L1 drives IFN in senescent cells and promotes age-associated inflammation
| Autor: | Jayakrishna Ambati, Vera Gorbunova, Alberto Caligiana, Nicholas J. Skvir, Stephen L. Helfand, Amy E. Elias, Nicola Neretti, Takahiro Ito, Anna P. Petrashen, Matthew Simon, P. Eline Slagboom, Christian Beauséjour, Marco De Cecco, Jef D. Boeke, John M. Sedivy, Emily M. Adney, Steven W. Criscione, Andrei Seluanov, Greta Brocculi, Oanh Le, Kameshwari Ambati |
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| Přispěvatelé: | De Cecco M., Ito T., Petrashen A.P., Elias A.E., Skvir N.J., Criscione S.W., Caligiana A., Brocculi G., Adney E.M., Boeke J.D., Le O., Beausejour C., Ambati J., Ambati K., Simon M., Seluanov A., Gorbunova V., Slagboom P.E., Helfand S.L., Neretti N., Sedivy J.M. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Senescence Male Aging Down-Regulation Retrotransposon Inflammation Biology Nucleoside Reverse Transcriptase Inhibitor 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Interferon medicine Long Interspersed Nucleotide Element Cellular Senescence Multidisciplinary Animal RNA-Directed DNA Polymerase Reverse transcriptase Cell biology 030104 developmental biology Phenotype Lamivudine Interferon Type I Fibroblast Reverse Transcriptase Inhibitors Female medicine.symptom 030217 neurology & neurosurgery Interferon type I medicine.drug Human |
| Zdroj: | Nature, 566(7742), 73 |
| Popis: | 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. During cellular senescence in human and mouse cells, L1 transposons become transcriptionally derepressed and trigger a type-1 interferon response, which contributes to age-associated inflammation and age-related phenotypes. |
| Databáze: | OpenAIRE |
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