An excerpt from the medical textbook Contemporary Ayurveda
by H. Sharma, M.D., and C. Clark, M.D.
(Edinburgh: Churchill Livingstone, 1998; ISBN: 0 443 05594 7)
ghostwritten by Bernard D. Sherman.

Cancers, strokes, and cataracts seem as different from one another as any diseases could be. It's hard to imagine them sharing a single cause. Yet a growing body of research suggests that they do. The causal chain behind these and many other diseases, perhaps behind aging itself, includes a common link: a class of molecules known as free radicals.

Some researchers believe that the discovery of the effects of free radicals may be as big an advance as Pasteur's insights into infectious disease. In a sense, free radicals take medical theory one level deeper. While the mechanisms of infectious disease involve microorganisms and cells, free radicals involve something more fundamental: the subatomic realm of electrons.

Free radicals are molecules, usually of oxygen, that have lost an electron. That loss makes them unstable (in chemical terms, reactive). They begin to covet their neighboring molecules' electrons. In stealing an electron, they operate as terrorists in the body. They can attack DNA, leading to dysfunction, mutation, and cancer. They can attack enzymes and proteins, disrupting normal cell activities, or cell membranes, producing a chain reaction of destruction. Such membrane damage in the cells that line our blood vessels can lead to hardening and thickening of the arteries and eventually to heart attacks and strokes. Free-radical attacks on collagen can cause cross-linking of protein molecules, resulting in stiffness in the tissue.

The most dangerous free radicals are the small, mobile, and highly reactive oxy radicals. Other dangerous atomic and molecular varieties of oxygen are known as reactive oxygen species (ROS). While ROS are not technically free radicals, they are no less unstable and are highly reactive with the molecules around them.

Biomedical research shows increasingly that oxidative stress - the constant attack by oxy radicals and ROS - contributes to both the initiation and the promotion of many major diseases. Oxidative attacks help cause the disease in the first place, then add impetus to its spread in the body. In the case of heart disease, oxidative stress can cause major damage even after treatment has been applied.

The implications of free radicals and ROS go further. It now seems that the 'clinical presentation' of many diseases - how the illness appears when a patient arrives at a clinic - may in part reflect not different causal mechanisms, but variations in the protection provided by the body's antioxidant (anti-oxidative stress) defenses. In a hurricane, the weakest section of a house collapses first, whether it is a window, a door, or a roof. Under oxidative stress, the weakest link in the body may be the first to give way.

A long and disturbing list of diseases is now linked to oxy radicals and ROS (see Box 8.1). The onslaught of free radicals and ROS also contributes to many of the less serious but still troubling symptoms of aging, such as wrinkled skin, gray hair, balding, and bodily stiffness. Oxy radicals have also been linked to such minor but bothersome conditions as dandruff and hangovers. One of the most experienced free-radical researchers, the Japanese biochemist Yukie Niwa, estimates that at least 85% of chronic and degenerative diseases result from oxidative damage (Niwa & Hansen, 1989, p. 9).

Box 8.1 Diseases linked to oxy radicals and reactive oxygen species

· Cancer.

· Arteriosclerosis, atherosclerosis.

· Heart disease.

· Cerebrovascular disease.

· Stroke.

· Emphysema (Cross et al 1987).

· Diabetes mellitus (Sato et al 1979).

· Rheumatoid arthritis (Cross et al 1987, Greenwald & Moy 1979, 1980, Halliwell 1981, 1989, Del Maestro et al 1982, Fligiel et al 1984).

· Osteoporosis (Hooper 1989, Stringer et al 1989).

· Ulcers.

· Sunburn.

· Cataracts (Niwa & Hansen, 1989, Yagi 1977).

· Crohn's disease (Niwa & Hansen 1989).

· Behcet's disease

· Aging

· Senility

BENEFITS OF FREE RADICALS

The many chemical reactions that occur in the body inevitably produce free radicals. The body can, however, usually keep these free radicals under control. Moreover, despite the long list of problems they cause, free radicals are not all bad. They play an essential role in a healthy human body. The body tries to harness the destructive power of the most dangerous free radicals - the oxy radicals and ROS - for use in the immune system and in inflammatory reactions. Certain cells in these systems engulf bacteria or viruses, take up oxygen molecules from the bloodstream, remove an electron to create a flood of oxy radicals and ROS, and bombard the invader with the resulting toxic shower. This aggressive use of toxic oxygen species is remarkably effective in protecting the body against infectious organisms.

