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Cited by 288interferon and immune responsesImmune Response and InflammationGenetics, Aging, and Longevity in Model Organisms

Cytoplasmic DNA: sources, sensing, and role in aging and disease

Open access
Miller, Karl N., Victorelli, Stella G., Salmonowicz, Hanna, Dasgupta, Nirmalya, Liu, Tianhui, Passos, João F., Adams, Peter D.·2021·Cell
DOI 10.1016/j.cell.2021.09.034PMC PMC8627867
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Abstract

Summary Endogenous cytoplasmic DNA (cytoDNA) species are emerging as key mediators of inflammation in diverse physiological and pathological contexts. While the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood. Here we summarize current knowledge in this rapidly progressing field with emphases on similarities and differences between distinct cytoDNAs, their underlying molecular mechanisms of formation and function, interactions between cytoDNA pathways, and therapeutic opportunities in the treatment of age-associated diseases.

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Crossref · 10.1016/j.cell.2021.09.034

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  • Premisecitation

    Misrepair can produce chromosome bridges.

    “The latter can lead to the formation of chromosome bridges (McClintock, 1939; Umbreit et al., 2020), where a fused chromosome with two centromeres can either break during cytokinesis or persist and form a bridge between two newly forming nuclei after anaphase (Liu et al., 2014; Maciejowski et al., 2015).”
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    • cites Umbreit et al., 2020 source

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    STING acts as a scaffold for TBK1-mediated IRF3 phosphorylation and IRF3 dimerization.

    “STING also functions as a scaffold for IRF3 phosphorylation by TBK1 and subsequent dimerization of IRF3 (Tanaka and Chen, 2012).”
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    Sterile inflammation and altered immune function are considered hallmarks of aging, sometimes called inflamm-aging.

    “Altered immune function, including sterile inflammation, is considered a hallmark of the aging process, sometimes referred to as “inflamm-aging” (Franceschi et al., 2007; Lopez-Otin et al., 2013).”
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  • Interpretationnone given

    Endogenous cytoplasmic DNA species act as important mediators of inflammation across diverse physiological and pathological settings.

    “Endogenous cytoplasmic DNA (cytoDNA) species are emerging as key mediators of inflammation in diverse physiological and pathological contexts.”
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    cGAS activation caused by rupture of the MN nuclear envelope is thought to be the main trigger of an interferon-based inflammatory response.

    “Similarly, cGAS activation due to rupture of the MN nuclear envelope is thought to be the major trigger of an interferon-based inflammatory response (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
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    Premisecitation

    cGAS is the best-studied sensor and the paradigm for cytoDNA sensing.

    “Although many DNA sensors have been described (Dempsey and Bowie, 2015), the best-studied sensor and paradigm for sensing of cytoDNA is cyclic GMP-AMP synthase (cGAS).”
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    Premisenone given

    The role of endogenous cytoDNA in activating innate immunity is well established.

    “While the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood.”
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    Activated cGAS generates cGAMP from ATP and GTP upon DNA recognition; cGAMP binds and activates STING.

    “Upon DNA recognition, activated cGAS generates the second messenger cyclic-GMP-AMP (cGAMP) from ATP and GTP, which binds to and activates stimulator of IFN genes (STING) (Gao et al., 2013a; Li et al., 2013b; Sun et al., 2013; Wu et al., 2013).”
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    Premisenone given

    Mislocalized endogenous cytoDNA can activate pathways similar to those triggered by infection and drive cell-autonomous responses without infection.

    “Similar pathways can also be activated by mislocalized endogenous cytoplasmic DNA (cytoDNA) (see Box 1, Glossary), which can drive cell-autonomous responses in the absence of infection.”
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    Premisecitation

    Mitotic defects cause mis-segregation of whole lagging chromosomes in anaphase, while defective DNA repair causes mis-segregation of chromosome fragments.

    “While mitotic defects are associated with mis-segregation of whole, “lagging” chromosomes in anaphase, defective DNA repair is associated with mis-segregation of chromosome fragments.”
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    Premisecitation

    Endogenous cytoDNA contributes to sterile inflammation, which is linked to chronic age-associated conditions such as cancer, cardiovascular disease, and neurodegenerative disorders.

    “Endogenous cytoDNA is a contributor to so-called sterile inflammation, inflammation in the absence of pathogenic infection, which is associated with many chronic age-associated conditions, including cancer, cardiovascular disease, and neurodegenerative disorders (Ferrucci and Fabbri, 2018; Franceschi et al., 2007; Furman et al., 2019).”
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    Premisecitation

    A fused chromosome with two centromeres can break during cytokinesis or persist as a bridge between daughter nuclei after anaphase.

    “where a fused chromosome with two centromeres can either break during cytokinesis or persist and form a bridge between two newly forming nuclei after anaphase (Liu et al., 2014; Maciejowski et al., 2015).”
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    Premisecitation

    Mouse knockout studies show cGAS is required for DNA ligand- and viral-induced interferon responses, suggesting cGAS is the predominant cytoplasmic DNA sensor in those contexts.

    “Knockout studies in mice have demonstrated that cGAS is required for DNA ligand and viral-induced interferon responses, suggesting that cGAS is the predominant cytoplasmic DNA sensor in these contexts (Gao et al., 2013a; Lahaye et al., 2013; Li et al., 2013b; Schoggins et al., 2014).”
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    Premisecitation

    MN formation occurs during cell division and is linked to two mechanisms of chromosome mis-segregation: mitotic defects and DNA misrepair.

    “MN formation occurs in the context of cell division and is associated with two related mechanisms of chromosome mis-segregation, dependent on: 1) mitotic defects including defective metaphase centromere-kinetochore assembly or defects in anaphase, and 2) DNA misrepair (Fenech et al., 2011; Ye et al., 2019) (Fig. 1A).”
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    Chromosome fragments can arise from unrepaired DSBs or misrepair of DSBs and telomere ends that leads to fusions between chromosome fragments.

    “These fragments can be generated through unrepaired DNA double strand breaks (DSBs) or misrepair of DSBs and telomere ends leading to fusions between chromosome fragments.”
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    Premisecitation

    Breakage of a chromosome bridge causes extensive rearrangement of the bridge region by non-homologous end joining and generates chromosome fragments lacking centromeres or with centromeric defects.

    “Breakage of this bridge leads to extensive rearrangement of the bridge region by non-homologous end joining (Ly et al., 2017) and formation of chromosome fragments lacking centromeres or with other centromeric defects.”
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    Premisereasoning

    Dimerized IRF3 enters the nucleus and triggers the type-I interferon response.

