The genomes of virtually all organisms contain repetitive sequences that are generated by the activity of transposable elements (transposons). Transposons are mobile genetic elements that can move from one genomic location to another; in this process, they amplify and increase their presence in genomes, sometimes to very high copy numbers. In this Review we discuss new evidence and ideas that the activity of retrotransposons, a major subgroup of transposons overall, influences and even promotes the process of ageing and age-related diseases in complex metazoan organisms, including humans. Retrotransposons have been coevolving with their host genomes since the dawn of life. This relationship has been largely competitive, and transposons have earned epithets such as ‘junk DNA’ and ‘molecular parasites’. Much of our knowledge of the evolution of retrotransposons reflects their activity in the germline and is evident from genome sequence data. Recent research has provided a wealth of information on the activity of retrotransposons in somatic tissues during an individual lifespan, the molecular mechanisms that underlie this activity, and the manner in which these processes intersect with our own physiology, health and well-being.
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Huang, C. R., Burns, K. H. & Boeke, J. D. Active transposition in genomes. Annu. Rev. Genet. 46, 651–675 (2012).
Bourque, G. et al. Ten things you should know about transposable elements. Genome Biol. 19, 199 (2018).
Molaro, A. & Malik, H. S. Hide and seek: how chromatin-based pathways silence retroelements in the mammalian germline. Curr. Opin. Genet. Dev. 37, 51–58 (2016).
Cosby, R. L., Chang, N. C. & Feschotte, C. Host-transposon interactions: conflict, cooperation, and cooption. Genes Dev. 33, 1098–1116 (2019).
Pardue, M. L. & DeBaryshe, P. G. Retrotransposons that maintain chromosome ends. Proc. Natl Acad. Sci. USA 108, 20317–20324 (2011).
Chuong, E. B., Elde, N. C. & Feschotte, C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science 351, 1083–1087 (2016).
Burns, K. H. Our conflict with transposable elements and its implications for human disease. Annu. Rev. Pathol. 15, 51–70 (2020).
Jacques, P. E., Jeyakani, J. & Bourque, G. The majority of primate-specific regulatory sequences are derived from transposable elements. PLoS Genet. 9, e1003504 (2013).
Mita, P. & Boeke, J. D. How retrotransposons shape genome regulation. Curr. Opin. Genet. Dev. 37, 90–100 (2016).
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).
Flasch, D. A. et al. Genome-wide de novo L1 retrotransposition connects endonuclease activity with replication. Cell 177, 837–851 (2019).
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).
Denli, A. M. et al. Primate-specific ORF0 contributes to retrotransposon-mediated diversity. Cell 163, 583–593 (2015).
Kulpa, D. A. & Moran, J. V. Cis-preferential LINE-1 reverse transcriptase activity in ribonucleoprotein particles. Nat. Struct. Mol. Biol. 13, 655–660 (2006).
Khazina, E. et al. Trimeric structure and flexibility of the L1ORF1 protein in human L1 retrotransposition. Nat. Struct. Mol. Biol. 18, 1006–1014 (2011).
Doucet, A. J., Wilusz, J. E., Miyoshi, T., Liu, Y. & Moran, J. V. A 3′ poly(A) tract is required for LINE-1 retrotransposition. Mol. Cell 60, 728–741 (2015).
Mita, P. et al. LINE-1 protein localization and functional dynamics during the cell cycle. eLife 7, e30058 (2018).
Cost, G. J., Feng, Q., Jacquier, A. & Boeke, J. D. Human L1 element target-primed reverse transcription in vitro. EMBO J. 21, 5899–5910 (2002). Using biochemical studies, this paper developed the TPRT model of L1 retrotransposition.
Ardeljan, D. et al. Cell fitness screens reveal a conflict between LINE-1 retrotransposition and DNA replication. Nat. Struct. Mol. Biol. 27, 168–178 (2020).
Mita, P. et al. BRCA1 and S phase DNA repair pathways restrict LINE-1 retrotransposition in human cells. Nat. Struct. Mol. Biol. 27, 179–191 (2020).
