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

Cell Metab. 2019 Apr 2;29(4):871-885.e5. doi: 10.1016/j.cmet.2019.02.014. Epub 2019 Mar 7.

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.

Keywords: SIRT6; aging; longevity; nucleotide reverse-transcriptase inhibitors; retrotransposition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Dideoxynucleotides
  • ECAT11 protein, mouse
  • RNA-Binding Proteins
  • Thymine Nucleotides
  • Zidovudine
  • 3'-azido-3'-deoxythymidine 5'-triphosphate
  • Stavudine
  • Sirt6 protein, mouse
  • Sirtuins