Free-Radical Theory of Aging Gains Support
Hopes but little success have characterized humanity’s search for something, anything, that will hold back the process of aging. No magic elixir, no secret formula has come from centuries of effort.
But the quest is not over. Recent research into the activities of oxygen-free radicals--tiny reactive molecules made during normal metabolism--suggests that they can do the kinds of damage that lead to heart disease, cancer, brain disorders, even aging of the skin.
Recent studies in animals, for example, have shown that enzymes that shut down the activities of free radicals can limit the damage done in heart attacks and stroke. Research also indicates that a little-known drug given to aged gerbils apparently restores youthful activity.
“Accumulating data clearly support the notion that free radicals influence the aging process,” said molecular toxicologist Robert A. Floyd of the Oklahoma Medical Research Foundation in Oklahoma City. “We’re quite excited.”
Although no one yet understands why or how aging occurs, these and other experiments hint strongly that the free radicals created during normal metabolism act as internal saboteurs, inflicting damage on cells and damaging tissues.
Joe McCord of the University of Colorado in Denver describes a free radical as “any molecule that has an odd number of electrons.” Because of its unbalanced condition, the radical is eager to grab an electron from another molecule or to discharge a surplus electron into a neighboring molecule. Sometimes this action sets off a chain reaction involving thousands of other molecules. It is the kind of oxidative damage that occurs as butter turns rancid, McCord said.
Such chemical changes inside living cells can cause genetic mutations, alter the structure of important proteins or fatty molecules, the lipids, that make up vital membranes. And if the damage accumulates faster than it can be repaired, disease or aging may be the result.
Huber R. Warner, deputy associate director of the National Institute of Aging, says that the presence of free radicals in living cells was not a surprise, biochemically speaking. “Free radicals are produced as a normal byproduct of the metabolism of the body, so it is inevitable that these things are going to be around” in living tissues, he said.
“To survive,” he said, “a cell needs to have a variety of defense mechanisms against the damage, or to destroy the free radicals before they do the damage.”
One free radical, called super-oxide, is so threatening that cells have devised a special enzyme system to get rid of it. “Super-oxide dismutase is an enzyme that converts super-oxide into hydrogen peroxide. And then catalase, another enzyme, destroys the hydrogen peroxide by turning it into water plus oxygen,” Warner said.
“The cell also has enzymes which recognize oxidized bases and remove them from DNA” so that other enzymes can reinsert the correct chemical base, repairing the genetic damage, Warner said.
“Proteins cannot be repaired that way,” however, he said. So “to repair proteins, you just get rid of them,” using protease enzymes to degrade them into amino acids. “Somehow the protease recognizes” a damaged protein “and just chews it up,” he said.
Other enzymes, phospholipases, repair damaged membranes by removing altered fatty acids, then replacing them with normal lipid molecules.
Thus, aging may involve accelerated or accumulated damage caused by free radicals, a general slowdown of critical damage-repair mechanisms, or a combination of both.
To protect themselves directly, living cells also use natural chemicals, antioxidants such as vitamins C and E, to avoid free-radical damage. McCord said vitamin E molecules sit in cell membranes, where they block damaging chemical reactions set off by free radicals. Then vitamin C acts to restore vitamin E to full activity.
Warner also noted that free radicals are not altogether bad. Under certain conditions, the body will learn to exploit them as weapons against infection. One type of white blood cell, neutrophil, uses free radicals as a sort of bug spray, zapping and killing any bacteria encountered.
Many scientists are not yet convinced, however, that free-radical damage is an important part of the aging story. Rather, they see evidence that aging is pre-programmed into one’s genes. After a certain number of cell division cycles, an organism’s cells slow down and lose their ability to divide and rebuild important tissues. The result is a gradual decline in vigor, and, eventually, death.
The strongest evidence for that idea was found about 20 years ago by Stanford University scientist Leonard Hayflick, who found that normal cells naturally stop growing after about 50 cycles of cell division. Senescence, the decline toward death, begins as cells stop dividing.
Another, more recent, idea about aging is that chromosomes--the carriers of genes--become unstable and begin unraveling at their ends as they age. Evidence reported by scientists at the Cold Spring Harbor Laboratory and the University of California, Berkeley, suggests that gradual shortening of the telomeres--the chromosomes’ ends--occurs as they get older. Perhaps when the telomeres get too short, the theory goes, the chromosomes unravel and the cells die.
As Floyd notes in a recent issue of Science magazine, however, the basic question remains unanswered. “Why do biological systems age? This question has puzzled experimentalists and creative thinkers for centuries. Increasing age leads to many changes in behavior and physiological function.” And despite accumulating evidence and his own enthusiasm for the idea, “the proposition that free radicals may be an important factor in aging remains to be rigorously proven.”
But the free radical idea is gaining support.
Free radicals and the damage they do are increasingly implicated as scientists look in detail into the demage seen in high blood pressure, in autoimmune disorders, memory loss and other disabilities associated with aging.
In Floyd’s own recent experiments in Oklahoma, which were done in collaboration with scientists in Kentucky and Maryland, the idea that free radicals underlie the aging process was strongly supported. He also found evidence that drug treatments may be able to halt or even repair such damage.
“We’re quite excited” by the recent results in laboratory animals, Floyd said in a telephone interview. Free radicals, as a prominent factor in aging, “seem to be very important, based on really a lot of work that we’ve done recently. I don’t know how you’d interpret it other than that it is important.”
Floyd said the researchers were originally studying the role free radicals play in damaging brain tissue after a stroke. All measurements showed that the amount of injury done to cells by free radicals increases once blood begins flowing again into an area where circulation was blocked. But the researchers also got a surprise: “What we observed was that older animals were more sensitive” to oxidative damage “than younger animals. We don’t know why,” Floyd said.
Further experiments showed that a so-called spin-trapping drug--a compound that traps free radicals--protects brain tissues from damage by the dangerous chemicals.
The results led them to ask, “What would happen if we gave these agents” in advance of injury? Might damage be avoided or repaired faster?
“What we found was that after chronic administration of this compound, there was a decrease in the amount of oxidized protein in the older gerbils’ brains.” The drug also seems to increase the activity level of the enzymes that protect against free-radical damage, he said.
The protective effect was dramatic; the amount of damage was far less, almost down to the low levels normally seen in the brains of the younger animals, Floyd said. The drug used is called PBN (N-tert-butyl-a-phenyl nitrone).
