Short-term gain, long-term pain: the senescence life cycle and cancer
Open accessAbstract
Originally thought of as a stress response end point, the view of cellular senescence has since evolved into one encompassing a wide range of physiological and pathological functions, including both protumorignic and antitumorigenic features. It has also become evident that senescence is a highly dynamic and heterogenous process. Efforts to reconcile the beneficial and detrimental features of senescence suggest that physiological functions require the transient presence of senescent cells in the tissue microenvironment. Here, we propose the concept of a physiological “senescence life cycle,” which has pathological consequences if not executed in its entirety.
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Written from the paper’s full text.
TL;DR
This review by Chan and Narita argues that senescence is an autonomous tumor suppressor but a nonautonomous tumor "modulator," and that its net effect on cancer depends on whether the full "senescence life cycle"—induction, SASP-mediated microenvironment modulation, and immune clearance—runs to completion. Failure to clear senescent cells, particularly at early/pre-neoplastic stages, can instead promote tumorigenesis through a chronically inflamed, protumorigenic microenvironment.
Key findings
- Senescence is best viewed as a "syndrome"—the incremental acquisition of multiple effector phenotypes (chromatin reorganization, gene expression, secretome, metabolism) rather than a binary event, which explains the lack of a single specific biomarker and the marked heterogeneity of senescent cells.
- In telomere-driven tumor suppression, apoptosis is dispensable: in a telomerase-deficient Burkitt's lymphoma mouse model, p53-intact mice remain tumor-resistant even with apoptosis blocked, and microlymphomas staining positive for senescence markers are observed (Feldser and Greider 2007).
- Oncogenic dose matters for OIS: high-level but not low-level Ras induces senescence in mammary glands in vivo; low-level Ras tumors eventually arise and are accompanied by spontaneous up-regulation of oncogenic Ras to senescence-inducing levels, with senescent mosaicism observed (Sarkisian et al. 2007).
- Most (>90%) human cancers aberrantly up-regulate telomerase (Kim et al. 1994; Shay and Bacchetti 1997; Jafri et al. 2016).
- The cGAS–STING cytosolic DNA-sensing pathway, triggered by cytoplasmic chromatin fragments, is a critical upstream activator of the NFkB-driven inflammatory SASP; loss of this pathway reduces senescence surveillance and increases tumorigenesis in the liver OIS model.
- Autophagy regulates the SASP non-unidirectionally: general autophagy is activated in senescence and couples spatially with mTOR to promote SASP translation/stabilization, while p62-mediated selective autophagy is inhibited, stabilizing GATA4 to drive NFkB-dependent SASP genes.
Methods
- Narrative review; no primary experimental data, samples, or statistical analyses are reported.
- Synthesizes published literature on telomere shortening, oncogene-induced senescence (OIS), PTEN loss-induced cellular senescence (PICS), therapy-induced senescence (TIS), SASP biology, chromatin/epigenetic changes, autophagy, and senolytics.
- Organizes the argument around a conceptual "senescence life cycle" model (Fig. 1) and a model of OIS as a response to spontaneous up-regulation of oncogenic signaling (Fig. 2), with a schematic of autophagy-related SASP regulation (Fig. 3).
Limitations
- The paper states no explicit limitations; as a review it presents no new data and its conclusions rest on synthesis of cited primary studies.
- The text itself makes evident that several key points remain unresolved: whether Notch signaling is activated during progressive HSC senescence is stated as not yet elucidated; the causal relevance of epigenetic changes during senescence is described as "elusive"; and whether DNA methylation and chromatin accessibility are physically or functionally related "has not been tested."
- The authors note that the antitumor effect of TIS is "less evident and highly context- and model-dependent," and that the relevance of autophagy in senescence is "highly context-dependent," limiting generalization.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Interpretationreasoning
Senescence-associated disorders can be viewed as a consequence of failure in execution of the senescence life cycle.
“Senescence-associated disorders can perhaps be viewed as a consequence of a failure in the execution of the “senescence life cycle” (Fig. 1).”
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Phenotypic heterogeneity of senescent cells depends on cell type, context, and the nature of the upstream stressor.
“This may further explain the well-described phenotypic heterogeneity of senescent cells, which manifests from the level of gene expression, where the phenotype depends on cell type, context, and the nature of the upstream stressor”
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- cites van Deursen 2014
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- cites Marthandan et al. 2016
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- Premisecitation
Stromal cell senescence can be either antitumorigenic or protumorigenic depending on the context.
“This is also important for stromal cell senescence, which can be either antitumorigenic or protumorigenic depending on the context (for review, see Pérez-Mancera et al. 2014).”
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- Premisecitation
Misregulation of senescence within tissues can promote pathological conditions, including cancer and other age-related disorders.
“Misregulation of senescence within tissues can promote pathological conditions, including cancer and other age-related disorders (Burton and Krizhanovsky 2014; Muñoz-Espín and Serrano 2014; He and Sharpless 2017).”
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- cites Muñoz-Espín and Serrano 2014
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- cites He and Sharpless 2017
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- Interpretationcitation
At least in some contexts, senescence can be seen as a progressive process initiated by cellular activation, developing senescence effectors, modulating the tissue microenvironment, and finally recruiting immune cells to mediate resolution.
“At least in some contexts, senescence can be seen as a progressive process that is initiated by cellular activation, develops senescence effectors, modulates the tissue microenvironment, and, finally, recruits immune cells to mediate resolution (Krizhanovsky et al. 2008).”
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- Premisenone given
Senescent cells typically secrete diverse factors, known as the senescence-associated secretory phenotype (SASP), that affect the tumor microenvironment.
“Known as the senescence-associated secretory phenotype (SASP), senescent cells typically secrete diverse factors that affect the tumor microenvironment.”
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Functions of senescent cells in tumor suppression or tissue homeostasis are often reinforced by or dependent on their transient presence within the microenvironment, where senescent cells are eventually removed by immune cells.
“These functions of senescent cells in tumor suppression or tissue homeostasis are often reinforced by or dependent on their transient presence, respectively, within the microenvironment, where senescent cells are eventually removed by immune cells (Ito et al. 2017).”
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- Premisecitation
OIS is an alternative autonomous tumor-suppressive function of senescence where some mitogenic oncogenes or loss of tumor suppressors can paradoxically induce persistent proliferative arrest.
“an alternative autonomous tumor-suppressive function of senescence can be seen in OIS, where some “mitogenic” oncogenes (or loss of tumor suppressors, as exemplified by PTEN loss-induced cellular senescence [PICS]) can paradoxically induce persistent proliferative arrest”
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- Premisecitation
Exceptions where short telomeres promote cancer tend to be associated with a p53 defect.
“Importantly, these exceptions, where short telomeres counterintuitively promote the incidence of cancer, tend to be associated with a p53 defect (Chin et al. 1999; Artandi et al. 2000).”
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- cites Artandi et al. 2000
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- Premisecitation
Replicative senescence can be at least partially rescued by ectopic expression of telomerase in culture.
“Indeed, replicative senescence can be at least partially rescued by ectopic expression of telomerase in culture (Bodnar et al. 1998; Vaziri and Benchimol 1998)”
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- cites Vaziri and Benchimol 1998
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- Premisecitation
High-level but not low-level Ras induces senescence in mammary glands in vivo in a titratable mouse breast cancer model.
“this study also showed that high-level but not low-level Ras induces senescence in mammary glands in vivo.”