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).
Küry, P. et al. Human endogenous retroviruses in neurological diseases. Trends Mol. Med. 24, 379–394 (2018).
Wolf, D. & Goff, S. P. Embryonic stem cells use ZFP809 to silence retroviral DNAs. Nature 458, 1201–1204 (2009).
Castro-Diaz, N. et al. Evolutionally dynamic L1 regulation in embryonic stem cells. Genes Dev. 28, 1397–1409 (2014).
Jacobs, F. M. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014). The above three papers show that KZFPs provide DNA sequence specificity to target retrotransposon silencing in mammalian genomes, and uncover the role of KZFPs in the co-evolutionary ‘arms race’ of primate L1s with their hosts.
Bulut-Karslioglu, A. et al. Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells. Mol. Cell 55, 277–290 (2014).
Kato, M., Takemoto, K. & Shinkai, Y. A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing. Nat. Commun. 9, 1683 (2018).
de Wit, E., Greil, F. & van Steensel, B. Genome-wide HP1 binding in Drosophila: developmental plasticity and genomic targeting signals. Genome Res. 15, 1265–1273 (2005).
Ishak, C. A. et al. An RB–EZH2 complex mediates silencing of repetitive DNA sequences. Mol. Cell 64, 1074–1087 (2016).
Liu, N. et al. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature 553, 228–232 (2018).
Van Meter, M. et al. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat. Commun. 5, 5011 (2014).
Helleboid, P. Y. et al. The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. EMBO J. 38, e101220 (2019).
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.
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.
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.
Deniz, Ö., Frost, J. M. & Branco, M. R. Regulation of transposable elements by DNA modifications. Nat. Rev. Genet. 20, 417–431 (2019).
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).
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).
Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116–117 (1998).
Woodcock, D. M., Lawler, C. B., Linsenmeyer, M. E., Doherty, J. P. & Warren, W. D. Asymmetric methylation in the hypermethylated CpG promoter region of the human L1 retrotransposon. J. Biol. Chem. 272, 7810–7816 (1997).
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).
Zhang, G. et al. N6-methyladenine DNA modification in Drosophila. Cell 161, 893–906 (2015).
Imbeault, M., Helleboid, P. Y. & Trono, D. KRAB zinc-finger proteins contribute to the evolution of gene regulatory networks. Nature 543, 550–554 (2017).
Wolf, G. et al. KRAB-zinc finger protein gene expansion in response to active retrotransposons in the murine lineage. eLife 9, e56337 (2020).
Rowe, H. M. et al. KAP1 controls endogenous retroviruses in embryonic stem cells. Nature 463, 237–240 (2010).
Sanchez-Luque, F. J. et al. LINE-1 evasion of epigenetic repression in humans. Mol. Cell 75, 590–604.e12 (2019).
Castel, S. E. & Martienssen, R. A. RNA interference in the nucleus: roles for small RNAs in transcription, epigenetics and beyond. Nat. Rev. Genet. 14, 100–112 (2013).
Goodier, J. L. Restricting retrotransposons: a review. Mob. DNA 7, 16 (2016).
Feng, Y., Goubran, M. H., Follack, T. B. & Chelico, L. Deamination-independent restriction of LINE-1 retrotransposition by APOBEC3H. Sci. Rep. 7, 10881 (2017).
Chung, H. et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell 172, 811–824 (2018).
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).
Zhao, K. et al. Modulation of LINE-1 and Alu/SVA retrotransposition by Aicardi-Goutières syndrome-related SAMHD1. Cell Rep. 4, 1108–1115 (2013).
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.
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
Booth, L. N. & Brunet, A. The aging epigenome. Mol. Cell 62, 728–744 (2016).
Pal, S. & Tyler, J. K. Epigenetics and aging. Sci. Adv. 2, e1600584 (2016).
Sen, P., Shah, P. P., Nativio, R. & Berger, S. L. Epigenetic mechanisms of longevity and aging. Cell 166, 822–839 (2016).
