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

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 Beauséjour, Jayakrishna Ambati, Kameshwari Ambati, Matthew Simon, Andrei Seluanov, Vera Gorbunova, P. Eline Slagboom, Stephen L. Helfand, Nicola Neretti and John M. Sedivy ()
Additional contact information
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
Greta Brocculi: Brown University
Emily M. Adney: NYU Langone Health
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
John M. Sedivy: Brown University

Nature, 2019, vol. 566, issue 7742, 73-78

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-018-0784-9

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