LINE1 Derepression in aged wild-type and SIRT6-deficient mice drives inflammation
Open accessAbstract
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.
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Repeated triggering of the RCM response disrupts youthful gene expression and releases retrotransposons, including those normally silenced by SIRT1 and SIRT6.
“Studies of these proteins indicate that repeated triggering of the RCM response disrupts youthful gene expression patterns and liberates retrotransposons, such as those silenced by SIRT1/SIRT6 (De Cecco et al., 2019; Oberdoerffer et al., 2008; Simon et al., 2019).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Simon et al., 2019
The Discussion reports elevated LINE1 expression in aged wild-type and SIRT6-deficient mice and suggests that loss of silencing or redistribution of chromatin modifiers such as SIRT1 and SIRT6 may explain its activation. It does not establish that repeated triggering of an RCM response disrupts youthful gene-expression patterns or causes retrotransposon release. The indexed passages provide section labels but no page numbers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredNucleoside reverse-transcriptase inhibitors, which block retrotransposition of transposable elements, reduce the detrimental SASP effects of senescence and improve chronic inflammation in aged animals.
“Treatment with nucleoside reverse-transcriptase inhibitors, which inhibit retrotransposition of transposable elements, limits the senescence-associated detrimental effects of SASP and ameliorates chronic inflammation in aged animals62,119.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [119]
In Results (‘L1 misexpression and sterile inflammation in aged mice’), d4T treatment significantly reduced type I interferons in several tissues of aged wild-type mice, supporting the inflammation claim. The paper reports only a trend toward lower plasma levels of SASP-associated cytokines, however, so the claim that treatment limits the detrimental effects of SASP is stronger than the reported finding. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIn aged mouse tissues, SIRT6 is lost from L1 elements, likely due to increased recruitment to sites of oxidative DNA damage, and its overexpression opposes age-related increases of L1 expression in diverse tissues.
“In aged mouse tissues, SIRT6 is lost from L1 elements, likely due to increased recruitment to sites of oxidative DNA damage, and its overexpression opposes age-related increases of L1 expression in diverse tissues34.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
The Results section reports that SIRT6 overexpression prevented the age-related increase in L1 transcription in aged mouse livers, but it does not establish this effect across diverse tissues. The Discussion suggests that redistribution of chromatin modifiers such as SIRT6 may contribute to L1 activation; it does not report SIRT6 loss from L1 elements in aged tissues or attribute such loss to recruitment to oxidative DNA-damage sites. No page numbers are available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredTreatment with NRTIs that inhibit L1 reverse transcriptase, or knockdown of L1 expression with shRNAs against active L1 families, decreased cytoplasmic L1 DNAs and ameliorated cGAS and IFN-I activation.
“Importantly, treatment with nucleoside reverse transcriptase inhibitor (NRTI) drugs that inhibit L1 reverse transcriptase, or a knockdown of L1 expression with shRNAs against active L1 families, decreased cytoplasmic L1 DNAs and ameliorated cGAS and IFN-I activation33, 34, 92.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
The Results sections on L1 inhibition and the interferon response report that RNAi targeting active L1 families reduced L1 RNA, while both L1 RNAi and NRTI treatment rescued IFN-α and IFN-β1 expression. The Discussion says NRTIs rescued cytoplasmic L1 accumulation, and the Results link cytoplasmic L1 DNA to cGAS signaling. Our copy does not show that L1-targeting RNAi reduced cytoplasmic L1 DNA or that either intervention directly reduced cGAS activation; those parts are stronger than the reported results (page numbers unavailable). (LLM, conf=0.83)
Experimental — accuracy not yet measuredTreatment of middle-aged normal mice with NRTIs retarded the progression of aging biomarkers, in particular DNA methylation age and p16INK4A expression.