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- Premisecitation
OIS was first described in human diploid fibroblasts in culture following ectopic expression of constitutively active HRas or its downstream effectors MEK or RAF1.
“OIS was first described in human diploid fibroblasts in culture, where a phenotype similar to replicative senescence was observed following ectopic expression of constitutively active HRas (Serrano et al. 1997) or its downstream effectors: MEK (Lin et al. 1998) or RAF1 (Zhu et al. 1998).”
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- cites Lin et al. 1998
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DDR markers can accumulate at telomeres that are not yet critically shortened, independently of telomere length.
“This can occur independently of telomere length, as markers of DDR can accumulate at telomeres that are not yet critically shortened (Fumagalli et al. 2012).”
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- Premisecitation
Tumors derived from low-level Ras are accompanied by spontaneous up-regulation of oncogenic Ras to a level similar to that of high-level Ras, which induces senescence.
“Interestingly, these tumors (derived from low-level Ras) are accompanied by the spontaneous up-regulation of oncogenic Ras to a level similar to that of high-level Ras, which induces senescence.”
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- Premisecitation
DNA damage can induce senescence in cancer cells in some contexts, called therapy-induced senescence (TIS).
“Importantly, DNA damage can induce senescence even in cancer cells in some contexts (called therapy-induced senescence [TIS]) (Schmitt et al. 2002; Nardella et al. 2011; Acosta and Gil 2012)”
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- cites Nardella et al. 2011
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- Premisecitation
Senescent cell populations possess a high degree of cell-to-cell variability that exceeds that of quiescent cells.
“Senescent cell populations have also been described to possess a high degree of cell-to-cell variability that exceeds that of quiescent cells (Wiley et al. 2017)”
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- Interpretationcitation
Senescence is an effector of tumor suppression in short telomere-mediated tumor suppression in a mouse Burkitt's lymphoma model.
“Instead, microlymphomas, which stain positive for markers of senescence, are observed, demonstrating the importance of senescence as an effector of tumor suppression in this context (Feldser and Greider 2007).”
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- Premisecitation
Most (>90%) human cancers aberrantly up-regulate telomerase.
“most (>90%) human cancers aberrantly up-regulate telomerase (Kim et al. 1994; Shay and Bacchetti 1997; Jafri et al. 2016).”
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- cites Shay and Bacchetti 1997
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- cites Jafri et al. 2016
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- Interpretationreasoning
There is a trade-off between aging and cancer, considering the autonomous aspect of senescence.
“This appears to support the idea of a trade-off between aging and cancer (Kirkwood and Austad 2000; Tyner et al. 2002), although this view considers only the autonomous aspect of senescence”
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Residual DNA damage foci contribute to maintenance of cell cycle arrest.
“These residual DNA damage foci appear to contribute to the maintenance of cell cycle arrest (Passos et al. 2010; Rodier et al. 2011)”
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- Interpretationcitation
The antitumor effect of TIS is less evident and highly context- and model-dependent.
“However, the antitumor effect of TIS is less evident and highly context- and model-dependent (Dörr et al. 2013; Tato-Costa et al. 2016; Demaria et al. 2017; Yang et al. 2017b).”
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- cites Tato-Costa et al. 2016
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- cites Demaria et al. 2017
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- Premisecitation
Oncogene dose and the presence of cooperating mutations influence cellular outcome between entry into senescence and tumorigenesis.
“the nature of the activating oncogenic signal influences the balance between entry into senescence and tumorigenesis, where oncogene dose and the presence of other cooperating mutations have been suggested to influence cellular outcome”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Quintanilla et al. 1986
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- cites Tuveson et al. 2004
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- cites Sarkisian et al. 2007
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Senescent mosaicism is observed within low-Ras-initiated tumors with spontaneous up-regulation of oncogenic Ras.
“Furthermore, they observed senescent mosaicism within those low-Ras-initiated tumors with spontaneous up-regulation of oncogenic Ras.”
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- Premisecitation
Apoptosis is dispensable for short telomere-mediated tumor suppression provided p53 is intact.
“Feldser and Greider (2007) report that apoptosis is dispensable for short telomere-mediated tumor suppression. Provided that p53 is intact, mice remain resistant to tumor formation even following the blockade of apoptosis.”
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- Interpretationcitation
Intrinsic limitation of proliferative capacity can contribute to a reduction in both tissue-regenerative capacity and cancer initiation.
“These data suggest that the intrinsic limitation of proliferative capacity can contribute to a reduction in both tissue-regenerative capacity and cancer initiation (Chang 2005; Liu et al. 2011).”
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- cites Liu et al. 2011
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- Premisecitation
Expression of retrotransposable elements and satellite sequences increases during replicative senescence.
“Indeed, expression of retrotransposable elements and satellite sequences has been shown to increase during replicative senescence (De Cecco et al. 2013b).”
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- Premisecitation
Several modes of senescence-associated cell-cell communication have been shown, including the SASP, cell fusion, cytoplasmic bridges, cell-cell contact, and secreted extracellular vesicles.
“Several modes of senescence-associated cell–cell communication have been shown, including the SASP, cell fusion (Chuprin et al. 2013), cytoplasmic bridges (Biran et al. 2015), cell–cell contact (Nelson et al. 2012; Hoare et al. 2016; Ito et al. 2017; Parry et al. 2018), and secreted extracellular vesicles (Takasugi et al. 2017).”
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- Premisecitation
Senescent cells actively engage in communication with other cells and the extracellular matrix within the tissue microenvironment.
“senescent cells are actively engaged in communication with other cells and the extracellular matrix (ECM) within the tissue microenvironment.”
Quote in the paperSubstantial claim - Interpretationcitation
Cells that have escaped from senescence would be more susceptible to subsequent transformation.
“This suggests that cells that have escaped from senescence would be more susceptible to subsequent transformation (Cruickshanks et al. 2013).”
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- Interpretationcitation
Decline in DNA methylation of heterochromatic regions with repetitive sequences in senescence or cancer potentially causes genome instability through reactivation of transposons.
“the decline in DNA methylation of heterochromatic regions with repetitive sequences (e.g., transposons, satellite DNAs) in senescence or cancer potentially causes genome instability through a reactivation of transposons for instance.”
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Higher levels of p16 and HMGA are correlated with the irreversibility of the senescence arrest.
“Interestingly, higher levels of p16 and HMGA, both of which are critical for SAHF formation, are correlated with the irreversibility of the senescence arrest (Beauséjour et al. 2003; Narita et al. 2006)”
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- cites Narita et al. 2006
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Lamin B1 declines during senescence.
“the level of Lamin B1 declines during senescence (Shimi et al. 2011; Freund et al. 2012; Sadaie et al. 2013; Shah et al. 2013; Criscione et al. 2016).”
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- cites Freund et al. 2012
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SADS appears to be more universal than SAHFs.
“SADS appears to be more universal than SAHFs (Swanson et al. 2013).”
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- Premisereasoning
Chromatin structural changes in senescence are mediated by a differential association with the nuclear membrane.
“Instead, these chromatin structural changes are mediated by a differential association with the nuclear membrane.”
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Leaked cytoplasmic DNA can trigger nonautonomous activity via activation of the cGAS/STING pathway.
“emerging evidence indicates that leaked cytoplasmic DNA in turn can also trigger a discrete aspect of senescence, the nonautonomous activity, via activation of the cGAS/STING pathway”
Quote in the paperSubstantial claim - Interpretationcitation
SAHFs are formed through the spatial repositioning of pre-existing repressive histone marks.
