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...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Cell metabolism Ročník 29; číslo 4; s. 871
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 02.04.2019
Témata:	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
On-line přístup:	Zjistit podrobnosti o přístupu
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1932-7420 1932-7420
DOI:	10.1016/j.cmet.2019.02.014