Wood, J. G. et al. Chromatin remodeling in the aging genome of Drosophila. Aging Cell 9, 971–978 (2010).
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).
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).
Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).
Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017).
Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). This paper reports the discovery of the senescence-associated secretory phenotype (SASP) in senescent cells and implicates its pro-inflammatory effects as the major deleterious consequence of senescent cell accumulation in aging.
Pignolo, R. J., Passos, J. F., Khosla, S., Tchkonia, T. & Kirkland, J. L. Reducing senescent cell burden in aging and disease. Trends Mol. Med. 26, 630–638 (2020).
Chandra, T. & Kirschner, K. Chromosome organisation during ageing and senescence. Curr. Opin. Cell Biol. 40, 161–167 (2016).
De Cecco, M. et al. Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging Cell 12, 247–256 (2013).
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).
De Cecco, M. et al. Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues. Aging 5, 867–883 (2013).
Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008).
Issa, J. P. Aging and epigenetic drift: a vicious cycle. J. Clin. Invest. 124, 24–29 (2014).
Klutstein, M., Nejman, D., Greenfield, R. & Cedar, H. DNA methylation in cancer and aging. Cancer Res. 76, 3446–3450 (2016).
Horvath, S. & Raj, K. DNA methylation-based biomarkers and the epigenetic clock theory of ageing. Nat. Rev. Genet. 19, 371–384 (2018).
Cruickshanks, H. A. et al. Senescent cells harbour features of the cancer epigenome. Nat. Cell Biol. 15, 1495–1506 (2013).
Cole, J. J. et al. Diverse interventions that extend mouse lifespan suppress shared age-associated epigenetic changes at critical gene regulatory regions. Genome Biol. 18, 58 (2017).
Wahl, D., Cavalier, A.N., Smith, M., Seals, D.R. & LaRocca, T.J. Healthy aging interventions reduce repetitive element transcripts. J. Gerontol. A Biol. Sci. Med. Sci. 76, 805–810 (2021).
Wang, T. et al. Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment. Genome Biol. 18, 57 (2017).
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).
Hancks, D. C. & Kazazian, H. H., Jr Roles for retrotransposon insertions in human disease. Mob. DNA 7, 9 (2016).
Wimmer, K., Callens, T., Wernstedt, A. & Messiaen, L. The NF1 gene contains hotspots for L1 endonuclease-dependent de novo insertion. PLoS Genet. 7, e1002371 (2011).
Evrony, G. D. et al. Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. Cell 151, 483–496 (2012).
Upton, K. R. et al. Ubiquitous L1 mosaicism in hippocampal neurons. Cell 161, 228–239 (2015).
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).
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).
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).
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.
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.
Helman, E. et al. Somatic retrotransposition in human cancer revealed by whole-genome and exome sequencing. Genome Res. 24, 1053–1063 (2014).
Tubio, J. M. C. et al. Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes. Science 345, 1251343 (2014).
Rodriguez-Martin, B. et al. Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nat. Genet. 52, 306–319 (2020).
Mir, A. A., Philippe, C. & Cristofari, G. euL1db: the European database of L1HS retrotransposon insertions in humans. Nucleic Acids Res. 43, D43–D47 (2015).
Hartmann, G. Nucleic acid immunity. Adv. Immunol. 133, 121–169 (2017).
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).
Hopfner, K. P. & Hornung, V. Molecular mechanisms and cellular functions of cGAS–STING signalling. Nat. Rev. Mol. Cell Biol. 21, 501–521 (2020).
Shi, X., Seluanov, A. & Gorbunova, V. Cell divisions are required for L1 retrotransposition. Mol. Cell. Biol. 27, 1264–1270 (2007).
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).
Roulois, D. et al. DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts. Cell 162, 961–973 (2015).
Chiappinelli, K. B. et al. Inhibiting DNA methylation causes an interferon response in cancer via dsRNA including endogenous retroviruses. Cell 162, 974–986 (2015).
