LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.

LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.
Cell Metab. 2019 Mar 05;:
Authors: Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, Neretti N, Roichman A, Cohen HY, Meer MV, Gladyshev VN, Antoch MP, Gudkov AV, Sedivy JM, Seluanov A, Gorbunova V
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 strong 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.
PMID: 30853213 [PubMed - as supplied by publisher]

Source: Cell Metabolism - March 4, 2019 Category: Cytology Authors: Simon M, Van Meter M, Ablaeva J, Ke Z, Gonzalez RS, Taguchi T, De Cecco M, Leonova KI, Kogan V, Helfand SL, Neretti N, Roichman A, Cohen HY, Meer MV, Gladyshev VN, Antoch MP, Gudkov AV, Sedivy JM, Seluanov A, Gorbunova V Tags: Cell Metab Source Type: research