LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation
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.
From the paper
- Harms
One of the phenotypes of SIRT6 KO mice is hypoglycemia, which was not rescued by NRTI treatment.
Results, NRTI-treatment alleviates progeroid phenotypes and extends lifespan in SIRT6 KO mice
- Limitation
Such copies can potentially arise from reverse transcription in the cytoplasm primed by random RNA fragments or L1 DNAs can escape from the nucleus.
Quoted word for word from the full text on PubMed Central.
The paper
University of Rochester
Cell Metabolism, 7 Mar 2019, Open access