“These observations have led to the model in which SAHFs are formed through the spatial repositioning of pre-existing repressive histone marks (Chandra et al. 2012, 2015).”
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SAHFs and SADS appear not to require alterations in repressive marks H3K9me3 and H3K27me3.
“both of these newly formed heterochromatins (SAHFs) and unfolding of constitutive heterochromatins (SADS) appear not to require alterations in repressive marks H3K9me3 and H3K27me3 (Chandra et al. 2012; Swanson et al. 2013).”
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Lamin B1 is a substrate of autophagic degradation.
“Lamin B1 is also a substrate of autophagic degradation (see below; Dou et al. 2015; Lenain et al. 2015).”
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SADS represents a distension of α-satellite and satellite II sequences during senescence.
“senescence-associated distension of satellites (SADS) represents a distension of α-satellite and satellite II sequences, which are heterochromatic and normally compacted at the (peri)centromere, during senescence.”
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Transformation-associated changes in DNA methylation status do not stem from senescence escape but reflect alterations independently associated with both aging and increased cancer risk.
“the investigators propose that transformation-associated changes in DNA methylation status do not stem from senescence escape but rather reflect alterations that can be associated independently with both aging and increased cancer risk (Xie et al. 2018).”
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- Premisecitation
A progressive switch of secretory factors has been shown in the classical senescence model in culture, where NOTCH signaling is transiently activated during an early phase of senescence triggered by oncogenic HRas or DNA damage.
“More recently, a progressive switch of secretory factors has also been shown in the classical senescence model in culture, where NOTCH signaling is transiently activated during an early phase of senescence triggered by oncogenic HRas or DNA damage (Hoare et al. 2016).”
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Inflammatory cytokines reinforce the activity of those transcription factors through a positive feedback loop, locally amplifying signaling.
“these inflammatory cytokines in turn reinforce the activity of those transcription factors through a positive feedback loop; thus, the signaling is locally amplified (Kuilman et al. 2008; Orjalo et al. 2009; Acosta et al. 2013; Pérez-Mancera et al. 2014).”
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Innate immune cells, in this case natural killer cells, are sufficient in mediating tumor-suppressive clearance of senescent cells in mice lacking T and B cells.
“A follow-up study in mice lacking T and B cells reinforced the sufficiency of innate immune cells (in this case, natural killer cells) in mediating tumor-suppressive clearance of senescent cells (Iannello et al. 2013).”
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The central mode of SASP regulation is a hierarchical model where genes encoding proximal inflammatory cytokines IL1 and IL6 are induced by NFkB and C/EBPβ cooperatively with cofactors such as BRD4.
“The central mode of SASP regulation is a hierarchical model, where the genes encoding the proximal inflammatory cytokines, such as IL1 and IL6, are induced by the inflammatory transcription factors NFkB and C/EBPβ cooperatively with cofactors such as BRD4 (Tasdemir et al. 2016).”
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An association between fibrogenic senescence and chronic tissue damage/inflammation has been reported in an idiopathic pulmonary fibrosis mouse model.
“Association between fibrogenic senescence and chronic tissue damage/inflammation has also been reported in an idiopathic pulmonary fibrosis mouse model (Schafer et al. 2017).”
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- Premisereasoning
The SASP is a highly dynamic process associated with diverse composites, regulatory mechanisms, and functionalities.
“Increasing evidence has revealed that the SASP is a highly dynamic process associated with diverse composites, regulatory mechanisms, and functionalities.”
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Senescent HSCs can be eliminated by innate immune cells, including natural killer cells and tumor-inhibiting M1-state macrophages, through the SASP.
“Through the SASP, senescent HSCs can be eliminated by innate immune cells, including natural killer cells and tumor-inhibiting M1-state macrophages (Krizhanovsky et al. 2008; Lujambio et al. 2013).”
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In the liver OIS model, inhibition of NOTCH signaling in NRas-expressing hepatocytes facilitates their elimination.
“Consistently, in the liver OIS model described above, the inhibition of NOTCH signaling in NRas-expressing hepatocytes facilitates their elimination (Ito et al. 2017).”
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- Interpretationcitation
Senescence surveillance involves multileveled and distinct aspects of the immune system depending on context.
“These studies suggest that the senescence surveillance involves multileveled and distinct aspects of the immune system depending on the context”
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A recent addition to SASP functionality includes its role in cellular reprograming.
“A recent addition to the SASP functionality includes its role in cellular reprograming (for review, see Taguchi and Yamada 2017).”
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A similar role for senescence in tissue repair and wound healing has been shown in liver, kidney, skin, and heart tissue damage models.
“A similar role for senescence in tissue repair and wound healing has been shown in other tissue damage models: the liver (Kong et al. 2012; Kim et al. 2013; Borkham-Kamphorst et al. 2014), kidney (Wolstein et al. 2010), skin (Jun and Lau 2010b; Pitiyage et al. 2011; Demaria et al. 2014), and heart (Zhu et al. 2013).”
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Innate immune system is intact and sufficient for clearance of senescent cells in athymic nude mice in the p53 liver cancer model.
“Although this experiment was conducted in athymic nude mice, which are immunocompromised, their innate immune system is intact and sufficient for the clearance of senescent cells in this particular context.”
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Activated HSCs produce ECM components, contributing to liver fibrosis.
“Activated HSCs produce ECM components, contributing to liver fibrosis.”
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NOTCH signaling negatively regulates the expression of primary inflammatory cytokine production through suppressing the activity of the transcription factor C/EBPβ.
“Mechanistically, it was shown that NOTCH signaling negatively regulates the expression of primary inflammatory cytokine production through suppressing the activity of the transcription factor C/EBPβ.”
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The SASP components of senescent HSCs contain ECM degradation enzymes, thus countering excessive fibrosis.
“Importantly, the SASP components of senescent HSCs contain ECM degradation enzymes, thus countering the excessive fibrosis.”
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Restoration of endogenous p53 after cancer was established led to induction of senescence and tumor regression due to immune clearance of senescent liver tumor cells, not apoptosis.
“Restoration of endogenous p53 after the cancer was established led to the induction of senescence and tumor regression, which was due not to apoptosis but to immune clearance of senescent liver tumor cells.”
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MHCII on OIS melanocytes appears to be sufficient for T-cell activation.
“In contrast to the liver model, however, MHCII on OIS melanocytes appears to be sufficient for T-cell activation (van Tuyn et al. 2017).”
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Upon liver damage, quiescent HSCs become activated and proliferate before developing senescence.
“upon liver damage, quiescent HSCs become activated and proliferate before developing senescence (Krizhanovsky et al. 2008).”
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In the liver model, persistence of senescent HSCs due to failure of immune-mediated elimination promotes liver fibrosis.
“Notably, Krizhanovsky et al. (2008) also showed in the liver model that persistence of senescent HSCs due to the failure of immune-mediated elimination of senescent HSCs rather promotes liver fibrosis, reinforcing the idea of a senescence life cycle.”
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The senescence machinery autonomously serves as a barrier to reprogramming into induced pluripotent stem cells in response to expression of the four Yamanaka factors.
