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

Lu, Yu-Xuan, Regan, Jennifer C, Eßer, Jacqueline, Drews, Lisa F, Weinseis, Thomas, Stinn, Julia, Hahn, Oliver, Miller, Richard A, Grönke, Sebastian, Partridge, Linda·2021·eLife
DOI 10.7554/elife.62233PMC PMC8186904
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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 organisation, induces intestinal autophagy through transcriptional regulation, and 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 that the mTORC1-histone axis is at least partially conserved in mammals and may offer new targets for anti-ageing interventions.

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  • Aging relies on the integration of cell-autonomous and non-cell-autonomous mechanisms.

    “This type of experiment demonstrates that aging relies on the integration of cell-autonomous and non-cell-autonomous mechanisms”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [52]

    The Results section reports that changing histone expression specifically in fly enterocytes affected intestinal stem-cell proliferation and whole-fly lifespan, supporting a link between changes within cells and effects beyond those cells. The paper does not establish the broader claim that ageing generally relies on the integration of cell-autonomous and non-cell-autonomous mechanisms. No page numbers are available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Increased histone expression extends lifespan in Drosophila.

    “Increased histone expression extends lifespan in Drosophila 52 , while increased histone H4K16 acetylation or H3K4 trimethylation, and decreased levels of H3K9 or H3K27 trimethylation are found in fibroblasts from aged individuals and progeroid patients.”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [52]

  • Increasing autophagy solely in enterocytes of the intestine increases Drosophila lifespan.

    “For example, increasing autophagy solely in the enterocytes of the intestine increases Drosophila lifespan 52 .”

    From Hallmarks of aging: An expanding universe (2023) · cites this paper as [52]

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Metadata

Authors
Lu, Y.-X., Regan, J. C., Eßer, J., Drews, L. F., Weinseis, T., Stinn, J., Hahn, O., Miller, R. A., Grönke, S., & Partridge, L.
Affiliations
  • Max Planck Institute for Biology of Ageing, Cologne, Germany
  • Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, United Kingdom
  • Department of Pathology, University of Michigan, Ann Arbor, United States
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2021-05-14
Volume
10
ISSN
2050-084X
DOI
10.7554/elife.62233
PMC
PMC8186904
Cited by
76
References
19
Language
en
Licence
Funders
  • Horizon 2020 Framework Programme (741989)
  • European Molecular Biology Organization (ALTF419-2014)
  • Glenn Foundation for Medical Research
  • Max Planck Institute for Biology of Ageing (Open-access funding)

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