probably a variety of biochemical bodily processes involved. For example, it may have something to do with the health of the arteries that supply blood to the brain.

Keeping it in perspective
It's important to remember that this was an observational study, meaning that the researchers didn't give subjects any particular treatment - they just observed what happened when some women took supplements by their own choice and others did not. Therefore, these results cannot prove that antioxidant supplements actually cause improvement in mental function - only that they are associated with improvement in mental function.

The women who took supplements may have been healthier overall, and that might have played a role in their better mental function. Also, this study's subjects are a fairly similar group of people, and the results can't necessarily be applied to men or to people of other ages or different education levels.

Still, these results add to the evidence that antioxidant supplements may benefit health, and they may lead to randomized clinical trials studying the use of antioxidants in preventing mental decline.

If you're thinking about taking antioxidant supplements, be sure to consult your doctor first, to make sure you don't have any conditions or take any medications that may interact with the supplements, or trigger potentially harmful side effects.

Source
High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. F. Grodstein, J. Chen, WC. Willett, Am J Clin Nutr, 2003, vol. 77, pp. 975--984

High Antioxidant Intake May Reduce Alzheimer's Risk
 
Posted on: 06/26/2002

ROTTERDAM, The Netherlands--High intakes of antioxidant vitamins C and E may lower the risk of Alzheimer's disease, according to Marianne J. Engelhart, M.D., and researchers from Erasmus Medical Center. Their paper, published in the June 26 issue of the Journal of the American Medical Association (JAMA) (287, 24:3223-9, 2002) (www.jama.com), was an analysis of the Rotterdam Study, a population-based prospective cohort study.

All of the 5,395 participants were free of dementia at baseline. After a mean follow-up of six years, 197 participants were diagnosed with dementia--146 of these were Alzheimer's cases. Researchers noted that the use of antioxidant supplements, including a high intake of vitamins C and E, was associated with a lower risk of Alzheimer's. And, smokers who took antioxidants seemed to gain the most benefit from vitamins C and E, as well as beta-carotene.

A second study published in the June 26 issue of JAMA (287, 24:3230-7, 2002) and conducted by Martha Clare Morris, Sc.D., of Chicago's Rush Institute for Healthy Aging, and colleagues, indicated that vitamin E from food may be associated with a reduced risk of Alzheimer's. Morris and her team analyzed food frequency questionnaires, which were collected 1.7 years after baseline from a random sample of 815 community-dwelling subjects (aged 65 and older). The data was analyzed for intake of antioxidants--vitamins C, E and beta-carotene--after a follow-up of nearly four years.

The Atlanta researchers found that increased vitamin E intake from food sources decreased the risk of Alzheimer's; however, this decreased risk was only noted in patients lacking the APOE-e4 allele, a protein associated with an increased risk of late-onset Alzheimer's. And, in contrast to the Engelhart study, intakes of vitamin C, beta-carotene and vitamin E supplements were not significantly associated with the risk of Alzheimer's.

In an editorial accompanying the two studies, Daniel J. Foley, M.S., of the National Institute on Aging in Bethesda, Md., and Lon R. White, M.D., of the Pacific Health Research Institute in Honolulu, stated the two studies do not provide final answers to whether antioxidant vitamins are "truly protective" against Alzheimer's. They noted that while the subjects in the Engelhart study with the highest intakes of vitamin E from food were 70 percent less likely to develop Alzheimer's, and the subjects in the highest tertile of vitamin E intake from the Morris study were 43 percent less likely to develop the disease, neither study compared supplement intake to food intake. "There is no clear explanation for this apparent divergence in protective effect of vitamin intake from dietary sources versus from supplement use," Foley and White wrote. "If this reflects a biologic difference, then attributing the influence of these foods to their vitamin content would appear to be at least partially unjustified. This finding suggests the involvement of some other nutritional phenomena related to accurate measurement of supplement use or nutrient intake."

The authors suggested there may have been inaccurate self-reporting due to patients' cognitive decline, or that supplement use may have begun as a result of cognitive decline. "Despite these problems, the consistency of findings in the two independent cross-national epidemiological investigations is notable," they continued. "The similarity of these results, which were generated using similar, standardized methods for assessments ... provides persuasive support for the idea that antioxidant vitamins may have a beneficial impact on the development of Alzheimer's."