“Earlier studies had shown that the senescence machinery autonomously serves as a barrier to reprogramming into induced pluripotent stem cells (iPSCs) in response to expression of the four Yamanaka factors (Oct3/4, Sox2, Klf4, and c-Myc) (Banito et al. 2009; Hong et al. 2009; Kawamura et al. 2009; Krizhanovsky and Lowe 2009; Li et al. 2009; Marión et al. 2009; Utikal et al. 2009).”
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Senescent fibroblasts promote the tumorigenesis of coexisting premalignant epithelial cells.
“because senescent fibroblasts promote the tumorigenesis of coexisting premalignant epithelial cells (Krtolica et al. 2001).”
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- Interpretationreasoning
Accumulation of senescent cells favors the pathogenesis of aging and age-related disorders.
“as accumulation of senescent cells conversely favors the pathogenesis of aging and age-related disorders.”
Quote in the paperSubstantial claim - Premisecitation
In mice expressing the Yamanaka factors, senescent cells nonautonomously facilitate the reprogramming of surrounding cells through an NFkB-driven secretome, particularly IL6.
“However, using mice expressing those Yamanaka factors, recent studies have shown that senescent cells nonautonomously facilitate the reprogramming of surrounding cells through an NFkB-driven secretome, particularly IL6 (Mosteiro et al. 2016; Chiche et al. 2017).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Mosteiro et al. 2016
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- cites Chiche et al. 2017
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In an obesity-induced liver cancer model, the effect of SASP derived from senescent HSCs on liver cancer is diminished in Sting knockout mice.
“and this effect was diminished in Sting knockout mice (Dou et al. 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dou et al. 2017
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- Premisecitation
The SASP locally facilitates epithelial-mesenchymal transition.
“The SASP also modulates other key hallmarks of cancers through locally facilitating vascularization (Coppé et al. 2006), epithelial-mesenchymal transition (Coppé et al. 2008; Kuilman et al. 2008), tumor invasion (Kim et al. 2017; He et al. 2018), and cellular plasticity (Ritschka et al. 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Coppé et al. 2008
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- cites Kuilman et al. 2008
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In an obesity-induced liver cancer model, the SASP derived from senescent HSCs promotes liver cancer.
“Indeed, in an obesity-induced liver cancer model, the SASP derived from senescent HSCs promotes liver cancer (Yoshimoto et al. 2013), and this effect was diminished in Sting knockout mice (Dou et al. 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Yoshimoto et al. 2013
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- Premisecitation
The cGAS-STING cytosolic DNA-sensing pathway is a critical upstream event to trigger the SASP.
“However, how the inflammatory cascade is initiated had not been clear until a recent series of publications showed that the cGAS–STING cytosolic DNA-sensing pathway, described in the previous section, is a critical upstream event to trigger the SASP (Dou et al. 2017; Glück et al. 2017; Li and Chen 2018; Takahashi et al. 2018).”
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- cites Glück et al. 2017
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- cites Li and Chen 2018
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- Premisecitation
Type I IFNs are not necessarily overrepresented in the SASP, depending on the cell type.
“However, type I IFNs are not necessarily overrepresented in the SASP, depending on the cell type (Dou et al. 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dou et al. 2017
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- Premisecitation
Low levels of cGAS or STING are correlated with poor prognosis in some cancer types.
“and low levels of cGAS or STING are correlated with poor prognosis in some cancer types (Song et al. 2017; Yang et al. 2017a).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Song et al. 2017
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- cites Yang et al. 2017a
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- Interpretationreasoning
The cGAS-STING pathway is critical in the activation of the NFkB-driven SASP.
“Thus, the cGAS–STING pathway is critical in the activation of the NFkB-driven SASP.”
Quote in the paperSubstantial claim - Interpretationreasoning
The physiological roles of senescent cells in facilitating tissue repair in response to injury rely on their clearance after the cessation of the wound healing processes.
“The physiological roles of senescent cells in facilitating tissue repair in response to injury relies on their clearance after the cessation of the wound healing processes, as accumulation of senescent cells conversely favors the pathogenesis of aging and age-related disorders.”
Quote in the paperNot a substantial claim - Premisecitation
Transient or low-level, but not prolonged, exposure to the OIS SASP promotes cellular plasticity and regenerative capacity in mouse skin keratinocytes.
“Consistently, Ritschka et al. (2017) showed that a transient or low-level, but not prolonged, exposure to the OIS SASP promotes cellular plasticity and regenerative capacity in mouse skin keratinocytes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ritschka et al. 2017
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- Premisecitation
The SASP locally facilitates cellular plasticity.
“The SASP also modulates other key hallmarks of cancers through locally facilitating vascularization (Coppé et al. 2006), epithelial-mesenchymal transition (Coppé et al. 2008; Kuilman et al. 2008), tumor invasion (Kim et al. 2017; He et al. 2018), and cellular plasticity (Ritschka et al. 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Ritschka et al. 2017
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- Interpretationreasoning
The inflammatory SASP appears to be controlled through multiple effectors.
“The inflammatory SASP appears to be controlled through multiple effectors.”
Quote in the paperNot a substantial claim - Premisecitation
The SASP locally facilitates vascularization.
“The SASP also modulates other key hallmarks of cancers through locally facilitating vascularization (Coppé et al. 2006), epithelial-mesenchymal transition (Coppé et al. 2008; Kuilman et al. 2008), tumor invasion (Kim et al. 2017; He et al. 2018), and cellular plasticity (Ritschka et al. 2017).”
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- Premisecitation
Autophagy contributes to the senescence phenotype in part through modulating the SASP.
“Functionally, it has been suggested that autophagy contributes to the senescence phenotype in part through modulating the SASP (Patschan et al. 2008; Young et al. 2009).”
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- cites Young et al. 2009
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The SASP is also controlled through macroautophagy, another effector of senescence.
“It has been shown that the SASP is also controlled through macroautophagy (referred to here simply as autophagy), another effector of senescence (Hoare et al. 2011).”
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- Premisecitation
The cGAS-STING pathway appears to be provoked during senescence, sensing CCFs.
“Interestingly, the same pathway appears to be provoked during senescence, sensing CCFs (Ivanov et al. 2013; Dou et al. 2015).”
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- cites Dou et al. 2015
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The SASP locally facilitates tumor invasion.
“The SASP also modulates other key hallmarks of cancers through locally facilitating vascularization (Coppé et al. 2006), epithelial-mesenchymal transition (Coppé et al. 2008; Kuilman et al. 2008), tumor invasion (Kim et al. 2017; He et al. 2018), and cellular plasticity (Ritschka et al. 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Kim et al. 2017
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- cites He et al. 2018
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The SASP is typically promoted by a persistent DDR.
“For example, the SASP is typically promoted by a persistent DDR (Rodier et al. 2009; Ciccia and Elledge 2010).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Rodier et al. 2009
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- cites Ciccia and Elledge 2010
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- Interpretationreasoning
Senescent cells appear to nonautonomously contribute to maintaining the tissue stem cell niche.
“In contrast to this autonomous effect of senescence, much like the case of cellular reprograming to iPSCs, senescent cells appear to nonautonomously contribute to maintaining the tissue stem cell niche.”
Quote in the paperNot a substantial claim - Interpretationcitation
Through the SASP, the chronic presence of senescent cells within a tumor microenvironment would maintain a chronically inflamed microenvironment that is inherently tumorigenic.