    “Dimerized IRF3 enters the nucleus and triggers the type-I interferon response.”
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    Premisecitation

    MN are initially enclosed by a nuclear envelope, but this envelope can spontaneously lose integrity and rupture.

    “MN are initially surrounded by a nuclear envelope which compartmentalizes MN away from the cytoplasm; however, the integrity of this nuclear envelope can be spontaneously lost, leading to rupture (Hatch et al., 2013) (Fig. 1B).”
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    MN have defective nuclear envelope assembly, with deficient nuclear pore complexes and attenuated nuclear transport.

    “MN have defective nuclear envelope assembly, characterized by deficiency of nuclear pore complexes and attenuated nuclear transport (Liu et al., 2018), which affects many processes in MN, including defective replication and repair of MN DNA (Crasta et al., 2012; Hatch et al., 2013; Umbreit et al., 2020; Zhang et al., 2015).”
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    Loss of MN nuclear envelope integrity is linked to MN rupture and to sensing of MN DNA by cytoDNA sensors.

    “Loss of MN nuclear envelope integrity is associated with MN rupture and sensing of MN DNA by cytoDNA sensors.”
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    Interpretationreasoning

    DNA damage may directly or indirectly facilitate cGAS activation.

    “so DNA damage might directly or indirectly facilitate cGAS activation.”
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    cGAS-STING activation in senescent cells leads to NF-κB activation of SASP genes rather than an interferon gene program, potentially because p38-MAPK represses interferon genes.

    “cGAS-STING activation leads to NF-κB activation of SASP genes downstream of STING instead of an interferon gene program, potentially due to p38-MAPK repression of interferon genes in senescent cells (Dou et al., 2017).”
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    Premisecitation

    Removal of senescent cells by genetic or pharmacological senolytic approaches extends median lifespan in old mice and prevents onset of age-associated disease.

    “Accordingly, removal of senescent cells by genetic or pharmacological “senolytic” approaches extends median lifespan in old mice and prevents the onset of age-associated disease (Baker et al., 2016; Baker et al., 2011; Xu et al., 2018; Zhu et al., 2015).”
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    Most DNA repair factors are downregulated in senescent cells, decreasing repair activity, especially homologous repair.

    “Most DNA repair factors are downregulated in senescent cells resulting in decreased repair activity, especially homologous repair pathway activity (Mao et al., 2012; Seluanov et al., 2004).”
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    Nucleoplasmic bridges between daughter nuclei share defective nuclear envelope assembly with MN, leading to replication/repair defects and rupture.

    “Nucleoplasmic bridges formed between daughter nuclei have similar defects in nuclear envelope assembly compared to MN, leading to defects in replication and repair and ultimately rupture (Umbreit et al., 2020).”
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    Premisecitation

    Cellular senescence is a response to severe stress characterized by morphological/metabolic changes, permanent cell-cycle exit, resistance to cell death, and an inflammatory SASP.

    “Among the contributing factors to age-associated sterile inflammation and disease is cellular senescence, which is a cellular response to severe stress primarily characterized by morphological and metabolic changes, permanent exit from the cell cycle, resistance to cell death, and development of an inflammatory senescence-associated secretory phenotype (SASP) (Acosta et al., 2008; Coppe et al., 2”
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    Premisecitation

    Reducing the SASP through senostatic or senomorphic approaches may be less toxic and has been effective in animal models.

    “As an alternative approach, reduction of the SASP through “senostatic” or “senomorphic” approaches may be less toxic and has been shown to be effective in animal models (Birch and Passos, 2017; Georgilis et al., 2018; Laberge et al., 2015; Laberge et al., 2012; Niedernhofer and Robbins, 2018; Xu et al., 2015; Yoshimoto et al., 2013).”
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    Interpretationreasoning

    Under acute stress, senescent cells act as a potent tumor suppressor mechanism by arresting growth and promoting immune clearance of potentially malignant cells through SASP.

    “Under conditions of acute stress, senescent cells act as a potent tumor suppressor mechanism by arresting cell growth and promoting clearance of potentially malignant cells through SASP-dependent activation of the immune system.”
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    Premisecitation

    DNA damage, especially DSBs, is a potent inducer of cellular senescence, partly through a feedback circuit linking altered mitochondrial function to persistent DNA damage via anterograde and retrograde nucleus-mitochondria pathways.

    “DNA damage, particularly the formation of DSBs, is a potent inducer of cellular senescence, in part through a positive feedback circuit linking altered mitochondrial function in senescent cells to persistent DNA damage via nucleus-mitochondria (anterograde) and mitochondria-nucleus (retrograde) pathways (Passos et al., 2010).”
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    Interpretationcitation

    Overexpression of Lamin B1 delays senescence onset, suggesting Lamin B1 loss may be upstream of CCF formation.

    “while the overexpression of Lamin B1 delays onset of senescence (Shimi et al., 2011), suggesting that Lamin B1 loss may be upstream of CCF formation.”
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    Premisecitation

    Loss of Lamin B1 is a well-known feature of cell senescence.

    “Loss of Lamin B1 is a well-known feature of cell senescence (Freund et al., 2012; Shimi et al., 2011).”
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    Premisecitation

    CCF are strongly positive for γH2AX but lack 53BP1, which negatively regulates CCF formation.

    “CCF are strongly positive for the DNA damage marker γH2AX but lack the typically colocalized DNA repair protein 53BP1, which acts as a negative regulator of CCF formation (Ivanov et al., 2013; Vizioli et al., 2020).”
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    Premisecitation

    A portion of cGAS normally localizes to nucleosomes, and its activation by DNA/chromatin binding is highly regulated.

    “Given that a proportion of cGAS ordinarily localizes to nucleosomes and activation of cGAS by DNA/chromatin binding is highly regulated (see Perspective and Conclusion), MN rupture alone is not sufficient for cGAS activation (de Oliveira Mann and Hopfner, 2021).”
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    Premisecitation

    Lamin B1 mRNA levels are decreased in senescent cells, suggesting multiple mechanisms regulate Lamin B1 expression in senescence.

    “In addition, there is evidence that Lamin B1 mRNA levels are also decreased in senescent cells (Freund et al., 2012), suggesting that multiple mechanisms may regulate expression of Lamin B1 in senescence.”
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    Interpretationcitation

    MN activation of cGAS-STING signaling is a cell-intrinsic mechanism to surveil genome instability and has cancer therapeutic implications.

