title: Chronic rapamycin treatment or lack of S6K1 does not reduce ribosome activity in vivo.
abstract: Reducing activity of the mTORC1/S6K1 pathway has been shown to extend lifespan in both vertebrate and invertebrate models. For instance, both pharmacological inhibition of mTORC1 with the drug rapamycin or S6K1 knockout extends lifespan in mice. Since studies with invertebrate models suggest that reducing translational activity can increase lifespan, we reasoned that the benefits of decreased mTORC1 or S6K1 activity might be due, at least in part, to a reduction of general translational activity. Here, we report that mice given a single dose of rapamycin have reduced translational activity, while mice receiving multiple injections of rapamycin over 4 weeks show no difference in translational activity compared with vehicle-injected controls. Furthermore, mice lacking S6K1 have no difference in global translational activity compared with wild-type littermates as measured by the percentage of ribosomes that are active in multiple tissues. Translational activity is reduced in S6K1-knockout mice following single injection of rapamycin, demonstrating that rapamycin's effects on translation can occur independently of S6K1. Taken together, these data suggest that benefits of chronic rapamycin treatment or lack of S6K1 are dissociable from potential benefits of reduced translational activity, instead pointing to a model whereby changes in translation of specific subsets of mRNAs and/or translation-independent effects of reduced mTOR signaling underlie the longevity benefits.
authors.affiliation: Department of Biochemistry; University of Washington; Seattle, WA USA; Buck Institute for Age Research; Novato, CA USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Garelick
authors.forename: Vivian L
authors.initials: VL
authors.lastname: Mackay
authors.forename: Aya
authors.initials: A
authors.lastname: Yanagida
authors.forename: Emmeline C
authors.initials: EC
authors.lastname: Academia
authors.forename: Katherine H
authors.initials: KH
authors.lastname: Schreiber
authors.forename: Warren C
authors.initials: WC
authors.lastname: Ladiges
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008136:Longevity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation; D011132:Polyribosomes / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: S6 kinase; TOR; aging; rapamycin; signal transduction; translation