“Through the SASP (derived from either tumorous or stromal senescent cells), the chronic presence of senescent cells within a tumor microenvironment would maintain a chronically inflamed microenvironment that is inherently tumorigenic (Lecot et al. 2016; Baker et al. 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Lecot et al. 2016
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- cites Baker et al. 2017
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- Interpretationreasoning
Disruption of the senescence life cycle may create a tumorigenic microenvironment collectively through these SASP functionalities.
“Disruption of the senescence life cycle may create a tumorigenic microenvironment collectively through these SASP functionalities (Fig. 1).”
Quote in the paperSubstantial claim - Premisecitation
A number of small molecules that selectively kill senescent cells (senolytics) have been developed.
“a number of small molecules that selectively kill senescent cells (collectively called senolytics) have been developed (Zhu et al. 2015, 2016; Yosef et al. 2016; Baar et al. 2017; Kirkland and Tchkonia 2017).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Zhu et al. 2015, 2016
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- cites Yosef et al. 2016
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- cites Baar et al. 2017
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- Interpretationreasoning
The autonomous and nonautonomous programs of senescence appear to be mechanistically linked.
“Interestingly, however, these autonomous and nonautonomous programs appear to be mechanistically linked.”
Quote in the paperSubstantial claim - Premisecitation
The distinct epigenetic landscape in senescence has been correlated with the SASP.
“While the causal relevance of epigenetic changes during senescence remains elusive, the distinct epigenetic landscape in senescence has been correlated with the SASP (Aird et al. 2016; Tasdemir et al. 2016; Parry et al. 2018).”
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- cites Tasdemir et al. 2016
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- cites Parry et al. 2018
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- Interpretationnone given
Autophagy, an autonomous effector by nature, also affects the SASP.
“Autophagy, an autonomous effector by nature, also affects the SASP (Fig. 3).”
Quote in the paperNot a substantial claim - Premisecitation
Genetic ablation of senescent cells provides beneficial effects on healthy life span in mice.
“After the seminal work by van Deursen and colleagues (Baker et al. 2011) showing that the genetic ablation of senescent cells provides beneficial effects on healthy life span in mice, a number of small molecules that selectively kill senescent cells (collectively called senolytics) have been developed (Zhu et al. 2015, 2016; Yosef et al. 2016; Baar et al. 2017; Kirkland and Tchkonia 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baker et al. 2011
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- Interpretationnone given
Senescence-or even the SASP-is mostly tumor-suppressive in the early stages, particularly when the senescent cells are eliminated by the immune system.
“Senescence—or even the SASP—is mostly tumor-suppressive in the early stages, particularly when the senescent cells are eliminated by the immune system.”
Quote in the paperSubstantial claim - Premisecitation
GATA4 positively controls the NFkB-driven SASP.
“Kang et al. (2015) have shown that the transcription factor GATA4 positively controls the NFkB-driven SASP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2015
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- Premisecitation
In the cancer context, killing stromal senescent cells induced by chemotherapy reduces associated side effects, such as cardiac and liver dysfunction and general fatigue.
“In the cancer context, it was shown that killing stromal senescent cells induced by chemotherapy reduces the associated side effects, such as cardiac and liver dysfunction and general fatigue (Baar et al. 2017; Demaria et al. 2017).”
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- cites Demaria et al. 2017
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Increased lysosomal biogenesis and compartmentalization during senescence have been shown in several models.
“Increased lysosomal biogenesis and compartmentalization during senescence have been shown in several models (Young et al. 2009; Narita et al. 2011; Dörr et al. 2013).”
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- cites Narita et al. 2011
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- cites Dörr et al. 2013
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- Premisecitation
Selective targeting of TIS cells using sugar-coated nanoparticles encapsulating cytotoxic drugs is beneficial in xenograft models.
“A more recent study also suggests that selective targeting of TIS cells using sugar-coated (thus sensitive to β-galactosidase) nanoparticles encapsulating cytotoxic drugs is beneficial in xenograft models (Muñoz-Espín et al. 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Muñoz-Espín et al. 2018
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- Interpretationcitation
OIS might be most relevant at the stage of oncogenic "amplification" (genetically or functionally) after somatic mutations, which are often found in normal tissues.
“We propose that OIS might be most relevant at the stage of oncogenic “amplification” (genetically or functionally) after somatic mutations, which are often found in normal tissues (Fig. 2; Risques and Kennedy 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Risques and Kennedy 2018
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- Premisecitation
Prolonged activation of autophagic protein degradation activates mTOR on the surface of (auto)lysosomes through degradation products (amino acids).
“Interestingly, prolonged activation of autophagic protein degradation was shown to activate the anabolic counterpart of autophagy, mTOR, on the surface of (auto)lysosomes through degradation products (i.e., amino acids) (Yu et al. 2010; Efeyan et al. 2012).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Yu et al. 2010
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- cites Efeyan et al. 2012
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- Premisecitation
Genetic inhibition of Notch signaling in the hepatocyte OIS model facilitates senescence surveillance.
“For example, it was shown that genetic inhibition of Notch signaling in the hepatocyte OIS model facilitates senescence surveillance (Hoare et al. 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hoare et al. 2016
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- Interpretationnone given
Autophagy affects a nonautonomous aspect of senescence (the SASP) in the context of chronic stress-induced autophagy.
“However, in addition to this autonomous activity of autophagy, autophagy affects a nonautonomous aspect of senescence (i.e., the SASP) in the context of chronic stress-induced autophagy.”
Quote in the paperSubstantial claim - Premisecitation
Autophagy contributes to other senescence effectors, such as (epi)genetic modulation through Lamin B1 degradation.
“In addition, autophagy also contributes to other senescence effectors, such as (epi)genetic modulation through Lamin B1 degradation (Dou et al. 2015; Lenain et al. 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dou et al. 2015
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- cites Lenain et al. 2015
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- Interpretationreasoning
Overall, autophagy appears to affect the SASP at multiple levels in a nonunidirectional manner.
“Thus, overall, autophagy appears to affect the SASP at multiple levels in a nonunidirectional manner (Fig. 3).”
Quote in the paperSubstantial claim - Premisecitation
Georgilis et al. (2018) identified a number of druggable targets whose inhibition can induce senescence without the inflammatory SASP.
“Georgilis et al. (2018) recently identified a number of druggable targets, the inhibition of which can induce senescence without the inflammatory SASP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Georgilis et al. 2018
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- Premisecitation
The relevance of autophagy in senescence appears to be highly context-dependent.
“The relevance of autophagy in senescence appears to be highly context-dependent (Kwon et al. 2017).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kwon et al. 2017
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- Interpretationnone given
Senescence blocks the proliferation of unnecessary or unwanted cells in both physiological and pathological contexts.
“Senescence blocks the proliferation of unnecessary or unwanted cells in both physiological and pathological contexts.”
Quote in the paperSubstantial claim
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- Classified as probably not a substantial claim. 13
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PremisecitationEnforced killing of senescent cells in mice extends their life span, establishing a causal role of senescence in aging.
“more recent evidence that enforced killing of senescent cells in mice extends their life span has firmly established the causal role of senescence in aging (Baker et al. 2011, 2016).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Baker et al. 2011, 2016
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PremisecitationSenescent cells have physiological roles beyond cancer and aging, including shaping embryonic development, contributing to maturation of certain cell types, and maintaining tissue integrity by facilitating wound healing.