    “MN activation of cGAS-STING signaling is a cell-intrinsic mechanism to surveil genome instability with cancer therapeutic implications.”
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    Premisecitation

    Compared with normal proliferating or quiescent cells, senescent cells have increased mitochondrial mass, decreased mitochondrial membrane potential, potentially altered mitophagy, and increased mitochondrial ROS.

    “Compared to normal proliferating or quiescent cells, senescent cells have increased mitochondrial mass, decreased mitochondrial membrane potential, potentially altered mitophagy, and increased levels of mitochondrial reactive oxygen species (Chapman et al., 2019).”
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    Premisecitation

    mtROS activates JNK1/2, which interacts with the CCF suppressor 53BP1.

    “Mechanistically, mtROS has been reported to activate the stress-activated kinases JNK1/2, which interacts with the CCF suppressor 53BP1.”
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    Premisecitation

    Mitochondrial ablation or inhibition of mtROS formation in senescent cells inhibits the SASP and prevents CCF formation, suggesting mito-nuclear communication contributes to CCF formation.

    “Interestingly, mitochondrial ablation from senescent cells, or inhibition of mtROS formation, inhibits the SASP and prevents the formation of CCF, suggesting that mito-nuclear communication plays a role in CCF formation (Correia-Melo et al., 2016; Vizioli et al., 2020).”
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    Interpretationreasoning

    Expulsion and degradation of failed, potentially unstable repair intermediates as CCF may preserve genome integrity and/or suppress excessive DDR signaling.

    “This suggests that expulsion and degradation of failed, potentially unstable, repair intermediates as CCF may be a mechanism to preserve genome integrity and/or suppression of excessive DNA damage response (DDR) signaling.”
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    Premisereasoning

    CCF have chromatin modifications including heterochromatin-associated H3K27me3 and relative absence of euchromatin-associated H3K9Ac, suggesting they originate from heterochromatin, though their genomic locus of origin is unclear.

    “CCF are characterized by a suite of chromatin modifications, including the presence of heterochromatin-associated H3K27me3 and relative absence of euchromatin-associated H3K9Ac, suggesting they are formed from heterochromatin, although their genome locus of origin remains unclear.”
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    Premisecitation

    Many cytoplasmic chromatin structures in senescent cells form independently of cell cycle progression via apparent blebbing from an intact nucleus and have distinct markers, suggesting a different formation mechanism from true MN.

    “however, unlike true micronuclei, many of these observed structures are formed independently of cell cycle progression, by apparent blebbing of chromatin into the cytoplasm from a seemingly intact nucleus, and contain distinct molecular markers (Table 1), suggesting a different mechanism of formation of these cytoplasmic chromatin fragments (CCF) (Ivanov et al., 2013).”
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    Premisenone given

    Mitochondrial fission is important for proper nucleoid distribution and removal of damaged mtDNA.

    “Mitochondria fission is important to ensure proper nucleoid distribution and removal of damaged mtDNA.”
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    Premisecitation

    TFAM-deficient cells show heightened type I interferon and ISG expression upon HSV-1 infection and are more resistant to infection than wild-type cells.

    “Consistent with a role for mtDNA in priming the anti-viral immune response, TFAM-deficient cells display heightened expression of type I interferon and ISG upon infection with Herpes Simplex Virus 1 (HSV-1) and are more resistant to infection compared to wild type cells (West et al., 2015).”
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    Premisecitation

    Upon apoptotic signals, BAX and BAK become activated and form macropores in the outer mitochondrial membrane, inducing MOMP.

    “Upon receiving apoptotic signals, pro-apoptotic proteins BAX and BAK become activated, and form macropores in the outer mitochondrial membrane, inducing mitochondrial outer-membrane permeabilization (MOMP) (Tait and Green, 2013) (Fig. 3).”
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    Interpretationcitation

    Anti-viral priming and resistance in TFAM-deficient fibroblasts can be ablated by ddC, which inhibits mtDNA replication and reduces mtDNA stress, suggesting cytosolic mtDNA potentiates anti-viral innate immunity.

    “Anti-viral priming and resistance to viral infection could be ablated by treating TFAM-deficient fibroblasts with dideoxycytidine (ddC), which inhibits mtDNA replication and reduces mtDNA stress in these cells, suggesting that cytosolic mtDNA potentiates anti-viral innate immunity (West et al., 2015).”
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    Interpretationcitation

    Cytoplasmic mtDNA accumulating due to mitochondrial endonuclease γ deficiency induces ISG expression in mouse fibroblasts, suggesting cytosolic mtDNA is a major trigger of inflammatory pathways.

    “Moreover, cytoplasmic mtDNA that accumulates in response to mitochondrial endonuclease γ deficiency, has also been shown to induce expression of ISGs in mouse fibroblasts (Kim et al., 2019), suggesting that cytosolic mtDNA is a major trigger of inflammatory pathways.”
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    Premisecitation

    Nucleoids consist of one mtDNA copy and proteins such as TFAM, which is responsible for nucleoid architecture, abundance, and segregation.

    “which consist of one copy of mtDNA and different proteins, such as mitochondrial transcription factor A (TFAM), a protein responsible for nucleoid architecture, abundance and segregation (Kanki et al., 2004; Kasashima et al., 2011).”
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    Interpretationcitation

    Structural similarities between mtDNA and bacterial DNA likely reflect the bacterial origin of mtDNA and appear to underlie shared roles in immune signaling.

    “Interestingly, the similarities between mtDNA and bacterial DNA at the structural level likely reflect the bacterial origin of mtDNA (Roger et al., 2017), and even now appear to be a basis for shared roles in immune signaling.”
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    Premisecitation

    HDAC inhibitors including Vorinostat prevent CCF formation and SASP indirectly by activating mitochondrial function in senescent cells and mouse liver, suggesting this pathway is therapeutically targetable in vivo.

    “It has recently been shown that histone deacetylase inhibitors (HDACi) including Vorinostat, an HDACi approved for use in humans to treat some cancers, prevent CCF formation and SASP indirectly through activation of mitochondrial function in senescent cells and in mouse liver, suggesting that this pathway is therapeutically targetable in vivo (Vizioli et al., 2020).”
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    Premisereasoning

    Formation of these other cytoDNA species is directly or indirectly associated with γH2AX, but how their formation relates to MN and CCF mechanisms is unknown.

