A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing

  1. Yu-Xuan Lu
  2. Jennifer C Regan
  3. Jacqueline Eßer
  4. Lisa F Drews
  5. Thomas Weinseis
  6. Julia Stinn
  7. Oliver Hahn
  8. Richard A Miller
  9. Sebastian Grönke
  10. Linda Partridge  Is a corresponding author
  1. Max Planck Institute for Biology of Ageing, Germany
  2. University College London, United Kingdom
  3. University of Michigan, United States

Abstract

Age-related changes to histone levels are seen in many species. However, it is unclear whether changes to histone expression could be exploited to ameliorate the effects of ageing in multicellular organisms. Here we show that inhibition of mTORC1 by the lifespan-extending drug rapamycin increases expression of histones H3 and H4 post-transcriptionally, through eIF3-mediated translation. Elevated expression of H3/H4 in intestinal enterocytes in Drosophila alters chromatin organization, induces intestinal autophagy through transcriptional regulation, prevents age-related decline in the intestine. Importantly, it also mediates rapamycin-induced longevity and intestinal health. Histones H3/H4 regulate expression of an autophagy cargo adaptor Bchs (WDFY3 in mammals), increased expression of which in enterocytes mediates increased H3/H4-dependent healthy longevity. In mice, rapamycin treatment increases expression of histone proteins and Wdfy3 transcription, and alters chromatin organisation in the small intestine, suggesting the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

Data availability

Sequencing data have been deposited in GEO under accession code GSE148002.

The following data sets were generated

Article and author information

Author details

  1. Yu-Xuan Lu

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6751-5250
  2. Jennifer C Regan

    Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Jacqueline Eßer

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Lisa F Drews

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Thomas Weinseis

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Julia Stinn

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Oliver Hahn

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Richard A Miller

    University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sebastian Grönke

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1539-5346
  10. Linda Partridge

    Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany
    For correspondence
    Linda.Partridge@age.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9615-0094

Funding

Horizon 2020 Framework Programme (GEROPROTECT project,741989)

  • Linda Partridge

European Molecular Biology Organization (EMBO Long-Term Fellowship,ALTF419-2014)

  • Yu-Xuan Lu

Glenn Foundation for Medical Research

  • Richard A Miller

Max Planck Institute for Biology of Ageing (Open-access funding)

  • Linda Partridge

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

Ethics

Animal experimentation: The work on mice at Michigan was reviewed and approved by the Institutional Animal Care and Use Committee. The original protocol was PRO00008130, approved February 13, 2018. This was renewed as Protocol PRO00009981 on December 7, 2020.

Reviewing Editor

  1. Weiwei Dang, Baylor College of Medicine, United States

Publication history

  1. Received: August 19, 2020
  2. Accepted: May 13, 2021
  3. Accepted Manuscript published: May 14, 2021 (version 1)
  4. Version of Record published: June 8, 2021 (version 2)

Copyright

© 2021, Lu 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. Yu-Xuan Lu
  2. Jennifer C Regan
  3. Jacqueline Eßer
  4. Lisa F Drews
  5. Thomas Weinseis
  6. Julia Stinn
  7. Oliver Hahn
  8. Richard A Miller
  9. Sebastian Grönke
  10. Linda Partridge
(2021)
A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing
eLife 10:e62233.
https://doi.org/10.7554/eLife.62233

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