“with functions in shaping embryonic development (Chuprin et al. 2013; Muñoz-Espín et al. 2013; Storer et al. 2013), contributing to the maturation of certain cell types (Besancenot et al. 2010; Helman et al. 2016), and maintaining tissue integrity in adult organisms by facilitating wound healing”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Chuprin et al. 2013
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- cites Muñoz-Espín et al. 2013
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- cites Storer et al. 2013
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InterpretationcitationSenescence is an autonomous tumor suppressor but a nonautonomous tumor modulator.
“It is perhaps safe to say that senescence is an autonomous tumor suppressor but a nonautonomous tumor “modulator” (Hoare and Narita 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hoare and Narita 2018
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PremisecitationLow-level Ras is not immediately sufficient for cancer development, but mice eventually develop tumors.
“while low-level Ras (comparable with the level expressed from the endogenous Kras-G12D allele in the mouse pancreas model described above) is not immediately sufficient for cancer development, the mice eventually develop tumors.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Sarkisian et al. 2007
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PremisecitationMEFs expressing endogenous levels of single-allelic Kras-G12V or Kras-G12D fail to undergo senescence, although they are not fully transformed.
“mouse embryonic fibroblasts (MEFs) expressing endogenous levels of the single-allelic Kras-G12V or Kras-G12D fail to undergo senescence, although they were not fully transformed (Guerra et al. 2003; Tuveson et al. 2004).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Guerra et al. 2003
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- cites Tuveson et al. 2004
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PremisecitationDNA damage in telomeres is effectively unrepairable, causing persistent DDR and formation of telomere-associated foci (TAFs) in aging- and stress-induced senescence.
“It has been suggested that DNA damage in telomeres is effectively unrepairable, causing a persistent DDR and the formation of telomere-associated foci (TAFs) in aging- and stress-induced senescence (Takai et al. 2003; Fumagalli et al. 2012; Hewitt et al. 2012).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Takai et al. 2003
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- cites Fumagalli et al. 2012
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- cites Hewitt et al. 2012
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PremisecitationTelomerase deficiency alone in mice can lead to an increase in spontaneous cancer incidence mainly in rapidly proliferating cell types, exemplified by an unusually high incidence of teratocarcinomas, probably due to increased genome instability.
“However, telomerase deficiency alone in mice can lead to an increase in spontaneous cancer incidence mainly in rapidly proliferating cell types, exemplified by the unusually high incidence of teratocarcinomas, probably due to increased genome instability, a hallmark of cancer (Rudolph et al. 1999).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Rudolph et al. 1999
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PremisecitationOIS senescent phenotype is accompanied by accumulation of p53 and p16, and ablation of these tumor suppressors leads to transformation, supporting OIS as an intrinsic tumor suppressor mechanism.
“This senescent phenotype is accompanied by accumulation of the tumor suppressor proteins p53 and p16, and a concomitant ablation of these tumor suppressors leads instead to transformation, supporting the notion of OIS as an intrinsic tumor suppressor mechanism (Serrano et al. 1997; Lin et al. 1998).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Serrano et al. 1997
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- cites Lin et al. 1998
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Premisenone givenSAHF formation is model-dependent, which may represent the heterogeneity of senescence.
“It is important to note that SAHF formation is model-dependent, which may represent the heterogeneity of senescence.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationIn OIS, a general increase in chromatin accessibility has been reported, and different oncogenes induce different profiles of accessible regions upon senescence entry.
“In OIS too, a general increase in chromatin accessibility has been reported, and different oncogenes induce different profiles of accessible regions upon senescence entry (Parry et al. 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Parry et al. 2018
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PremisecitationSAHFs are readily visualized by microscopy as DAPI-dense foci in the nucleus.
“senescence-associated heterochromatic foci (SAHFs) are readily visualized by microscopy as DAPI-dense foci in the nucleus (Narita et al. 2003; Zhang et al. 2005).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Narita et al. 2003
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- cites Zhang et al. 2005
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PremisecitationIn replicative senescence in human fibroblasts, DNA methylation is globally reduced at heterochromatic regions but focally increased at a subset of CpG islands.
“Using a model of replicative senescence in human fibroblasts, Cruickshanks et al. (2013) demonstrated that DNA methylation is globally reduced at heterochromatic regions but focally increased at a subset of CpG islands.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cruickshanks et al. 2013
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PremisecitationDNA accessibility exhibits a global increase with focal declines during replicative senescence.
“DNA accessibility exhibits a global increase with focal declines (De Cecco et al. 2013a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites De Cecco et al. 2013a
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PremisecitationCCFs together with Lamin B1 can be degraded by autophagy, proposed as a mechanism used by senescent cells to remove damaged genomic material.
“Indeed, CCFs, together with Lamin B1, can be degraded by autophagy; thus, this process was proposed as a mechanism used by senescent cells to remove damaged genomic material (Ivanov et al. 2013; Dou et al. 2015, 2017).”
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- cites Dou et al. 2015, 2017
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PremisecitationLamin B1 down-regulation during senescence is mediated by RB-dependent silencing.
“Although it was reported that Lamin B1 down-regulation during senescence is mediated by RB-dependent silencing (Shimi et al. 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Shimi et al. 2011
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InterpretationreasoningThe OIS culture system may model a tumor-suppressive event at the critical step of Ras-driven tumorigenesis.
“Perhaps the OIS culture system models a tumor-suppressive event at this critical step of Ras-driven tumorigenesis (Fig. 2).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSenescence escapers exhibit a stem-like signature with high tumor-initiating potential.
“the recent study suggesting that senescence escapers exhibit a stem-like signature with high tumor-initiating potential (Milanovic et al. 2018).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Milanovic et al. 2018
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PremisecitationSenescence, unlike quiescence, uses distinct alterations in the chromatin landscape.
“It has been proposed that senescence, unlike quiescence (a state of physiological and readily reversible cell cycle arrest), uses distinct alterations in the chromatin landscape (Parry and Narita 2016).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Parry and Narita 2016
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PremisecitationHMGA chromatin architectural proteins and histone cochaperones HIRA/ASF1a are necessary for SAHF formation, whereas loss of linker histone H1 is correlated with SAHFs.
“HMGA chromatin architectural proteins and histone cochaperones HIRA/ASF1a have been shown to be necessary for SAHF formation, whereas loss of linker histone H1 is correlated with SAHFs (Zhang et al. 2005; Funayama et al. 2006; Narita et al. 2006).”
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- cites Funayama et al. 2006
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- cites Narita et al. 2006
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PremisecitationLoss of Lamin B1 is not sufficient for senescence or SAHF induction, but liberates H3K9me3-rich heterochromatin from the nuclear periphery and facilitates SAHF formation.
“Although the loss of Lamin B1 is not sufficient for senescence or SAHF induction, it liberates H3K9me3-rich heterochromatin from the nuclear periphery and facilitates SAHF formation (Sadaie et al. 2013).”
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InterpretationcitationThe pattern of hypermethylated CpG islands in replicative senescence is reminiscent of cancers, suggesting senescence and cancer share features of epigenetic change.
“Interestingly, the pattern of hypermethylated CpG islands in replicative senescence is reminiscent of that of cancers, leading to the hypothesis that senescence and cancer share features of epigenetic change.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Cruickshanks et al. 2013
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PremisecitationDNA methylation patterns evolve separately during tumorigenesis and progression to senescence: tumorigenesis is stochastic and senescence is highly reproducible.
