RT Journal Article
SR Electronic
T1 Inhibition of retrotransposition improves health and extends lifespan of SIRT6 knockout mice
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 460808
DO 10.1101/460808
A1 Matthew Simon
A1 Michael Van Meter
A1 Julia Ablaeva
A1 Zhonghe Ke
A1 Raul S. Gonzalez
A1 Taketo Taguchi
A1 Marco De Cecco
A1 Katerina I. Leonova
A1 Valeria Kogan
A1 Stephen L. Helfand
A1 Nicola Neretti
A1 Asael Roichman
A1 Haim Y. Cohen
A1 Marina Antoch
A1 Andrei Gudkov
A1 John M. Sedivy
A1 Andrei Seluanov
A1 Vera Gorbunova
YR 2018
UL http://biorxiv.org/content/early/2018/11/04/460808.abstract
AB 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