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By
Gwen Ericson
Jan.
13, 2005 — A class of anti-seizure medications slows
the rate of aging in roundworms, according to researchers
at Washington University School of Medicine in St. Louis.
When exposed to drugs used to treat epilepsy in humans,
worms lived longer and retained youthful functions longer
than normal.
Because
the drugs affect nerve signals, the researchers' observations
suggest that the nervous system influences aging processes.
The findings are reported in the January 14 issue of
the journal Science.
The
anti-aging effect was revealed in a random screening
of 19 drugs approved for treating a variety of disorders
in humans. "We didn't start with a hypothesis about
what causes aging," says senior author Kerry Kornfeld,
M.D., Ph.D., associate professor of molecular biology
and pharmacology. "We wanted to look in an unbiased
way at available compounds to see if any of them happened
to have anti-aging activity."
The
researchers grew the roundworm C. elegans in the presence
of the 19 drugs and found that an anticonvulsant, ethosuximide,
extended the worms' lives from an average of 17 days
to an average of 20 days. Further tests on anticonvulsants
revealed that they also increased life span, with the
drug trimethadione having the largest effect and extending
the worms' lives by 47 percent.
The
group then sought to uncover the underlying mechanism
for the effect of the anticonvulsants. It was apparent
that the drugs did not mimic the anti-aging effects
of caloric restriction, because the worms had abundant
food and looked well-fed. The researchers also demonstrated
that anticonvulsants did not extend life by protecting
the worms from pathogenic bacteria in their environment.
Ethosuximide
and trimethadione did, however, significantly delay
age-related declines in neuro-muscular activity. Treated
worms continued to display the youthful traits of fast
body movement and fast pumping of mouthparts during
the latter phase of their extended lives. Further tests
showed that the anticonvulsants stimulated transmission
of signals in nerves that control body movement.
Scientists
previously had found genetic mutations in C. elegans
that affect both the nervous system and life span. The
researchers used these mutant worms to further pin down
the mechanism by which the anticonvulsants increased
longevity.
The
worms' mutated genes affect the function of sensory
neurons that regulate the release of an insulin-like
hormone. "Sensory inputs from the outside regulate
the level of insulin signaling inside the body, which
then in turn regulates longevity in the worms,"
Kornfeld says.
Testing
the anticonvulsants on longer-lived mutant worms, the
researchers found the drugs further extended their lives,
although not to the same degree they extended the lives
of worms with no mutations. That indicates the anticonvulsants
may affect aging partly through their influence on the
neural system involved in the insulin signaling pathway
and partly through an independent mechanism, according
to Kornfeld.
"Our
experiments show there is an important connection between
neural function and longevity," Kornfeld says.
"We're continuing this line of research to identify
the precise functions of the nervous system that cause
the worms to live longer."
Because
the researchers found that anticonvulsants affect the
nervous system of C. elegans, they also plan to use
the worms as model organisms to investigate how the
drugs inhibit seizures in epileptic patients, a mechanism
that currently is not well understood. Such research
could lead to more effective treatments for epilepsy.
------------------------------------------------------------------------------------------------------------------------------
Evason
K, Huang C, Yamben I, Covey DF, Kornfeld K. Anticonvulsant
medications extend worm life-span. Science, Jan. 14,
2005.
Funding
from the National Institutes of Health, the Washington
University Alzheimer's Disease Research Center and the
Longer Life Foundation supported this research.
Washington
University School of Medicine's full-time and volunteer
faculty physicians also are the medical staff of Barnes-Jewish
and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked
second in the nation by U.S. News & World Report.
Through its affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of Medicine is
linked to BJC HealthCare.
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