title: Chemical activation of a food deprivation signal extends lifespan.
abstract: Model organisms subject to dietary restriction (DR) generally live longer. Accompanying this lifespan extension are improvements in overall health, based on multiple metrics. This indicates that pharmacological treatments that mimic the effects of DR could improve health in humans. To find new chemical structures that extend lifespan, we screened 30 000 synthetic, diverse drug-like chemicals in Caenorhabditis elegans and identified several structurally related compounds that acted through DR mechanisms. The most potent of these NP1 impinges upon a food perception pathway by promoting glutamate signaling in the pharynx. This results in the overriding of a GPCR pathway involved in the perception of food and which normally acts to decrease glutamate signals. Our results describe the activation of a dietary restriction response through the pharmacological masking of a novel sensory pathway that signals the presence of food. This suggests that primary sensory pathways may represent novel targets for human pharmacology.
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lucanic
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.
authors.forename: Theo
authors.initials: T
authors.lastname: Garrett
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.|Dominican University of California, 50 Acacia Avenue, San Rafael, CA, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Yu
authors.affiliation: Center for Biological Sciences, Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: Fernando
authors.initials: F
authors.lastname: Calahorro
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.|Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
authors.forename: Azar
authors.initials: A
authors.lastname: Asadi Shahmirzadi
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Miller
authors.affiliation: Department of Metabolism & Aging, The Scripps Research Institute-Scripps Florida, 130 Scripps Way, Jupiter, FL, 33458.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Gill
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hughes
authors.affiliation: Center for Biological Sciences, Institute for Life Sciences, University of Southampton, Southampton, UK.
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
authors.affiliation: Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Lithgow
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D031204:Caloric Restriction; D018118:Chloride Channels / Q000378:metabolism; D005247:Feeding Behavior / Q000187:drug effects; D005508:Food Deprivation / Q000502:physiology*; D005971:Glutamates / Q000378:metabolism; D008136:Longevity / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D010614:Pharynx / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D029742:Caenorhabditis elegans Proteins; D018118:Chloride Channels; D005971:Glutamates; D011976:Receptors, Muscarinic; D054852:Small Molecule Libraries
keywords: Aging; Caenorhabditis; Drug Discovery; Pharmacogenetics; dietary restriction