Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver

Authors

  • Wilson C. Fok,

    1. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Alex Bokov,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Department of Epidemiology & Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Jonathan Gelfond,

    1. Department of Epidemiology & Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Zhen Yu,

    1. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
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  • Yiqiang Zhang,

    1. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Department of Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Mark Doderer,

    1. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Yidong Chen,

    1. Department of Epidemiology & Biostatistics, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    3. Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • Martin Javors,

    1. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
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  • William H. Wood III,

    1. National Institute on Aging, Baltimore, MD, USA
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  • Yongqing Zhang,

    1. National Institute on Aging, Baltimore, MD, USA
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  • Kevin G. Becker,

    1. National Institute on Aging, Baltimore, MD, USA
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  • Arlan Richardson,

    1. Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    2. Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
    3. Research Service, Audie Murphy VA Hospital (STVHCS), San Antonio, TX, USA
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  • Viviana I. Pérez

    Corresponding author
    1. Linus Pauling Institute, Oregon State University, Corvallis, OR, USA
    2. Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR, USA
    • Correspondence

      Viviana I. Pérez, Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, 307 Linus Pauling Science Center, Corvallis, OR 97331, USA. Tel.: 541-737-9551; fax: 541-737-5077; e-mail: viviana.perez@oregonstate.edu

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Summary

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.

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