Neil Buckholtz, Ph.D., head of the Dementias of Aging Branch at the National Institute on Aging commented on this latest research in a press release from the National Institutes of Health. "This and a number of important population studies have pointed to vitamin E as possibly protective against oxidative damage or other mechanisms associated with cognitive decline and dementia," he said. "The only way this association can really be tested is through clinical studies and trials now underway. These will help us determine whether vitamin E in food or in supplements--or taken together--can prevent or slow down the development of mild cognitive impairment or [Alzheimer's disease]."

Buckholtz also noted that it is not advisable, based on the evidence currently available, to take high-dose vitamin E or antioxidant supplements because little is known about safety, efficacy and dosages of these supplements that are purported to have neuroprotective effects. He also noted that interactions with prescription medicine is another potential concern, especially among the elderly.

AHA Science Advisory
Antioxidant Consumption and Risk of Coronary Heart Disease: Emphasis on Vitamin C, Vitamin E, and ß-Carotene
A Statement for Healthcare Professionals From the American Heart Association

Diane L. Tribble, PhD
For the Nutrition Committee

Key Words: AHA Science Advisory • nutrition • coronary disease • antioxidants • cardiovascular diseases

Dietary recommendations aimed at reducing the risk of coronary heart disease have focused largely on the intake of nutrients that affect established risk factors, including plasma lipid and lipoprotein levels, blood pressure, and body weight. Recent developments in our understanding of the atherosclerotic process and factors that trigger ischemic events have led to the consideration of dietary constituents that may alter risk through other mechanisms. Prominent among these are antioxidants, which are proposed to inhibit multiple proatherogenic and prothrombotic oxidative events in the artery wall. This report provides a brief overview of evidence concerning a role for dietary antioxidants in disease prevention, with emphasis on studies in human populations, and describes a number of issues that should be resolved before it would be prudent to make recommendations regarding the prophylactic use of antioxidant supplements.

Proposed Influence of Oxidants and Antioxidants on the Development of
Atherosclerosis and Its Complications

Atherosclerosis is a complex process involving the deposition of plasma lipoproteins and the proliferation of cellular elements in the artery wall. This chronic condition advances through a series of stages beginning with fatty streak lesions composed largely of lipid-engorged macrophage foam cells and ultimately progressing to complex plaques consisting of a core of lipid and necrotic cell debris covered by a fibrous cap.1 These plaques provide a barrier to arterial blood flow and may precipitate clinical events, particularly under conditions that favor plaque rupture and thrombus formation.

Over the past 2 decades, considerable evidence has been gathered in support of the hypothesis that free-radical–mediated oxidative processes and specific products arising therefrom play a key role in atherogenesis.2 3 At the center of this hypothesis are low-density lipoproteins (LDLs), which undergo multiple changes on oxidation that are thought to be proatherogenic (see FigureF1F1). Oxidation of LDL lipids leads to the production of a diverse array of biologically active compounds, including some that influence the functional integrity of vascular cells. Among the most well-characterized effects are increases in the expression of endothelial cell surface adhesion molecules that facilitate the mobilization and uptake of circulating inflammatory cells4 5 and alterations in the chemotactic properties of monocytes and monocyte-derived macrophages6 7 in a manner expected to increase their residence within the artery wall. Oxidation of the apolipoprotein B component alters LDL receptor recognition properties, leading to avid internalization of LDLs by macrophages via scavenger receptors,8 9 a key step in the formation of macrophage-derived foam cells.

Figure 1. Proposed role of LDL oxidation in the initiation of fatty streak lesions. LDL crosses the endothelium in a concentration-dependent manner and can become trapped in the extracellular matrix (1). The subendothelium is an oxidizing environment, and if the LDL remains trapped for a sufficiently long period of time, it undergoes oxidative changes (2). Mildly oxidized forms of LDL contain biologically active phospholipid oxidation products that affect the pattern of gene expression in endothelial cells (ECs), leading to, among other things, changes in the expression of monocyte binding molecules (designated X-CAM), monocyte chemoattractant protein (MCP-1), and macrophage colony stimulating factors (CSFs) (3). These factors in turn promote the recruitment of monocytes (4) and drive their phenotypic differentiation to macrophages (5). Further oxidation leads to alterations in apolipoprotein B such that LDL particles are recognized and internalized by macrophages (6), progenitors of the lipid-laden foam cells. Marked increases in lipid and cholesterol oxidation products render the LDL particles cytotoxic, leading to further endothelial injury (7) and favoring further entry of LDL and circulating monocytes and thus a continuation of the disease process.

