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See Inside May 2009

Free Radical Shift: Antioxidants may not increase life span

Antioxidants, abundant in pomegranates, counter free radical damage but may not delay aging

Companies have started putting antiox­i­dants in goods as different as face creams and soda, claiming that they clean out cells, prevent cancer and even stave off death. The idea is to prevent unstable oxygen molecules, which are normal by-products of metabolism, from damaging cells. But a recent study suggests that when it comes to living longer, those antioxidants may not be the answer.

The antioxidant theory of aging states that some of the oxygen molecules used by the body become negatively charged, making them reactive. As a result, they compromise health and age the body by damaging cell structures, proteins and DNA. Cells have a natural defense—superoxide dismutase (SOD), a special class of antioxidant that neutralizes the chemicals and prevents them from harming cells. According to the theory, proposed in 1956 by Denham Harman, now emeritus professor of medicine at the University of Nebraska, when the body gets older, SODs become less efficient at preventing oxidative stress. Over the past 50 years this widely accepted theory has held up in studies: when the SOD gene is knocked out in mice, flies or yeast, the organisms develop cancers and have shorter life spans.

But in the February PLoS Genetics, Siegfried Hekimi and Jeremy M. Van Raamsdonk, both at McGill University, report that removing SODs from tiny Caenorhabditis elegans soil worms has the exact opposite effect—they live longer. In the experiment, each of the worms’ five SOD genes, which primarily work in the mitochondria (the cells’ energy-producing organelles), was disabled in different combinations, hampering the worms’ ability to make the antioxidant. When the researchers turned off one SOD gene (namely, sod-2), the nematodes actually lived 30 percent longer. When four were disabled in follow-up work, the worms still had a normal life span.

Hekimi believes that the findings throw a wrench in the entire free radical theory of aging. Instead he claims that cell damage is a product of aging, not the actual cause. “It’s like the sun coming up every morning—they can’t prove that it will,” he says in reference to free radical proponents. “But I have to prove that it won’t.”

These modified worms are not healthy, though; they show evidence of oxidative stress. Without the antioxidants, their cells are left unprotected, and outside the lab the worms would have died from disease or cancer. But Hekimi separates such a condition from having a normal life span. The organism may be sicker, he observes, but it is living longer.

Other scientists doubt that the findings discredit free radicals entirely. “You can’t take a single paper studying a single gene in a single organism and make sweeping conclusions about a theory,” remarks John Phillips of the University of Guelph in Ontario, who has examined SODs in the fruit fly Drosophila melanogaster. Moreover, C. elegans has five SOD genes, whereas humans have two. “I think we need to know where the extra SODs are operating, like in tissues or muscles, and in which cellular compartments” to fully understand oxygen metabolism in C. elegans, Phillips says. Knowing the biological idiosyncrasies in the worm would elucidate how SODs work in general.

Hekimi proposes that his findings could bolster an alternative aging theory—specifically, the idea that a slower metabolism or lower temperatures decelerate the body and allow an organism to live longer. Several studies have challenged the rate of living theory of aging, but Hekimi thinks that “you have to take a broader version of the theory, that the rate at which things happen affects life span.” As he sees it, in SOD-deficient worms, free radicals damage the mitochondria, which produce less energy and thereby slow the organism down.

Hekimi’s idea stands in contrast with that of Bart Braeckman of Ghent University in Belgium, whose own 2007 experiments with C. elegans led him to rule out the metabolic theory of aging. But Braeckman also does not think that the free radical theory is the only answer. He notes that Hekimi’s work joins other recent studies that challenge the simplistic version of the theory. “The final conclusion was similar in all these papers: there is a problem with the free radical theory,” he states.

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