@article{70f88fa08efe400aa3f10482388dd155,
title = "L1 drives IFN in senescent cells and promotes age-associated inflammation",
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.",
author = "{De Cecco}, Marco and Takahiro Ito and Petrashen, {Anna P.} and Elias, {Amy E.} and Skvir, {Nicholas J.} and Criscione, {Steven W.} and Alberto Caligiana and Greta Brocculi and Adney, {Emily M.} and Boeke, {Jef D.} and Oanh Le and Christian Beaus{\'e}jour and Jayakrishna Ambati and Kameshwari Ambati and Matthew Simon and Andrei Seluanov and Vera Gorbunova and Slagboom, {P. Eline} and Helfand, {Stephen L.} and Nicola Neretti and Sedivy, {John M.}",
note = "Funding Information: Acknowledgements The following funding sources are acknowledged: M.D., Glenn/AFAR Postdoctoral Fellowship, NIH P20 GM119943 COBRE pilot award; T.I., NIH F31 AG043189; A.P.P. and A.E.E., NIH T32 AG041688; S.W.C., NIH F31 AG050365; A.C. and G.B., Biotechnology and Sport Medicine Fellowships, School of Pharmacy, University of Bologna, Bologna, Italy; E.M.A. and J.D.B., NIH P01 AG051449; C.B., Canadian Institute of Health Research MOP-102709; J.A., NIH DP1 GM114862, R01 EY022238, R01 EY024068, R01 EY028027, John Templeton Foundation Grant ID 60763; M.S., A.S. and V.G., NIH R01 AG046320, R01 AG027237, R01 AG047200, P01 AG051449, Life Extension Foundation; S.L.H., NIH R37 AG016667, R01 AG024353, P01 AG051449, Glenn-AFAR Breakthroughs in Gerontology Award; N.N., NIH R01 AG050582, P20 GM109035; J.M.S., NIH R37 AG016694, P01 AG051449. We are grateful to A. Maier, M. Waaijer, R. Westendorp and the participants of the Leiden Longevity Study (LLS) for assistance with the human specimens. We thank D. Baker for guidance with the glomerulosclerosis assay. The biomaterials collection of the LLS (P.E.S., principal investigator) was supported by the Netherlands Genomics Initiative of the Netherlands Organization for Scientific Research (NWO), within the framework of the Netherlands Consortium of Healthy Ageing (NCHA, 050-060-810) and the Leiden University Medical Center.",
year = "2019",
month = feb,
day = "7",
doi = "10.1038/s41586-018-0784-9",
language = "English (US)",
volume = "566",
pages = "73--78",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "7742",
}