In addition to these effects, oxidative processes are proposed to play a role in lesion maturation and the precipitation of clinical events. This may involve effects on intimal proliferation, fibrosis, calcification, endothelial function and vasoreactivity, plaque rupture, and thrombosis.10 11 To date, the role of oxidation in these processes has received less attention than that in the early stages of the disease, but this appears to be changing, in part because of findings from secondary prevention trials (discussed below).

Oxidants are products of normal aerobic metabolism and the inflammatory response. They constitute a chemically and compartmentally diverse group, and it is presently unknown which, if any, are critical to the disease process. In addition to the different sources and types of oxidants, ambiguity in relating specific oxidants to the disease process arises from the multitude of pathophysiological events linked to oxidation, the paucity of methods for measuring these short-lived species within the sequestered environment of the artery wall, and the variable modulating effects of counteractive antioxidants. With regard to the latter, although oxidant formation is an inevitable feature of aerobic life, oxidant-mediated disease promotion is proposed to occur only under circumstances in which these agents overwhelm antioxidant defenses.

Like oxidants, antioxidants constitute a diverse group of compounds with different properties. They operate by inhibiting oxidant formation, intercepting oxidants once they have formed, and repairing oxidant-induced injury. In terms of the coronary heart disease process, several points of antioxidant intervention have been proposed, as recently reviewed in detail.10 11 Inhibition of LDL oxidation is the most well characterized of these and includes effects on the concentration or reactivity of oxidants capable of modifying LDL and on the susceptibility or resistance of LDL to these oxidants. Better definition of these and other disease processes in which antioxidants may intervene will allow optimization of conditions for testing the importance of antioxidants in disease prevention and ultimately for intervening in the disease process should antioxidants prove to be effective in this regard.

Investigations of the Disease-Preventive Effects of Dietary Antioxidants in Humans

Although the antioxidant defense system includes both endogenously and exogenously (diet) derived compounds, dietary antioxidants including vitamin C (ascorbic acid), vitamin E (eg, -tocopherol), and ß-carotene (provitamin A) have received the greatest attention with regard to coronary heart disease prevention. -Tocopherol and ß-carotene have been of particular interest because both are carried within LDL particles. Enrichment with -tocopherol increases LDL oxidative resistance in vitro.12 13 This has rarely been observed for ß-carotene,13 14 however. A number of other dietary factors are proposed to act as antioxidants and have been suggested to protect against coronary heart disease. Among these are trace elements, including selenium, copper, zinc, and manganese,15 some of which serve as cofactors for enzymes with antioxidant activity (eg, glutathione peroxidase and superoxide dismutase). Because little information is available on the preventive effects of these other nutrients in human populations, they will not be discussed further herein.

Observational Studies

Support for the importance of dietary antioxidants in coronary heart disease prevention has come from observational studies, including descriptive, case-control, and cohort studies, in which disease outcomes have been examined in relation to measures of antioxidant intake or tissue levels.16 17 18 In many cases, increased antioxidant intake has been shown to be associated with reduced disease risk. This generally has involved increased consumption of antioxidant-rich foods (see TableT1T1), although some19 20 21 but not all22 recent results have suggested the possible importance of supplemental levels of antioxidants.

Two particularly illustrative prospective cohort studies were published as companion papers in 1993.19 20 The first, by Stampfer et al,19 involved analyses of data from >85 000 Nurses' Health Study participants who were followed up for periods of 8 years. Risk of major coronary disease was lowest in women within the highest compared with those within the lowest quintile of reported vitamin E intake after adjustment for age and smoking status (relative risk, 0.66; 95% CI, 0.50 to 0.87). Lower risk was associated with levels of vitamin E intake that were achievable only by supplementation. Subsequent analyses revealed a 43% lower risk for vitamin E supplement users versus nonusers and an inverse relationship between risk and duration of supplement use. The second study, by Rimm et al,20 described a similar benefit for vitamin E based on data from >39 000 male participants of the Health Professionals Follow-up Study (HPFS) who were followed up for 4 years.

Rimm et al20 also observed a lower risk of major coronary events in men reporting high versus those reporting low intakes of ß-carotene, but in subgroup analyses, this relationship was only significant in current and former smokers. These findings are consistent with several other studies that indicated an inverse association between dietary intake of ß-carotene or provitamin A carotenoids and risk of cardiovascular disease, particularly among smokers (eg, References 23 to 2523 24 25 ).

