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�Our studies indicate that lifespan extension by mianserin involves
mechanisms associated with lifespan extension by dietary restriction,�
said Buck, a member of the Basic Sciences Division of the Fred
Hutchinson Cancer Research Center in Seattle. �We don't have an
explanation for this. All we can say is that if we give the drug to
caloric restricted animals, it doesn't increase their lifespan any
further. That suggests the same mechanism may be involved.�
Researchers don�t yet understand exactly how mianserin staves off the
effects of aging. But the drug appears to act the same way in both C.
elegans and humans: by blocking certain receptors for the
neurotransmitter serotonin. Serotonin is a chemical that cells use to
communicate, helping them regulate many functions, including mood,
appetite, and sensory perception.
Buck said it was a surprise to find that a drug used to treat
depression in humans could extend lifespan in worms. The researchers
in Buck�s lab found that in addition to inhibiting certain serotonin
receptors in the worm, it also blocked receptors for another
neurotransmitter, octopamine.
A number of observations support the idea that serotonin and
octopamine may complement one another in a physiological context, Buck
explained, with serotonin signaling the presence of food and
octopamine signaling its absence or a state of starvation. C. elegans,
for instance, usually only lays eggs when food is on hand. But
serotonin stimulates egg laying in the absence of food, while
octopamine inhibits egg laying even when food is nearby. Another
example of interplay between the two chemicals is that pharyngeal
pumping, the mechanism by which worms ingest food, is jump-started by
serotonin and thwarted by octopamine.
�In our studies, mianserin had a much greater inhibitory effect on the
serotonin receptor than the octopamine receptor,� she said. �One
possibility is that there is a dynamic equilibrium between serotonin
and octopamine signaling and the drug tips the balance in the
direction of octopamine signaling, producing a perceived, though not
real, state of starvation that activates aging mechanisms downstream
of dietary restriction.�
Buck and her colleagues chose to focus on the effects of mianserin
based on the results of a search through 88,000 chemicals for agents
that extended the lifespan of nematodes. They found 115 such chemicals.
In follow-up studies of one chemical, they found four additional
compounds, including mianserin, that extended lifespan by 20-33
percent. All four compounds inhibit certain types of serotonin
receptors in humans.
�We screened a wide variety of chemicals without knowing anything
about them except that they were small molecules,� Buck noted. �By
screening adult animals with this extremely varied panel of compounds,
we hoped to identify drugs that could increase lifespan in adults,
even though some might have a deleterious effect on the developing
animal.�
By identifying drugs that influence lifespan, Buck added, it may be
possible to home in on how those drugs act and contribute to a growing
body of knowledge about the genetic mechanisms of aging.
�Other researchers have done beautiful work using molecular genetic
approaches to identify genes involved in aging,� she said. �We decided
to take a chemical approach. By finding chemicals that enhance
longevity, and then finding the targets of those chemicals, it may be
possible to identify additional genes important in aging. In addition,
the chemical approach could point to drugs suitable for testing in
mammals.�
Buck said that her group has yet to identify what kinds of cells are
affected by the drug, because while the serotonin receptors involved
are only found on neurons, many types of cells - not just cells of the
nervous system - have receptors for octopamine.
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