“Treatment of middle-aged normal mice with NRTIs retarded the progression of aging biomarkers, in particular DNA methylation age and p16INK4A expression34.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
The Results section (page unavailable) reports lower DNA methylation age in d4T-treated mice and a difference in the p16 reporter in female wild-type mice treated from 46 weeks of age. The p16 difference was not statistically significant in males, and the paper reports a treatment-group difference in methylation age rather than directly measuring a slower rate of progression for that biomarker. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Cytoplasmic L1 DNA was found in normal cells in association with cellular senescence and aging.
“Recently, cytoplasmic L1 DNA was found in normal cells in association with cellular senescence and aging33, 34.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
The Results section, “L1 misexpression and sterile inflammation in aged mice coincide with cytoplasmic L1 DNA” (page unavailable), reports increased cytoplasmic L1 DNA in aged wild-type mice, supporting its association with normal aging. The paper discusses cellular senescence and reports changes in the p16 senescence marker, but the cited passages do not show cytoplasmic L1 DNA specifically in senescent normal cells. (LLM, conf=0.82)
Experimental — accuracy not yet measuredLoss of heterochromatin factors reduces heterochromatin at retrotransposons and allows their transcriptional derepression.
“Loss of these factors reduces heterochromatin at retrotransposons and allows their transcriptional derepression26, 29, 31, 33–35.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
L1 DNA was identified in association with the DNA sensor cGAS.
“Importantly, L1 DNA was identified in association with the DNA sensor cGAS34.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
In mice, treatment with NRTIs doubled the lifespan of progeroid SIRT6-deficient mice and improved overall health including bone density, muscle mass, intestinal function and exercise performance.
“In mice, treatment with NRTIs doubled the lifespan of progeroid SIRT6-deficient mice, and improved overall health including bone density, muscle mass, intestinal function and exercise performance34.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [34]
SIRT6-deficient mice display accelerated aging phenotypes and have increased L1 expression in a number of tissues.
“Consistent with this, SIRT6-deficient mice, which display accelerated aging phenotypes, have increased L1 expression in a number of tissues (Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
Increased cytosolic L1 DNA and expression of IFN genes have been observed in a number of tissues of aged mice.
“Interestingly, increased cytosolic L1 DNA and expression of IFN genes has been observed in a number of tissues of aged mice (De Cecco et al., 2019; Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
Similar improvements in healthspan have been observed in SIRT6 knockout progeroid mice treated with NRTIs.
“Similar improvements in healthspan have also been observed in SIRT6 knockout progeroid mice treated with NRTIs (Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
Immunoprecipitation analysis of these cells showed an increase in the abundance of L1 DNA bound to cGAS, corroborating that L1 DNA in the cytosol binds to cGAS and activates an IFN-I response.
“Immunoprecipitation analysis of these cells showed an increase in the abundance of L1 DNA bound to cGAS, corroborating that L1 DNA in the cytosol binds to cGAS and activates an IFN-I response (Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
Activation of retrotransposon contributes to age-associated chronic inflammation.
“Activation of retrotransposon has also been shown to contribute to age-associated chronic inflammation (De Cecco et al., 2019; Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
NRTIs abrogate the accumulation of cytoplasmic L1 DNA in senescent cells.
“In addition, NRTIs have been shown to abrogate the accumulation of cytoplasmic L1 DNA in senescent cells (De Cecco et al., 2019; Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
Treating aged mice with NRTIs effectively reduces L1 cytoplasmic DNA and the ensuing inflammation in a variety of tissues, and improves age-related phenotypes such as tissue macrophage infiltration, glomerulosclerosis of the kidney, and skeletal muscle atrophy.
“Indeed, treating aged mice with NRTIs effectively reduced L1 cytoplasmic DNA and the ensuing inflammation in a variety of tissues (De Cecco et al., 2019; Simon et al., 2019), and improved a number of age-related phenotypes, such as tissue macrophage infiltration, glomerulosclerosis of the kidney, and skeletal muscle atrophy (De Cecco et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
SIRT6-knockout mouse fibroblasts display L1 activation, accumulation of cytoplasmic L1 cDNA and increased expression of type I IFN genes.
