Sci. Aging Knowl. Environ., 29 October 2003
Wrinkle Treatment for Worms
Drugs appear to squelch life-shortening oxygen compounds in nematodes
Key Words: enzyme mimetics Euk-8 Euk-134 paraquat
It's every young starlet's dream: a miracle pill that thwarts aging. Although scientists generally take a more realistic view, compounds that combat age-related damage and extend life span could be gaining credibility, thanks in part to a new study. The research describes how two such drugs prevent oxygen-induced deterioration in nematodes.
In 2000, molecular biologist Gordon Lithgow of the Buck Institute for Age Research in Novato, California, and colleagues showed that synthetic enzymes called SCMs extend the life span of the roundworm Caenorhabditis elegans. In the test tube and in mice, SCMs behave like naturally occurring enzymes that smother harmful oxygen radicals (see "Drugs Protect Mice From Pernicious Forms of Oxygen"). From these results, the researchers concluded that oxidative stress curtails life span in worms and suggested that the drugs could counteract its life-shortening effects. To gauge the chemicals' therapeutic potential, the team has now determined whether SCMs shelter worms from oxidative injury.
The researchers fed the worms a pesticide that generates reactive oxygen species (ROS). More than two-thirds of worms that had swallowed SCMs survived the pesticide treatment, compared with only one-tenth of those that didn't receive the drug, suggesting that the SCMs shielded the animals from oxidative damage. Doses of SCMs also protected the nematodes against lethally high temperatures. The link between antioxidant activity and thermal stress remains unclear, but other studies have shown that long-lived animals resist both oxidative and heat damage.
Mutations that stem signaling by an insulin/insulin-like growth factor 1 (IGF-1)-like pathway dramatically expand worm life span and bolster resistance to oxidative stress. To find out whether SCMs confer protection through this pathway, the investigators tested nematodes that lack a protein called DAF-16. Without this molecule, mutations that obstruct the insulin/IGF-1-like pathway cannot boost stress resistance and prolong life. One SCM protected animals without DAF-16 from a deadly dose of pesticide nearly as well as it protected normal worms, indicating that the drug does not thwart ROS by inhibiting insulin-related signaling.
The researchers also tested whether SCMs protect against ROS by mobilizing a general stress response. One marker of this stress response is the protein HSP-16. Treatment with SCMs did not incite HSP-16 production, however, suggesting that SCMs work by mopping up ROS directly, not by activating cellular defenses.
Still, the key question--whether the protection conferred by these drugs extends longevity--remains controversial. In 2003, molecular geneticists Michelle Keaney and David Gems of University College London reported that SCMs did not stretch the life span of C. elegans in their lab and that the chemicals proved toxic at certain doses (see "Casting Doubt"). The new findings, Gems says, "may or may not be interesting, depending on whether the life-span data are reproducible." Molecular biologist John Tower of the University of Southern California in Los Angeles agrees. He calls the paper "a step in the right direction" because it shows that the drugs fight oxidative stress, but he cautions that the evidence isn't conclusive. More experiments to nail down the drugs' molecular behavior might yet bring Hollywood's fantasy of eternal youth closer to reality.
October 29, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150