Scientists discover worm enzyme that extends life

Nature - May 13, 1999

Scientists have found an enzyme in worms that helps them live longer - a discovery that raises hopes of finding treatments for Alzheimer's and other human diseases associated with aging.

The next step is to determine whether a similar enzyme exists in humans.

The finding "gets us closer to understanding what's involved in the aging process and where we can intervene," said Anna McCormick, a biochemist at the National Institute on Aging.

The research was led by biologist Martin Chalfie at Columbia University. The findings were published in Thursday's issue of the journal Nature.

The researchers studied a nearly microscopic roundworm known as Caenorhabditis elegans. When it is well-fed, it survives only about three weeks, but it can withstand food shortages in a larval state for at least two months. Several genes in this worm were already linked to the larva's longer life, but their mechanism wasn't known.

The research team from Columbia and Dartmouth College identified an enzyme known as a cytosolic catalase that seems to act as a central agent in allowing some worms to live longer.

When the normal gene that makes the enzyme, ctl-1, is removed, the worms die sooner.

The researchers argue that cytosolic catalase allows longer life by performing a function it was already known to serve: blocking cell damage caused by oxygen compounds.

Such oxidative damage - analogous to metal rusting - is already implicated in human aging and diseases like Alzheimer's, Lou Gehrig's and Parkinson's. Vitamin E, an antioxidant, is now used to prevent heart attacks and treat Alzheimer's in some patients.

The discovery of the catalase gene bolsters the theory that oxidative damage is central to both aging and its diseases.

The worm gene "should give impetus to people working on the human genes to try to look for things like this," Chalfie said. It may eventually be possible to protect human nerve cells by boosting catalase with a drug, McCormick suggested.

Siegfried Hakimi, a McGill University biologist who also studies life span in roundworms, said researchers should now seek to establish if higher levels of cytosolic catalase alone will make worms live longer, not just block cell damage.

Tom Johnson, a University of Colorado geneticist who also works with roundworms, cautioned that their life-extending mechanisms may ultimately have limited relevance to human disease.

But he said researchers have made roundworms live five times longer with genetic manipulations. Johnson thinks such work suggests that people can also live longer with the right drug - or mix of drugs - in the future.

Researchers identify body's fat building enzymes

San Francisco -October 26, 1998

Scientists said Monday they had discovered a major piece in the puzzle of how the human body builds and regulates fat, a finding that may lead to new approaches for treating obesity. A research team led by scientists at the Gladstone Institute of Cardiovascular Disease and the University of California, San Francisco (UCSF), said it was able to isolate a key enzyme that the body uses to produce fat.

The enzyme, called DGAT, joins with other molecules to produce a specific group of fats called triglycerides, which make up more than 95 percent of fatty tissue in humans. Robert Farese, Jr., the principal investigator at Gladstone in San Francisco, said researchers have known about DGAT for several decades but have until now been unable to isolate the elusive enzyme.

Farese said his team's discovery, which was due to be summarized Tuesday in The Proceedings of the National Academy of Sciences, could lead to new drug therapies aimed at treating obesity by blocking DGAT.

"The neat thing about that is that most (obesity) therapies now deal with perturbing brain transmitters that influence a person's appetite, whereas this could work directly at fat tissue to inhibit fat production," Farese said in a telephone interview.

Farese said the finding also could have applications in agriculture because DGAT plays an important role in the synthesis of seed oils, such as canola oil, in plants.

"The DGAT enzyme is the last step in making the triglycerides that become the plant oil, so if you could boost the amount of this enzyme in the plants, you could potentially get more oil per plant," Farese said.

Farese and his fellow researchers were able to isolate the tricky enzyme by using a kind of genetic fingerprinting.

The group had been studying a related enzyme called ACAT, which is involved in cholesterol metabolism. Using the known genetic sequence of ACAT, the researchers were able to then compare it to other unidentified genetic sequences that are available to the public through computer databases.

"Using these databases, we were able to identify a similar gene. We didn't know what it was at first so we tried to see if it was ACAT, and it wasn't. We found that it was this DGAT enzyme," Farese said. Farese said the finding was the "most exciting" he had been involved with but he also warned against overstating the importance of the discovery. Still, he noted that UCSF had filed a for patent on the discovered gene. "We now have the tools to look at this important enzyme and it could lead to important therapies, but it's too early to tell," he said.