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. Simon et al. show that LINE1 retrotransposon elements are derepressed in aged and progeroid mice. Cytoplasmic accumulation of LINE1 cDNA copies induced a type I interferon response, through the cGAS DNA sensing pathway, resulting in pathological inflammation. Inhibiting L1 replication significantly improved the health and lifespan of aged mice.
| Original language | English |
|---|---|
| Pages (from-to) | 871-885.e5 |
| Journal | Cell Metabolism |
| Volume | 29 |
| Issue number | 4 |
| DOIs | |
| State | Published - 2 Apr 2019 |
Bibliographical note
Publisher Copyright:© 2019 Elsevier Inc.
Funding
We thank Jef Boeke and Emily Adney for the ORF1p antibody. This work was supported by grants from the NIH, USA to S.L.H. J.M.S. A.S. A.V.G. and V.G.; Roswell Park Alliance Foundation to A.V.G.; and Life Extension Foundation to A.S. and V.G. M.S. A.S. and V.G. designed research and wrote the manuscript with input from all authors. M.S. performed all experiments related to L1 activity, DNA damage, and mouse phenotypic characterization. M.V.M. performed initial experiments described in Figure 1; J.A. performed mouse NRTI treatment and mouse pathology analysis; Z.K. performed analysis of stem cells; R.S.G. performed pathology evaluation of tissues; T.T. synthesized Methyl D4T; M.D.C. contributed to qRT-PCR analysis and performed in situ staining for ORF2; K.I.L. performed analysis of cytokine arrays; V.K. and N.N. contributed to bioinformatics analysis; S.L.H. contributed to data analysis; A.R. and H.Y.C. provided tissues from MOSES mice; M.V.M. and V.N.G. performed the analysis of methylation clock; and M.P.A. A.V.G. and J.M.S. performed NRTI treatment of aged mice, and analysis of cytokines and p16 expression (M.P.A. and A.V.G.), and contributed to study design, discussion, manuscript writing, and data analysis. The authors declare no competing interests. We thank Jef Boeke and Emily Adney for the ORF1p antibody. This work was supported by grants from the NIH , USA to S.L.H., J.M.S., A.S., A.V.G., and V.G.; Roswell Park Alliance Foundation to A.V.G.; and Life Extension Foundation to A.S. and V.G.
| Funders | Funder number |
|---|---|
| Life Extension Foundation | |
| National Institutes of Health | |
| National Institute on Aging | P01AG047200 |
| Roswell Park Alliance Foundation, Roswell Park Cancer Institute | |
| Norges Idrettshøgskole |
Keywords
- SIRT6
- aging
- longevity
- nucleotide reverse-transcriptase inhibitors
- retrotransposition