Abstract

The process wherein dividing cells exhaust proliferative capacity and enter into replicative senescence has become a prominent model for cellular aging in vitro. Despite decades of study, this cellular state is not fully understood in culture and even much less so during aging. Here, we revisit Leonard Hayflick’s original observation of replicative senescence in WI-38 human lung fibroblasts equipped with a battery of modern techniques including RNA-seq, single cell RNA-seq, proteomics, metabolomics, and ATAC-seq. We find evidence that the transition to a senescent state manifests early, increases gradually, and corresponds to a concomitant global increase in DNA accessibility in nucleolar and lamin associated domains. Furthermore, we demonstrate that senescent WI-38 cells acquire a striking resemblance to myofibroblasts in a process similar to the epithelial to mesenchymal transition (EMT) that is regulated by the transcription factors YAP1/TEAD1 and TGF-𝛽2. Lastly, we show that verteporfin inhibition of YAP1/TEAD1 activity in aged WI-38 cells robustly attenuates this gene expression program.

Data availability

Sequencing data have been deposited in GEO under accession code GSE175533.Proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository under accession code EBI PRIDECode for processing and analyzing data modalities have been deposited at https://github.com/dghendrickson/hayflickSource data for figures and analysis have been deposited at https://github.com/dghendrickson/hayflick and/or uploaded as source data files.

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

Article and author information

Author details

  1. Michelle Chan

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Michelle Chan, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  2. Han Yuan

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Han Yuan, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  3. Ilya Soifer

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Ilya Soifer, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  4. Tobias M Maile

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Tobias M Maile, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  5. Rebecca Y Wang

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Rebecca Y Wang, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  6. Andrea Ireland

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Andrea Ireland, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
  7. Jonathon J O'Brien

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Jonathon J O'Brien, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9660-4797
  8. Jérôme Goudeau

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Jérôme Goudeau, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2483-1955
  9. Leanne JG Chan

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Leanne JG Chan, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  10. Twaritha Vijay

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Twaritha Vijay, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  11. Adam Freund

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Adam Freund, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7956-5332
  12. Cynthia Kenyon

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Cynthia Kenyon, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3446-2636
  13. Bryson D Bennett

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Bryson D Bennett, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  14. Fiona E McAllister

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Fiona E McAllister, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  15. David R Kelley

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    David R Kelley, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  16. Margaret Roy

    Calico Life Sciences LLC, South San Francisco, United States
    Competing interests
    Margaret Roy, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  17. Robert L Cohen

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Robert L Cohen, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  18. Arthur D Levinson

    Calico Life Sciences, LLC, South San Francisco, United States
    Competing interests
    Arthur D Levinson, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  19. David Botstein

    Calico Life Sciences, LLC, South San Francisco, United States
    For correspondence
    botstein@calicolabs.com
    Competing interests
    David Botstein, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
  20. David G Hendrickson

    Calico Life Sciences, LLC, South San Francisco, United States
    For correspondence
    dgh@calicolabs.com
    Competing interests
    David G Hendrickson, is affiliated with Calico Life Sciences, LLC. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1884-5234

Funding

The authors are employed by Calico Sciences, and no external funding was received.

Reviewing Editor

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

Publication history

  1. Preprint posted: May 4, 2021 (view preprint)
  2. Received: May 12, 2021
  3. Accepted: January 31, 2022
  4. Accepted Manuscript published: February 4, 2022 (version 1)
  5. Accepted Manuscript updated: February 8, 2022 (version 2)
  6. Version of Record published: March 18, 2022 (version 3)

Copyright

© 2022, Chan 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. Michelle Chan
  2. Han Yuan
  3. Ilya Soifer
  4. Tobias M Maile
  5. Rebecca Y Wang
  6. Andrea Ireland
  7. Jonathon J O'Brien
  8. Jérôme Goudeau
  9. Leanne JG Chan
  10. Twaritha Vijay
  11. Adam Freund
  12. Cynthia Kenyon
  13. Bryson D Bennett
  14. Fiona E McAllister
  15. David R Kelley
  16. Margaret Roy
  17. Robert L Cohen
  18. Arthur D Levinson
  19. David Botstein
  20. David G Hendrickson
(2022)
Novel insights from a multiomics dissection of the Hayflick limit
eLife 11:e70283.
https://doi.org/10.7554/eLife.70283
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