The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function

  1. Zachary Clemens
  2. Sruthi Sivakumar
  3. Abish Pius
  4. Amrita Sahu
  5. Sunita Shinde
  6. Hikaru Mamiya
  7. Nathaniel Luketich
  8. Jian Cui
  9. Purushottam Dixit
  10. Joerg D Hoeck
  11. Sebastian Kreuz
  12. Michael Franti
  13. Aaron Barchowsky
  14. Fabrisia Ambrosio  Is a corresponding author
  1. University of PIttsburgh, United States
  2. University of Pittsburgh, United States
  3. University of Florida, United States
  4. Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
  5. Boehringer Ingelheim Pharma GmbH & Co. KG, United States

Abstract

Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

Data availability

Sequencing data has been deposited in GEO accession: GSE156343.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Zachary Clemens

    Department of Physical Medicine and Rehabilitation, University of PIttsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2230-9151
  2. Sruthi Sivakumar

    Department of BIoengineering, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0649-8551
  3. Abish Pius

    Department of Physical Medicine and Rehabilitation, Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  4. Amrita Sahu

    Department of PHysical Medicine and Rehabilitation, University of PIttsburgh, PIttsburgh, United States
    Competing interests
    No competing interests declared.
  5. Sunita Shinde

    Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  6. Hikaru Mamiya

    Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  7. Nathaniel Luketich

    Department of BIoengineering, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  8. Jian Cui

    Department of Computational and Systems Biology, University of PIttsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
  9. Purushottam Dixit

    University of Florida, Gainesville, United States
    Competing interests
    No competing interests declared.
  10. Joerg D Hoeck

    Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
    Competing interests
    Joerg D Hoeck, J.H. is an employee of Boehringer INgelheim Pharmaceutical Company.
  11. Sebastian Kreuz

    Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany
    Competing interests
    Sebastian Kreuz, S.K. is an employee of Boehringer INgelheim Pharmaceutical Company.
  12. Michael Franti

    Boehringer Ingelheim Pharma GmbH & Co. KG, Boston, United States
    Competing interests
    Michael Franti, M.F. is an employee of Boehringer Ingelheim Pharmaceutical Company.
  13. Aaron Barchowsky

    Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1268-8159
  14. Fabrisia Ambrosio

    Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, United States
    For correspondence
    ambrosiof@upmc.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5497-5968

Funding

National Institute on Aging (R01AG052978)

  • Fabrisia Ambrosio

National Institute on Aging (R01AG061005)

  • Fabrisia Ambrosio

Boehringer Ingelheim

  • Fabrisia Ambrosio

J.H., S.K. and M.F. are employees of Boehringer Ingelheim Pharmaceutical Company. They contributed to development, testing and validation of the AAV-Klotho vector, as well as the overall study design.

Ethics

Animal experimentation: All animal experiments were performed with prior approval from the Institutional Animal Care and Use Committee of the University of Pittsburgh. These experiments were conducted in accordance with protocol 17080802 (University of Pittsburgh ARO: IS00017744). All surgeries and invasive procedures were performed under isoflurane anesthesia, with painkillers administered afterwards. Every effort was made to minimize suffering.

Reviewing Editor

  1. Yousin Suh, Columbia University, United States

Publication history

  1. Received: July 16, 2020
  2. Accepted: April 6, 2021
  3. Accepted Manuscript published: April 20, 2021 (version 1)
  4. Version of Record published: May 13, 2021 (version 2)

Copyright

© 2021, Clemens 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. Zachary Clemens
  2. Sruthi Sivakumar
  3. Abish Pius
  4. Amrita Sahu
  5. Sunita Shinde
  6. Hikaru Mamiya
  7. Nathaniel Luketich
  8. Jian Cui
  9. Purushottam Dixit
  10. Joerg D Hoeck
  11. Sebastian Kreuz
  12. Michael Franti
  13. Aaron Barchowsky
  14. Fabrisia Ambrosio
(2021)
The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function
eLife 10:e61138.
https://doi.org/10.7554/eLife.61138

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