L1 Drives IFN in Senescent Cells and Promotes Age-Associated Inflammation

Nature. 2019 Feb;566(7742):73-78. doi: 10.1038/s41586-018-0784-9. Epub 2019 Feb 6.

Abstract

Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

Publication types

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

MeSH terms

  • Aging / genetics
  • Aging / pathology
  • Animals
  • Cellular Senescence / genetics*
  • Down-Regulation
  • Female
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Inflammation / genetics*
  • Inflammation / pathology
  • Interferon Type I / metabolism*
  • Lamivudine / pharmacology
  • Long Interspersed Nucleotide Elements / genetics*
  • Male
  • Mice
  • Phenotype
  • RNA-Directed DNA Polymerase / genetics
  • RNA-Directed DNA Polymerase / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology

Substances

  • Interferon Type I
  • Reverse Transcriptase Inhibitors
  • Lamivudine
  • RNA-Directed DNA Polymerase