    “In each case, formation of these cytoDNA is directly or indirectly associated with the DNA damage marker γH2AX; however, it is unknown how these mechanisms of formation are related to the specific mechanisms of MN and CCF formation described above.”
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    Interpretationcitation

    Knockdown of MxB leads to mitochondrial fragmentation, disruption of the inner mitochondrial membrane, and increased cytosolic mtDNA, supporting that imbalance in mitochondrial network homeostasis contributes to mtDNA release.

    “In line with this, a recent study demonstrated that knockdown of MxB, a GTPase located in the inner mitochondrial membrane, leads to mitochondria fragmentation, disruption of the inner mitochondrial membrane and increased cytosolic mtDNA (Cao et al., 2020), supporting the notion that imbalance in mitochondria network homeostasis is a contributor to mtDNA release into the cytoplasm.”
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    Premisecitation

    Treating cells with dysfunctional mitochondria with LPS or ATP increased cytosolic mtDNA, which contributed to IL-1β and IL-18 secretion via the NLRP3 inflammasome.

    “One study showed that treating cells that have dysfunctional mitochondria with lipopolysaccharide (LPS) or ATP resulted in increased levels of cytosolic mtDNA, which contributed to secretion of IL-1β and IL-18 via the NLRP3 inflammasome (Nakahira et al., 2011).”
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    Premisecitation

    mtDNA is recognized as foreign when outside mitochondria and can trigger inflammation.

    “MtDNA is recognized as foreign when found outside of mitochondria and can trigger inflammation (Maekawa et al., 2019; Shimada et al., 2012; Zhang et al., 2010).”
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    Premisecitation

    The mPTP is a transmembrane protein in the inner mitochondrial membrane that normally opens in response to calcium accumulation, oxidative stress, and other stressors.

    “The mPTP is a transmembrane protein located in the mitochondrial inner membrane, and normally opens in response to calcium accumulation in the mitochondrial matrix, oxidative stress and other stressors (Briston et al., 2017).”
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    Interpretationcitation

    Blocking sub-lethal apoptotic signaling impairs the ability of cells to control pathogenic infection, implicating BAX/BAK-mediated mtDNA cytosolic release as a mechanism for efficient immune defense.

    “Blocking sub-lethal apoptotic signaling impaired the ability of cells to control pathogenic infection, implicating BAX/BAK-mediated mtDNA cytosolic release as a mechanism for efficient immune defense (Brokatzky et al., 2019).”
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    Premisecitation

    mtDNA typically localizes to the inner mitochondrial matrix and encodes 37 genes: 13 mRNAs for oxidative phosphorylation subunits, 2 rRNAs, and 22 tRNAs.

    “Typically located in the inner mitochondrial matrix, mtDNA encodes for 37 genes: 13 mRNAs that are translated into subunits of components of the oxidative phosphorylation system, 2 ribosomal RNAs (rRNA) and 22 transfer RNAs (tRNAs) (Taanman, 1999).”
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    • cites Taanman, 1999 source

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    Premisecitation

    After MOMP, BAX/BAK pores widen, allowing inner mitochondrial membrane extrusion into the cytosol, where it permeabilizes and facilitates mtDNA release.

    “Following MOMP, BAX and BAK pores gradually widen, allowing the extrusion of the inner mitochondrial membrane into the cytosol, where it becomes permeabilized, facilitating mtDNA release (McArthur et al., 2018; Riley et al., 2018).”
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    • cites McArthur et al., 2018 source

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    • cites Riley et al., 2018 source

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    Premisecitation

    VDAC oligomerization has been proposed to mediate mtDNA release into the cytoplasm.

    “Interestingly, a recent study has proposed a role for voltage-dependent anion channel (VDAC) oligomerization in mediating mtDNA release into the cytoplasm (Kim et al., 2019).”
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    • cites Kim et al., 2019 source

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    Premisecitation

    Infection of human cells with dengue virus DENV-2 increases cytoplasmic mtDNA, coinciding with cGAS activation, providing a mechanism for RNA virus activation of innate immune signaling.

    “One study demonstrated that infecting human cells with the dengue virus (DENV-2), which has an RNA genome, resulted in increased mtDNA in the cytoplasm, which coincided with cGAS activation, thus providing a mechanism through which RNA viruses activate innate immune signaling (Sun et al., 2017).”
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    • cites Sun et al., 2017 source

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    Premisecitation

    The mPTP only transports molecules smaller than 1.5 kDa, which is smaller than an mtDNA nucleoid, consistent with only mtDNA fragments being released through the mPTP.

    “The aforementioned studies showing that only fragments of mtDNA are released through the mPTP are in line with the fact that the mitochondrial permeability transition pore only allows the transport of molecules smaller than 1.5kDa, which is smaller than a mtDNA nucleoid (Halestrap et al., 2002).”
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    • cites Halestrap et al., 2002 source

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    Interpretationcitation

    These DNA damage-associated cytoDNA species have been connected to cGAS-STING activation, except for cGAS-STING-independent KU complex cytoDNA sensing in aged T cells, and likely play important roles in physiology and disease.

    “Despite these apparent differences, these DNA damage-associated cytoDNA species have been connected to cGAS-STING pathway activation, with the exception of cGAS-STING-independent KU complex cytoDNA sensing in aged T cells (Wang et al., 2021), and likely play important roles in physiology and disease.”
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    • cites Wang et al., 2021 source

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    Premisecitation

    mtDNA is present at thousands of copies per cell and is densely packaged into nucleoids.

    “Mitochondrial DNA (mtDNA) is present at thousands of copies per cell and is densely packaged into nucleoids (Spelbrink, 2010), which consist of one copy of mtDNA and different proteins, such as mitochondrial transcription factor A (TFAM), a protein responsible for nucleoid architecture, abundance and segregation (Kanki et al., 2004; Kasashima et al., 2011).”
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    • cites Spelbrink, 2010 source

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    Premisecitation

    Mouse fibroblasts deficient in mitochondrial endonuclease γ have increased oxidative stress and higher cytosolic mtDNA, which can be attenuated by knocking down VDAC 1 and 3.

    “It was shown that mouse fibroblasts deficient in the mitochondrial endonuclease γ, which display increased oxidative stress, had higher levels of cytosolic mtDNA and this could be attenuated by knocking down VDAC 1 and 3 (Kim et al., 2019).”
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    • cites Kim et al., 2019 source

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    Premisecitation

    These other cytoDNA species include those in ataxia-telangiectasia, Dnase2a deficiency, telomere damage crisis-induced CCF-like structures, HGPS nuclear abnormalities, Exo1 hyperexcision-driven chromosomal instability, and small DNA-damage associated fragments.