None of the aforementioned analyses revealed a relationship between vitamin C intake and disease risk, in contrast to the results of Enstrom et al21 based on data from >11 000 US adults examined in the first National Health and Nutrition Examination Survey (NHANES I). Individuals reporting high intakes of vitamin C exhibited significantly lower risk of death from all causes, particularly from coronary heart disease, over a 10-year follow-up period. Among men, multivariate-adjusted relative risk was 0.75 (95% CI, 0.53 to 0.97) in individuals within the highest versus those within the lowest vitamin C intake group (50 mg/d dietary vitamin C plus regular supplements containing vitamin C versus <50 mg/d dietary vitamin C). Results were not adjusted for the intake of other antioxidants, however.

Primary Prevention Trials

Although observational studies have provided support for the potential health benefits of antioxidants, there remains a deficiency of direct experimental evidence from randomized trials. This deficiency may in part reflect the fact that few large-scale trials have been completed to date, although recently published results from several intervention trials have not supported hypotheses generated on the basis of results from observational studies.

A major case in point is the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, a randomized trial that tested the effects of daily doses of 50 mg (50 IU) of vitamin E (all-racemic -tocopheryl acetate), 20 mg of ß-carotene, both, or placebo for 5 to 8 years in a population of >29 000 male smokers.26 The major end point was lung cancer, but the investigators also evaluated coronary heart disease. No reduction in risk of lung cancer or major coronary events was observed with any of the treatments. Moreover, with vitamin E supplementation, there was an unexpected increase in risk of death from hemorrhagic stroke, and with ß-carotene supplementation, there were unexpected increases in mortality from lung cancer and ischemic heart disease. Increases in risk of both lung cancer and cardiovascular disease mortality also were observed in the Beta-Carotene and Retinol Efficacy Trial (CARET),27 which tested the effects of combined treatment with ß-carotene (30 mg/d) and retinyl palmitate (25 000 IU/d) in 18 000 men and women with a history of cigarette smoking or occupational exposure to asbestos.

There was no evidence of a significant beneficial or harmful effect of ß-carotene on cancer or cardiovascular disease in the Physicians' Health Study, which involved 22 071 US male physicians randomized to ß-carotene (50 mg every other day), aspirin (325 mg), both, or neither for 12 years.28 A small absolute increase in risk could not be ruled out in smokers, however. These results are considered to be particularly informative because of the large sample size and long duration and may be more generalizable than those of the ATBC and CARET studies because the population was not limited to smokers or high-risk individuals.

A number of factors could account for the lack of correspondence between observational studies and randomized trials. In addition to the usual caveats regarding the interpretation of observational studies, including self-selection and uncontrolled confounding (eg, see Reference 2929 ), it is worth noting that the observed associations between antioxidant intake and disease risk could reflect the importance of other dietary factors. In general, diets rich in antioxidants are also lower in saturated fat and cholesterol and higher in fiber. Moreover, other potentially important micronutrients distribute similarly within foods. For example, foods rich in vitamins C and E and ß-carotene also contain minerals, flavonoids, and indoles, as well as carotenoids other than ß-carotene.30 It is often not possible to decipher the influence of these other dietary variables because many of them are not currently included in nutrient databases.

Antioxidant dose could also be an important factor, particularly for ß-carotene. Results from observational studies suggest that the relationship between carotenoid intake and disease risk may not be linear and, with notable exceptions (eg, Reference 2020 ), that carotenoid-related variations in disease outcomes may occur largely at the lower end of the intake spectrum (eg, References 24 and 3124 31 ). In contrast, most of the intervention trials completed to date have involved supplementation with moderate to high levels of antioxidants in relatively well-nourished populations. It is perhaps relevant that the 1 trial that did show a trend toward decreased cardiovascular mortality involved low-dose supplementation (with a combined regimen of vitamin E, ß-carotene, and selenium) in a poorly nourished population in Linxian, China.32

Secondary Prevention Trials

Results from secondary prevention trials have been more supportive of the potential health benefits of antioxidants. The Cambridge Heart Antioxidant Study (CHAOS) tested the effects of high doses (400 or 800 IU/d) of -tocopherol on subsequent cardiovascular events in patients with angiographic evidence of coronary atherosclerosis.33 On the basis of the combined results for the 2 dose levels, risks of myocardial infarction (MI) and all cardiovascular events were reduced by 77% and 47%, respectively, in the treatment group, with a delay in the onset of treatment benefit of 200 days. Similar reductions were not observed for fatal cardiovascular end points. Although there are some concerns regarding the design of the CHAOS trial, including the use of 2 vitamin E doses, similar results have been obtained in other recent trials. Less impressive but consistent with the CHAOS study were results from a secondary analysis of the ATBC Study.34 In individuals with a history of MI at the start of the study, risk of subsequent nonfatal MI was reduced by 38% in the -tocopherol group; in contrast, risk of fatal coronary end points was not reduced. As in the larger study, risk of fatal coronary end points was increased with ß-carotene supplementation (both with and without -tocopherol).