“Consistent with this, SIRT6-knockout mouse fibroblasts display L1 activation, accumulation of cytoplasmic L1 cDNA and increased expression of type I IFN genes (Simon et al., 2019).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Simon et al., 2019
L1 activation results in cDNA accumulation in the cytoplasm that reinforces cGAS signaling activation to produce the SASP response in senescent cells and chronic inflammation in aged mice.
“As L1 displays high reverse transcriptase activity, its activation results in cDNA accumulation in the cytoplasm that reinforces cGAS signaling activation to produce the SASP response in senescent cells and chronic inflammation in aged mice [177,178].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [178]
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Self-citationChronic inflammation and the hallmarks of aging
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Mechanisms and Regulation of Cellular Senescence
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Resurrection of endogenous retroviruses during aging reinforces senescence
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Cytoplasmic DNA: sources, sensing, and role in aging and disease
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The World Goes Bats: Living Longer and Tolerating Viruses
Gorbunova, V., Seluanov, A., & Kennedy, B. K. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.06.013 · Cited by 162 · see citing works
Self-citationMechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
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Targeting aging mechanisms: pharmacological perspectives
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The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
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The role of cellular senescence and SASP in tumour microenvironment
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Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication
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The Information Theory of Aging
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Transposon-triggered innate immune response confers cancer resistance to the blind mole rat
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Self-citationChung, S., Jeong, J.-H., Park, J.-C., Han, J. W., Lee, Y., Kim, J.-I., & Mook-Jung, I. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01295-y · Cited by 103 · see citing works
“Furthermore, the relationship between microglial APOE4 and the cGAS-STING pathway in AD has not been previously reported.”
InfluentialChromatin basis of the senescence-associated secretory phenotype
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SIRT7 mediates L1 elements transcriptional repression and their association with the nuclear lamina
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Detection of senescence using machine learning algorithms based on nuclear features
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Repetitive elements in aging and neurodegeneration
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Cytoplasmic chromatin fragments-from mechanisms to therapeutic potential.
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The struggle of a good friend getting old: cellular senescence in viral responses and therapy
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The functional impact of nuclear reorganization in cellular senescence
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Self-citationErosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals
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Self-citationResveratrol blocks retrotransposition of LINE-1 through PPAR α and sirtuin-6
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- Authors
- Simon, M., Van Meter, M., Ablaeva, J., Ke, Z., Gonzalez, R. S., Taguchi, T., De Cecco, M., Leonova, K. I., Kogan, V., Helfand, S. L., Neretti, N., Roichman, A., Cohen, H. Y., Meer, M. V., Gladyshev, V. N., Antoch, M. P., Gudkov, A. V., Sedivy, J. M., Seluanov, A., & Gorbunova, V.
- Affiliations
- University of Rochester (US)
- Roswell Park Comprehensive Cancer Center (US)
- Ariel University (IL)
- Brown University (US)
- Bar-Ilan University (IL)
- Brigham and Women's Hospital (US)
- Corresponding author
- Seluanov, Andrei
- Gorbunova, Vera
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-04
- Volume
- 29
- Issue
- 4
- Pages
- 871-885.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6449196
- OpenAlex
- W2921681769
- Cited by
- 498
- References
- 54
- Citations by year
- 2026: 73 · 2025: 80 · 2024: 75 · 2023: 66 · 2022: 78 · 2021: 60 · 2020: 45 · 2019: 19 · 2018: 2
- FWCI
- 26.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH
- Roswell Park Alliance Foundation
- Life Extension Foundation
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- aging, sterile inflammation, type I interferon response, cGAS, nucleoside reverse transcriptase inhibitors, DNA damage, lifespan, age-related diseases
- MeSH terms
- Age Factors, Animals, Female, Inflammation, Male, Mice, Inbred Strains, Thymine Nucleotides, Zidovudine, RNA-Binding Proteins, Stavudine, Mice, Knockout, Sirtuins, Mice, Dideoxynucleotides
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