Depletion of Rictor, an essential protein component of mTORC2, decreases male lifespan

Authors

  • Dudley W. Lamming,

    Corresponding author
    1. Department of Medicine, University of Wisconsin, Madison, WI, USA
    2. William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
    3. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    4. Department of Biology, MIT, Cambridge, MA, USA
    5. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    6. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    7. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    • Correspondence

      Dudley W. Lamming, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Room C3127 Research 151, Madison, WI 53705, USA. Tel.:

      608-256-1901 ×12861; fax: 608-263-9983; e-mail: dlamming@medicine.wisc.edu

      and

      David M. Sabatini, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Tel.: 617-258-6407; fax: 617-452-3566; e-mail: sabatini@wi.mit.edu

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  • Maria M. Mihaylova,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
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  • Pekka Katajisto,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    Current affiliation:
    1. Institute of Biotechnology, University of Helsinki, Helsinki, Finland
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  • Emma L. Baar,

    1. Department of Medicine, University of Wisconsin, Madison, WI, USA
    2. William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
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  • Omer H. Yilmaz,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
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  • Amanda Hutchins,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    Current affiliation:
    1. Salk Institute for Biological Studies, San Diego, CA, USA
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  • Yetis Gultekin,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    Current affiliation:
    1. The Rockefeller University, New York, NY, USA
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  • Rachel Gaither,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
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  • David M. Sabatini

    Corresponding author
    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, MIT, Cambridge, MA, USA
    3. Howard Hughes Medical Institute, MIT, Cambridge, MA, USA
    4. Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, MA, USA
    5. The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA
    • Correspondence

      Dudley W. Lamming, William S. Middleton Memorial Veterans Hospital, 2500 Overlook Terrace, Room C3127 Research 151, Madison, WI 53705, USA. Tel.:

      608-256-1901 ×12861; fax: 608-263-9983; e-mail: dlamming@medicine.wisc.edu

      and

      David M. Sabatini, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Tel.: 617-258-6407; fax: 617-452-3566; e-mail: sabatini@wi.mit.edu

    Search for more papers by this author

Summary

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.

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