A TORC1-histone axis regulates chromatin organisation and non-canonical induction of autophagy to ameliorate ageing
- Max Planck Institute for Biology of Ageing, Germany
- University College London, United Kingdom
- 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.
Article and author information
Author details
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.
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.
Metrics
-
- 9,467
- views
-
- 1,188
- downloads
-
- 53
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Cell Biology
Oscillations in insulin secretion, driven by islet Ca2+ waves, are crucial for glycemic control. Prior studies, performed with single-plane imaging, suggest that subpopulations of electrically coupled β-cells have privileged roles in leading and coordinating the propagation of Ca2+ waves. Here, we used three-dimensional (3D) light-sheet imaging to analyze the location and Ca2+ activity of single β-cells within the entire islet at >2 Hz. In contrast with single-plane studies, 3D network analysis indicates that the most highly synchronized β-cells are located at the islet center, and remain regionally but not cellularly stable between oscillations. This subpopulation, which includes ‘hub cells’, is insensitive to changes in fuel metabolism induced by glucokinase and pyruvate kinase activation. β-Cells that initiate the Ca2+ wave (leaders) are located at the islet periphery, and strikingly, change their identity over time via rotations in the wave axis. Glucokinase activation, which increased oscillation period, reinforced leader cells and stabilized the wave axis. Pyruvate kinase activation, despite increasing oscillation frequency, had no effect on leader cells, indicating the wave origin is patterned by fuel input. These findings emphasize the stochastic nature of the β-cell subpopulations that control Ca2+ oscillations and identify a role for glucokinase in spatially patterning ‘leader’ β-cells.
-
- Cell Biology
Functional subpopulations of β-cells emerge to control pulsative insulin secretion in the pancreatic islets of mice through calcium oscillations.
