An antidepressant that extends lifespan in adult Caenorhabditis elegans

The mechanisms that determine the lifespan of an organism are still largely a mystery1. One goal of ageing research is to find drugs that would increase lifespan and vitality when given to

an adult animal. To this end, we tested 88,000 chemicals for the ability to extend the lifespan of adult Caenorhabditis elegans nematodes. Here we report that a drug used as an

antidepressant in humans increases C. elegans lifespan. In humans, this drug blocks neural signalling by the neurotransmitter serotonin. In C. elegans, the effect of the drug on lifespan is

reduced or eradicated by mutations that affect serotonin synthesis, serotonin re-uptake at synapses, or either of two G-protein-coupled receptors: one that recognizes serotonin and the other

that detects another neurotransmitter, octopamine. In vitro studies show that the drug acts as an antagonist at both receptors. Testing of the drug on dietary-restricted animals or animals

with mutations that affect lifespan indicates that its effect on lifespan involves mechanisms associated with lifespan extension by dietary restriction. These studies indicate that lifespan

can be extended by blocking certain types of neurotransmission implicated in food sensing in the adult animal, possibly leading to a state of perceived, although not real, starvation.

We are grateful to J. Priess for critical reading of an earlier version of the manuscript, to members of the Priess and Buck laboratories for advice and discussions, and to J. Vazquez for

technical assistance. We thank S. Suo for providing the VN11 strain (ser-3(ad1774);tzIs3[cre::gfp, lin-15(+)]) and J. Ying Sze for the ser-4(ok512);yzEx205[ser-4(+); pRF4(rol-6(su1006))]

strain. All other strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH, and the international C. elegans Gene Knockout Consortium. This project was

supported by the Howard Hughes Medical Institute and the Ellison Medical Foundation.

Basic Sciences Division, Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA,

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A large-scale screen for lifespan-enhancing chemicals in Caenorhabditis elegans has come up with a surprise: mianserin, used as an antidepressant in humans, increases the 3-week lifespan of

the nematode by almost a third. In humans, this drug blocks signalling by the neurotransmitter serotonin, and the life-prolonging effect in C. elegans also involves serotonin receptors, and

shows similarities to lifespan extension by dietary restriction. One possibility is that mianserin induces a state of perceived — rather than real — starvation. Intriguingly, appetite

stimulation is a side effect of mianserin in humans, raising the possibility of linkage between appetite and lifespan.