The Hottest Theory On The Reversal Of Aging -- The Oxygen We Breathe May Slowly Be Killing US

Second of two parts

BETHESDA, Md. - They zip madly through the cellular sea of our bodies and rip at our molecules like sharks. They mean nothing to most people, yet understanding them could lead to reversing the effects of aging.

Oxygen free radicals, the byproducts of burning oxygen in our cells, possess the power to sustain life or destroy it.

We couldn't exist without them. But growing evidence suggests that free radicals make us age, hurt and die.

Research also is beginning to show how the damage can be prevented. Scientists are making strong connections between free-radical damage and such killers as heart disease and cancer.

Free radicals also have been implicated in brain damage, arthritis, cataracts and emphysema.

"Free-radical damage is a very important part of the aging process - much more important than scientists were willing to accept in the past," said protein repair specialist Dr. Earl Stadtman of the National Heart, Lung and Blood Institute.

Now the free-radical theory of aging is the hottest in biogerontology, the discipline that studies why we age in hopes of retarding, or even reversing, the process.

Recent discoveries suggest we can minimize free-radical damage with dietary and other supplements to bolster the body's defenses as they weaken with age.

The march of the free-radical theory to center stage delights its long-suffering founder, Dr. Denham Harman, 75. He came up with his grand notion in 1954 and has been fighting the establishment view, which failed to give his theory any credence until recently.

"Chances are 99 percent (free radicals) are the basis for aging," said the University of Nebraska emeritus professor of medicine and biochemistry. "Aging is the ever-increasing accumulation of changes caused or contributed to by free radicals."

Stadtman agrees. His research at the National Institutes of Health shows that when cells reach the end of their lives, 30 percent of their proteins are junk, irreparably fractured by free radicals.

As you read these words, free radicals are being mass-produced in your body, but most will be squelched by one of nature's most ferocious protective systems. Called anti-oxidants, this army of chemicals degrades, neutralizes and detoxifies free radicals. Plants, fortunately for the humans who eat them, produce anti-oxidants such as vitamins A, C and E.

"Most of your cells get repaired," Harman said.

But enough free radicals survive our protective system and sabotage the proteins that make up cells at such an astounding rate that the body must replace each of its billions of proteins every three days, on average.

Proteins, composed of and orchestrated by genes, are notes in the body's basic symphony. All our parts, inside and out - our brain, flesh, blood, nails, hair - are made of proteins.

Working in counterpoint, proteins also make up the operating systems that keep us humming: our muscles and nerves; our immune cells and antibodies; our hormones and neurotransmitters that carry chemical tunes from cell to cell, tissue to tissue, organ to vital organ.

A TOXIC FUEL FOR THE BODY

But the proteins' fuel - oxygen - can be toxic.

Humans can tolerate breathing pure oxygen for no more than 48 hours before sustaining lung damage that can kill them. We survive the air we breathe only because it is just 20 percent oxygen.

As iron oxide, oxygen rusts iron. Oxygen free radicals make butter turn bad; they eat away the toughest granite of the Canadian Rockies; they love to catch fire.

Nature intended us to breathe oxygen only about 30 years, biogerontologists estimate. That's sufficient time for us to mature, breed and pass on our genes according to nature's plan.

If scientists like Harman and Stadtman are right, the longer we breathe, the more we age because of oxygen. What would happen if the tired genes that protect us against oxidation damage could be rejuvenated, or if the proteins they generate could be synthesized in the laboratory and taken as drugs? Could the aging process be forestalled?

The answers are being sought by biogerontologists around the world as they test the free-radical theory.

Free radicals result when molecules are torn apart and thrown out of electrical balance. In chemical terms, a free radical is a molecule with an unpaired electron; simply put, it is a confused particle that has lost its mate.

Electrons - electrically charged particles that whirl about all atoms and molecules - ordinarily orbit in pairs. But when an oxygen atom is being broken down by the body as it produces energy, the reaction strips away an electron. That leaves an unpaired electron - a free radical. The molecule desperately looks for another electron to mate with and make itself whole again. The only way it can is by stealing an electron from somewhere else, thereby throwing another molecule out of balance.

"These things keep going down the line, causing a chain reaction," Harman said. "Eventually two free radicals come together and form a stable molecule." But before that happens, countless erratic electrons crash about in search of mates, wreaking molecular havoc.

In their frenzy, Harman said, free radicals explode the fragile equilibrium of cells. They shatter the intricate process in which the messages of genes are transcribed into proteins. They demolish enzymes and other molecules.

Not everything that free radicals do is unhealthy. When our immune system eats toxic organisms, like viruses, it destroys them with a burst of free radicals.

Other radicals make their presence known from birth on.

"One of life's most beautiful and dramatic moments occurs when a newborn infant takes its first breath," said Dr. Howard Halperin of the University of Chicago. The baby's ability to switch quickly from living on its mother's circulation to taking oxygen into its own lungs is generated by a type of free radical.

Until recently it was impossible to detect radicals because they never stick around long enough to be seen; they live only millionths of a second. But free-radical "footprints" may be tracked, and researchers are identifying the wreckage they leave behind.

Free radicals are being linked to a host of diseases associated with aging, and foremost among them are cancer and heart disease, the major killer of Americans.

