LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.
Age Factors
Animals
Dideoxynucleotides
/ administration & dosage
Female
Inflammation
/ metabolism
Male
Mice
Mice, Inbred Strains
Mice, Knockout
RNA-Binding Proteins
/ antagonists & inhibitors
Sirtuins
/ deficiency
Stavudine
/ administration & dosage
Thymine Nucleotides
/ administration & dosage
Zidovudine
/ administration & dosage
SIRT6
aging
longevity
nucleotide reverse-transcriptase inhibitors
retrotransposition
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
02 04 2019
02 04 2019
Historique:
received:
31
07
2018
revised:
02
11
2018
accepted:
22
02
2019
pubmed:
12
3
2019
medline:
2
6
2020
entrez:
12
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30853213
pii: S1550-4131(19)30120-2
doi: 10.1016/j.cmet.2019.02.014
pmc: PMC6449196
mid: NIHMS1522926
pii:
doi:
Substances chimiques
Dideoxynucleotides
0
ECAT11 protein, mouse
0
RNA-Binding Proteins
0
Thymine Nucleotides
0
Zidovudine
4B9XT59T7S
zidovudine triphosphate
6RGF96R053
Stavudine
BO9LE4QFZF
Sirt6 protein, mouse
EC 2.4.2.31
Sirtuins
EC 3.5.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
871-885.e5Subventions
Organisme : NIA NIH HHS
ID : R37 AG046320
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG047200
Pays : United States
Organisme : NIAMS NIH HHS
ID : R61 AR076807
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG027237
Pays : United States
Organisme : NIA NIH HHS
ID : R37 AG016694
Pays : United States
Organisme : NIA NIH HHS
ID : DP1 AG047745
Pays : United States
Organisme : NIA NIH HHS
ID : P01 AG051449
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG046320
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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