Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice

  1. Christine Müller
  2. Laura M Zidek
  3. Tobias Ackermann
  4. Tristan de Jong
  5. Peng Liu
  6. Verena Kliche
  7. Mohamad Amr Zaini
  8. Gertrud Kortman
  9. Liesbeth Harkema
  10. Dineke S Verbeek
  11. Jan P Tuckermann
  12. Julia von Maltzahn
  13. Alain de Bruin
  14. Victor Guryev
  15. Zhao-Qi Wang
  16. Cornelis F Calkhoven  Is a corresponding author
  1. University Medical Center Groningen, Netherlands
  2. Leibniz Institute on Ageing - Fritz Lipmann Institute, Germany
  3. University of Ulm, Germany
  4. Utrecht University, Netherlands

Abstract

Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPβ-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-mRNA. Here we describe that reduced C/EBPβ-LIP expression due to genetic ablation of the uORF delays the development of age-associated phenotypes in mice. Moreover, female C/EBPβΔuORF mice display an extended lifespan. Since LIP levels increase upon aging in wild type mice, our data reveal an important role for C/EBPβ in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPβ-LIP may offer new possibilities to treat age-related diseases and to prolong healthspan.

Data availability

For transcriptome dataset see: Müller, C., de Jong, T, Guryev, V, Calkhoven, CF. (2018). Transcriptome profiling of liver samples of C/EBPβΔuORF mice. Retrieved from: https://www.ebi.ac.uk/arrayexpress/

The following data sets were generated

Article and author information

Author details

  1. Christine Müller

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Laura M Zidek

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Tobias Ackermann

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Tristan de Jong

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Peng Liu

    Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Verena Kliche

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Mohamad Amr Zaini

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Gertrud Kortman

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Liesbeth Harkema

    Dutch Molecular Pathology Centre, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Dineke S Verbeek

    Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. Jan P Tuckermann

    Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Julia von Maltzahn

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Alain de Bruin

    Dutch Molecular Pathology Centre, Utrecht University, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. Victor Guryev

    European Research Institute for the Biology of Ageing, University Medical Centre Groningen, University Medical Center Groningen, Groningen, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  15. Zhao-Qi Wang

    Leibniz Institute on Ageing - Fritz Lipmann Institute, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  16. Cornelis F Calkhoven

    European Research Institute for the Biology of Ageing, University Medical Center Groningen, Groningen, Netherlands
    For correspondence
    c.f.calkhoven@umcg.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6318-7210

Funding

Deutsche Forschungsgemeinschaft (CA 283/1-1)

  • Laura M Zidek
  • Cornelis F Calkhoven

Leibniz-Gemeinschaft (LGSA)

  • Tobias Ackermann
  • Cornelis F Calkhoven

Deutsche Forschungsgemeinschaft (MA 3975/2-1)

  • Laura M Zidek
  • Julia von Maltzahn

Deutsche Forschungsgemeinschaft (INST 40/492-1)

  • Peng Liu
  • Jan P Tuckermann

Deutsche Forschungsgemeinschaft (TU 220/6)

  • Peng Liu
  • Jan P Tuckermann

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the Thüringer Landesamt für Verbraucherschutz (#03-005/13) and University of Groningen (#6996A).

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Publication history

  1. Received: January 11, 2018
  2. Accepted: April 27, 2018
  3. Accepted Manuscript published: April 30, 2018 (version 1)
  4. Version of Record published: June 4, 2018 (version 2)

Copyright

© 2018, Müller et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Christine Müller
  2. Laura M Zidek
  3. Tobias Ackermann
  4. Tristan de Jong
  5. Peng Liu
  6. Verena Kliche
  7. Mohamad Amr Zaini
  8. Gertrud Kortman
  9. Liesbeth Harkema
  10. Dineke S Verbeek
  11. Jan P Tuckermann
  12. Julia von Maltzahn
  13. Alain de Bruin
  14. Victor Guryev
  15. Zhao-Qi Wang
  16. Cornelis F Calkhoven
(2018)
Reduced expression of C/EBPβ-LIP extends health- and lifespan in mice
eLife 7:e34985.
https://doi.org/10.7554/eLife.34985

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