oxidantive damage and disease

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Enzyme Required To Prolong Life In

Worms Identified By Researchers At

Columbia; Key Enzyme Appears To

Protect Animal Cells From Oxidative

Damage

Researchers at Columbia University have discovered an

enzyme that is

required to prolong the life span of microscopic

roundworms and that strains

of long-lived worms appear to produce in greater

quantity than normal.

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 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

Taub, a graduate

student, and 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 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.