Antidepressants Make Worms Live Longer, but Humans?

In an interesting breakthrough, US researchers said Wednesday that an antidepressant helped worms live longer by tricking the brain into thinking the body was starving.

The drug, called mianserin, extended the life span of the nematode Caenorhabditis elegans by about 30 percent, the researchers reported in the journal Nature.

Cutting back on calories is a sure way to extend the lifespan of any organism, from yeast to mice. The drug seems to make the worms into thinking they're on a diet, pushing their fleeting lifespan of three weeks to more than four.

Such biochemical tinkering could form the basis for drugs that attempt to prevent the onset of age-related diseases, says Linda Buck, a molecular biologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, who led the work.

The nematode worm, Caenorhabditis elegans , has been used as a model of ageing for decades, helping scientists to uncover details about what happens to human bodies as they grow old.

Scientists are just starting to find drugs that slow ageing. To speed the search, Buck and colleague Michael Petrascheck tested 88,000 chemicals from a chemical library to see if any of them made worms live longer.

Their five-year hunt turned up more than 100 chemicals that boosted the worms’ lifespan. But there was little known about how these chemicals react in biological systems. So Petrascheck scoured catalogues of better studied drugs to see if any had a similar structure to the experimental chemicals. He then checked to see if the drug had the same effect as their chemical had on the worms. “It was a long shot in the dark,” he says.

But it worked. Petrascheck chanced on several drugs that resembled a chemical unmemorably named 272N18, which had increased lifespan by a fifth in his first round of tests. One of the drugs, mianserin, lengthened the worms' lives by a third.

Mianserin interacts with two brain chemicals involved in hunger: serotonin, which signals the presence of food, and octopamine, which signals starvation. The drug preferentially blocks one kind of serotonin receptor, hindering this receptor from doing its normal job. “We may tip the balance in the direction of a starvation response,” Buck says.

The drug didn’t cause the worms to eat any less, suggesting that it did not slow ageing by actual calorie restriction. “They don't look like they're starving and they’re quite active,” Buck says.

But the researchers do think mianserin works by the same mechanism as calorie restriction. Worms on a strict diet don't get an additional lifespan boost from mianserin, suggesting that whatever benefit is gained by either calorie restriction or the drug gets 'topped out' by that factor. And worms missing some genes known to be involved in the youth-giving effect of calorie restriction get less of a lifespan benefit from mianserin.

Finding drugs that slow ageing in worms is an important first step towards addressing ageing in humans, says David Sinclair, a biologist at Harvard University in Cambridge, Massachusetts, who is affiliated with a company that is seeking to develop anti-ageing drugs for people.

But Buck cautions against taking her team’s preliminary findings to suggest that humans could get the same benefit from mianserin. She plans to test the drug next in mice. Her team will also tackle the 100 or so other chemicals their search turned up to learn more about what causes animals to age - and how to slow the process.

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