    “These include cytoDNA in human patient-derived cells and mouse models of ataxia-telangiectasia (Song et al., 2019), Dnase2a deficiency (Lan et al., 2019; Lan et al., 2014), telomere damage crisis-induced CCF-like structures (Nassour et al., 2019), HGPS nuclear abnormalities (Kreienkamp et al., 2018), Exo1 hyperexcision-driven chromosomal instability (Guan et al., 2021), and small DNA-damage ass”
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    • cites Song et al., 2019 source

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    • cites Lan et al., 2019 source

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    • cites Nassour et al., 2019 source

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    Premisecitation

    The level of plasma mtDNA is associated with disease progression and predicts mortality in IPF.

    “The level of plasma mtDNA was associated with disease progression and was shown to predict mortality (Ryu et al., 2017).”
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    • cites Ryu et al., 2017 source

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    Premisecitation

    Components of the SASP act in a paracrine manner, inducing senescence in surrounding cells, and this is thought to be a mechanism by which senescent cells contribute to age-related tissue dysfunction.

    “Components of the SASP have been shown to act in a paracrine manner, inducing senescence in surrounding cells, and this is thought to be a mechanism by which senescent cells contribute to age-related tissue dysfunction (Acosta et al., 2013; Baker et al., 2016; Coppé et al., 2010; Nelson et al., 2012).”
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    • cites Acosta et al., 2013 source

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    • cites Baker et al., 2016 source

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    • cites Coppé et al., 2010 source

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    Premisecitation

    Normal human lung fibroblasts treated with isolated mtDNA express high levels of α-smooth muscle actin, suggesting mtDNA plays a role in the pathophysiology of IPF.

    “Moreover, normal human lung fibroblasts treated with isolated mtDNA expressed high levels of α-smooth muscle actin, which is a characteristic of fibrotic disease, suggesting that mtDNA plays a role in the pathophysiology of IPF (Ryu et al., 2017).”
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    • cites Ryu et al., 2017 source

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    Premisecitation

    Priming of macrophages generates newly synthesized, oxidized mtDNA fragments that activate the NLRP3 inflammasome, suggesting NLRP3 preferably binds oxidized mtDNA.

    “Furthermore, a more recent study also demonstrated that priming of macrophages generates newly synthesized, oxidized mtDNA fragments that activate the NLRP3 inflammasome, suggesting that NLRP3 preferably binds oxidized mtDNA (Zhong et al., 2018).”
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    • cites Zhong et al., 2018 source

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    Premisecitation

    Pharmacological elimination of senescent cells from old donor animals significantly reduces circulating mtDNA, improves age-associated inflammation, and prolongs survival of mice receiving organ transplant from old animals.

    “Pharmacological elimination of senescent cells from old donor animals significantly reduced circulating mtDNA, improved age-associated inflammation and prolonged the survival of mice receiving organ transplant from old animals (Iske et al., 2020).”
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    • cites Iske et al., 2020 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    During TPRT, the endonuclease encoded by L1 cleaves the bottom strand of the target DNA, exposing a 3'-hydroxyl group that serves as a primer for reverse transcription of L1 mRNA by ORF2p.

    “During TPRT, it is proposed that the endonuclease encoded by L1 cleaves the bottom strand of the target DNA, which exposes a 3’-hydroxyl group, to serve as a primer for reverse transcription of the L1 mRNA by ORF2p.”
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    • cites Kazazian and Moran, 2017

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    Premisecitation

    Upon activation, LINEs are transcribed by RNA polymerase II, the mRNA is exported to the cytoplasm and translated into ORF1p and ORF2p, which form complexes with the mRNA and relocate to the nucleus where retrotransposition occurs by target-primed reverse transcription (TPRT).

    “Upon activation, LINEs are transcribed by RNA polymerase II, and the resulting mRNA transcript is then exported into the cytoplasm, where it is translated into two proteins: ORF1p, an RNA-binding protein, and ORF2p, which acts both as an endonuclease and a reverse transcriptase (Fig. 4).”
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    • cites Kazazian and Moran, 2017

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    Premisecitation

    Patients with type 2 diabetes mellitus display increased levels of TNF-α and mtDNA in the circulation, and mtDNA correlates with insulin resistance.

    “Patients with type 2 diabetes mellitus also display increased levels of the pro-inflammatory factor TNF-α and mtDNA in the circulation, and the latter correlates with insulin resistance (Yuzefovych et al., 2019).”
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    • cites Yuzefovych et al., 2019 source

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    Premisecitation

    Inhibiting VDAC oligomerization with VBIT-4 decreases mtDNA release and IFN signaling in a mouse model of systemic lupus erythematosus and ameliorates disease severity.

    “Furthermore, inhibiting VDAC oligomerization by using the inhibitor VBIT-4 has been shown to decrease mtDNA release and IFN signaling in a mouse model of systemic lupus erythematosus and ameliorated the disease severity (Kim et al., 2019), suggesting that inhibition of VDAC oligomerization and perhaps mPTP might represent an effective therapeutic strategy to improve diseases involving cytosolic mt”
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    • cites Kim et al., 2019 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Evidence for L1 retrotransposition during early embryogenesis has been reported in humans.

    “Evidence for L1 retrotransposition during early embryogenesis has also been reported in humans, (Brouha et al., 2002; van den Hurk et al., 2007).”
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    • cites Brouha et al., 2002 source

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    • cites van den Hurk et al., 2007 source

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    Premisecitation

    Methylation of CpG sites at the 5' UTR hinders L1 promoter activity and prevents retrotransposition.

    “In the case of L1, methylation of CpG sites at the 5’ UTR hinders L1 promoter activity and prevents retrotransposition (Hata and Sakaki, 1997; Woodcock et al., 1997).”
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    • cites Hata and Sakaki, 1997

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    • cites Woodcock et al., 1997 source

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    Premisecitation

    The LINE-1 (L1) family can reach up to 6 kb in length, with more than 500,000 copies, is the most abundant human LINE, and comprises 17% of human genetic material.