“looking at individual genomic regions conversely suggested that methylation patterns evolved separately during tumorigenesis and progression to senescence: The former is stochastic and the latter is highly reproducible”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xie et al. 2018
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InterpretationreasoningSenescence-associated epigenetic alterations might contribute to a tumor-suppressive senescence phenotype but also encompass oncogenic properties, explaining the dual effect of senescence in cancer.
“This idea—that senescence-associated epigenetic alterations might contribute to a tumor-suppressive senescence phenotype but, at the same time, encompass oncogenic properties—appears to explain well the dual effect of senescence in cancer”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationOIS-associated DNA methylation alterations appear to be minimal, underscoring the diversity of the senescence phenotype.
“In contrast to replicative senescence, OIS-associated DNA methylation alterations appear to be minimal, underscoring the diversity of the senescence phenotype (Sakaki et al. 2017; Xie et al. 2018).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Sakaki et al. 2017
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- cites Xie et al. 2018
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InterpretationreasoningRas activity needs to be increased for full malignant transformation but this is counteracted by senescence programs.
“It is possible that, even when it is initiated by a single copy mutation, Ras activity needs to be increased for full malignant transformation but that this is counteracted by senescence programs.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationDNA methylation globally declines during senescence, forming the basis for the heterochromatin loss model.
“It has been long known that DNA methylation globally declines during senescence, forming the basis for the well-known “heterochromatin loss model””
Quote in the paperSubstantial claim0 of 1 sources checked- cites Villeponteau 1997
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PremisecitationEctopic expression of oncogenic NRas induces senescence in hepatocytes in mice, and those OIS hepatocytes are eliminated primarily by macrophages, requiring activation of mutant NRas-specific CD4+ T cells.
“As shown by Kang et al. (2011), ectopic expression of oncogenic NRas induces senescence in hepatocytes in mice, and those OIS hepatocytes are eliminated primarily by macrophages, but this process requires activation of mutant NRas-specific CD4+ T cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2011
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PremisecitationCCl4 induces senescence in the liver, mainly in hepatic stellate cells.
“Krizhanovsky et al. (2008) showed that the liver-damaging agent CCl4 induces senescence in the liver, but those senescent cells are mainly hepatic stellate cells (HSCs).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Krizhanovsky et al. 2008
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PremisecitationThe NOTCH phase is correlated with a distinct secretome representing TGFβ and other fibrogenic factors, and subsequent down-regulation of NOTCH signaling is required for switching to the typical inflammatory and fibrolytic SASP in the late phase of senescence.
“The NOTCH phase is correlated with a distinct secretome, representing TGFβ and other fibrogenic factors, and subsequent down-regulation of NOTCH signaling is required for switching to the typical inflammatory and fibrolytic SASP in the late phase of senescence.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hoare et al. 2016
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InterpretationreasoningTissue repair and integrity are controlled through a timely switch from a fibrogenic to a fibrolytic secretory program, and this switch is coupled with the eventual elimination of senescent cells by immune cells.
“Thus, tissue repair and integrity are controlled through a timely switch from a fibrogenic to a fibrolytic secretory program, and this switch is coupled with the eventual elimination of senescent cells by immune cells.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationThe SASP is the best characterized of these mechanisms, and the nonautonomous functionality of senescent cells has been mostly attributed to the SASP.
“The SASP is the best characterized of these mechanisms (Kuilman and Peeper 2009; Malaquin et al. 2016), and the nonautonomous “functionality” of senescent cells has been mostly attributed to the SASP.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Kuilman and Peeper 2009
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- cites Malaquin et al. 2016
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InterpretationcitationThe functionality of the SASP is not limited to mediating immune clearance of senescent cells from the tissue; it also plays a role in the maintenance of tissue integrity.
“The functionality of the SASP is not limited to mediating immune clearance of senescent cells from the tissue. It also plays a role in the maintenance of tissue integrity.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationPAI1 is a downstream effector of the p53 pathway during replicative senescence and contributes to cell cycle arrest, while IL6 and IL8 reinforce senescence arrest through paracrine activities.
“PAI1 was shown to be a downstream effector of the p53 pathway during replicative senescence, which contributes to cell cycle arrest, while IL6 and IL8 (an inflammatory cytokine and chemokine, respectively) reinforce senescence arrest through paracrine activities (Kortlever et al. 2006; Acosta et al. 2008; Kuilman et al. 2008; Wajapeyee et al. 2008).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Kortlever et al. 2006
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- cites Acosta et al. 2008
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- cites Kuilman et al. 2008
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PremisecitationThe major outcome of the inflammatory SASP in vivo is not just senescence reinforcement but also activation of an immune reaction.
“The major outcome of the inflammatory SASP in vivo is not just senescence reinforcement but also activation of an immune reaction (Fig. 1).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenSenescence surveillance involves multileveled and distinct aspects of the immune system depending on the context, such as the senescence trigger and cell type.
“suggest that the senescence surveillance involves multileveled and distinct aspects of the immune system depending on the context, such as the senescence trigger and cell type.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationImmune clearance of OIS hepatocytes is diminished in immunocompromised mice, which eventually develop liver cancer.
“Indeed, immune clearance of OIS hepatocytes was diminished when the experiment was conducted in immunocompromised mice, which eventually developed liver cancer (Kang et al. 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2011
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Interpretationcitationp53-deficient HSCs bypass senescence and secrete factors that stimulate macrophages into a tumor-promoting M2 state, suggesting a nonautonomous tumor suppressor activity for p53.
“Interestingly, p53-deficient HSCs bypass senescence and secrete factors that stimulate macrophages into a tumor-promoting M2 state, suggesting a nonautonomous tumor suppressor activity for p53 (Lujambio et al. 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Lujambio et al. 2013
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PremisecitationA fraction of OIS hepatocytes expresses a higher level of MHCII, which is required but not sufficient for senescence surveillance.
“a fraction of the OIS hepatocytes appears to express a higher level of MHCII, which, although not sufficient (i.e., professional APCs are necessary), is required for senescence surveillance (Kang et al. 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2011
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PremisecitationAutophagy is activated during senescence, and SA-β-gal reflects increased lysosomal mass, at least in some contexts.
“Earlier studies have suggested that autophagy is activated during senescence, and SA-β-gal reflects increased lysosomal mass, at least in some contexts (Kurz et al. 2000; Gerland et al. 2003; Narita et al. 2011).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Kurz et al. 2000
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- cites Narita et al. 2011
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PremisecitationActivation of p38MAPK, another positive regulator of the SASP, can inhibit STING-mediated IFN induction, which was proposed to explain in part why type I IFNs are not necessarily overrepresented in the SASP.
“The investigators proposed that this is due in part to the activation of p38MAPK (another positive regulator of the SASP) (Freund et al. 2011), which can inhibit STING-mediated IFN induction (Dou et al. 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Freund et al. 2011
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- cites Dou et al. 2017
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PremisecitationActivation of STING typically leads to the engagement of two canonical downstream pathways: a type I interferon response mediated by IRF3 and an inflammatory response through NFkB activation.
“This typically leads to the engagement of two canonical downstream pathways: a type I interferon (IFN) response mediated by IRF3 and an inflammatory response through NFkB activation (Abe and Barber 2014; Barber 2015).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Abe and Barber 2014
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PremisecitationSA-β-gal is derived from a lysosomal enzyme.
