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 thei
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
"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.
Source:Washington University in St.Louis
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