Ahmad, S. et al. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell 172, 797–810 (2018).
Tunbak, H. et al. The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nat. Commun. 11, 5387 (2020).
Zhao, K. et al. LINE1 contributes to autoimmunity through both RIG-I- and MDA5-mediated RNA sensing pathways. J. Autoimmun. 90, 105–115 (2018).
Brisse, M. & Ly, H. Comparative structure and function analysis of the RIG-I-like receptors: RIG-I and MDA5. Front. Immunol. 10, 1586 (2019).
Gasior, S. L., Wakeman, T. P., Xu, B. & Deininger, P. L. The human LINE-1 retrotransposon creates DNA double-strand breaks. J. Mol. Biol. 357, 1383–1393 (2006).
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).
Li, W. et al. Activation of transposable elements during aging and neuronal decline in Drosophila. Nat. Neurosci. 16, 529–531 (2013). This works connects the age-associated activation of retrotransposons in Drosophila with cognitive decline and proposes the ‘retrotransposon storm’ theory of neurodegeneration.
Hagan, C. R., Sheffield, R. F. & Rudin, C. M. Human Alu element retrotransposition induced by genotoxic stress. Nat. Genet. 35, 219–220 (2003).
Yu, Q. et al. Type I interferon controls propagation of long interspersed element-1. J. Biol. Chem. 290, 10191–10199 (2015).
Seluanov, A., Gladyshev, V. N., Vijg, J. & Gorbunova, V. Mechanisms of cancer resistance in long-lived mammals. Nat. Rev. Cancer 18, 433–441 (2018).
Kim, E. B. et al. Genome sequencing reveals insights into physiology and longevity of the naked mole rat. Nature 479, 223–227 (2011).
Ray, D. A. et al. Multiple waves of recent DNA transposon activity in the bat, Myotis lucifugus. Genome Res. 18, 717–728 (2008).
Gorbunova, V., Seluanov, A. & Kennedy, B. K. The world goes bats: living longer and tolerating viruses. Cell Metab. 32, 31–43 (2020).
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).
Ambati, J. et al. Repurposing anti-inflammasome NRTIs for improving insulin sensitivity and reducing type 2 diabetes development. Nat. Commun. 11, 4737 (2020).
Neidhart, M. et al. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum. 43, 2634–2647 (2000).
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).
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).
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).
Isenberg, D. A., Manson, J. J., Ehrenstein, M. R. & Rahman, A. Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology 46, 1052–1056 (2007).
Carter, V. et al. High prevalence and disease correlation of autoantibodies against p40 encoded by long interspersed nuclear elements in systemic lupus erythematosus. Arthritis Rheumatol. 72, 89–99 (2020).
Crow, Y. J. & Manel, N. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15, 429–440 (2015).
Beck-Engeser, G. B., Eilat, D. & Wabl, M. An autoimmune disease prevented by anti-retroviral drugs. Retrovirology 8, 91 (2011).
Hu, S. et al. SAMHD1 inhibits LINE-1 retrotransposition by promoting stress granule formation. PLoS Genet. 11, e1005367 (2015).
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).
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).
Rice, G. I. et al. Reverse-transcriptase inhibitors in the Aicardi-Goutières syndrome. N. Engl. J. Med. 379, 2275–2277 (2018). This phase I open-label clinical trial provides evidence that treatment with NRTIs reduces IFN-I activation in patients with AGS.
Kitkumthorn, N. & Mutirangura, A. Long interspersed nuclear element-1 hypomethylation in cancer: biology and clinical applications. Clin. Epigenetics 2, 315–330 (2011).
Benci, J. L. et al. Tumor interferon signaling regulates a multigenic resistance program to immune checkpoint blockade. Cell 167, 1540–1554 (2016).
Terry, D. M. & Devine, S. E. Aberrantly high levels of somatic LINE-1 expression and retrotransposition in human neurological disorders. Front. Genet. 10, 1244 (2020).
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).
