Once formed, free radicals can damage proteins, lipids (fats) and DNA anywhere in the cell. But the components of mitochondria--including the ATP-synthesizing machinery and the mitochondrial DNA that gives rise to some of that machinery--are believed to be most vulnerable. Presumably they are at risk in part because they reside at or near the "ground zero" site of free-radical generation and so are constantly bombarded by the oxidizing agents. Moreover, mitochondrial DNA lacks the protein shield that helps to protect nuclear DNA from destructive agents. Consistent with this view is that mitochondrial DNA suffers much more oxidative damage than does nuclear DNA drawn from the same tissue.
Proponents of the mitochondrial free-radical hypothesis of aging suggest that damage to mitochondria by free radicals eventually interferes with the efficiency of ATP production and increases the output of free radicals. The rise in free radicals, in turn, accelerates the oxidative injury of mitochondrial components, which inhibits ATP production even more. At the same time, free radicals attack cellular components outside the mitochondria, further impairing cell functioning. As cells become less efficient, so do the tissues and organs they compose, and the body itself becomes less able to cope with challenges to its stability. The body does try to counteract the noxious effects of the oxidizing agents. Cells possess antioxidant enzymes that detoxify free radicals, and they make other enzymes that repair oxidative damage. Neither of these systems is 100 percent effective, though, and so such injury is likely to accumulate over time.
THE PROPOSAL that aging stems to a great extent from free-radical-induced damage to mitochondria and other cellular components has been buttressed by a number of findings. In one striking example, Rajindar S. Sohal of the University of Southern California, William C. Orr of Southern Methodist University and their colleagues investigated rodents and several other organisms, including fruit flies, houseflies, pigs and cows. They noted increases with age in free-radical generation by mitochondria and in oxidative changes to the inner mitochondrial membrane (where ATP is synthesized) and to mitochondrial proteins and DNA. They also observed that greater rates of free-radical production correlate with shortened average and maximum life spans in several of the species.
It turns out, too, that ATP manufacture decreases with age in the brain, heart and skeletal muscle, as would be expected if mitochondrial proteins and DNA in those tissues were irreparably impaired by free radicals. Similar decreases also occur in human tissues and may help explain why degenerative diseases of the nervous system and heart are common late in life and why muscles lose mass and weaken.
Some of the strongest support for the proposition that calorie restriction retards aging by slowing oxidative injury of mitochondria comes from Sohals group. When the workers looked at mitochondria harvested from the brain, heart and kidney of mice, they discovered that the levels of the superoxide radical and of hydrogen peroxide were markedly lower in animals subjected to long-term calorie restriction than in normally fed controls. In addition, a significant increase of free-radical production with age seen in the control groups was blunted by calorie restriction in the experimental group. This blunted increase was, moreover, accompanied by lessened amounts of oxidative insult to mitochondrial proteins and DNA. Other work indicates that calorie restriction helps to prevent age-related changes in the activities of some antioxidant enzymes--although many investigators, including me, suspect that strict dieting ameliorates oxidative damage mainly through slowing free-radical production.
Applications to Humans?
BY WHAT MECHANISM might calorie restriction reduce the generation of free radicals? No one yet knows. One proposal holds that a lowered intake of calories may somehow lead to slower consumption of oxygen by mitochondria--either overall or in selected cell types. Alternatively, low-calorie diets may increase the efficiency with which mitochondria use oxygen, so that fewer free radicals are made per unit of oxygen consumed. Less use of oxygen or more efficient use would presumably result in the formation of fewer free radicals. Studies also intimate that calorie control may minimize free-radical generation in mitochondria by reducing levels of a circulating thyroid hormone known as triiodothyronine, or T3, through unknown mechanisms.