Unfortunately, the process may go out of control, creating a chain reaction that leads to over-production of free radicals. These reactions are no less damaging to the body than other formations of free radicals.

 

THE CAUSES OF FREE RADICALS

Production of free radicals in the body is continuous and inescapable. The basic causes include the following:

The immune system

As we have just seen, immune system cells deliberately create oxy radicals and ROS as weapons.

Energy production

The energy-producing process in every cell generates oxy radicals and ROS as toxic waste, continuously and abundantly. Oxygen is used to burn glucose molecules that act as the body's fuel. In this energy-freeing operation, oxy radicals are thrown off as destructive by-products. Given the insatiable hunger of oxygen, there is no way to have it suffusing the body's energy-producing processes without the constant creation of oxy radicals and ROS.

The cell includes a number of metabolic processes, each of which can produce different free radicals. Thus, even a single cell can produce many different kinds of free radicals.

Stress

The pressures common in industrial societies can trigger the body's stress response. In turn, the stress response creates free radicals in abundance. The stress response races the body's energy-creating apparatus, increasing the number of free radicals as a toxic by-product. Moreover, the hormones that mediate the stress reaction in the body - cortisol and catecholamines - will themselves degenerate into particularly destructive free radicals. Researchers now know one way in which stress may cause disease. A stressful life mass-produces free radicals.

Pollution and other external substances

The pollutants produced by modern technologies often generate free radicals in the body. The food most of us buy contains farm chemicals, including fertilizers and pesticides, that produce free radicals when we ingest them. Prescription drugs often have the same effect; their harmful side-effects may be caused by the free radicals they generate.

Processed foods frequently contain high levels of lipid peroxides, which produce free radicals that damage the cardiovascular system. Cigarette smoke generates high free-radical concentrations; much of the lung damage associated with smoking is caused by free radicals. Air pollution has similar effects. Alcohol is a potent generator of free radicals (although red wine contains antioxidants that counteract this effect).

In addition, free radicals can result from all types of electromagnetic radiation-including sun-light. Exposure to sunlight generates free radicals that age the skin, causing roughness and wrinkles. If the exposure is prolonged, skin cancer may result. (See Box 8.2).

Box 8.2 Some common external causes of free radicals

· Toxins

- carbon tetrachloride

- paraquat

- benzo(a)pyrene

- aniline dyes

- Toluene

 

· Drugs

- adriamycin

- bleomycin

- mitomycin C

- nitrofurantoin

- chlorpromazine

 

· Air pollution

Primary sources

- carbon monoxide

- nitric oxide

- aldehydes

- alkyl nitrates

 

· Radiation, sunlight

 

· Ingested substances

- alcohol

- smoked and barbecued food

- peroxidized fats in meat and cheese

- deep-fried foods

 

FREE RADICAL DEFENSES

Given the many sources of free radicals, it is not surprising that all aerobic forms of life maintain elaborate anti-free-radical defense systems, also known as antioxidant systems.

Enzymes

Every cell in the body creates its own "bomb squad"-antioxidant enzymes (complex, machine-like proteins) whose specialty is defusing oxy radicals and ROS. The most thoroughly studied defense enzyme, superoxide dismutase (SOD), takes hold of molecules of superoxide - a particularly destructive free radical-and changes them to a much less reactive form.

SOD and another important antioxidant enzyme set, the glutathione system, work within the cell. By contrast, circulating biochemicals such as uric acid and ceruloplasmin react with free radicals in the intercellular spaces and bloodstream.

Nutrients

The substances that plants create to fight free radicals can help the human body do the same thing. Thus, as a second line of defense, the body makes use of many standard vitamins and other nutrients to quench the oxy radicals' thirst for electrons. Among the many substances used are Vitamins C and E, beta-carotene, and bioflavonoids. Some free radical researchers believe that to quench free radicals effectively, the general level of all of these free-radical-fighting nutrients needs to be much higher than nutritional experts have generally thought.

