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Nature. 2019 Feb;566(7742):73-78. doi: 10.1038/s41586-018-0784-9. Epub 2019 Feb 6.

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

Author information

1
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA.
2
Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy.
3
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Langone Health, New York, NY, USA.
4
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5
Centre de Recherche CHU Ste-Justine, and Department of Pharmacology and Physiology, Université de Montréal, Montréal, Québec, Canada.
6
Center for Advanced Vision Science and Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
7
Department of Biology, University of Rochester, Rochester, NY, USA.
8
Department of Molecular Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.
9
Center for Computational Molecular Biology, Brown University, Providence, RI, USA.
10
Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI, USA. john_sedivy@brown.edu.

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.

PMID:
30728521
PMCID:
PMC6519963
DOI:
10.1038/s41586-018-0784-9
[Indexed for MEDLINE]
Free PMC Article

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