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

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. Remarka...

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Published in:Cell metabolism Vol. 29; no. 4; p. 871
Main Authors: Simon, Matthew, Van Meter, Michael, Ablaeva, Julia, Ke, Zhonghe, Gonzalez, Raul S, Taguchi, Taketo, De Cecco, Marco, Leonova, Katerina I, Kogan, Valeria, Helfand, Stephen L, Neretti, Nicola, Roichman, Asael, Cohen, Haim Y, Meer, Margarita V, Gladyshev, Vadim N, Antoch, Marina P, Gudkov, Andrei V, Sedivy, John M, Seluanov, Andrei, Gorbunova, Vera
Format: Journal Article
Language:English
Published: United States 02.04.2019
Subjects:
Age Factors
Animals
Dideoxynucleotides - administration & dosage
Dideoxynucleotides - pharmacology
Female
Inflammation - metabolism
Male
Mice
Mice, Inbred Strains
Mice, Knockout
RNA-Binding Proteins - antagonists & inhibitors
RNA-Binding Proteins - metabolism
Sirtuins - deficiency
Sirtuins - metabolism
Stavudine - administration & dosage
Stavudine - pharmacology
Thymine Nucleotides - administration & dosage
Thymine Nucleotides - pharmacology
Zidovudine - administration & dosage
Zidovudine - analogs & derivatives
Zidovudine - pharmacology
longevity
nucleotide reverse-transcriptase inhibitors
SIRT6
aging
retrotransposition
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary: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.
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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2019.02.014