When free radicals attack genetic material, they cause damage that over time is believed to trigger the eruption of cancer. Dr. Donald Malins, a cancer researcher at the Pacific Northwest Research Foundation in Seattle, reported recently that he had found the first "smoking gun" in the form of free radicals still attached, like spent bullets, to damaged DNA in human breast cancer cells.

Malins said a free radical known as hydroxyl inflicts severe damage on the breast's DNA, impairing its ability to construct healthy cells.

Malins doesn't claim that hydroxyl radicals are the sole cause of cancer. "But we believe the damage to DNA is part of the cause," he said.

REPAIRING THE DAMAGE

Another cancer researcher studying the effects of free radicals is Dr. Bruce Ames of the University of California at Berkeley.

According to Ames' latest research, the genes in each human cell receive an estimated 10,000 damaging hits from potentially dangerous oxidants each day. Special enzymes and other proteins routinely race to the accident scenes in the cell, splice out the damage and fix the genes. Our repair rate is 99 to 99.9 percent effective, Ames has shown.

His research shows that the lifespans of animals are directly related to their ability to repair free-radical damage. Humans come equipped with far more of the needed anti-oxidants than other animals, said Ames, whose latest work shows that vitamin C may help prevent genetic defects.

Recent research into heart disease has found that free radicals give us high blood pressure and make our blood abnormally clot. When they ricochet through the lining of arteries, they trigger the events that permit clumps of cholesterol to build up, block the arteries and cause heart attacks.

Hoping to develop therapies to head off diseases caused by free radicals, the National Institutes of Health is launching an unprecedented five-year study involving more than 40,000 women. The $17 million study, scheduled to begin next year, will observe the role of vitamin E and another anti-oxidant, beta carotene, in preventing cancer and heart disease.

Besides being linked to those two diseases, free radicals demolish brain cells and contribute to premature senility.

A THEORY GAINS CREDENCE

Harman said his free-radical theory evolved because he was looking for something pervasive in all living organisms, something that is essential to life and also makes them age.

In 1954, Harman was completing an internship at the University of California when he was struck by the flash of insight that linked free radicals to aging. "Here you have a system that makes chemical reactions occur," he said. "It's natural and irreversible."

He tried to get other scientists to listen. "They wouldn't," he recalled. "It sounded like too simple an answer to something as complex as aging."

Since then, by feeding anti-oxidants to lab animals over the years, Harman showed he could increase their average life expectancy.

Many gerontologists still aren't convinced that boosting protection against free radicals by dietary supplements makes people live healthier and longer. But Harman has been patient, laboring to find anti-oxidants that might work better in animals.

It is the molecular biologists - the gene splicers - who now are taking Harman seriously. Using their powerful new tools, they're measuring the cumulative effects of free radicals in cells and developing ways to counter them.

For example, as researchers identify more of the body's natural anti-oxidants, genetic engineering techniques often can be used in the laboratory to produce the chemicals in large quantities. These synthetic anti-oxidants then can be used as drugs when the body's natural supply begins to dwindle with age.

A new vitamin, called PPQ, was recently found by Dr. Paul Gallop of Harvard Medical School to be a crucial anti-oxidant. He suspects that PPQ, when missing or deficient in pregnant female alcoholics, may contribute to the severe retardation in many babies born with fetal alcohol syndrome.

The level of PPQ also may be low in those who have Parkinson's disease.

But the hottest anti-oxidant under investigation, the one that kicked off the current free-radical hoopla, is superoxide dismutase, or SOD, which controls the radical called superoxide.

Both superoxide and SOD were discovered by Duke University biochemist Irwin Fridovich and colleagues. Superoxide, found in 1968, provided the first evidence that the body made free radicals. Similarly, discovery of SOD showed that the body produced its own anti-oxidant against onslaughts by the free radical.

"It has now been well established that superoxide radicals can kill," Fridovich said. "They damage enzymes that synthesize amino acids and metabolize sugar."

Dr. Richard Cutler, at the Gerontology Research Center of the National Institutes of Health, has shown a correlation between the life span of a dozen mammalian species and their levels of SOD, which protects their genes. His work suggests that the lifespan of an animal is directly related to the total amount of SOD it can produce to manage the byproducts of its own metabolism.

Scientists say the SOD that is available in health food stores is useless when taken orally. "It merely gets digested like any other protein," Fridovich said.

BUT IT'S STILL A THEORY

Despite the wealth of circumstantial evidence, the link between free radicals and aging has yet to be conclusively proved. What is needed is a way to assess biological damage uniquely associated with free radicals that can be shown to increase over time.

The most dramatic evidence so far linking free radicals to aging has been found in aged gerbils that recovered their ability to remember after they were treated for two weeks with an industrial anti-oxidant called PBN.

Robert Floyd, a molecular toxicologist at the Oklahoma Medical Research Foundation, and John Garney of the University of Kentucky showed that PBN improved the animals' brain-cell chemistry.

"The experiment," said the NIH's Stadtman, "marked the first time that a physiological function - the return of youthful brain chemistry and the restoration of short-term memory - has been cleanly linked to the level of oxidized protein in the cell."

And the potential for humanity may be profound, said Stadtman: "The loss of memory with age can apparently be overcome."