    “In contrast, the LINE-1 (L1) family can reach up to 6 kb in length, and with more than 500,000 copies is the most abundant human LINE, comprising 17% of the human genetic material (Cardelli, 2018).”
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    • cites Cardelli, 2018 source

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    Premisecitation

    Deletion of Bax extends ovarian function in aged female mice and results in improvements in age-related phenotypes such as increased bone mineral density and strength, better retention of lean body mass, and decreased anxiety.

    “Furthermore, deletion of Bax has been shown to extend ovarian function in aged female mice, and also resulted in significant improvements in a number of age-related phenotypes, such as increased bone mineral density and strength, better retention of lean body mass, and decreased anxiety (Perez et al., 2007).”
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    • cites Perez et al., 2007 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

  • May combine two claims.

    Premisecitation

    MeCP2 represses L1 expression and retrotransposition.

    “In support of this, methyl-CpG-binding protein 2 (MeCP2) represses L1 expression and retrotransposition (Yu et al., 2001).”
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    • cites Yu et al., 2001

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    Premisecitation

    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).”
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    • cites Simon et al., 2019 source

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    Premisecitation

    Alu elements are 300 bp in length, present in more than one million copies, and represent 11% of the human genome.

    “The latter includes the Alu elements, which are 300 bp in length and are present in more than one million copies, representing 11% of the human genome (Cardelli, 2018).”
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    • cites Cardelli, 2018 source

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    Premisecitation

    Transposable elements make up approximately 50% of the human genome and contribute significantly to genetic variation at the population level.

    “TEs make up approximately 50% of the human genome and contribute significantly to genetic variation at the population level (Maxwell, 2016).”
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    • cites Maxwell, 2016 source

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    Premisecitation

    SIRT6 is a histone deacetylase that regulates longevity.

    “Another mechanism of age-related retrotransposon activation is reduced expression of SIRT6, a histone deacetylase that has been shown to regulate longevity (Kanfi et al., 2012).”
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    • cites Kanfi et al., 2012 source

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    Premisecitation

    Retrotransposons are the majority class of TEs in the human genome and are divided into LTR retrotransposons and non-LTRs, with non-LTRs subdivided into LINEs and SINEs.

    “Retrotransposons are the majority class of TEs present in the human genome, and are themselves divided into two types: LTR retrotransposons, which comprise long terminal repeats (LTRs) on both ends, and non-LTRs that do not contain these repeats and are subdivided into long-interspersed nuclear elements (LINEs) and short-interspersed nuclear elements (SINEs) (Goodier, 2016).”
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    • cites Goodier, 2016 source

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    Premisecitation

    The L1 family includes the only endogenous autonomous retroelements that retain the capacity to autonomously retrotranspose, and their protein products (Orf2p and Orf1p) mediate retrotransposition of SINE non-autonomous elements.

    “In addition, the L1 family includes the only endogenous autonomous retroelements that still retain the capacity to autonomously retrotranspose, and their protein products (Orf2p and Orf1p) are also responsible for mediating retrotransposition of SINE non-autonomous elements (Cardelli, 2018).”
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    • cites Cardelli, 2018 source

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    Premisecitation

    Treatment with Bax-inhibiting peptide V5 (BIP-V5) reduced inflammation and improved lung pathology and survival in a mouse model of IPF.

    “Consistent with that, treatment with Bax-inhibiting peptide V5 (BIP-V5), which inhibits Bax activation in the cytosol, reduced inflammation and improved lung pathology and survival in a mouse model of IPF (Suzuki et al., 2017).”
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    • cites Suzuki et al., 2017

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

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    Premisecitation

    Bax expression is increased in alveolar epithelial cells of patients with IPF, suggesting involvement of MOMP in the etiology of the disease.

    “For example, it has been shown that Bax expression is increased in alveolar epithelial cells of patients with IPF (Plataki et al., 2005), suggesting an involvement of MOMP in the etiology of the disease.”
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    • cites Plataki et al., 2005 source

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    Premisecitation

    Treating pregnant female mice with the nucleoside analogue azidothymidine (AZT) blocks oocyte attrition and improves oocyte viability in embryos.

    “It was shown that treating pregnant female mice with the nucleoside analogue azidothymidine (AZT) blocked oocyte attrition and improved the oocyte viability in embryos (Malki et al., 2014).”
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    • cites Malki et al., 2014 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

  • May combine two claims.

    Premisecitation

    Inhibiting the synthesis of cytoplasmic L1 DNA, either by using NRTIs or by shRNA knockdown of L1, reduces activation of IFN genes and the magnitude of the SASP, demonstrating that accumulation of L1 cDNA in the cytoplasm of senescent cells is an important contributor to the maintenance of the pro-inflammatory phenotype.

    “Inhibiting the synthesis of cytoplasmic L1 DNA, either by using nucleoside reverse transcriptase inhibitors (NRTIs) or by shRNA knockdown of L1, was sufficient to reduce the activation of IFN genes and the magnitude of the SASP, demonstrating that accumulation of L1 cDNA in the cytoplasm of senescent cells is an important contributor to the maintenance of the pro-inflammatory phenotype (De Cecco”
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    • cites De Cecco et al., 2019 source

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    Premisecitation

    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).”
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    • cites De Cecco et al., 2019 source

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    • cites Simon et al., 2019 source

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    Premisecitation

    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).”
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    • cites Simon et al., 2019 source

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    Premisecitation

    Reactivation of LINE-1 elements during late senescence is accompanied by accumulation of L1 cytoplasmic cDNA, due in part to a decrease in the levels of the exonuclease TREX1, and activation of a cGAS-STING-dependent IFN-I response and pro-inflammatory phenotype.

    “Reactivation of LINE-1 elements during late senescence is accompanied by accumulation of L1 cytoplasmic cDNA, due in part to a decrease in the levels of the exonuclease TREX1 (De Cecco et al., 2019), and activation of a cGAS-STING-dependent IFN-I response and pro-inflammatory phenotype (De Cecco et al., 2019).”
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    • cites De Cecco et al., 2019 source

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    Premisecitation

    Alu RNA activates the NLRP3 inflammasome, stimulating cytokine production and MyD88-induced cytotoxicity of RPE cells, thus contributing to the etiology of GA.

    “The latter then activates the NLRP3 inflammasome, stimulating cytokine production and MyD88-induced cytotoxicity of RPE cells, thus contributing to the etiology of GA (Tarallo et al., 2012).”
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    • cites Tarallo et al., 2012 source

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    Premisecitation

    NRTIs can also inhibit telomerase and are thought to contribute to accelerated aging phenotypes associated with HIV patients.