Self repair

The body also has systems to repair or replace damaged building blocks of cells. These systems are rapid and thorough. For example, the system for repairing damage to DNA and other nucleic acids is particularly elaborate and efficient, with various specialized enzymes that locate damaged areas, snip out ruined bits, replace them with the correct sequence of molecules, and seal up the strand once again. Every aspect of the cell receives similar attention. Most protein constituents in the cell, for example, are completely replaced every few days. Scavenger enzymes break used and damaged proteins into their component parts for reuse by the cell.

 

FINDING THE BALANCE

The body's elaborate biochemical responses to the free-radical challenge suggest that it is not necessary to reduce excess free radicals to zero. The body needs only to strike the right balance between the number of free radicals generated and the defense and repair mechanisms available. The goal is to keep oxidative stress from exceeding the capacity of the normal repair and replacement mechanisms. Oxy radicals might, for instance, slip through the enzyme and nutrient defenses and attack the DNA; but ideally these attacks would be few enough that the DNA repair mechanisms could fix the damage and maintain the genetic code intact.

How, then, can we keep the desired balance? That question is a major area of research, but the results have been mixed. Vitamins and beta-carotene have shown far fewer benefits than expected. One long-term, large-scale study found beta-carotene to have no effect whatsoever in reducing malignant neoplasms, cardiovascular disease, or death from all causes (Hennekens et al 1996). One problem may be that active ingredients like beta-carotene are not 'full spectrum' antioxidants: they affect certain free radicals but not others. Yet we have seen that each cell can produce a wide variety of free radicals.

Two recent studies suggest another problem. Beta-carotene and vitamin E were found not to prevent lung cancer in male smokers; in fact, beta-carotene was linked with higher incidence of lung cancer (Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group, 1994). Beta-carotene and vitamin A supplements, too, were found to increase the risk of lung cancer in smokers and in workers exposed to asbestos (Omerun et al 1996). A reason for the harmful effects may be that the vitamins, after quenching free radicals, become oxidized themselves unless they have been given in correct doses or regenerated by additional antioxidants, which must be in proper doses themselves. Moreover, beta-carotene works as an antioxidant only when oxygen concentrations are low; in high oxygen concentrations, such as those found in the lungs or heart, it becomes an oxidant itself (Burton & Ingold, 1984). In addition, large amounts of any one micronutrient may inhibit absorption of other micronutrients needed for proper nutritional balance.

Such problems might be offset if vitamins were taken in their natural condition, surrounded by dozens of apparently inactive ingredients that modulate their effects. This conclusion is suggested by a study that found vitamin E to have no effect in reducing death from coronary heart disease in postmenopausal women when taken in the form of supplements, but to have significant benefits when absorbed from food (Kushi et al 1996).

Even if these problems with vitamin supplements were solved, the supplements would still have a significant shortcoming. They are far less effective, molecule for molecule, than the body's natural enzymes. When a molecule of vitamin C or E sacrifices an electron to appease a free radical, the vitamin molecule becomes damaged and useless. Only if it is regenerated by a helpful companion can it re-enter the fray. Enzymes, however, can run through thousands of destructive free radicals and ROS without help and without pause.

Unfortunately, while internally produced enzymes are far more powerful than vitamins, they cannot be taken by mouth. They are gigantic protein molecules that cannot pass through the walls of the digestive system and into the bloodstream. Digestive juices break them down into their component amino acids. SOD has been injected directly into inflamed joints, but the procedure is not practical for home use. Moreover, it has limited effects, because SOD has only a brief half-life in the bloodstream. In less than 5 minutes, 50% of it is gone, broken down by natural bodily processes, and within an hour only 0.1% of it is left. Recently, the Japanese researcher Tatsuya Oda found a way around this: he succeeded in attaching SOD to artificial polymer molecules. Riding on the polymers, the SOD lasts in the bloodstream for at least 5 hours. As promising as this finding is, it raises questions about the long-term effects of adding an enzyme to the body in large quantities. These effects are not known as yet, and the question is far from trivial.

A preferred solution would be antioxidant substances with (1) low molecular weight, so they can slip from the digestive tract to the bloodstream undamaged, (2) the anti-oxidant ability, weight for weight, of an enzyme such as SOD, and (3) the ability to defuse a wide range of free radicals. In the next section, we will examine research on herbal compounds that appear to satisfy these criteria.