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L1 drives IFN in senescent cells and promotes age-associated inflammation

Author

Listed:
  • Marco Cecco

    (Brown University)

  • Takahiro Ito

    (Brown University)

  • Anna P. Petrashen

    (Brown University)

  • Amy E. Elias

    (Brown University)

  • Nicholas J. Skvir

    (Brown University)

  • Steven W. Criscione

    (Brown University)

  • Alberto Caligiana

    (Brown University
    University of Bologna)

  • Greta Brocculi

    (Brown University
    University of Bologna)

  • Emily M. Adney

    (NYU Langone Health
    Johns Hopkins University School of Medicine)

  • Jef D. Boeke

    (NYU Langone Health)

  • Oanh Le

    (Université de Montréal)

  • Christian Beauséjour

    (Université de Montréal)

  • Jayakrishna Ambati

    (University of Virginia School of Medicine)

  • Kameshwari Ambati

    (University of Virginia School of Medicine)

  • Matthew Simon

    (University of Rochester)

  • Andrei Seluanov

    (University of Rochester)

  • Vera Gorbunova

    (University of Rochester)

  • P. Eline Slagboom

    (Leiden University Medical Centre)

  • Stephen L. Helfand

    (Brown University)

  • Nicola Neretti

    (Brown University
    Brown University)

  • John M. Sedivy

    (Brown University)

Abstract

Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

Suggested Citation

  • Marco Cecco & Takahiro Ito & Anna P. Petrashen & Amy E. Elias & Nicholas J. Skvir & Steven W. Criscione & Alberto Caligiana & Greta Brocculi & Emily M. Adney & Jef D. Boeke & Oanh Le & Christian Beaus, 2019. "L1 drives IFN in senescent cells and promotes age-associated inflammation," Nature, Nature, vol. 566(7742), pages 73-78, February.
    • Handle: RePEc:nat:nature:v:566:y:2019:i:7742:d:10.1038_s41586-018-0784-9
    DOI: 10.1038/s41586-018-0784-9
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    Citations

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    Cited by:

    1. Bert I. Crawford & Mary Jo Talley & Joshua Russman & James Riddle & Sabrina Torres & Troy Williams & Michelle S. Longworth, 2024. "Condensin-mediated restriction of retrotransposable elements facilitates brain development in Drosophila melanogaster," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Yung-Heng Chang & Josh Dubnau, 2023. "Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Yang Yu & Xin Wang & Jordan Fox & Ruofan Yu & Pilendra Thakre & Brenna McCauley & Nicolas Nikoloutsos & Yang Yu & Qian Li & P. J. Hastings & Weiwei Dang & Kaifu Chen & Grzegorz Ira, 2024. "Yeast EndoG prevents genome instability by degrading extranuclear DNA species," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Alexandra M. D’Ordine & Gerwald Jogl & John M. Sedivy, 2024. "Identification and characterization of small molecule inhibitors of the LINE-1 retrotransposon endonuclease," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Vanessa López-Polo & Mate Maus & Emmanouil Zacharioudakis & Miguel Lafarga & Camille Stephan-Otto Attolini & Francisco D. M. Marques & Marta Kovatcheva & Evripidis Gavathiotis & Manuel Serrano, 2024. "Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Sudip Kumar Paul & Motohiko Oshima & Ashwini Patil & Masamitsu Sone & Hisaya Kato & Yoshiro Maezawa & Hiyori Kaneko & Masaki Fukuyo & Bahityar Rahmutulla & Yasuo Ouchi & Kyoko Tsujimura & Mahito Nakan, 2024. "Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Zhengyi Zhen & Yu Chen & Haiyan Wang & Huanyin Tang & Haiping Zhang & Haipeng Liu & Ying Jiang & Zhiyong Mao, 2023. "Nuclear cGAS restricts L1 retrotransposition by promoting TRIM41-mediated ORF2p ubiquitination and degradation," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Steven Andrew Baker & Shirley Kwok & Gerald J Berry & Thomas J Montine, 2021. "Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation," PLOS ONE, Public Library of Science, vol. 16(2), pages 1-17, February.
    9. Ioana Olan & Masami Ando-Kuri & Aled J. Parry & Tetsuya Handa & Stefan Schoenfelder & Peter Fraser & Yasuyuki Ohkawa & Hiroshi Kimura & Masako Narita & Masashi Narita, 2024. "HMGA1 orchestrates chromatin compartmentalization and sequesters genes into 3D networks coordinating senescence heterogeneity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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