Enzyme Required To Prolong Life In Worms Identified By Researchers At Columbia; Key Enzyme Appears To Protect Animal Cells From Oxidative Damage

They believe the enzyme, called cytosolic catalase, protects cells from oxidative damage, considered a key element in the aging process in all animals, including humans. Because oxidative damage has been implicated in Alzheimer's and Lou Gehrig's disease, the work may prompt medical researchers to ask new questions about such nervous system diseases.

"Our work demonstrates that oxidative damage is an important determinant of life span, and control of such damage might affect the life span of other organisms," said Martin Chalfie, professor of biological sciences at Columbia and leader of the team that produced the research, which is described in the May 13 issue of the British journal Nature.

The research was carried out in Caenorhabditis elegans, a soil worm about 1/25 of an inch long that is a common experimental animal. The tiny worm has been useful to aging research because its normal three-week life span can be extended by environmental factors. In situations of overcrowding, food shortages or both, the emerging worm goes into a dormant period that can last as long as two months. If food is provided within that time, the animal emerges from dormancy and goes on to live its normal three weeks.

Scientists studying a possible genetic component to life span have been fascinated by this extended larval phase, called the dauer stage. "Dauer" means "lasting" in German. Several scientific teams have found mutations that send the worm into the dauer state at elevated temperatures. But even at normal temperatures and without going into the dauer stage, these mutant adults live two to four times longer than non-mutants. Yet these same mutants, if also bred to lack cytosolic catalase, died after three weeks, the Columbia researchers report.

"Scientists in the past have found mutations in C. elegans that affect the development of dauer larva and also prolong adult life," Professor Chalfie said. "However, until this paper it was not clear how that was accomplished. We believe we have found a key component."

That key component is cytosolic catalase, a protein that is also called CTL-1, which protects cells in the long-lived mutant worms from oxidative damage, thereby keeping them healthy. Mutant adult worms with long life spans exhibited elevated levels of the enzyme, as did non-mutants in the dauer stage, the Columbia team reports, but cells in normal adults do not.

"Our explanation for the long life spans in the mutant worms is that the catalase is protecting the cells from oxidative damage and keeping them healthy," Professor Chalfie said.

Oxidative damage occurs when oxygen-based compounds react with components of cells, modifying them and in some cases making them harmful to the cell. Such oxygen species -- peroxides, hydroxides and superoxides -- can be produced both in chemical reactions in the cell and from reactions between oxygen and ultraviolet light, a component of sunlight. Anti-oxidants such as vitamin E are thought to provide some protection against these molecules.

Some chemical reactions in cells produce hydrogen peroxide, but those reactions are confined to subcellular compartments, called peroxisomes, that contain catalases to rid the cell of this harmful product. Until the Columbia paper, animal cells were thought to have only peroxisomal catalase, though cytosolic catalase had been seen in both plants and yeast. The new catalase just identified, the first such enzyme found in animals, resides in the cell fluid, not within a specific compartment. In this more general location, the cytosolic catalase could act as a kind of surveillance system, removing harmful peroxides from throughout the cell. The research team dubbed the catalase CTL-1, and named the gene that produces it ctl-l.

Because the cells in adult roundworms do not divide, the research may be applicable to non-dividing cells in other animals, such as human nerve cells. Damage from oxidative stress has been implicated in nervous system diseases, including Alzheimer's disease and amyotrophic lateral sclerosis, or Lou Gehrig's disease. Vitamin E is sometimes administered to combat Alzheimer's.

Past work on the dauer larvae suggested that a series of genes might control dauer formation and longevity. Professor Chalfie said there is as yet no evidence for any particular gene that controls life span either in worms or in humans, and that the Columbia research shows that cytosolic catalase simply protects cells from oxidative damage. In this view, the key to longer life spans would simply be to keep cells as healthy as possible by avoiding such hazards, rather than by activating some component of the genome.

"Our work suggests that the catalase pathway does not control adult longevity, but rather that when the pathway is disrupted, adults live longer," Professor Chalfie said. "In worms, genes do control the dauers to make them healthy, but there is no evidence so far that genes regulate life span in adults. The catalase genes are needed to make healthy, long-lived dauers, and in the mutants they are being inappropriately expressed to make adults live longer."

How could animals have acquired a gene that would have allowed them to live longer? An evolutionary argument can be made that acquiring a gene to extend adult life after reproduction would be difficult, if not impossible, Professor Chalfie said. However, a gene that would extend the dauer period, a dormancy period before reproductive maturity, might convey a selective advantage to the animal. Another explanation is that extended longevity in worms is a part of a more general mechanism that is a response to starvation, during which animals produce enzymes, such as cytosolic catalase, that protect cells.

The research team that made the discovery included James Taub, a graduate student, and Jonathan Rothblatt, a biologist, who had studied C. elegans catalases at Dartmouth but left to join the Chalfie laboratory. Columbia undergraduates Rafaz Hoque and Joe F. Lau contributed to the work, as did postdoctoral fellows Jang Hee Hahn and Charles Ma.

The research was funded by the National Institutes of Health and by the American Cancer Society. Some strains of roundworm were received from the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources.