@article {Simon460808, author = {Matthew Simon and Michael Van Meter and Julia Ablaeva and Zhonghe Ke and Raul S. Gonzalez and Taketo Taguchi and Marco De Cecco and Katerina I. Leonova and Valeria Kogan and Stephen L. Helfand and Nicola Neretti and Asael Roichman and Haim Y. Cohen and Marina Antoch and Andrei Gudkov and John M. Sedivy and Andrei Seluanov and Vera Gorbunova}, title = {Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice}, elocation-id = {460808}, year = {2018}, doi = {10.1101/460808}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6 deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA which triggers massive type I interferon response via activation of cGAS. Remarkably, nucleoside reverse transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number and type I interferons were elevated in the wild type aged mice. As sterile inflammation is a hallmark of aging we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.HighlightsSIRT6 KO mice accumulate L1 cDNA triggering type I interferon response via cGAS pathwayWild type aged mice accumulate L1 cDNA and display type I interferon responseReverse transcriptase inhibitors rescue type I interferon response and DNA damageReverse transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice}, URL = {https://www.biorxiv.org/content/early/2018/11/04/460808}, eprint = {https://www.biorxiv.org/content/early/2018/11/04/460808.full.pdf}, journal = {bioRxiv} }