Downregulation of the tyrosine degradation pathway extends Drosophila lifespan

  1. Andrey A Parkhitko  Is a corresponding author
  2. Divya Ramesh
  3. Lin Wang
  4. Dmitry Leshchiner
  5. Elizabeth Filine
  6. Richard Binari
  7. Abby L Olsen
  8. John M Asara
  9. Valentin Cracan
  10. Joshua D Rabinowitz
  11. Axel Brockmann
  12. Norbert Perrimon  Is a corresponding author
  1. Harvard Medical School, United States
  2. National Centre for Biological Sciences, India
  3. Lewis-Sigler Institute for Integrative Genomics, Princeton University, United States
  4. Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, United States
  5. Beth Israel Deaconess Medical Center, United States
  6. Scintillon Institute, United States
  7. Princeton University, United States

Abstract

Aging is characterized by extensive metabolic reprogramming. To identify metabolic pathways associated with aging, we analyzed age-dependent changes in the metabolomes of long-lived Drosophila melanogaster. Among the metabolites that changed, levels of tyrosine were increased with age in long-lived flies. We demonstrate that the levels of enzymes in the tyrosine degradation pathway increase with age in wild-type flies. Whole-body and neuronal-specific downregulation of enzymes in the tyrosine degradation pathway significantly extends Drosophila lifespan, causes alterations of metabolites associated with increased lifespan, and upregulates the levels of tyrosine-derived neuromediators. Moreover, feeding wild-type flies with tyrosine increased their lifespan. Mechanistically, we show that suppression of ETC complex I drives the upregulation of enzymes in the tyrosine degradation pathway, an effect that can be rescued by tigecycline, an FDA-approved drug that specifically suppresses mitochondrial translation. In addition, tyrosine supplementation partially rescued lifespan of flies with ETC complex I suppression. Altogether, our study highlights the tyrosine degradation pathway as a regulator of longevity.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Additional metabolomics data are available upon request.

The following previously published data sets were used

Article and author information

Author details

  1. Andrey A Parkhitko

    Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
    For correspondence
    aparkhitko@genetics.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9852-8329
  2. Divya Ramesh

    Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1387-7832
  3. Lin Wang

    Department of Chemistry, Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dmitry Leshchiner

    Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elizabeth Filine

    Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Richard Binari

    Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Abby L Olsen

    Department of Neurology, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. John M Asara

    Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Valentin Cracan

    Department of Chemistry, Scintillon Institute, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Joshua D Rabinowitz

    Department of Chemistry, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Axel Brockmann

    Tata Institute of Fundamental Research, National Centre for Biological Sciences, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  12. Norbert Perrimon

    Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, United States
    For correspondence
    perrimon@receptor.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7542-472X

Funding

NIA (K99/R00 AG057792)

  • Andrey A Parkhitko

NIH (5P01CA120964)

  • Norbert Perrimon

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

Reviewing Editor

  1. Pankaj Kapahi, Buck Institute for Research on Aging, United States

Version history

  1. Received: April 19, 2020
  2. Accepted: November 28, 2020
  3. Accepted Manuscript published: December 15, 2020 (version 1)
  4. Version of Record published: December 16, 2020 (version 2)

Copyright

© 2020, Parkhitko 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. Andrey A Parkhitko
  2. Divya Ramesh
  3. Lin Wang
  4. Dmitry Leshchiner
  5. Elizabeth Filine
  6. Richard Binari
  7. Abby L Olsen
  8. John M Asara
  9. Valentin Cracan
  10. Joshua D Rabinowitz
  11. Axel Brockmann
  12. Norbert Perrimon
(2020)
Downregulation of the tyrosine degradation pathway extends Drosophila lifespan
eLife 9:e58053.
https://doi.org/10.7554/eLife.58053

Share this article

https://doi.org/10.7554/eLife.58053

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