The apparent benefits of vitamin E (-tocopherol) in individuals with existing coronary disease are not consistent with the proposed role of oxidants in initiating lesions. Recent results from subgroup analyses of the Cholesterol Lowering Atherosclerosis Study (CLAS) suggest that high vitamin E intake could inhibit lesion progression.35 36 Consideration of this effect as well as other possible effects of vitamin E on the clinical expression of cardiovascular disease is warranted.

Effects of Dietary Antioxidants on Clinical Outcomes

Recent studies have suggested that antioxidants may affect clinical outcomes. The Indian Experiment of Infarct Survival Study37 tested the therapeutic efficacy of antioxidants in reducing post-MI complications, many of which are proposed to result from oxidative reperfusion injury. Infarct size (as assessed from plasma levels of cardiac enzymes and ECG changes) and angina and total cardiac events (within the study period) were significantly reduced in individuals receiving antioxidants in the post-MI period. It is unclear whether such benefits are limited to the administration of antioxidants after MI or whether better antioxidant nutriture, as determined by longer-term intake, would have similar effects.

Another potential therapeutic role for antioxidants is in the reduction of restenosis after angioplasty. This role has been addressed in several recent trials.38 39 40 41 The Multivitamins and Probucol (MVP) Study tested the effects of a combination of vitamin C (1000 mg/d), vitamin E (1400 IU/d), and ß-carotene (100 mg/d); probucol (a lipid-lowering drug with antioxidant effects; 1000 mg/d); the dietary antioxidants plus probucol (in the same amounts); or placebo alone on the rate and severity of restenosis.38 The Probucol Angioplasty Restenosis Trial (PART) compared probucol (1000 mg/d) with placebo.39 In both studies, treatments were initiated 1 month before and maintained for 6 months after elective angioplasty. Relative to placebo, probucol significantly reduced restenosis. The authors proposed that the beneficial effects of probucol were due to its antioxidant properties. Yet in the MVP study, similar results were not observed for the dietary antioxidants, which had no effect alone and appeared to negate the beneficial effects of probucol when given in combination.38 Beneficial effects have been observed for vitamins C and E in other studies,40 41 however. Because the long-term use of probucol in diseased individuals is of concern, owing to adverse effects on plasma high-density lipoprotein levels (a 41% reduction was noted in the MVP study), dietary antioxidants, if efficacious, could represent a good alternative. Clearly, more research is needed in this area.

Summary and Conclusions

Our concept of the relationship between diet and coronary heart disease has changed considerably over the past 2 decades, in large part because of the accrual and analysis of large population data sets, the availability of more detailed food composition information, and, particularly, critical breakthroughs in our understanding of disease mechanisms. With regard to the latter, considerable evidence now suggests that oxidants are involved in the development and clinical expression of coronary heart disease and that antioxidants may contribute to disease resistance. Consistent with this view is epidemiological evidence indicating that greater antioxidant intake is associated with lower disease risk. Although this increased antioxidant intake generally has involved increased consumption of antioxidant-rich foods, some recent observational studies have suggested the importance of levels of vitamin E intake achievable only by supplementation.19 20 There is currently no such evidence from primary prevention trials, but results from secondary prevention trials have shown beneficial effects of vitamin E supplements on some disease end points. In contrast, trials directly addressing the effects of ß-carotene supplements have not shown beneficial effects, and some have suggested deleterious effects, particularly in high-risk population subgroups.

In view of these findings, the most prudent and scientifically supportable recommendation for the general population is to consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains. This advice, which is consistent with the current dietary guidelines of the American Heart Association,42 considers the role of the total diet in influencing disease risk. Although diet alone may not provide the levels of vitamin E intake that have been associated with the lowest risk in a few observational studies,19 20 the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation. In the case of secondary prevention, the results from clinical trials of vitamin E have been encouraging, and if further studies confirm these findings, consideration of the merits of vitamin E supplementation in individuals with cardiovascular disease would be warranted.

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