Intercepting the Interloper

In the meantime, scientists hope to pinpoint exactly where oxidants do their dirtiest work – and easy to intervene. The idea, say molecular biologist John T.Phillips of the University of Guelph in Ontario, is to tailor therapies to the most important injured cells, rather than trying to fight oxidative damage throughout the body. Phillips has one candidate cell in mind: the motor neuron, which directs muscles from the brain and spinal cord. People with a paralyzing disease called familial amyotrophic lateral sclerosis die early, with heavily damaged motor neurons as well as mutations in SOD. Maybe, motor neurons are a critical target of oxidants, kick-starting or dominating the process of aging.

To test that idea, Phillips and his co-workers bred fruit flies with a jolt of one of the human superoxide dismutase compounds, SOD1, to be expressed only in the flies’ motor neurons. Sure enough, the bugs lived 40 percent longer than normal. And those extra days were lively ones. “We didn’t just delay dying, so that we had geriatric flies living longer,” Phillips says. “The extended time of life was youth.” In contrast, boosting SOD1 levels in unrelated muscle cells seems to have had no effect on the flies’ life span, he adds. Still, questions remain. “ We don’t really know why these animals are living longer,” Phillips concludes. To pin down SOD’s relevance the team has been spiking different types of neurons with the antioxidant to see how the various cells react.

Another target for protection is the mitochondria inside all cells. Because these tiny powerhouses are the very first cell structures to be clobbered by the chemicals. In a 1998 study Sohal and his co-worker Liang-Jun Yan exposed flies to high doses of pure oxygen and then went looking for signs of oxidant operating in the flies’ mitochondrial membranes. Rather than far-flung havoc, they found that oxidants targeted several vulnerable proteins, attaching to their strings of DNA, forcing them out of work and upsetting the entire cell’s ability to act normally. “Free radical damage during aging is not random, causing decline all around our cells,” Sohal says. “We’re talking about damage that’s very selective, and that may mean aging comes from specific biochemical losses.”

Proof of this notion would be good news, Ames says. “The key thing is to understand how aging really works. If it’s the decay of mitochondrial DNA, well we can do things to beef up these old mitochondria.”

Ames, Tory Hagen of Oregon State University and their colleagues have done just that. For several weeks in 1999, they fed a group of older rats food laced with lipoic acid (which converts to a potent antioxidant) and acetyl carnitine – chemicals used only by mitochondria. The rats’ liver cells deflected oxidant intruders with greater resiliency. What’s more, the senior rats scrambled around with new spirit, a sleeker look, and better functioning brains and immune systems. “I don’t want to say we’ve gone so far as turning old rats back into young rats,” Ames says, “but that sure looks like what’s going on in the mitochondria.”

Supermarket Solutions

If antioxidants work for flies and rats, what about us? Can you down a daily supplement that will extend your years? Don’t count on it. “Everybody is talking about popping antioxidant vitamins,” Phillips groans. “The evidence is strong that taking moderate amounts of vitamin C and E is not harmful, but the evidence that it’s actually useful for delaying aging is very thin.” For one thing, researchers say, your body can absorb only so much of these vitamins; the rest goes the way of other wastes. Also, in the industrial world, most of us get enough of the basic antioxidants in our daily diets. In contrast, lab animals that live unusually long with extra antioxidants may be deficient in those chemicals to begin with.

Even if antioxidant supplements do boost your defenses against free radicals, it’s tricky to know with ones – or how much – to take. As with any ingredient, too much can be a bad thing. In 1996, for instance, two large studies made news when researchers discovered that beta--carotene supplements – thought to help ward off some types of cancer – actually increased rates of lung cancer among smokers who were taking the pills. Some antioxidants hawked in health food stores will never do any good; walk right past those bottles of SOD, catalase and glutathione peroxidase, because these compounds must be created inside the body. When swallowed, they are simply broken down in digestion and rendered useless, researchers state.

Still, there are a few antioxidants that hold promise, Ames says, such as lipoic acid, which directly protects mitochondria. Perhaps, he adds, some of the more obscure antioxidants decrease in the body as we age, leaving us more vulnerable to oxidative damage. If that’s the case absorbing extra amounts of these conditional nutrients might slow cellular effects of aging. “We just don’t know yet”, Ames says.

Indeed, there are many unknowns. What proportion of aging changes in cells are the result of oxidative damage? Is there a way to reduce the rate of oxidants the body churns out, rather than simply boosting antioxidants? And what do all these long-lived lab mutants really explain about oxidative stress in people? Sohal worries that some of the most touted studies are misleading. For instance, biologists have won lots of attention by reporting that in worms, single mutations in a gene called daf-2 can double life span, partly by resisting oxidative stress. But this is a “bogus kind of life extension,” charges Sohal, because the worms’ metabolism (energy level) plummets during their extra time on earth. “It’s just like going to sleep for three years and call that three extra years of life,” he says. The extra time is akin to hibernation, Sohal adds, so any therapy based on it would rob people of the energy they normally have.

The most basic challenge is to understand aging itself. Growing old is a slow, subtle process that’s hard to define with blood tests or cellular studies. Oxidants can muddy the picture. After all, these omnipresent molecules can strike a cell’s proteins, fats or DNA, all very different beasts.

In the short run, researchers may first unravel the role of oxidants in specific diseases of aging, such as Alzheimer’s and Parkinson’s. People who suffer from these conditions show telltale signs of oxidative damage in the brain. Eventually these studies may inch scientists closer to understanding basic brain changes during aging. There may be reason for optimism. Some 10 years ago University of Kentucky researchers were first to report that high levels of a synthetic antioxidant, PBN, can decrease harmful oxidative proteins in the brains of old gerbils. Could aging be a treatable process?