    “Moreover, NRTIs can also inhibit telomerase and are thought to contribute to accelerated aging phenotypes associated with HIV patients (Hukezalie et al., 2012; Leeansyah et al., 2013).”
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    • cites Hukezalie et al., 2012 source

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    • cites Leeansyah et al., 2013 source

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    Premisecitation

    Caloric restriction extends lifespan in many organisms and decreases the burden of senescent cells.

    “an intervention which has been shown to extend lifespan in a plethora of organisms and decrease the burden of senescent cells (Fontana et al., 2018; Mercken et al., 2012).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Fontana et al., 2018 source

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    • cites Mercken et al., 2012 source

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    Premisecitation

    In a model of chronological aging in S. cerevisiae, Ty1 mobility is increased in yeast populations with advanced age, and retrotransposition is associated with chromosome rearrangements.

    “In a model of chronological aging in S. cerevisiae, Ty1 mobility was increased in yeast populations with advanced age, and retrotransposition was associated with chromosome rearrangements (Maxwell et al., 2011).”
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    • cites Maxwell et al., 2011 source

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    Premisecitation

    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).”
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    • cites Simon et al., 2019 source

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    Premisecitation

    Chronic NRTI treatment induces adverse side effects in human patients, such as hepatotoxicity, as it also inhibits the mitochondrial DNA polymerase γ.

    “Although mouse studies suggest that NRTIs are an effective treatment option for L1-driven age-associated inflammation and pathologies, chronic NRTI treatment has been shown to induce adverse side effects in human patients, such as hepatotoxicity, as it also inhibits the mitochondrial DNA polymerase γ (Montessori et al., 2003; Wu et al., 2017).”
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    • cites Montessori et al., 2003 source

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    • cites Wu et al., 2017

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    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites De Cecco et al., 2019 source

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    • cites Simon et al., 2019 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

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    Premisecitation

    Retrotransposition can occur during neuronal differentiation and influence cell fate.

    “In addition, retrotransposition can also occur during neuronal differentiation and influence cell fate (Muotri et al., 2005).”
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    • cites Muotri et al., 2005 source

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    Premisecitation

    NRTIs effectively inhibit the reverse transcriptase activity of the L1 protein ORF2p, consequently reducing retrotransposition.

    “Consistent with this, another group showed that NRTIs effectively inhibit the reverse transcriptase activity of the L1 protein, ORF2p, consequently reducing retrotransposition (Dai et al., 2011).”
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    • cites Dai et al., 2011 source

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    Premisecitation

    Unrestricted movement of L1s within the genome can be detrimental, with over 60 human genetic diseases attributed to retrotransposon insertions.

    “Unrestricted movement of L1s within the genome can be detrimental, with over 60 human genetic diseases being attributed to retrotransposon insertions (Goodier and Kazazian, 2008).”
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    • cites Goodier and Kazazian, 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The ability of foreign nucleic acids to stimulate immune responses has been known since the 1960s.

    “The ability of foreign nucleic acids to stimulate immune responses has been known since the 1960s (Isaacs et al., 1963; Rotem et al., 1963).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Isaacs et al., 1963 source

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    • cites Rotem et al., 1963 source

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    Premisecitation

    In senescence, RT activation appears months later, whereas CCF formation appears within days.

    “this activation only occurs late in senescence (a few months), versus CCF formation (a few days)”
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    • cites De Cecco et al., 2019 source

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    Premisecitation

    Senolytic treatment in animal models of COVID-19 eliminates virus-induced senescent cells and reduces inflammation and mortality, suggesting senescent cells are a potential therapeutic target in viral infections.

    “Notably, senolytic treatment in animal models of COVID-19 eliminates virus-induced senescent cells and reduces inflammation and mortality, suggesting that senescent cells are a potential therapeutic target in viral infections (Camell et al., 2021; Lee et al., 2021).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Camell et al., 2021 source

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    • cites Lee et al., 2021 source

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    • Rests on an assumption: Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

  • May combine two claims.

    Premisecitation

    cGAS itself can act as an autophagy ligand for MN degradation, suggesting autophagic degradation may be a common fate of cGAS-associated cytoDNA.

    “Recent work has shown that cGAS itself can act as an autophagy ligand for MN degradation, suggesting that autophagic degradation may be a common fate of cGAS-associated cytoDNA (Zhao et al., 2021).”
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    • cites Zhao et al., 2021 source

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    Premisecitation

    Single-cell genome sequencing has advanced knowledge of how MN form and how chromothripsis occurs.

    “Single cell genome sequencing has greatly improved understanding of the mechanism of MN formation and chromothripsis (Umbreit et al., 2020)”
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    • cites Umbreit et al., 2020 source

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    Premisecitation

    These parallels include nuclear envelope dysfunction, changes in lamina structure, accumulation of DNA damage, and downstream activation of cGAS.

    “These parallels include nuclear envelope dysfunction, changes in lamina structure, accumulation of DNA damage, and downstream activation of cGAS (Liu et al., 2018).”
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    • cites Liu et al., 2018 source

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    Premisecitation

    Senescence can be induced by viral infection, senescent cells activate anti-viral pathways, and replication of several viruses is impaired in senescent cells dependent on the SASP.

    “Specifically, senescence can be induced by viral infection (Seoane et al., 2020), senescent cells activate anti-viral pathways (Rai et al., 2017) and replication of several viruses is impaired in senescent cells dependent on the SASP (Baz-Martinez et al., 2016; Seoane et al., 2020).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Seoane et al., 2020

      Not checked in the free run.

    • cites Rai et al., 2017 source

      Not checked in the free run.

    • cites Baz-Martinez et al., 2016 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The observation of multiple cytoDNA species in senescent cells echoes the role of foreign DNAs as activators of cellular anti-virus mechanisms and reinforces the links between cell senescence and anti-virus programs.

    “Fourth, the observation of multiple cytoDNA species in senescent cells echoes the role of foreign DNAs as activators of cellular anti-virus mechanisms and reinforces the links between cell senescence and anti-virus programs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Under the microscope, CCF and MN are hard to tell apart at present and are frequently mixed up.

    “CCF and MN are currently difficult to distinguish microscopically and are often confused (Table 1)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Table 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells form CCF only after they arrest in the cell cycle, a pattern consistent with formation that does not require the cell cycle.

