An antidepressant that extends lifespan in adult Caenorhabditis elegans

Abstract

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.

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Figure 1: Increases in C. elegans lifespan by human serotonin receptor antagonists require serotonin and octopamine signalling.
Figure 2: Mianserin and methiothepin are antagonists of SER-3 octopamine and SER-4 serotonin receptors.
Figure 3: Lifespan extension by mianserin and dietary restriction are related.

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Acknowledgements

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.

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Correspondence to Linda B. Buck.

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The file contains Supplementary Figure 1 and Supplementary Tables 1-4 with Legends. (PDF 6204 kb)

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Petrascheck, M., Ye, X. & Buck, L. An antidepressant that extends lifespan in adult Caenorhabditis elegans. Nature 450, 553–556 (2007). https://doi.org/10.1038/nature05991

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