Flawed Enzyme Linked to Wizened Worms

When an aging power plant breaks down, a whole city can black out. A similar phenomenon may happen in animals: A defective enzyme in mitochondria--the cell's tiny power plants--poisons entire cells and tissues in roundworms, killing them when they are young. The findings, reported in today's Nature, could help explain how our bodies age and why certain people develop some kinds of diseases in which muscles and nerves waste away.

Biologists have long debated why we age. According to one popular theory, when mitochondria extract energy from chemicals, by-products called oxygen radicals damage mitochondrial DNA and other critical molecules. Over time, broken down mitochondria accumulate in cells, starving them of energy; when enough cells in a critical organ die, the organism goes too. Testing this scenario, Naoaki Ishii of Tokai University School of Medicine in Kanagawa, Japan, and his team a few years ago developed a strain of a tiny roundworm called Caenorhabditis elegans that lives about half as long as normal worms.

Now Ishii and Philip Hartman, a geneticist at Texas Christian University in Fort Worth, have found the genetic defect that causes the worms to die young. Their approach was to give the worms gene therapy to restore a normal life-span. The researchers injected 6 different DNA fragments from normal worms into the gonads of the mutant worms and then bred them. One DNA fragment did the trick. Its sequence resembled a gene for an enzyme called Complex II, which helps mitochondria consume energy in cows and humans. That enzyme turned out to be defective in the short-lived strain of roundworms, but it worked fine in normal worms and in strains rescued by gene therapy. That this enzyme was to blame "is logical and it fits," Hartman says. Scientists speculate that either normal Complex II is more efficient at sopping up oxygen radicals, or crippled Complex II spurs formation of more oxygen radicals.

The findings add to growing support for the oxygen radical theory of aging, says biochemist Irwin Fridovich of Duke University Medical Center. They could also give a clue to potential molecular errors behind some cancers and diseases such as amyotrophic lateral sclerosis, or Lou Gehrig's disease, that have been linked to oxygen radicals.

Posted in Biology