    “in senescent cells, CCF formation occurs after cell cycle arrest, which is consistent with a cell cycle-independent mechanism of formation (Ivanov et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ivanov et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple forms of cytoDNA may be secreted and act as a cell non-autonomous signal in physiology and disease, which has been proposed as a biomarker for sterile inflammation.

    “Multiple forms of cytoDNA may be secreted and act as a cell non-autonomous signal in physiology and disease, which has been proposed as a biomarker for sterile inflammation (Ruffatti et al., 1990).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ruffatti et al., 1990 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CytoDNA species share similar signaling pathways, most prominently the cGAS-STING pathway, although mtDNA, MN, and other DNA damage-associated DNA fragments are thought to also activate the AIM2 and NLRP3 inflammasome pathway.

    “Third, cytoDNA species share similar signaling pathways, most prominently the cGAS-STING pathway, although mtDNA, MN, and other DNA damage-associated DNA fragments are thought to also activate the AIM2 and NLRP3 inflammasome pathway (Di Micco et al., 2016; Motwani and Fitzgerald, 2017; Zhong et al., 2018).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Di Micco et al., 2016 source

      Not checked in the free run.

    • cites Motwani and Fitzgerald, 2017

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    • cites Zhong et al., 2018 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The antimicrobial peptide LL37 enhances transport of aggregated DNA to early endosomes, leading to TLR9 activation and interferon production.

    “the anti-microbial peptide LL37 has been shown to promote trafficking of aggregated DNA structures to the early endosome, promoting TLR9 activation and interferon production (Lande et al., 2007)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lande et al., 2007 source

      Not checked in the free run.

109 of 109

  • The paper relies on this without support.

    The cytoDNA field lacks sufficient characterization and distinction of cytoDNA species, and their formation mechanisms, functional scope, and disease contributions are incompletely understood.

    “While the role of endogenous cytoDNA in innate immune activation is well established, the cytoDNA species themselves are often poorly characterized and difficult to distinguish, and their mechanisms of formation, scope of function and contribution to disease are incompletely understood.”

  • The paper relies on this without support.

    Findings from mouse models of age-related conditions and interventions translate to human age-associated diseases.

    “These studies suggest that inhibition of MOMP by targeting Bax might represent a valuable strategy to improve age-related conditions and extend healthspan.”
    “Although mouse studies suggest that NRTIs are an effective treatment option for L1-driven age-associated inflammation and pathologies, chronic NRTI treatment has been shown to induce adverse side effects in human patients, such as hepatotoxicity, as it also inhibits the mitochondrial DNA polymerase γ (Montessori et al., 2003; Wu et al., 2017).”

  • The paper relies on this without support.

    CCF and mtDNA are partially localized in endosomes, where they can be sensed, degraded, or secreted.

    “Second, although the mechanisms involved are poorly understood, CCF and mtDNA are thought to be partially localized in endosomes, where they can be sensed, degraded, or potentially secreted by the cell.”

  • The paper relies on this without support.

    Degradation by DNases such as lysosomal DNase2 or cytoplasmic TREX acts as a negative feedback to downregulate DNA sensor activation for all forms of endogenous cytoDNA.

    “Degradation by DNases, such as lysosomal DNase2 or cytoplasmic TREX has been observed for all forms of endogenous cytoDNA, acting as a negative feedback to downregulate DNA sensor activation.”

  • The paper relies on this without support.

    Key regulators of the senescent cell phenotype are central to virus defense mechanisms and are often targeted by viruses.

    “At the molecular level, key regulators of the senescent cell phenotype are also central to virus defense mechanisms and often targeted by viruses, including tumor suppressors pRB and p53, histone chaperone HIRA, PML nuclear bodies, as well as cGAS, STING, and ISGs.”

  • The paper relies on this without support.

    Chronic diseases such as cardiovascular disease, neurodegenerative disease, and sarcopenia typically occur at advanced age.

    “These chronic diseases—also including cardiovascular disease, neurodegenerative disease, sarcopenia, etc.—share a common variable, the typically advanced age of the patient.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Senescence-associated DNA damage is sensed through the cGAS-STING pathway, which activates IRF3 and NF-κB and induces interferon and SASP responses.

    “Senescence-associated DNA damage is sensed via the cGAS–STING pathway, which activates the transcription factors interferon regulatory factor 3 (IRF3) and NF-κB, thereby inducing an interferon and SASP response55–58”

    From COVID-19 and cellular senescence (2023) · cites this paper as [57]

  • TLR9 binds double-stranded DNA in endosomes, recruits MYD88 to activate NFkB, and stimulates expression of inflammatory cytokines.

    “This includes TLR9 (Toll‐like receptor 9), which binds to double‐stranded DNA engulfed in endosomes, particularly bacterial DNA or mtDNA. This recruits adaptor protein MYD88 (myeloid differentiation primary response 88) to activate NFκB and stimulate the expression of inflammatory cytokines.”

    From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Miller et al, 2021

The citation lists haven’t been fetched yet

References 219 · Cited by 288

Research works printed but not linked: 1

  1. Pau, 2014, Antiretroviral therapy: current drugs, Infect. Dis. Clin. North Am., 28, 371, 10.1016/j.idc.2014.06.001 · DOI

Authors
Miller, K. N., Victorelli, S. G., Salmonowicz, H., Dasgupta, N., Liu, T., Passos, J. F., & Adams, P. D.
Affiliations
  • Sanford Burnham Prebys Medical Discovery Institute (US)
  • Mayo Clinic (US)
Corresponding author
  • Passos, João F.
  • Adams, Peter D.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2021-10
Volume
184
Issue
22
Pages
5506-5526
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2021.09.034
PMC
PMC8627867
OpenAlex
W3208824634
Semantic Scholar
f0c06e602ee1b6edad4eabee80e9ebbed9931cf1
Cited by
288
References
219
Citations by year
2026: 54 · 2025: 81 · 2024: 67 · 2023: 51 · 2022: 34 · 2021: 1
FWCI
3.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Newcastle University ePrints (Newcastle Univesity)
Funders
  • National Institutes of Health (UL1TR002377)
  • National Institute on Aging (P01AG031862, R01AG068048, F32AG066459, P01AG062413, R01AG071861)
  • National Cancer Institute (UH3CA268103, UG3CA268103)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
cytoplasmic DNA, innate immunity, inflammation, aging, age-related diseases, DNA sensing, therapeutic target
MeSH terms
Aging, Animals, Cytoplasm, Disease, DNA, Humans, Retroelements, Micronucleus, Germline

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