title: An antidepressant that extends lifespan in adult Caenorhabditis elegans.
abstract: The mechanisms that determine the lifespan of an organism are still largely a mystery. 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.
authors.affiliation: Howard Hughes Medical Institute, Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, Washington 98109-1024, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Petrascheck
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Ye
authors.forename: Linda B
authors.initials: LB
authors.lastname: Buck
mesh_terms: D000375:Aging; D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology*; D031204:Caloric Restriction; D006801:Humans; D008136:Longevity / Q000187:drug effects* / Q000502:physiology*; D008719:Methiothepin / Q000494:pharmacology; D008803:Mianserin / Q000494:pharmacology; D009655:Octopamine / Q000378:metabolism*; D017982:Receptors, Biogenic Amine / Q000037:antagonists & inhibitors / Q000378:metabolism; D044422:Receptors, Serotonin, 5-HT4 / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism*; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013217:Starvation / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D017982:Receptors, Biogenic Amine; D058832:Serotonin 5-HT4 Receptor Antagonists; D012702:Serotonin Antagonists; C027604:norsynephrine receptor; D009655:Octopamine; D044422:Receptors, Serotonin, 5-HT4; D008803:Mianserin; D012701:Serotonin; D008719:Methiothepin