title: Regulation of mTOR activity in Snell dwarf and GH receptor gene-disrupted mice.
abstract: The involvement of mammalian target of rapamycin (mTOR) in lifespan control in invertebrates, calorie-restricted rodents, and extension of mouse lifespan by rapamycin have prompted speculation that diminished mTOR function may contribute to mammalian longevity in several settings. We show here that mTOR complex-1 (mTORC1) activity is indeed lower in liver, muscle, heart, and kidney tissue of Snell dwarf and global GH receptor (GHR) gene-disrupted mice (GHR-/-), consistent with previous studies. Surprisingly, activity of mTORC2 is higher in fasted Snell and GHR-/- than in littermate controls in all 4 tissues tested. Resupply of food enhanced mTORC1 activity in both controls and long-lived mutant mice but diminished mTORC2 activity only in the long-lived mice. Mice in which GHR has been disrupted only in the liver do not show extended lifespan and also fail to show the decline in mTORC1 and increase in mTORC2 seen in mice with global loss of GHR. The data suggest that the antiaging effects in the Snell dwarf and GHR-/- mice are accompanied by both a decline in mTORC1 in multiple organs and an increase in fasting levels of mTORC2. Neither the lifespan nor mTOR effects appear to be mediated by direct GH effects on liver or by the decline in plasma IGF-I, a shared trait in both global and liver-specific GHR-/- mice. Our data suggest that a more complex pattern of hormonal effects and intertissue interactions may be responsible for regulating both lifespan and mTORC2 function in these mouse models of delayed aging.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology (G.D.), University of Michigan College of Literature, Science and the Arts, Ann Arbor, Michigan 48109; Edison Biotechnology Institute (D.E.B., E.O.L., J.J.K.), Ohio University, Athens, Ohio 45701; Department of Pathology (X.L., R.A.M., G.G.G.), University of Michigan School of Medicine Ann Arbor, Michigan 48109; and University of Michigan Geriatrics Center (R.A.M.), Ann Arbor, Michigan 48109.
authors.forename: Graham
authors.initials: G
authors.lastname: Dominick
authors.forename: Darlene E
authors.initials: DE
authors.lastname: Berryman
authors.forename: Edward O
authors.initials: EO
authors.lastname: List
authors.forename: John J
authors.initials: JJ
authors.lastname: Kopchick
authors.forename: Xinna
authors.initials: X
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Gonzalo G
authors.initials: GG
authors.lastname: Garcia
mesh_terms: D000818:Animals; D004393:Dwarfism, Pituitary / Q000378:metabolism*; D005215:Fasting / Q000502:physiology*; D005260:Female; D008099:Liver / Q000378:metabolism; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism*; D011986:Receptors, Somatotropin / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011986:Receptors, Somatotropin; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases