Antidepressant found to extend lifespan in C. elegans

Buck and colleagues Michael Petrascheck and Xiaolan Ye report in the November 22, 2007, issue of the journal Nature, that the antidepressant drug mianserin can extend the lifespan of the nematode Caenorhabditis elegans by about 30 percent.

Intriguingly, the drug may act by mimicking the effects of caloric restriction, which has been shown to retard the effects of aging in a variety of animals ranging from worms and flies to mammals.

“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.

Source: Howard Hughes Medical Institute

Probing Question: Fishhooks of addiction
When the American writer Theodore Roethke taught at Penn State from 1936 to 1943, he was known for three things: being a good poet, coaching the men’s tennis team, and falling down drunk, perhaps the latter more than the former. Roethke, a brilliant and tortured man, knew well the seduction of drink and the agony of addiction. In his poem “Journey Into the Interior,” Roethke writes, “In the long journey out of the self, / There are many detours, washed-out interrupted raw places / Where the shale slides dangerously / And the back wheels hang almost over the edge / At the sudden veering, the moment of turning.”
Protein on 'speed' linked to ADHD
A genetic change in the dopamine transporter – one of the brain's dopamine-handling proteins – makes it behave as if amphetamine is present and "run backward," Vanderbilt University Medical Center investigators report this week in The Journal of Neuroscience.
Researchers clarify function of glucose transport molecule
Researchers at the David Geffen School of Medicine at UCLA have solved the structure of a class of proteins known as sodium glucose co-transporters (SGLTs), which pump glucose into cells. These transport proteins are used in the treatment of chronic diarrhea via oral rehydration therapy, saving the lives of millions of children each year. The solution of the SGLT structure will accelerate development of new drugs designed to treat patients with diabetes and cancer.
Scientists develop a mouse model of sudden infant death syndrome
Sudden Infant Death Syndrome (SIDS) is a condition that unexpectedly and unexplainably takes the lives of seemingly healthy babies aged between a month and a year. Now researchers of the European Molecular Biology Laboratory in Monterotondo, Italy, have developed a mouse model of the so-called crib or cot death, which remains the leading cause of death during the first year of life in developed countries. The model, published in this week's issue of Science, reveals that an imbalance of the neuronal signal serotonin in the brainstem is sufficient to cause sudden death in mice.
Political participation is partially rooted in genetic inheritance
The decision to vote is partly genetic, according to a new study published in the American Political Science Review. The research, by James H. Fowler and Christopher T. Dawes, of the University of California, San Diego and Laura A. Baker, of the University of Southern California, is the first to show that genes influence participation in elections and in a wide range of political activities.
Spiritual effects of hallucinogens persist, researchers report
In a follow-up to research showing that psilocybin, a substance contained in "sacred mushrooms," produces substantial spiritual effects, a Johns Hopkins team reports that those beneficial effects appear to last more than a year.
Study of marine snail leads to new insights into long-term memory
UCLA cellular neuroscientists are providing new insights into the mechanisms that underlie long-term memory — research with the potential to treat long-term memory disorders.
Serotonin may affect our sense of fairness, scientists report
The neurotransmitter serotonin, which acts as a chemical messenger between nerve cells, plays a critical role in regulating emotions such as aggression during social decision-making, new research by scientists at England's University of Cambridge and UCLA suggests. Their findings appear June 6 in the peer-reviewed journal Science.

Antidepressant found to extend lifespan in C. elegans

Related stories:

News discussion: