The role of retrotransposable elements in ageing and age-associated diseases

In the paper

“Conversely, SINEs are not de-repressed by Dnmt1 deletion or treatment with DNA demethylating drugs and appear to be regulated primarily by histone-methylation41.”

What the sources say

• Supported

  The Results section, “SINE repression does not rely on DNA methylation” (page unavailable), reports no increase in B1 or B2 RNA after Dnmt1 deletion and no increase in B1, B2 or Alu expression after 5-azacytidine treatment. The Results section, “SUV39H1 suppresses pol III occupancy and expression of SINEs” (page unavailable), reports increased SINE expression after histone-methyltransferase inhibition, supporting the stated contrast in the cells studied. (LLM, conf=0.93)

  cites [41] Varshney, D. et al. SINE transcription by RNA polymerase III is suppressed by histone methylation but not by DNA methylation. Nat. Commun. 6, 6569 (2015). source

In the paper

“In mammals, retrotransposons are hypermethylated at CpG sites in adult somatic cells and in many (but not all) cases hypomethylation has been implicated in their de-repression37, 38.”

What the sources say

• ?Not checked — no full text of the sourcecites [37] Karimi, M. M. et al. DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs. Cell Stem Cell 8, 676–687 (2011). source
• Supported

  The Introduction (page unavailable) says that transposable elements are densely methylated in somatic cells and that DNA hypomethylation leads to their de-repression. It also identifies most mammalian transposable elements as retrotransposons; the Methods specify that the study assesses transposon methylation at CpG sites. (LLM, conf=0.90)

  cites [38] Walter, M., Teissandier, A., Pérez-Palacios, R. & Bourc’his, D. An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells. eLife 5, e11418 (2016). source

In the paper

“The human endogenous retrovirus K (HERV-K) appears to have become ‘extinct’ very recently, with the Gorilla genome still harboring some intact insertions21.”

What the sources say

• Supported

  The Significance passage (page not provided) says HML-2 appears functionally extinct in humans and chimpanzees, while gorilla-specific elements show very recent activity. The Results (page not provided) identify a gorilla provirus with full-length open reading frames for all four retroviral genes, supporting the reference to an intact insertion; whether it is infectious remains untested. (LLM, conf=0.86)

  cites [21] Holloway, J. R., Williams, Z. H., Freeman, M. M., Bulow, U. & Coffin, J. M. Gorillas have been infected with the HERV-K (HML-2) endogenous retrovirus much more recently than humans and chimpanzees. Proc. Natl Acad. Sci. USA 116, 1337–1346 (2019). source

In the paper

“LINE-1 (L1) comprises 17% of the human genome (~500,000 copies); however, only some 100–150 evolutionarily recent element copies are full-length and lack mutations that would be expected to affect function10–12.”

What the sources say

• Partly supported

  The Abstract states that L1 comprises 17% of the human genome, and the Results report 90 L1s with intact ORFs in a 95%-complete haploid genome draft. The copy does not give the claimed ~500,000 total copies or establish that 100–150 evolutionarily recent copies are full-length and lack function-affecting mutations. No page numbers are available in the indexed passages. (LLM, conf=0.86)

  cites [10] Brouha, B. et al. Hot L1s account for the bulk of retrotransposition in the human population. Proc. Natl Acad. Sci. USA 100, 5280–5285 (2003). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) states that L1 sequences comprise about 17% of human DNA and that a small number of retrotransposition-competent L1s account for most new insertions. It does not give the claimed ~500,000 total copies or 100–150 evolutionarily recent, full-length copies lacking function-affecting mutations. (LLM, conf=0.86)

  cites [11] Flasch, D. A. et al. Genome-wide de novo L1 retrotransposition connects endonuclease activity with replication. Cell 177, 837–851 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction states that L1 accounts for about 500,000 copies and 17% of the human genome, and that roughly 100 copies in the youngest L1HS subfamily remain retrotransposition-competent. It describes intact L1 elements separately, but does not explicitly say that the counted copies are full-length and lack function-affecting mutations, or give a count of 100–150 for copies meeting those criteria. (LLM, conf=0.84)

  cites [12] Sultana, T. et al. The landscape of L1 retrotransposons in the human genome is shaped by pre-insertion sequence biases and post-insertion selection. Mol. Cell 74, 555–570 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Pioneering work by Stetson et at.53 found that retrotransposon DNA was present in the cytoplasmic fractions of hearts from TREX1 mutant mice. Sequencing showed that L1, SINE, and LTR retrotransposon DNAs were significantly enriched compared to normal mice.”

What the sources say

• Partly supported

  In Results, ‘Identification of endogenous Trex1 DNA substrates’ (page unavailable), the authors describe extracting DNA from hearts under conditions intended to minimize extraction of organelles. They report retroelement-derived fragments among Trex1-knockout heart clones but not wild-type clones, including 12 L1, 10 LTR, and 3 SINE sequences. The copy does not establish that each of the three classes was statistically significantly enriched, so ‘significantly’ overstates the reported comparison. (LLM, conf=0.85)

  cites [53] Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008). This work shows that loss of TREX1 in AGS results in accumulation of retrotransposon single-stranded DNA that drives an IFN-I response, and implicates somatic retrotransposon activation as a causal factor in human disease. sourceExperimental — accuracy not yet measured

In the paper

“The signaling cascades start with a variety of sensors, such as RIG-I (retinoic acid-inducible gene I) and MDA5 (melanoma differentiation-associated protein 5) to detect cytoplasmic dsRNA, cGAS (cyclic GMP-AMP synthase) and AIM2 (absent in melanoma 2) to detect cytoplasmic DNA, and TLRs (toll-like receptors) to detect a variety of nucleic acids in the endosomal compartment91.”

What the sources say

• Supported

  The Immune-Sensing Receptors section identifies endolysosomal TLRs that detect RNA or DNA and cytoplasmic RIG-I and MDA5 that detect forms of double-stranded RNA. The same section identifies cytosolic AIM2 and cGAS as DNA sensors. Page numbers were not supplied with the passages. (LLM, conf=0.94)

  cites [91] Hartmann, G. Nucleic acid immunity. Adv. Immunol. 133, 121–169 (2017). source

In the paper

“Over 120 L1-mediated germline insertions have been linked to cases of human genetic diseases78.”

What the sources say

• Partly supported

  The Abstract reports 124 LINE-1-mediated insertions resulting in human genetic diseases, supporting “over 120.” It does not identify all 124 as germline insertions; the section “New reports of LINE-1-mediated insertions causing Mendelian disorders” also discusses a disease-causing insertion with somatic mosaicism. No page numbers are available in our copy. (LLM, conf=0.86)

  cites [78] Hancks, D. C. & Kazazian, H. H., Jr Roles for retrotransposon insertions in human disease. Mob. DNA 7, 9 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Cytosine methylation tends to decrease slowly with aging over large, gene-poor regions of the genome that are enriched for heterochromatin and repetitive sequences, whereas methylation at gene-associated CpG islands can increase or decrease more dramatically, with pronounced tissue-specific effects70, 71.”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [70] Issa, J. P. Aging and epigenetic drift: a vicious cycle. J. Clin. Invest. 124, 24–29 (2014). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [71] Klutstein, M., Nejman, D., Greenfield, R. & Cedar, H. DNA methylation in cancer and aging. Cancer Res. 76, 3446–3450 (2016). source

In the paper

“Evolutionarily young L1s in human ESCs are bound by the transcription factor YY1 (yin-yang-1) at a site in their 5’ UTR; in neuronal cells loss of this site is associated with hypomethylation and L1 activation46.”

What the sources say

• Supported

  The Figure 5 discussion (p. 8) reports pronounced YY1 binding at the 5′ end of young L1 families in human embryonic stem cells, with reduced binding when the site is disrupted. The Summary (p. 2) reports that a donor L1 lacking the site produced a somatic insertion in a hippocampal neuron and that it and other young L1s with altered YY1 sites were hypomethylated during neurodifferentiation. (LLM, conf=0.91)

  cites [46] Sanchez-Luque, F. J. et al. LINE-1 evasion of epigenetic repression in humans. Mol. Cell 75, 590–604.e12 (2019). source

In the paper

“However, DNA methylation changes are early events in senescence73, whereas retrotransposon activation occurs only much later33.”

What the sources say

• Supported

  The Results section (‘Hypomethylation occurs at late-replicating lamin-associated domains’) reports that hypomethylation was detectable in proliferating cells approaching senescence, before proliferation arrest. This supports the early DNA-methylation claim attributed to this paper; the later retrotransposon-activation claim carries a different citation. (LLM, conf=0.92)

  cites [73] Cruickshanks, H. A. et al. Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013). source
• Supported

  The citation is attached to the claim about late retrotransposon activation, not the separately cited claim about early DNA methylation changes. In “Activation of L1 and interferon in cellular senescence” (page unavailable), the paper describes L1 upregulation as a third, even later phase of senescence and reports a 4–5-fold increase by 16 weeks. (LLM, conf=0.93)

  cites [33] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). This study shows that upregulation of L1 triggers an IFN-I response in senescent cells and aged mice that can be therapeutically ameliorated with NRTIs. source

In the paper

“Retrotransposition during development or adulthood would lead to somatic mosaicism, and has been estimated to occur in adult neurons by qPCR or single-cell genomic studies at varying (but generally low) frequencies (events/cell): < 0.04–0.680, 13.781, 0.58–182, 0.283 and 0.63–1.6684.”

What the sources say

• Supported

  The Results section (‘Somatic L1Hs insertion rate in cortex and caudate neurons’; page unavailable) estimates 0.07 ± 0.15 somatic insertions per neuron after validation. The Discussion describes these events as rare in the adult cortical and caudate neurons studied and contrasts that estimate with a much higher qPCR estimate from bulk brain tissue, supporting the claim that reported frequencies vary. (LLM, conf=0.88)

  cites [80] Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012). source
• Supported

  The citation is attached to the 13.7-events-per-cell estimate. The Results section (page unavailable) reports an estimated 13.7 somatic L1 insertions per hippocampal neuron, based on single-cell sequencing and PCR validation. The sentence’s characterization of the estimates as generally low spans several citations, rather than describing this estimate alone. (LLM, conf=0.93)

  cites [81] Upton, K. R. et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161, 228–239 (2015). source
• Partly supported

  The Introduction reports that L1 retrotransposition creates somatic mosaicism and gives conflicting estimates of L1 insertions in neurons. The section on L1-associated variants estimates 0.58–1 events per cell, but says approximately half of those variants may occur independently of retrotransposition. That estimate therefore cannot be attributed wholly to retrotransposition. (LLM, conf=0.88)

  cites [82] Erwin, J. A. et al. L1-associated genomic regions are deleted in somatic cells of the healthy human brain. Nat. Neurosci. 19, 1583–1591 (2016). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction says retrotransposition occurs in the developing brain, while the Results (‘Corrected RC-seq somatic insertion rates’; page unavailable) reports low somatic L1 insertion estimates from single-neuron studies and its reanalysis. The Discussion says L1 mosaicism is not ubiquitous. These passages support the attributed point about somatic mosaicism and generally low, varying frequencies; they do not establish when insertions found in adult neurons occurred. (LLM, conf=0.90)

  cites [83] Evrony, G. D., Lee, E., Park, P. J. & Walsh, C. A. Resolving rates of mutation in the brain using single-neuron genomics. eLife 5, e12966 (2016). source
• Supported

  The Discussion reports varying estimates from prior qPCR and single-cell studies and gives this paper’s estimate of 0.63–1.66 somatic L1Hs insertions per healthy prefrontal-cortex neuron. The Introduction and Abstract describe somatic retrotransposition as contributing to genomic mosaicism. The paper does not establish when every insertion occurred, but the citing sentence does not require that inference for its adult-neuron frequency estimate. (LLM, conf=0.91)

  cites [84] Zhao, B. et al. Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals. PLoS Genet. 15, e1008043 (2019). source

In the paper

“Cellular senescence is an irreversible arrest of proliferation that can be elicited by a variety of stresses, in particular DNA damage61.”

What the sources say

• Partly supported

  The Definition and Characteristics section describes senescence as a stress-triggered state with prolonged, generally irreversible cell-cycle arrest, and Macromolecular Damage identifies DNA damage as a trigger. The claim omits an important qualification: the Cell-Cycle Arrest section says that cell-cycle re-entry can occur under certain circumstances, particularly in tumor cells. (LLM, conf=0.88)

  cites [61] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). sourceExperimental — accuracy not yet measured

In the paper

“While retrotransposition frequencies in other tissues have not been investigated in detail, they appear to be significantly lower, and hence the adult human brain might be a particularly permissive site for L1 activation84, 85.”

What the sources say

• Supported

  The Results (Genomic patterns of somatic and germline L1Hs insertions; page unavailable) report significantly more somatic L1Hs insertions in prefrontal-cortex neurons than in matched non-brain tissues. The Discussion likewise describes a higher rate in brain than non-brain tissues. The proposed permissiveness of the adult brain is a hedged interpretation consistent with that comparison, not a direct measurement of permissiveness. (LLM, conf=0.90)

  cites [84] Zhao, B. et al. Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals. PLoS Genet. 15, e1008043 (2019). source
• Partly supported

  The tissue-comparison passage (indexed as Abstract; page unavailable) reports significantly higher L1 ORF2 copy number in adult brain samples than in matched heart and liver samples, consistent with the suggestion that brain might be more permissive. But the paper did not measure retrotransposition frequencies across tissues, and its discussion says new events must be identified to establish that endogenous L1s retrotranspose in the brain. The frequency claim therefore goes beyond the evidence. (LLM, conf=0.84)

  cites [85] Coufal, N. G. et al. L1 retrotransposition in human neural progenitor cells. Nature 460, 1127–1131 (2009). This study reports an increase in L1 DNA in adult human neurons and hippocampus and implicates the brain as a particularly permissive organ for L1 activation with age. sourceExperimental — accuracy not yet measured

In the paper

“While senescence has beneficial functions (such as tumor suppression), senescent cells accumulate in most tissues with age, and they are important components of the overall aging process62.”

What the sources say

• Partly supported

  The Abstract says senescent cells accumulate over time and are directly linked to features of natural ageing. The Discovery and detection of SNCs section describes them in numerous aged rodent and primate tissues, but the passages do not establish the stronger claim that they accumulate in most tissues. (LLM, conf=0.83)

  cites [62] Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Retrotransposon activation is found in diverse species, including nematodes67 and Drosophila35, which appear to be devoid of cell senescence.”

What the sources say

• Partly supported

  The Results and Discussion (Figure 2b; page not provided) report an age-related increase in repetitive-element transcripts in C. elegans, supporting the nematode part of the claim. But the paper distinguishes increased transcripts from activation of transposable retrotransposons and does not establish that nematodes lack cellular senescence. The Drosophila part has a separate citation in the citing sentence. (LLM, conf=0.84)

  cites [67] LaRocca, T. J., Cavalier, A. N. & Wahl, D. Repetitive elements as a transcriptomic marker of aging: evidence in multiple datasets and models. Aging Cell 19, e13167 (2020). sourceExperimental — accuracy not yet measured
• Supported

  The Results section ('TE Transposition Increases with Age and Is Delayed by DR'; page not provided) reports a clear age-associated increase in gypsy retrotransposon mobilization in Drosophila. Citation 35 is attached to the Drosophila example; the sentence's characterization of cellular senescence is not specifically attributed to this source. (LLM, conf=0.91)

  cites [35] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl Acad. Sci. USA 113, 11277–11282 (2016). Using chromatin-modifying genetic interventions and NRTI treatments in Drosophila, this study causally links retrotransposon activation with aging. source

In the paper

“Older L1 families are bound by KAP1, and loss of DNMTs increases expression of younger L1s but not older ones24.”

What the sources say

• Partly supported

  The Results section reports that the youngest L1 subfamilies were most up-regulated after DNMT depletion, while older elements were unaffected or only very modestly affected. But the Discussion distinguishes KAP1-restricted older subfamilies from more ancient L1 lineages that lack KAP1 binding, so the claim is too broad about older families. Page numbers are not available in the supplied passages. (LLM, conf=0.87)

  cites [24] Castro-Diaz, N. et al. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev. 28, 1397–1409 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Cancer is characterized by genomic instability and in many cases increased expression of L1 elements86.”

What the sources say

• Partly supported

  The indexed copy (section labelled Abstract; page unavailable) describes genomic alterations in cancer, including somatic L1 insertions and a colorectal tumor with microsatellite instability. It also says DNA methylation suppresses TE RNA expression and is disrupted in cancers, but it does not report that L1 expression itself is increased in many cancer cases. Insertion frequency is not a measure of expression. (LLM, conf=0.84)

  cites [86] Lee, E. et al. Landscape of somatic retrotransposition in human cancers. Science 337, 967–971 (2012). This sequencing study from The Cancer Genome Atlas (TCGA) Research Network reveals the profound activation and retrotransposition of L1s in diverse human cancers. sourceExperimental — accuracy not yet measured

In the paper

“However, senescent cells comprise only a small fraction of cells in aged tissues61 and are unlikely to be responsible for all of the retrotransposon activation that has been observed.”

What the sources say

• ?Could not verify

  Citation 61 is attached to the claim that senescent cells make up only a small fraction of cells in aged tissues. The passages in “Challenges to Detect Senescent Cells in Humans” discuss how difficult these cells are to identify and quantify, but give no estimate of their fraction in aged tissues; searches for a small fraction, rarity, and low abundance found none. The subsequent inference about retrotransposon activation is not directly attached to this citation. (LLM, conf=0.72)

  cites [61] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Genetic interventions that promote heterochromatin formation and/or retrotransposon silencing attenuate age-related increases in retrotransposon expression and, remarkably, can increase life span35.”

What the sources say

• Supported

  The Results section reports that genetic interventions affecting heterochromatin attenuated age-related increases in transposable-element expression in fly lines. The Discussion states that manipulating genes involved in heterochromatin maintenance and transposable-element silencing suppressed age-related expression and extended life span. (LLM, conf=0.93)

  cites [35] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl Acad. Sci. USA 113, 11277–11282 (2016). Using chromatin-modifying genetic interventions and NRTI treatments in Drosophila, this study causally links retrotransposon activation with aging. source

In the paper

“Some evidence suggests that alterations in small RNA pathways occur with age7, 77 and these changes may contribute to increased retrotransposon expression.”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Burns, K. H. Our conflict with transposable elements and its implications for human disease. Annu. Rev. Pathol. 15, 51–70 (2020). source
• Supported

  The Discussion (page not provided) describes an age-related shift in miRNA loading between Ago1 and Ago2. It also reports that loss of Ago2 reduces endo-siRNAs and is correlated with transposon up-regulation, and notes increased transposon expression with age in Ago2 mutants. This supports the claim’s tentative wording in the Drosophila context. (LLM, conf=0.88)

  cites [77] Abe, M. et al. Impact of age-associated increase in 2′-O-methylation of miRNAs on aging and neurodegeneration in Drosophila. Genes Dev. 28, 44–57 (2014). source

In the paper

“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.”

What the sources say

• Partly supported

  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)

  cites [34] Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 (2019). This study shows that upregulation of L1 triggers an IFN-I response in Sirt6-knockout and normal aged mice, and that pathologies and lifespan of Sirt6 progeroid mice can be improved with NRTIs. sourceExperimental — accuracy not yet measured

In the paper

“However, the majority of de novo insertions in cancers are located in non-coding sequences and do not show hotspots near tumor suppressor or oncogene loci7, 90.”

What the sources say

• ?Not checked — no full text of the sourcecites [7] Burns, K. H. Our conflict with transposable elements and its implications for human disease. Annu. Rev. Pathol. 15, 51–70 (2020). source
• ?Could not verify

  The Introduction (page not provided) says L1HS can mobilize in many cancers, but does not describe where the new insertions occur. Searches for non-coding locations and hotspots near tumor-suppressor or oncogene loci found no passage addressing either part of the claim. (LLM, conf=0.73)

  cites [90] Mir, A. A., Philippe, C. & Cristofari, G. euL1db: the European database of L1HS retrotransposon insertions in humans. Nucleic Acids Res. 43, D43–D47 (2015). sourceExperimental — accuracy not yet measured

In the paper

“L1s are hypomethylated and their transcripts increased in patients with systemic lupus erythematosus (SLE) and Sjogren’s syndrome114, disorders also characterized by IFN-I induction.”

What the sources say

• Partly supported

  The Introduction reports increased L1 expression in Sjögren’s salivary-gland tissue and lupus kidney tissue, linked to type I interferon production. Results §3.1 reports reduced L1 promoter methylation in low-risk Sjögren’s patients and reduced methylation at several L1 sites in lupus blood. The claim omits the Sjögren’s subgroup distinction: methylation was not significantly reduced in the high-risk or lymphoma groups compared with controls. (LLM, conf=0.84)

  cites [114] Mavragani, C. P. et al. Defective regulation of L1 endogenous retroelements in primary Sjogren’s syndrome and systemic lupus erythematosus: role of methylating enzymes. J. Autoimmun. 88, 75–82 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Retrotransposon activation in Drosophila has been clearly linked with DNA damage, which is alleviated by interventions such as promotion of heterochromatin35, 59, 60.”

What the sources say

• Partly supported

  The Results section reports more DNA double-strand breaks in Dicer-2 mutant flies with disrupted TE silencing, and the Discussion describes an association between age-related TE mobilization and DNA damage. The paper shows that interventions affecting heterochromatin attenuate TE expression, but it does not show that those interventions alleviate DNA damage; the Abstract presents damage prevention as a possibility. (LLM, conf=0.84)

  cites [35] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl Acad. Sci. USA 113, 11277–11282 (2016). Using chromatin-modifying genetic interventions and NRTI treatments in Drosophila, this study causally links retrotransposon activation with aging. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (“DNA damage and metabolic dysregulation in piRNA mutants”; page not provided) reports increased DNA-damage-marker staining in piwi mutants and says TE reactivation may cause the damage. The paper also describes heterochromatin-mediated TE silencing, but does not show that promoting heterochromatin alleviates DNA damage. (LLM, conf=0.85)

  cites [59] Jones, B. C. et al. A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. Nat. Commun. 7, 13856 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on DNA damage in old Drosophila fat bodies reports that retrotransposon expression correlates with DNA-damage foci, and that repressing retrotransposons through AGO2 reduces those foci. Another Results section reports reduced foci after lamin-B (LAM) expression, while the heterochromatin analysis links LAM loss to reduced heterochromatin. The paper does not directly show that promoting heterochromatin alleviates DNA damage, and it presents the retrotransposon–damage mechanism as suggestive rather than definitively established. (LLM, conf=0.85)

  cites [60] Chen, H., Zheng, X., Xiao, D. & Zheng, Y. Age-associated de-repression of retrotransposons in the Drosophila fat body, its potential cause and consequence. Aging Cell 15, 542–552 (2016). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Partly supported

  In ‘Consequences of L1 activation’ (page unavailable), the paper reports that 3TC or L1 shRNA nearly blocked cytoplasmic L1 DNA synthesis and reduced the IFN-I response. It also shows that cGAS or STING knockdown inhibited that response, but does not report a direct measurement showing that 3TC or L1 shRNA reduced cGAS activation. The Methods describe shRNAs targeting L1 ORF1 and ORF2, rather than identifying them as targeting specific active L1 families. (LLM, conf=0.83)

  cites [33] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). This study shows that upregulation of L1 triggers an IFN-I response in senescent cells and aged mice that can be therapeutically ameliorated with NRTIs. sourceExperimental — accuracy not yet measured
• Partly supported

  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)

  cites [34] Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 (2019). This study shows that upregulation of L1 triggers an IFN-I response in Sirt6-knockout and normal aged mice, and that pathologies and lifespan of Sirt6 progeroid mice can be improved with NRTIs. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results sections report that 3TC and d4T reduced extranuclear ssDNA and type-I IFN expression in TREX1-deficient neural cells; they also report reduced IRF3 activation, which the authors interpret as evidence of cGAS/STING involvement. L1 shRNA reduced ssDNA in TREX1-deficient NPCs, but the paper does not report that shRNA reduced cGAS or IFN-I activation. The claim also states cGAS activation more definitively than the Results passage does. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [92] Thomas, C. A. et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell 21, 319–331 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Major sources of dsRNA, inverted Alu repeats, are normally deaminated by ADAR to reduce their double-stranded character; decreased processing can be sensed by MDA5, resulting in IFN-I activation50, 51, 98.”

What the sources say

• Partly supported

  The Results (page unavailable) show that ADAR1 edits Alu elements and that loss of ADAR1 in neuronal progenitor cells leads to MDA5-mediated IFNβ production. The paper also says inverted Alu elements can form dsRNA, but it does not establish that they are the major source of dsRNA or directly show that editing reduces their double-stranded character; the Introduction presents destabilization as a hypothesis. (LLM, conf=0.84)

  cites [50] Chung, H. et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 172, 811–824 (2018). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [51] Rice, G. I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012). source
• Supported

  The Results section identifies inverted-repeat Alus as forming Alu:Alu duplexes and as the primary ligands for MDA5 in ADAR1-deficient cells. Another Results passage states that ADAR1 editing weakens dsRNA integrity; the paper reports MDA5-dependent IFNβ induction when ADAR1 is absent. Page numbers are not available in our copy. (LLM, conf=0.92)

  cites [98] Ahmad, S. et al. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell 172, 797–810 (2018). source

In the paper

“TREX1 mutations have been identified in SLE115 and familial chilblain lupus116, implicating TREX1 as a safeguard against autoimmune inflammation.”

What the sources say

• ?Not checked — no full text of the sourcecites [115] Lee-Kirsch, M. A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 39, 1065–1067 (2007). source
• Supported

  Citation 116 is attached to familial chilblain lupus, not the separately cited SLE finding. The Abstract reports a heterozygous TREX1 mutation causing familial chilblain lupus and links impaired nuclease activity to an innate immune response (page not provided). (LLM, conf=0.92)

  cites [116] Rice, G. et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am. J. Hum. Genet. 80, 811–815 (2007). source

In the paper

“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.”

What the sources say

• Supported

  The Results section on NRTI-treated SIRT6 knockout mice reports more than a two-fold increase in mean and maximum lifespan, along with improvements in bone density, muscle mass, and physical performance on an inverted screen test. The Results section on the intestines reports improved epithelial integrity and reduced inflammation, supporting the claim of improved intestinal health. (LLM, conf=0.91)

  cites [34] Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 (2019). This study shows that upregulation of L1 triggers an IFN-I response in Sirt6-knockout and normal aged mice, and that pathologies and lifespan of Sirt6 progeroid mice can be improved with NRTIs. source

In the paper

“Retrotransposition is greatly diminished in non-dividing cells94, although low levels could be detected in senescent cells33 or neurons92, and it is possible that abortive products of these processes could accumulate.”

What the sources say

• Supported

  The citation is attached to the claim that retrotransposition is greatly diminished in non-dividing cells, not to the later claims about senescent cells or neurons. The Results report strong inhibition in arrested cells, and the Discussion quantifies a 10- to 70-fold reduction in this study. (LLM, conf=0.94)

  cites [94] Shi, X., Seluanov, A. & Gorbunova, V. Cell divisions are required for L1 retrotransposition. Mol. Cell. Biol. 27, 1264–1270 (2007). source
• Partly supported

  In “Consequences of L1 activation” (page unavailable), the paper reports L1-enriched cytoplasmic DNA and an increase in L1HS sequences in senescent cells, supporting detectable L1 activity. It does not establish a low rate of completed retrotransposition in those cells; the retrotransposition reporter described in the Extended Data was tested in early-passage cells. Citation 33 is attached to the senescent-cell clause, not the claims about non-dividing cells generally or neurons. (LLM, conf=0.82)

  cites [33] De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019). This study shows that upregulation of L1 triggers an IFN-I response in senescent cells and aged mice that can be therapeutically ameliorated with NRTIs. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section on L1 species in neural cells reports L1 activity in post-mitotic neurons, supporting the possibility of activity in non-dividing neurons. But this paper measures de novo retrotransposition in neural progenitor cells, not neurons, and does not establish that neuronal retrotransposition occurs at low levels. The separate claims about diminished activity in non-dividing cells and senescent cells are attached to other citations. (LLM, conf=0.79)

  cites [92] Thomas, C. A. et al. Modeling of TREX1-dependent autoimmune disease using human stem cells highlights L1 accumulation as a source of neuroinflammation. Cell Stem Cell 21, 319–331 (2017). sourceExperimental — accuracy not yet measured

In the paper

“More primitive mechanisms based on RNA sensing though Dicer-2 and a TLR are present, as is the NF-kB pathway, which activates the production of antimicrobial peptides; however, DNA sensing and the cGAS-STING axis are absent103.”

What the sources say

• Partly supported

  The Introduction and Discussion describe Dicer-2 sensing viral RNA, Toll and IMD signaling through NF-κB to induce antimicrobial peptides, and no functional cGAS–STING axis in Drosophila. They do not describe Toll as an RNA sensor or establish that all DNA sensing is absent. The paper also identifies a functional Drosophila STING protein that senses cyclic dinucleotides. (LLM, conf=0.86)

  cites [103] Martin, M., Hiroyasu, A., Guzman, R. M., Roberts, S. A. & Goodman, A. G. Analysis of Drosophila STING reveals an evolutionarily conserved antimicrobial function. Cell Rep. 23, 3537–3550.e6 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Chronic low-level stimulation of the immune system is now viewed as a hallmark of aging111 and is often referred to as ‘sterile’ inflammation, since occurs in the absence of obvious infection with pathogens.”

What the sources say

• Supported

  The Introduction (p. 5) describes ageing-associated inflammation as chronic, sterile, and low-grade, defines sterile as occurring in the absence of infection, and identifies chronic innate immune activation as a major characteristic. The Key points (p. 23) call inflammation a pillar of ageing and describe inflammaging as the long-term result of chronic stimulation of the innate immune system. (LLM, conf=0.92)

  cites [111] Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat. Rev. Endocrinol. 14, 576–590 (2018). source

In the paper

“Remarkably, interventions that silence retrotransposons extended normal life span in flies, and treatments with NRTIs partially rescued the shortened lifespans of several fly mutations that de-repress retrotransposons35, 59.”

What the sources say

• Partly supported

  The Results section on genetic interventions (page not provided) reports that interventions maintaining transposable-element silencing extended fly life span. The pharmacological Results section reports that one reverse transcriptase inhibitor, 3TC, significantly extended life span in one short-lived, TE-sensitized Dicer-2 mutant background. It does not report NRTI treatment rescuing the life spans of several different mutations. (LLM, conf=0.90)

  cites [35] Wood, J. G. et al. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila. Proc. Natl Acad. Sci. USA 113, 11277–11282 (2016). Using chromatin-modifying genetic interventions and NRTI treatments in Drosophila, this study causally links retrotransposon activation with aging. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('piRNA mutants show altered fat body function and lifespan'; page unavailable) reports that 3TC extended the shortened lifespan of flamenco mutants and recounts a similar finding for Dcr-2 mutants. It does not report an intervention in this study that extended normal fly lifespan; that finding appears only in the title of a cited study in the References. The paper also tests only one NRTI, 3TC, rather than multiple NRTI treatments. (LLM, conf=0.86)

  cites [59] Jones, B. C. et al. A somatic piRNA pathway in the Drosophila fat body ensures metabolic homeostasis and normal lifespan. Nat. Commun. 7, 13856 (2016). sourceExperimental — accuracy not yet measured

In the paper

“RNaseH2 digests the RNA strands of RNA:DNA hybrids122 and might reduce the levels of L1 nucleic acid species that interact with interferon sensors123.”

What the sources say

• Supported

  Citation 122 is attached to the claim that RNase H2 digests the RNA strand of RNA:DNA hybrids, not to the later statement about L1 and interferon sensors. The Introduction (page not provided) explicitly states that RNase H2 cleaves the RNA strand of RNA/DNA hybrids. (LLM, conf=0.94)

  cites [122] Uehara, R. et al. Two RNase H2 mutants with differential rNMP processing activity reveal a threshold of ribonucleotide tolerance for embryonic development. Cell Rep. 25, 1135–1145 (2018). source
• Supported

  Citation 122 is attached to the claim that RNase H2 digests the RNA strand of RNA:DNA hybrids. The Discussion states that RNase H2 can cleave the RNA moiety of an RNA/DNA hybrid containing more than four consecutive ribonucleotides. The separate L1 and interferon-sensor proposition carries citation 123, not the citation assessed here. (LLM, conf=0.93)

  cites [123] Bartsch, K. et al. RNase H2 loss in murine astrocytes results in cellular defects reminiscent of nucleic acid-mediated autoinflammation. Front. Immunol. 9, 587 (2018). source

In the paper

“L1s are activated by loss of DNA methylation, which often occurs during premalignant hyperplasia125; the resulting IFN-I response could then trigger cell death pathways.”

What the sources say

• Partly supported

  The section “LINE-1 methylation regulates gene expression in cis” (page unavailable) says LINE-1 transcriptional activity correlates with hypomethylation. “LINE-1 and other IRS methylation levels in cancer” reports hypomethylation in certain premalignant lesions, but does not establish that it often occurs during premalignant hyperplasia; it also reports hypermethylation in some lesions. The IFN-I and cell-death clause follows the citation and is not attributed to this source. (LLM, conf=0.87)

  cites [125] Kitkumthorn, N. & Mutirangura, A. Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. Clin. Epigenetics 2, 315–330 (2011). sourceExperimental — accuracy not yet measured

In the paper

“AMD has been associated with the downregulation DICER1, and the consequent elevation of Alu RNA levels activates the NLRP3 (NOD, LRR and pyrin domain containing protein 3) inflammasome in retinal pigmented epithelial cells, leading to cytotoxicity and degeneration128.”

What the sources say

• Supported

  The Introduction (page not provided) reports reduced DICER1 and accumulated Alu RNA in the RPE of human eyes with geographic atrophy, an advanced form of AMD. The Results section, “DICER1 loss induces cell death via inflammasome” (page not provided), links DICER1 loss and Alu RNA to inflammasome activation and RPE cell death; the Discussion links NLRP3 activation to RPE degeneration. (LLM, conf=0.93)

  cites [128] Tarallo, V. et al. DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149, 847–859 (2012). source

In the paper

“cGAS inhibitors are being developed145.”

What the sources say

• Supported

  The Discussion states that the authors developed potent, human-cGAS-specific small-molecule inhibitors active in primary human macrophages. This directly supports the broad claim that cGAS inhibitors are being developed. (LLM, conf=0.95)

  cites [145] Lama, L. et al. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat. Commun. 10, 2261 (2019). source

In the paper

“ATM kinase inhibition in glial cells of Drosophila activated an innate immune response and elicited neurodegeneration142.”

What the sources say

• Supported

  The paper’s opening summary reports that ATM knockdown in Drosophila glial cells increased expression of innate immune response genes and caused neuron and glial cell death. This supports both parts of the citing sentence. (LLM, conf=0.95)

  cites [142] Petersen, A. J., Rimkus, S. A. & Wassarman, D. A. ATM kinase inhibition in glial cells activates the innate immune response and causes neurodegeneration in Drosophila. Proc. Natl Acad. Sci. USA 109, E656–E664 (2012). source

In the paper

“TREX1 degrades cytoplasmic L1 DNA53 and its loss initiates a cGAS/STING response.”

What the sources say

• Partly supported

  The citation is attached to the L1 DNA clause, not the subsequent cGAS/STING clause. In Results (“Identification of endogenous Trex1 DNA substrates” and “Trex1 metabolizes DNA of endogenous retroelements”), L1-derived DNA accumulates in Trex1-deficient mouse hearts, and Trex1 reduces L1 retrotransposition. The paper does not establish that the L1 DNA Trex1 degrades is cytoplasmic; the Discussion says L1 reverse transcription is thought to occur in the nucleus. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [53] Stetson, D. B., Ko, J. S., Heidmann, T. & Medzhitov, R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134, 587–598 (2008). This work shows that loss of TREX1 in AGS results in accumulation of retrotransposon single-stranded DNA that drives an IFN-I response, and implicates somatic retrotransposon activation as a causal factor in human disease. sourceExperimental — accuracy not yet measured

In the paper

“Alu RNA was reverse transcribed in the cytoplasm and the cDNA activated cGAS/STING signaling95.”

What the sources say

• Partly supported

  The Results (p. 3) report that Alu cDNA accumulates predominantly in the cytoplasm and requires reverse-transcriptase activity. The Discussion (page not provided) places Alu cDNA synthesis upstream of inflammasome activation, but our copy does not say that the cDNA activates cGAS/STING signaling. (LLM, conf=0.88)

  cites [95] Fukuda, S. et al. Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration. Proc. Natl Acad. Sci. USA 118, e2022751118 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Interestingly, some old drugs such as aspirin146 and antimalarials quinacrine and chloroquine147 inhibit cGAS, further suggesting that downregulating this pathway might confer health benefits.”

What the sources say

• Supported

  Citation 146 is attached to aspirin, not to the antimalarials cited separately as 147. The Discussion states that aspirin inhibits cGAS activation and could be used to treat self-DNA-induced autoimmune diseases, supporting the aspirin portion and its proposed therapeutic relevance. (LLM, conf=0.92)

  cites [146] Dai, J. et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell 176, 1447–1460 (2019). source
• Supported

  The “cGAS inhibition” section states that chloroquine inhibits DNA binding to cGAS, while “Chemical structure of antimalarials: can we improve specificity?” reports that both quinacrine and chloroquine inhibit cGAS activity. Citation 147 is attached to the antimalarials, not aspirin; the health-benefits statement is the citing authors’ inference. (LLM, conf=0.92)

  cites [147] Piscianz, E. et al. Reappraisal of antimalarials in interferonopathies: new perspectives for old drugs. Curr. Med. Chem. 25, 2797–2810 (2018). source

In the paper

“Expression of a disease-associated human Tau protein in Drosophila neurons elicited loss of H3K9me2, widespread retrotransposon activation, DNA damage, and neuronal cell death that could be rescued with NRTIs139.”

What the sources say

• Partly supported

  The Results sections report altered retrotransposon expression and mobilization, neuronal death, and reduced neuronal death after treatment with 3TC, a nucleoside reverse-transcriptase inhibitor. The Drosophila-model section also lists DNA damage among the model’s phenotypes. Our copy discusses tau-induced heterochromatin relaxation but does not establish the claimed loss of H3K9me2; it reports a rescue experiment with one inhibitor, 3TC, rather than NRTIs generally. Page numbers were not available in our copy. (LLM, conf=0.85)

  cites [139] Sun, W., Samimi, H., Gamez, M., Zare, H. & Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21, 1038–1048 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Loss of ATM in microglia led to accumulation of cytoplasmic DNA, activation of the cGAS-STING axis and production of neurotoxic cytokines143.”

What the sources say

• Partly supported

  The Discussion (page not provided) states that ATM deficiency causes cytoplasmic DNA accumulation, activates STING-mediated inflammatory signaling in microglia, and leads to secretion of neurotoxic cytokines. The Results also show STING activation after ATM inhibition. Our copy does not identify or establish activation of cGAS, so it supports the STING pathway but not the more specific cGAS–STING axis. (LLM, conf=0.88)

  cites [143] Song, X., Ma, F. & Herrup, K. Accumulation of cytoplasmic DNA due to ATM deficiency activates the microglial viral response system with neurotoxic consequences. J. Neurosci. 39, 6378–6394 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Postmortem AD brain samples exhibited increased markers of open chromatin137 and elevated expression of retrotransposons138, 139.”

What the sources say

• Supported

  Citation 137 is attached to the open-chromatin finding, not the retrotransposon finding cited to 138 and 139. In Results, “Heterochromatin loss in vertebrate tauopathies” (page unavailable), the paper reports significantly depleted H3K9me2 in neurons isolated from postmortem AD brains, supporting chromatin relaxation. (LLM, conf=0.90)

  cites [137] Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). source
• Supported

  The Results section (“Tau Pathologic Burden Is Associated with Altered TE Expression in Human Brains”; page unavailable) reports increased transcription of several retrotransposons in postmortem human brains in association with AD tangle burden. This supports the elevated-expression clause attributed to this source; the open-chromatin clause has a separate citation. (LLM, conf=0.92)

  cites [138] Guo, C. et al. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 23, 2874–2880 (2018). source
• Partly supported

  The Results section (‘Aberrant transposable element transcription in human tauopathy’; page unavailable) reports increased expression of endogenous retroviruses in postmortem Alzheimer’s disease brain, but decreased expression of non-LTR retrotransposons. Thus, this source supports elevated expression of a subgroup, not an unqualified increase in retrotransposons. The open-chromatin clause carries a different citation (137) and is not attributed to this source. (LLM, conf=0.88)

  cites [139] Sun, W., Samimi, H., Gamez, M., Zare, H. & Frost, B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat. Neurosci. 21, 1038–1048 (2018). sourceExperimental — accuracy not yet measured

In the paper

“SAMHD1 interacts with L1 in multiple ways52 and might sequester ORF1 into stress granules121.”

What the sources say

• Supported

  Citation 52 attaches to the claim that SAMHD1 interacts with L1 in multiple ways, not to the stress-granule suggestion, which has a separate citation. The Results report that SAMHD1 inhibits L1 retrotransposition, reduces ORF2p expression, and suppresses ORF2p-mediated reverse transcription. These support multiple functional effects on L1; the paper does not establish direct physical binding. (LLM, conf=0.85)

  cites [52] Zhao, K. et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1. Cell Rep. 4, 1108–1115 (2013). source
• Supported

  Citation 121 is attached to the suggestion that SAMHD1 might sequester ORF1 in stress granules, not to the preceding claim about multiple interactions. In the Results section on ORF1p sequestration (page not provided), the paper says SAMHD1 promotes ORF1p sequestration in stress granules by an indirect mechanism and reports increased ORF1p association with foci bearing stress-granule markers. (LLM, conf=0.94)

  cites [121] Hu, S. et al. SAMHD1 inhibits LINE-1 retrotransposition by promoting stress granule formation. PLoS Genet. 11, e1005367 (2015). source

In the paper

“Retrotransposon expression was positively associated with tangle burden in human cortical samples, as well as enrichment of the open chromatin mark H3K9ac at some HERV loci138.”

What the sources say

• Supported

  The Results section reports increased retrotransposon transcription associated with tangle burden in human dorsolateral prefrontal cortex samples. It also reports positive associations between tangle burden and H3K9Ac at several HERV-Fc1 genomic regions. Page numbers were not supplied in our copy. (LLM, conf=0.93)

  cites [138] Guo, C. et al. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 23, 2874–2880 (2018). source

In the paper

“Another possibility is the reported anti-inflammatory property of NRTIs to alleviate activation of the NLRP3 inflammasome without engaging reverse transcriptase129.”

What the sources say

• Supported

  The paper states that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independently of reverse transcriptase inhibition. It also reports that AZT inhibited caspase-1 maturation in cells where its phosphorylation, required for reverse transcriptase inhibition, was impaired. (LLM, conf=0.94)

  cites [129] Fowler, B. J. et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346, 1000–1003 (2014). source

In the paper

“the deleterious effects of retrotransposons increasingly being linked with aging appear to be largely dependent on the activities of their encoded proteins, and fall into three general mechanisms: genetic and epigenetic effects associated with retrotransposition, DNA damage associated with active or abortive retrotransposition, and activation of immune pathways associated with detection of retrotr”

In the paper

“Although LTR retrotransposons (including endogenized retroviruses) comprise approximately 8% of the human genome, all known sequences are mutated and no single element appears to be capable of retrotransposition.”

In the paper

“Free DNA or dsRNA in the cytoplasm are generally perceived as invading pathogens. In vertebrates their presence triggers the interferon system, which then orchestrates immune responses.”

In the paper

“Collectively, these studies suggest that retrotransposons causally contribute to the aging process, and that interventions that oppose retrotransposon activity might improve healthy longevity.”

In the paper

“Retrotransposon dsRNA species are processed into siRNAs in the nucleus and normally do not reach the cytoplasm in sufficient numbers to overcome self-tolerance.”

In the paper

“We suggest that mis-recognition of retrotransposons activated during aging as invading pathogens is an important driver of sterile inflammation, which in turn contributes to many aging-associated diseases.”

In the paper

“Hence, there may not be a direct correlation between life span and transposon abundance but instead long-lived species may evolve better ways to respond to retrotransposons and associated inflammation.”

In the paper

“Given the current paucity of quantitative data, the frequency of DNA damage that can directly be attributed to retrotransposons is uncertain, and might be quite low, especially during natural aging.”

In the paper

“Aicardi–Goutières syndrome (AGS) is a childhood encephalopathy with similarities to SLE and strong IFN-I induction119.”

What the sources say

• ?Not checked — no full text of the sourcecites [119] Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015). source

In the paper

“It is caused by recessive mutations in TREX1, SAMHD1, ADAR and RNaseH2 or dominant mutations in MDA5, all of which are involved in nucleic acid processing or sensing, DNA repair, or retrotransposon restriction.”

In the paper

“Small molecule inhibitors of STING have recently been reported144 and found to ameliorate STING-mediated inflammatory conditions in mouse models.”

What the sources say

• ?Not checked — no full text of the sourcecites [144] Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018). source

In the paper

“ADAR edits Alu RNA51, and gain of function mutations in MDA5 suggest that RNA-sensing mechanisms are involved in some AGS cases119.”

What the sources say

• ?Not checked — no full text of the sourcecites [51] Rice, G. I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243–1248 (2012). source
• ?Not checked — no full text of the sourcecites [119] Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015). source

In the paper

“The disadvantage of treatments that overly target immunity mechanisms is that they might increase susceptibility to infections.”

In the paper

“The loss and redistribution of heterochromatin that occur during aging thus warrant further investigation.”

In the paper

“This finding is intriguing given that some aspects of the retrotransposon lifecycle, such as transcription of the elements or stimulation of RNA sensors, should not be directly affected by NRTIs.”

In the paper

“It appears that L1 has alternative lifecycles in proliferating and senescent/postmitotic cells, but the latter are not understood at all.”

In the paper

“Given the good safety record of recent NRTIs in HIV treatment, repurposing these drugs for a variety of indications is feasible and would generate a wealth of new information.”

In the paper

“Recent discoveries reviewed here show a convergent theme in which advancing age weakens host mechanisms that control retrotransposons, leading to their derepression and eventual activation of innate immune pathways, toxicity and degeneration.”