“One of the best-known markers of senescence is an increase in senescence-associated β-galactosidase activity (SA-β-gal), which is derived from a lysosomal enzyme (Lee et al. 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Lee et al. 2006
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PremisecitationThe cGAS-STING pathway is an intrinsic tumor suppressor and is deregulated in carcinomas.
“The cGAS–STING pathway, an intrinsic tumor suppressor, is deregulated in carcinomas (Xia et al. 2016), and low levels of cGAS or STING are correlated with poor prognosis in some cancer types (Song et al. 2017; Yang et al. 2017a).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xia et al. 2016
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PremisecitationSenescence arrest in tissue stem cell or progenitor cells reduces regenerative capacity in some tissues.
“It has been suggested that senescence arrest in tissue stem cell or progenitor cells reduces regenerative capacity in some tissues (Sharpless and DePinho 2007).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sharpless and DePinho 2007
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PremisecitationTumors have long been dubbed "wounds that do not heal" due to similarities between the phases of wound healing and those of tumor stroma formation.
“Tumors have long been dubbed as “wounds that do not heal” (Dvorak 1986, 2015; Byun and Gardner 2013) due to similarities between the phases of wound healing and those of tumor stroma formation.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dvorak 1986, 2015
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PremisecitationThe cGAS-STING pathway evolved as a defense response to viral and microbial infections and promotes inherent antitumor immunity.
“Evolved as a defense response to viral and microbial infections, this pathway promotes inherent antitumor immunity (Deng et al. 2014; Woo et al. 2014; Bose 2017).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Deng et al. 2014
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PremisecitationLoss of the cGAS-STING pathway results in reduced senescence surveillance and increased tumorigenesis in the liver OIS model.
“Consistently, the loss of this pathway results in reduced senescence surveillance and increased tumorigenesis in the liver OIS model (Dou et al. 2017; Glück et al. 2017).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Dou et al. 2017
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PremisecitationGATA4 is a substrate of p62-mediated selective autophagy, which is inhibited during senescence, indicating that selective autophagy can negatively regulate the inflammatory SASP.
“They found that GATA4 is a substrate of p62-mediated selective autophagy, which, in contrast to general autophagy, is inhibited during senescence, indicating that selective autophagy can negatively regulate the inflammatory SASP.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2015
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PremisecitationAutophagy-mediated degradation of Lamin B1 promotes CCF formation, which up-regulates SASP genes through the cGAS-STING pathway.
“Autophagy-mediated degradation of Lamin B1 also promotes CCF formation, which up-regulates SASP genes through the cGAS–STING pathway.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Dou et al. 2015
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PremisecitationLoss of Lamin B1 appears to orchestrate high-order chromatin structural alterations, genomic instability, and the formation of CCFs, which in turn triggers the SASP.
“Loss of Lamin B1 appears to orchestrate high-order chromatin structural alterations, genomic instability, and the formation of CCFs, which in turn triggers the SASP (Sadaie et al. 2013; Shah et al. 2013; Dou et al. 2015, 2017).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Sadaie et al. 2013
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- cites Dou et al. 2015, 2017
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PremisecitationProlonged activation of autophagy leads to the simultaneous activation of mTOR, which facilitates protein synthesis.
“It was proposed that prolonged activation of autophagy leads to the simultaneous activation of mTOR (which is typically regulated in the direction opposite to autophagy), which facilitates protein synthesis (Narita et al. 2011).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Narita et al. 2011
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PremisecitationBasal autophagy prevents senescence of muscle satellite cells, thus maintaining stemness.
“For instance, a role of basal autophagy in preventing senescence of muscle satellite cells, thus maintaining stemness, has been reported previously (García-Prat et al. 2016).”
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PremisecitationTargeting metabolic pathways increased in senescent cells (e.g., autophagy or glucose utilization) in TIS lymphoma cells leads to selective killing of TIS cells and an improved treatment outcome.
“In fact, it was shown that targeting the metabolic pathways increased in senescent cells (e.g., autophagy or glucose utilization) in TIS lymphoma cells leads to the selective killing of TIS cells and an improved treatment outcome (Dörr et al. 2013).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Dörr et al. 2013
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Interpretationnone givenSenescent cells are metabolically active and have a profound impact, often deleterious in the long term, on their neighbors through their nonautonomous activities.
“Senescent cells are metabolically active and have a profound impact (often deleterious in the long term) on their neighbors through their nonautonomous activities.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationActivation of general autophagy during senescence is accompanied by an inhibition of p62-mediated selective autophagy, allowing stabilization of the GATA4 transcription factor, which regulates SASP genes via NFkB.
“However, the activation of general autophagy during senescence is accompanied by an inhibition of p62-mediated selective autophagy, allowing stabilization of the GATA4 transcription factor, which regulates SASP genes via NFkB.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Kang et al. 2015
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PremisecitationSenolytics have mostly been used in the context of aging and tissue damage.
“Mostly, these reagents have been used (Demaria et al. 2017) in the context of aging and tissue damage (Xu et al. 2018).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Demaria et al. 2017
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InterpretationreasoningWhile senescence arrest can be an intrinsic tumor suppressor mechanism, particularly at the early stages of tumorigenesis, this view is too simplistic.
“While the senescence arrest can be an intrinsic tumor suppressor mechanism, particularly at the early stages of tumorigenesis, this view turns out to be too simplistic.”
Quote in the paperSubstantial claim
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?
Autophagy-mediated CCF formation together with reduced histone synthesis might lead to global loss of core histones during senescence, affecting the chromatin landscape.
“Autophagy-mediated CCF formation (Dou et al., 2015) together with reduced histone synthesis (O'Sullivan et al., 2010) might also lead to a global loss of core histones during senescence, affecting the chromatin landscape (Chan and Narita, 2019; Ivanov et al., 2013).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Chan and Narita, 2019
The Chromatin dynamics section (page not available) says autophagy can degrade cytoplasmic chromatin fragments and that chromatin loss would affect the chromatin landscape. The Autophagy section also links autophagic Lamin B1 degradation to CCF formation. Our copy does not state that these processes, together with reduced histone synthesis, cause a global loss of core histones; its specific histone-loss example concerns linker histone H1. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe senescence-associated secretory phenotype exhibits deleterious side effects such as chronic inflammation and/or tumourigenesis depending on biological context.
“it also exhibits deleterious side effects such as chronic-inflammation and/or tumourigenesis, depending on the biological context2,3,11–13.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [2]
The citation lists haven’t been fetched yet
References 228 · Cited by 80
- Authors
- Chan, A. S. L., & Narita, M.
- Affiliations
- University of Cambridge (GB)
- Corresponding author
- Narita, Masashi
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-02-01
- Volume
- 33
- Issue
- 3-4
- Pages
- 127-143
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC6362810
- OpenAlex
- W2914204349
- Cited by
- 80
- References
- 228
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 18 · 2020: 18 · 2019: 2
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- University of Cambridge
- Cancer Research UK
- Hutchison Whampoa
- Cancer Research UK Cambridge Institute (C14303/A17197)
- Cancer Research UK Early Detection Pump Priming (C20/A20976)
- Medical Research Council (MR/R010013/1)
- Tokyo Tech World Research Hub Initiative
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cellular senescence, cancer, senescent cells, tissue microenvironment, senescence heterogeneity, stress response
- MeSH terms
- Cell Cycle, Humans, Neoplasms, Precancerous Conditions, Cellular Senescence, Epigenomics, Telomere Shortening, Cellular Microenvironment
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