title: Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan.
abstract: Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR), robustly extends the lifespan of model organisms including mice. We recently found that chronic treatment with rapamycin not only inhibits mTOR complex 1 (mTORC1), the canonical target of rapamycin, but also inhibits mTOR complex 2 (mTORC2) in vivo. While genetic evidence strongly suggests that inhibition of mTORC1 is sufficient to promote longevity, the impact of mTORC2 inhibition on mammalian longevity has not been assessed. RICTOR is a protein component of mTORC2 that is essential for its activity. We examined three different mouse models of Rictor loss: mice heterozygous for Rictor, mice lacking hepatic Rictor, and mice in which Rictor was inducibly deleted throughout the body in adult animals. Surprisingly, we find that depletion of RICTOR significantly decreases male, but not female, lifespan. While the mechanism by which RICTOR loss impairs male survival remains obscure, we find that the effect of RICTOR depletion on lifespan is independent of the role of hepatic mTORC2 in promoting glucose tolerance. Our results suggest that inhibition of mTORC2 signaling is detrimental to males, which may explain in part why interventions that decrease mTOR signaling show greater efficacy in females.
authors: Department of Medicine, University of Wisconsin, Madison, WI, 53705, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, 53705, USA; Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA; Department of Biology, MIT, Cambridge, MA, 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA, 02139, USA; Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, 02139, USA.
authors: Dudley W
authors: DW
authors: Lamming
authors: Maria M
authors: MM
authors: Mihaylova
authors: Pekka
authors: P
authors: Katajisto
authors: Emma L
authors: EL
authors: Baar
authors: Omer H
authors: OH
authors: Yilmaz
authors: Amanda
authors: A
authors: Hutchins
authors: Yetis
authors: Y
authors: Gultekin
authors: Rachel
authors: R
authors: Gaither
authors: David M
authors: DM
authors: Sabatini
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D008136:Longevity / Q000502:physiology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D012737:Sex Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: Rapamycin; Rictor; aging; gender dimorphism; longevity; mTORC2