Sci. Aging Knowl. Environ., 15 January 2003
New results challenge antioxidant's life-extending capabilities
Key Words: catalase enzyme mimetics
Subtle changes in stage lighting can turn a beautiful face hideous. A potential life-extension drug has taken a similar turn: The agent, which mimics an enzyme that protects cells from oxidative damage, made waves previously when it dramatically increased nematode life-span. A new study fails to duplicate the effect, suggesting that the compound delays death only under certain conditions.
As organisms age, reactive oxygen species (ROS) wreak havoc on cells (see "The Two Faces of Oxygen"). Some researchers hope to combat aging with compounds that imitate a cell's defenses against ROS. Two years ago, molecular biologist Gordon Lithgow of the Buck Institute for Age Research in Novato, California, and his colleagues discovered that a chemical called EUK-8 prolongs life-span in Caenorhabditis elegans when added to the worms' food. The drug imitates a worm enzyme that extinguishes the ROS superoxide. The team concluded that oxidative damage ages the worms and that countering the destruction can extend life-span.
Michelle Keaney and David Gems of University College London attempted to reproduce the effect on life-span. They found, however, that with increasing doses of EUK-8, worms' lives were shorter rather than longer. Now, both research groups are scrutinizing their experimental conditions to explain the different outcomes. "[We're] basically putting up a big yellow sign saying 'Watch out,' " says Gems. "We just wanted to alert people that there might be a problem; we haven't proved that the work is irreproducible."
One key factor, Lithgow says, could be that the Gems group refreshed the worms' food--and drug supply--every other day; Lithgow's team did so every day. Replenishment disposes of toxic byproducts generated from drug breakdown and keeps the active agent in ample supply. The discrepancy in the results also highlights the need to better understand the pharmacology, Lithgow adds. "Let's go in there and show where [EUK-8] is working and when it's working," he says. "Squirting some antioxidants on worms" won't extend life-span every time.
Although EUK-8 scavenges oxygen radicals in the test tube, and it can compensate for missing superoxide dismutase in mice (see "Drugs Protect Mice From Pernicious Forms of Oxygen"), no one knows whether worms take up the drug and keep it in a useable form. However, preliminary data from Gems's lab indicate that the drug enters worm cells and mops up damaging oxygen radicals, he says. Because life-span does not increase despite a reduction in oxidative damage, he suggests that oxygen radicals don't play a major role in aging. But "not all oxidative damage is the same," says molecular biologist John Tower of the University of Southern California in Los Angeles. A reduction in certain indicators of oxidative damage might not reflect a decrease in types of damage that limit life-span, he says.
"[The study] doesn't really say anything about the free radical theory of aging," agrees molecular geneticist Cynthia Kenyon of the University of California, San Francisco, but it does temper enthusiasm about the drug's ability to prolong life. "It's a little bit discouraging." Future work might clarify what conditions illuminate the drug from its good side.
January 15, 2003 Citation: C. Seydel, Casting Doubt. Science's SAGE KE (15 January 2003), http://sageke.sciencemag.org/cgi/content/full/sageke;2003/2/nw8
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