• Open Access

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Authors

  • Evi M. Mercken,

    1. Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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    • These authors contributed equally to this research.
  • Seth D. Crosby,

    1. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
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    • These authors contributed equally to this research.
  • Dudley W. Lamming,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, Massachusetts Institute of Technology (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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  • Lellean JeBailey,

    1. GeneGo Inc., St. Joseph, MI, USA
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  • Susan Krzysik-Walker,

    1. Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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  • Dennis T. Villareal,

    1. Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, USA
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  • Miriam Capri,

    1. CIG - Interdepartmental Centre “Galvani”, University of Bologna- ALMA MATER STUDIORUM, Bologna, Italy
    2. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna- ALMA MATER STUDIORUM, Bologna, Italy
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  • Claudio Franceschi,

    1. CIG - Interdepartmental Centre “Galvani”, University of Bologna- ALMA MATER STUDIORUM, Bologna, Italy
    2. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna- ALMA MATER STUDIORUM, Bologna, Italy
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  • Yongqing Zhang,

    1. Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
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  • Kevin Becker,

    1. Gene Expression and Genomics Unit, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA
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  • David M. Sabatini,

    1. Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    2. Department of Biology, Massachusetts Institute of Technology (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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  • Rafael de Cabo,

    Corresponding author
    • Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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  • Luigi Fontana

    Corresponding author
    1. Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, USA
    2. Department of Medicine, Salerno University Medical School, Salerno, 84081, Italy
    3. CEINGE Biotecnologie Avanzate, Napoli, 80145, Italy
    • Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
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Correspondence

Luigi Fontana, Division of Geriatrics and Nutritional Science, Washington University School of Medicine, St. Louis, MO, 63108, USA. Tel.: +1 314 747 1485; fax: +1 314 362 7657; e-mail: lfontana@dom.wustl.edu and

Rafael de Cabo, Laboratory of Experimental Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA. Tel.: +1 410 558 8510 ; fax: +1 410 558 8302; e-mail: decabora@grc.nia.nih.gov

Summary

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.

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