Fowler, B. J. et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346, 1000–1003 (2014).
Liu, E. Y. et al. Loss of nuclear TDP-43 is associated with decondensation of LINE retrotransposons. Cell Rep. 27, 1409–1421 (2019).
Prudencio, M. et al. Repetitive element transcripts are elevated in the brain of C9orf72 ALS/FTLD patients. Hum. Mol. Genet. 26, 3421–3431 (2017).
Tam, O. H. et al. Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia. Cell Rep. 29, 1164–1177 (2019).
Hu, Y. et al. Increased peripheral blood inflammatory cytokine levels in amyotrophic lateral sclerosis: a meta-analysis study. Sci. Rep. 7, 9094 (2017).
Wang, R., Yang, B. & Zhang, D. Activation of interferon signaling pathways in spinal cord astrocytes from an ALS mouse model. Glia 59, 946–958 (2011).
Chang, Y. H. & Dubnau, J. The Gypsy endogenous retrovirus drives non-cell-autonomous propagation in a Drosophila TDP-43 model of neurodegeneration. Curr. Biol. 29, 3135–3152.e4 (2019).
Krug, L. et al. Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet. 13, e1006635 (2017).
Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014).
Guo, C. et al. Tau activates transposable elements in Alzheimer’s disease. Cell Rep. 23, 2874–2880 (2018).
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).
Lee, M. H. et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature 563, 639–645 (2018).
Coufal, N. G. et al. Ataxia telangiectasia mutated (ATM) modulates long interspersed element-1 (L1) retrotransposition in human neural stem cells. Proc. Natl Acad. Sci. USA 108, 20382–20387 (2011).
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).
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).
Haag, S. M. et al. Targeting STING with covalent small-molecule inhibitors. Nature 559, 269–273 (2018).
Lama, L. et al. Development of human cGAS-specific small-molecule inhibitors for repression of dsDNA-triggered interferon expression. Nat. Commun. 10, 2261 (2019).
Dai, J. et al. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell 176, 1447–1460 (2019).
Piscianz, E. et al. Reappraisal of antimalarials in interferonopathies: new perspectives for old drugs. Curr. Med. Chem. 25, 2797–2810 (2018).
Kanfi, Y. et al. The sirtuin SIRT6 regulates lifespan in male mice. Nature 483, 218–221 (2012).
Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).
Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).
West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).
Correia-Melo, C. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35, 724–742 (2016).
Vizioli, M. G. et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 34, 428–445 (2020).
The following funding sources are acknowledged: V.G. and A.S., NIH R37 AG046320, R01 AG027237, P01 AG047200 and P01 AG051449; P.M. and J.D.B., NIH P01 AG051449 and R21 CA235521; F.H.G., NIH R01 AG056306, R01 AG057706, the American Heart Association, Paul G. Allen Frontiers Group Grant no. 19PABHI34610000, the Grace Foundation, the JPB Foundation and A. C. Merle-Smith; J.A.K., NIH P20 GM119943 and P01 AG051449; J.R.T., NIH K99 AG057812; S.L.H., NIH R01 AG024353, P01 AG051449 and R01 AG067306; and J.M.S., NIH R01 AG016694 and P01 AG051449.
V.G. and A.S. are cofounders of Persimmon Bio; V.G. is a member of the scientific advisory board (SAB) of DoNotAge, Centaura and Elysium; J.D.B. is a founder of Neochromosome, founder and director of CDI Labs, and founder and SAB member of ReOpen Diagnostics, and is also an SAB member of Sangamo, Modern Meadow, Sample6 and the Wyss Institute; F.H.G. is an SAB member of Transposon Therapeutics; and J.M.S. is a cofounder and SAB chair of Transposon Therapeutics and consults for Atropos Therapeutics, Gilead Sciences and Oncolinea.
Peer review information Nature thanks Peter Adams, Jan Vijg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Gorbunova, V., Seluanov, A., Mita, P. et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature 596, 43–53 (2021). https://doi.org/10.1038/s41586-021-03542-y