title: Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster.
abstract: The target of rapamycin (TOR) pathway is a major nutrient-sensing pathway that, when genetically downregulated, increases life span in evolutionarily diverse organisms including mammals. The central component of this pathway, TOR kinase, is the target of the inhibitory drug rapamycin, a highly specific and well-described drug approved for human use. We show here that feeding rapamycin to adult Drosophila produces the life span extension seen in some TOR mutants. Increase in life span by rapamycin was associated with increased resistance to both starvation and paraquat. Analysis of the underlying mechanisms revealed that rapamycin increased longevity specifically through the TORC1 branch of the TOR pathway, through alterations to both autophagy and translation. Rapamycin could increase life span of weak insulin/Igf signaling (IIS) pathway mutants and of flies with life span maximized by dietary restriction, indicating additional mechanisms.
authors.affiliation: Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, UK.
authors.forename: Ivana
authors.initials: I
authors.lastname: Bjedov
authors.forename: Janne M
authors.initials: JM
authors.lastname: Toivonen
authors.forename: Fiona
authors.initials: F
authors.lastname: Kerr
authors.forename: Cathy
authors.initials: C
authors.lastname: Slack
authors.forename: Jake
authors.initials: J
authors.lastname: Jacobson
authors.forename: Andrea
authors.initials: A
authors.lastname: Foley
authors.forename: Linda
authors.initials: L
authors.lastname: Partridge
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001343:Autophagy; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000502:physiology*; D008136:Longevity; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases
chemical_list: D029721:Drosophila Proteins; D011494:Protein Kinases; C416303:target of rapamycin protein, Drosophila; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus