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Cited by 398Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Mechanisms and Regulation of Cellular Senescence

Open access
Roger, Lauréline, Tomas, Fanny, Gire, Véronique·2021·International Journal of Molecular Sciences
DOI 10.3390/ijms222313173PMC PMC8658264
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Abstract

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes mechanisms and regulation of cellular senescence, emphasizing heterogeneity, cell-cycle arrest via p53/p21 and p16/RB, the SASP, metabolic/chromatin changes, and positive feedback loops. It discusses senescence’s dual roles in cancer and aging and therapeutic implications including senolytics.

Key findings

  • Senescence is an essentially irreversible proliferative arrest with continued metabolic activity and a SASP; cell-cycle exit can occur in G1 or G2, with p53/p21 as early markers and p16/ARF as late markers. Acute DNA damage can trigger rapid exit within 24 h, and the G2/M checkpoint responds to 10–20 DNA breaks.
  • Replicative senescence is driven by telomere erosion; mean telomere length in human senescent fibroblasts ranges between 6 and 8 kbp, with a few extremely short telomeres. Persistent DDR at telomeres, partly because TRF2 blocks repair, sustains arrest.
  • The SASP is regulated by NF-κB/C/EBP-β, ATM, p38MAPK, GATA4, mTOR, epigenetic factors, and cGAS–STING signaling; it can reinforce senescence and drive inflammaging and paracrine senescence.
  • Senescence has dual roles: it acts as a barrier to tumorigenesis, but SASP factors can promote cancer progression; senescent cell accumulation contributes to aging, and clearance via senolytics or INK-ATTAC alleviates age-related dysfunction and extends healthspan in mice.

Methods

  • Narrative review; no primary experiments. It synthesizes published literature on mammalian cellular senescence mechanisms, regulation, and roles in cancer and aging.
  • Covers in vitro and in vivo studies, including mouse models, human cells/tissues, and clinical observations; main analysis is thematic synthesis of signaling pathways, transcriptional/post-transcriptional control, metabolism, organelles, autophagy, epigenetics, and immune clearance.
  • No systematic search or meta-analysis is described.

Limitations

  • Stated: lack of specific biomarkers to identify and follow senescent cells in vivo; much knowledge comes from cultured cells that do not recapitulate organism complexity; findings need in vivo confirmation; heterogeneity complicates assigning exact roles.
  • Stated: it remains challenging to study how senescent cells are induced in vivo, how the SASP changes over time, when the SASP acquires damaging traits, and how senescent cell clearance is regulated.
  • Evident: as a narrative review, it does not provide a systematic or quantitative synthesis and reports no primary data to assess causality.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/ijms222313173

Cites

371 of 371 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 530 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    The capacity of senescent cells to survive in a nondividing state requires changes in core cellular programs.

    “This capacity requires changes in core cellular programs.”
    Quote in the paperSubstantial claim
  • Interpretationcitation

    The proliferative arrest imposed by cellular senescence represents an early barrier against cancer initiation by preventing the propagation of damaged DNA to the next generation of cells.

    “The proliferative arrest imposed by cellular senescence represents an early barrier against cancer initiation by preventing the propagation of damaged DNA to the next generation of cells [18,20].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Collado, 2005, Senescence in premalignant tumours, Nature source

      Not checked in the free run.

    • cites [20] Weinberg, 2005, The signals and pathways activating cellular senescence, Int. J. Biochem. Cell Biol. source

      Not checked in the free run.

  • Premisecitation

    Senescence can be triggered by intrinsic and extrinsic factors including replicative stress, oxidative damage, metabolism dysfunctions, cytokines, oncogene activation, and chemotherapy agents.

    “Senescence can also be triggered by many other intrinsic and extrinsic factors, particularly, replicative stress, oxidative damage, metabolism dysfunctions, cytokines, oncogene activation, and chemotherapy agents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

      Not checked in the free run.

  • Premisecitation

    Senescence is an important contributor to cancer and aging.

    “Senescence is an important contributor to cancer and aging, two processes characterized by a time-dependent accumulation of cell damage and dysfunction.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

      Not checked in the free run.

  • Premisecitation

    Cellular senescence occurs not only in vitro but also in various tissues in vivo.

    “Cellular senescence occurs not only in vitro (i.e., cell culture models), but also in various tissues in vivo [13,14,15,16].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Baker, 2016, Naturally occurring p16Ink4a-positive cells shorten healthy lifespan, Nature source

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    • cites [14] Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat. Med. source

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    • cites [15] Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat. Commun. source

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    • cites [16] 2017, The Fountain of Youth by Targeting Senescent Cells?, Trends Mol. Med. source

      Not checked in the free run.

  • May combine two claims. 114
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Premisecitation

    Cellular senescence entails an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype.

    “Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source

      Not checked in the free run.

    • cites [2] Childs, 2014, Senescence and apoptosis: Dueling or complementary cell fates?, EMBO Rep. source

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    • cites [3] Zhu, 2015, The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs, Aging Cell source

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    • cites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

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  • May combine two claims.

    Interpretationnone given

    All senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response.

    “Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells display high metabolic activities, remain viable, and actively suppress apoptosis.

    “These cells display high metabolic activities [1], remain viable, and actively suppress apoptosis [2,3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source

      Not checked in the free run.

    • cites [2] Childs, 2014, Senescence and apoptosis: Dueling or complementary cell fates?, EMBO Rep. source

      Not checked in the free run.

    • cites [3] Zhu, 2015, The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Replicative senescence is induced after serial propagation of normal human cells in culture and is caused by telomere erosion and the consequent increase in DNA lesions.

    “It is induced after serial propagation of normal human cells in culture and is caused by telomere erosion and the consequent increase in DNA lesions [9,10,11,12].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

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    • cites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source

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    • cites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source

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    • cites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals.

    “There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Elimination of senescent cells can promote stem cell proliferation and delay the appearance of aging features.

    “Importantly, elimination of senescent cells can promote stem cell proliferation and delay the appearance of aging features [13,14,15].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [13] Baker, 2016, Naturally occurring p16Ink4a-positive cells shorten healthy lifespan, Nature source

      Not checked in the free run.

    • cites [14] Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat. Med. source

      Not checked in the free run.

    • cites [15] Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat. Commun. source

      Not checked in the free run.

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

    Premisecitation

    All these factors can induce DNA damage and senescence in normal and cancer cells in some contexts.

    “All these factors can induce DNA damage and senescence in normal and cancer cells (in some contexts) [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

      Not checked in the free run.

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

    Premisecitation

    Cellular senescence is generally an irreversible proliferative arrest in damaged normal cells that have exited the cell cycle.

    “Cellular senescence is generally an irreversible proliferative arrest in damaged normal cells that have exited the cell cycle.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source

      Not checked in the free run.

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

    Premisecitation

    The hallmarks of cellular senescence include prolonged cell cycle arrest, transcriptional changes, acquisition of a bioactive secretome known as SASP, macromolecular damage, and deregulated metabolism.

    “The hallmarks of cellular senescence include: prolonged cell cycle arrest, transcriptional changes, acquisition of a bioactive secretome, known as the senescence-associated secretory phenotype (SASP), macromolecular damage, and deregulated metabolism [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

      Not checked in the free run.

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

    Interpretationreasoning

    Senescence escape is required for tumor progression to overt malignancy.

    “Therefore, it has been proposed that senescence escape is required for tumor progression to overt malignancy [18,21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [18] Collado, 2005, Senescence in premalignant tumours, Nature source

      Not checked in the free run.

    • cites [21] Collado, 2010, Senescence in tumours: Evidence from mice and humans, Nat. Rev. Cancer source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Senescent cells are heterogeneous and perform various biological functions.

    “Senescent cells are heterogeneous and perform various biological functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    In cultured fibroblasts, p21 levels reach a peak during the final two to three passages before senescence, but p21 may not be essential for senescence because its expression does not persist in senescent cells.

    “In cultured fibroblasts, p21 levels reach a peak during the final two to three passages before senescence, but it may not be essential for senescence because its expression does not persist in senescent cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A decrease in the activity or levels of CDK inhibitors can lead to senescence escape, and their inactivation results in senescent cell reentry into the cell cycle.

    “A decrease in the activity or levels of CDK inhibitors can lead to senescence escape, and their inactivation results in senescent cell reentry into the cell cycle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced.

    “Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced [41,42].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [41] Brown, 1997, Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts, Science source

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    • cites [42] Reyes, 2018, Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest, Mol. Cell source

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  • May combine two claims.

    Premisecitation

    p21 inhibition in fully senescent fibroblasts leads to aberrant S phase reentry with some DNA replication, but this is not sufficient to drive these cells through a complete cell cycle.

    “Conversely, p21 inhibition in fully senescent fibroblasts leads to aberrant S phase reentry with some DNA replication, but this is not sufficient to drive these cells through a complete cell cycle [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Ma, 1999, Microinjection of anti-p21 antibodies induces senescent Hs68 human fibroblasts to synthesize DNA but not to divide, Cancer Res.

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Inhibition of the cell cycle machinery is the defining characteristic and is critical for both the establishment and maintenance of all cellular senescence phenotypes.

    “Although the causes of senescence are multiple, inhibition of the cell cycle machinery is the defining characteristic and is critical for both the establishment and maintenance of all cellular senescence phenotypes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Senescent cells are not effectively removed in aging tissues, which might reflect the age-related decline in immune functions.

    “However, senescent cells are not effectively removed in aging tissues and this might reflect the age-related decline in immune functions [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Serrano, 2014, Cellular senescence: From physiology to pathology, Nat. Rev. Mol. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    Replicative senescence is bypassed upon loss of p21 but not upon loss of p16 function.

    “Replicative senescence is bypassed upon loss of p21 [41] but not upon loss of p16 function [45,46].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [41] Brown, 1997, Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts, Science source

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    • cites [45] Wei, 2003, Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts, EMBOJ source

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    • cites [46] Bond, 2004, Direct evidence from siRNA-directed “knock down” that p16INK4a is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation, Exp. Cell Res. source

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

    Interpretationreasoning

    Active p16 signaling can compensate for p53 activity decline after full senescence establishment.

    “It has been proposed that active p16 signaling can compensate for p53 activity decline after full senescence establishment [49,50].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

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    • cites [50] Bond, 1999, Control of Replicative Life Span in Human Cells: Barriers to Clonal Expansion Intermediate Between M1 Senescence and M2 Crisis, Mol. Cell. Biol. source

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  • May combine two claims.

    Premisecitation

    Cells without cyclin B1-CDK1 activity are refractory to reactivation upon damage resolution and do not progress into mitosis, marking a point-of-no-return for irreversible cell cycle arrest in G2.

    “Consequently, these cells without cyclin B1–CDK1 activity are refractory to reactivation upon damage resolution, and they do not progress into mitosis, thus marking a point-of-no-return for the irreversible cell cycle arrest in G2 [58,62,63].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [58] Krenning, 2014, Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence, Mol. Cell source

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    • cites [62] Cascales, 2014, Nuclear translocation of Cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase, Cell Cycle source

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    • cites [63] Cascales, 2017, Residual Cdk1/2 activity after DNA damage promotes senescence, Aging Cell source

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  • May combine two claims.

    Premisereasoning

    Activation of p53 at G2 leads to p21 upregulation, followed by the nuclear sequestration of cyclin B1 and mitosis entry inhibition.

    “Activation of p53 at G2 leads to p21 upregulation, followed by the nuclear sequestration of cyclin B1 and mitosis entry inhibition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cyclin B1-CDK1 complexes bound to p21 in the nucleus are inactive and cannot be activated upon CDK1 dephosphorylation by phosphatase CDC25C.

    “In fact, cyclin B1–CDK1 complexes bound to p21 in the nucleus are inactive and cannot be activated upon CDK1 dephosphorylation by phosphatase CDC25C [60,61].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Baus, 2003, Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts, EMBO J. source

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    • cites [61] Gire, 2004, p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress, Mol. Biol. Cell source

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  • May combine two claims.

    Premisecitation

    Cells with low baseline p16 levels do not undergo OIS but show anchorage-independent growth, a feature of cell transformation.

    “Moreover, cells with low baseline p16 levels do not undergo OIS but show anchorage-independent growth (a feature of cell transformation) [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Benanti, 2004, Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence, Mol. Cell. Biol. source

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  • May combine two claims.

    Premisecitation

    In this setting, p16 responds adequately to telomere damage because p53 inactivation only partially relieves the cell cycle arrest imposed by telomere signaling.

    “In this setting, p16 responds adequately to telomere damage because p53 inactivation only partially relieves the cell cycle arrest imposed by telomere signaling.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

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  • May combine two claims.

    Premisecitation

    DDR can also signal to p16, although p16 may act as a secondary mechanism to mediate the senescence-related proliferative arrest following telomere dysfunction.

    “DDR can also signal to p16, although p16 may act as a secondary mechanism to mediate the senescence-related proliferative arrest following telomere dysfunction [48,49].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source

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    • cites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

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  • May combine two claims.

    Premisenone given

    Some senescence markers identify the early stage, such as p53 and p21, while others identify the late stage, such as p16 and ARF.

    “Some markers identify the early stage (p53 and p21), while others identify the late stage (p16 and ARF, gene products of the CDKN2A locus).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Although frequently used, p53 and p16 are not exclusively senescence markers, but can indicate other biological functions depending on the cell context.

    “Although frequently used, p53 and p16 are not exclusively senescence markers, but can indicate other biological functions depending on the cell context.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This mitotic fidelity loss with age generates daughter cells with aneuploidy and micronuclei that ultimately lead to permanent cell cycle arrest in G1 and full senescence phenotypes.

    “This mitotic fidelity loss with age generates daughter cells with aneuploidy and micronuclei that ultimately lead to permanent cell cycle arrest in G1 and full senescence phenotypes [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Macedo, 2018, FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence, Nat. Commun. source

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  • May combine two claims.

    Premisecitation

    Mitotic duration increases with age, whereas mitotic transcripts decrease, leading to a higher rate of chromosome mis-segregation events during mitosis.

    “Mitotic duration increases with age, whereas mitotic transcripts decrease, leading to a higher rate of chromosome mis-segregation events during mitosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The signaling pathway responsible for OIS is p53-dependent in murine cells, while the RB pathway might play a predominant role in human cells.

    “It appears that the signaling pathway responsible for OIS is p53-dependent in murine cells, while the RB pathway might play a predominant role in human cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The p53 and RB pathways are needed for OIS initiation and maintenance in most systems, but their specific requirement may differ in humans and mice and might be cell type-dependent.

    “The p53 and RB pathways are needed for OIS initiation and also maintenance in most systems, but their specific requirement may differ in humans and mice and might be cell type-dependent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The activation of only one or both pathways for the execution and maintenance of the senescence program is dictated by the type of stress signal, the tissue, and the species of origin, or by a compensatory response to signaling imbalances.

    “The activation of only one or both pathways for the execution and maintenance of the senescence program is dictated by the type of stress signal, the tissue, and the species of origin [67], or by a compensatory response to signaling imbalances.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [67] Jones, 2008, Many roads lead to oncogene-induced senescence, Oncogene source

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  • May combine two claims.

    Premisecitation

    Neither p53 nor p16 are implicated in human mammary epithelial cells or melanocytes undergoing Ras-induced senescence.

    “However, neither p53 nor p16 are implicated in human mammary epithelial cells [77] or melanocytes [78] undergoing Ras-induced senescence.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [77] Cipriano, 2011, TGF- signaling engages an ATM-CHK2-p53-independent RAS-induced senescence and prevents malignant transformation in human mammary epithelial cells, Proc. Natl. Acad. Sci. USA source

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    • cites [78] Denoyelle, 2006, Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway, Nat. Cell Biol. source

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    Premisecitation

    Overexpression of BMI1, CBX7, or CBX8 results in the direct repression of p16 and senescence delay in human and mouse cells.

    “Overexpression of BMI1 [80], CBX7 [81], or CBX8 [82] results in the direct repression of p16 and senescence delay in human and mouse cells.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [80] Jacobs, 1999, The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus, Nature source

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    • cites [81] Gil, 2004, Polycomb CBX7 has a unifying role in cellular lifespan, Nat. Cell Biol. source

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    • cites [82] Dietrich, 2007, Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus, EMBO J. source

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  • May combine two claims.

    Premisecitation

    Telomere shortening is the signal for replicative senescence in human fibroblasts because telomerase reconstitutes telomere function and restores the proliferative capacity that ultimately leads to cell immortalization.

    “Telomere shortening is the signal for replicative senescence in human fibroblasts because telomerase reconstitutes telomere function and restores the proliferative capacity that ultimately leads to cell immortalization [8,9].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [8] Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. source

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    • cites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

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  • May combine two claims.

    Premisecitation

    Acute telomere deprotection by inactivation of the shelterin protein TRF2 leads to robust telomeric ATM signaling, NHEJ-dependent telomere end-to-end fusion, and rapid cell cycle arrest.

    “Similarly, acute telomere deprotection by inactivation of the shelterin protein TRF2 leads to robust telomeric ATM signaling, NHEJ-dependent telomere end-to-end fusion, and rapid cell cycle arrest [71,95].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Takai, 2003, DNA Damage Foci at Dysfunctional Telomeres, Curr. Biol. source

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    • cites [95] Celli, 2005, DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion, Nat. Cell Biol. source

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  • May combine two claims.

    Premisecitation

    The mean telomere length in human senescent fibroblasts ranges between 6 and 8 kbp, but senescent cells might contain a few extremely short telomeres that have lost completely their protective function and expose telomere-free ends, leading to DDR activation and cell cycle arrest.

    “The mean telomere length in human senescent fibroblasts ranges between 6 and 8 kbp, but senescent cells might contain a few extremely short telomeres [94] that have lost completely their protective function and expose telomere-free ends, leading to DDR activation and cell cycle arrest [10,57].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [94] Baird, 2003, Extensive allelic variation and ultrashort telomeres in senescent human cells, Nat. Genet. source

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    • cites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source

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    • cites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

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  • May combine two claims.

    Premisecitation

    During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2, and recruitment of JMJD3 lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.

    “During senescence, PRC delocalization from the CDKN2A locus, transcriptional downregulation of EZH2 [83], and recruitment of JMJD3 [84,85], a histone lysine demethylase that catalyzes H3K27 demethylation, lead to removal of the repressive H3K27me3 mark at the CDKN2A locus and facilitate p16 transcription.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [83] Bracken, 2007, The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells, Genes Dev. source

      Not checked in the free run.

    • cites [84] Agger, 2009, The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A–ARF locus in response to oncogene- and stress-induced senescence, Genes Dev. source

      Not checked in the free run.

    • cites [85] Barradas, 2009, Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TRF2 overexpression delays replicative senescence onset, indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.

    “In agreement, TRF2 overexpression delays replicative senescence onset [101], indicating that TRF2 capacity to sequester the telomere terminus via the t-loop conformation [88] might suppress the DNA damage signal from too short telomere ends and protect them from ATM signaling.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [101] Karlseder, 2002, Senescence Induced by Altered Telomere State, Not Telomere Loss, Science source

      Not checked in the free run.

    • cites [88] Doksani, 2013, Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-loop Formation, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A clear loss of shelterin association with telomeres has been observed in senescent fibroblasts, which is consistent with the progressive displacement of these complexes from short telomeres.

    “A clear loss of shelterin association with telomeres has been observed in senescent fibroblasts, which is consistent with the progressive displacement of these complexes from short telomeres [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomeres are repetitive DNA sequences bound by the six-subunit shelterin complex that facilitates the formation of telomere loops to hide the telomere end, thus protecting chromosome ends from DNA break signaling pathways.

    “Telomeres are repetitive DNA sequences, bound by the six-subunit shelterin complex [86] that facilitates the formation of telomere loops (t-loop) to hide the telomere end [87,88], thus protecting the natural chromosome ends from signaling pathways that sense and act at DNA breaks.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [86] 2005, Shelterin: The protein complex that shapes and safeguards human telomeres, Genes Dev. source

      Not checked in the free run.

    • cites [87] Griffith, 1999, Mammalian Telomeres End in a Large Duplex Loop, Cell source

      Not checked in the free run.

    • cites [88] Doksani, 2013, Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-loop Formation, Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The activation in senescing cells of G2/M phase checkpoint markers clearly indicates that their telomeres are somehow dysfunctional, most likely after telomere losses during DNA replication.

    “The activation in senescing cells of G2/M phase checkpoint markers clearly indicates that their telomeres are somehow dysfunctional, most likely after telomere losses during DNA replication [57].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Most somatic cells lack telomerase activity, and this progressive telomere erosion ultimately results in the loss of telomere function and triggers a permanent proliferative senescence arrest.

    “However, most somatic cells lack telomerase activity, and this progressive telomere erosion ultimately results in the loss of telomere function and triggers a permanent proliferative senescence arrest [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Acute loss of telomere end protection is unlikely to mimic the events leading to replicative senescence because in senescent cells, fusions between dysfunctional sister chromatids in end-to-end joining events are more frequent than inter-chromosomal end-to-end fusions.

    “This acute loss of telomere end protection is unlikely to mimic the events leading to replicative senescence because in senescent cells, fusions between dysfunctional sister chromatids in end-to-end joining events are more frequent than inter-chromosomal end-to-end fusions (a consequence of complete exposure of the telomeric tract to the NHEJ pathway) [57].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Damage signals are observed also at chromosome ends that still contain significant telomeric repeats, so complete disappearance of telomeric repeats is not required to signal dysfunction.

    “However, as damage signals are observed also at chromosome ends that still contain significant telomeric repeats, complete disappearance of telomeric repeats is not required to signal dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    TRF2 binds all along the telomeric array and inhibits DSB repair completion by blocking the recruitment of ligase IV to DNA breaks that are located in or next to telomeric DNA.

    “TRF2 binds all along the telomeric array [116] and inhibits DSB repair completion by blocking the recruitment of ligase IV to DNA breaks that are located in or next to telomeric DNA [109,115].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [116] Broccoli, 1997, Human telomeres contain two distinct Myb–related proteins, TRF1 and TRF2, Nat. Genet. source

      Not checked in the free run.

    • cites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source

      Not checked in the free run.

    • cites [115] Fumagalli, 2012, Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Due to the accumulation of repair-resistant telomeres, the DDR is continually active, and cell cycle arrest is sustained.

    “Therefore, due to the accumulation of repair-resistant telomeres, the DDR is continually active, and cell cycle arrest is sustained.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Conversely, DNA breaks in the rest of the genome are efficiently repaired, and DDR activation and cell cycle arrest are transient.

    “Conversely, DNA breaks in the rest of the genome are efficiently repaired, and DDR activation and cell cycle arrest are transient.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning

    A threshold number of dysfunctional telomeres must accumulate before the signal is sufficiently high to enforce persistent DDR signaling and to force cells to exit in G2 through sustained p53 activation.

    “Presumably, a threshold number of dysfunctional telomeres must accumulate before the signal is sufficiently high to enforce persistent DDR signaling and to force cells exit in G2 through sustained p53 activation.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The G2/M checkpoint only responds to 10–20 DNA breaks.

  • May combine two claims.

    Premisecitation

    Senescence of MEFs in culture is independent of telomere shortening because mouse fibroblasts have long telomeres and express the enzyme telomerase but is induced by high ambient oxygen levels (20%) that cause oxidative damage.

    “Likewise, senescence of MEFs in culture is independent of telomere shortening because mouse fibroblasts have long telomeres and express the enzyme telomerase but is induced by high ambient oxygen levels (20%) that cause oxidative damage [111].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [111] Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this case, telomere damage is attributed to specific features of telomeres that render them particularly susceptible to oxidation-induced damage, a type of damage that increases with aging.

    “In this case, telomere damage is attributed to specific features of telomeres that render them particularly susceptible to oxidation-induced damage, a type of damage that increases with aging [91,110].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] 2002, Oxidative stress shortens telomeres, Trends Biochem. Sci. source

      Not checked in the free run.

    • cites [110] Blackburn, 2005, Telomeres and telomerase: Their mechanisms of action and the effects of altering their functions, FEBS Lett. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ARF might not play a role in senescence induction as a first-line defense against oncogenic events in melanocytes, whereas ARF is an important component in melanoma suppression.

    “ARF might not play a role in senescence induction as a first-line defense against oncogenic events in melanocytes, whereas ARF is an important component in melanoma suppression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    This arrest can be suppressed by inactivating the ATM or CHK2 kinases, supporting the causative role of DNA damage signaling in response to oncogenic activation in OIS.

    “Importantly, this arrest can be suppressed by inactivating the ATM or CHK2 kinases, supporting the causative role of DNA damage signaling in response to oncogenic activation in OIS [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] Fumagalli, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regulation of ARF expression in humans and mice differs significantly in response to oncogenic signals, possibly because of limited homology between mouse and human CDKN2A promoter sequences.

    “However, the regulation of ARF expression in humans and mice differs significantly in response to oncogenic signals, possibly because of the limited homology between the mouse and human CDKN2A promoter sequences [124].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [124] Ortega, 2002, Cyclin D-dependent kinases, INK4 inhibitors and cancer, Biochim. Biophys. Acta BBA-Rev. Cancer

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increasing ARF levels often correlate with more advanced stages of cancer development and less frequently with pronounced DDR activation in response to persistent oncogenic activation.

    “It is now acknowledged that increasing ARF levels often correlate with more advanced stages of cancer development and less frequently with pronounced DDR activation in response to persistent oncogenic activation [129].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [129] Evangelou, 2013, The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis, Cell Death Differ. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The separate INK4A and ARF promoters can differentially respond to input signals and can be independently silenced in tumors.

    “The separate INK4A and ARF promoters can differentially respond to input signals and can be independently silenced in tumors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The two genes are largely coregulated in rodents, although some stimuli can selectively regulate p16 or ARF alone, whereas co-regulation of human p16 and p14ARF is uncommon.

    “The two genes are largely coregulated in rodents, although some stimuli can selectively regulate p16 or ARF alone [128], whereas co-regulation of human p16 and p14ARF is uncommon [123].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [128] Krishnamurthy, 2004, Ink4a/Arf expression is a biomarker of aging, J. Clin. Investig. source

      Not checked in the free run.

    • cites [123] Kim, 2006, The Regulation of INK4/ARF in Cancer and Aging, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SASP regulation is considerably heterogeneous and is influenced by cell type and the level and exposure duration to the initial senescence inducer.

    “Although the SASP is a feature shared by different senescence types, its regulation is considerably heterogeneous and is influenced by the cell type and the level and exposure duration to the initial senescence inducer [149].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Desprez, 2010, The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression, Annu. Rev. Pathol. Mech. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    GATA4 accumulates in senescent cells and induces the expression of IL-1α and TRAF3IP2 that activate NF-κB to initiate and amplify the SASP response.

    “GATA4 accumulates in senescent cells and induces the expression of IL-1α and TRAF3IP2 (an E3 ubiquitin ligase) that activate NF-κB to initiate and amplify the SASP response [160].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [160] Kang, 2015, The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The chromatin reader BRD4 is recruited to super-enhancer elements adjacent to key SASP genes and is required for their expression.

    “More directly, the chromatin reader BRD4 is recruited to super-enhancer elements that form adjacent to key SASP genes and is required for their expression [170].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [170] Tasdemir, 2016, BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance, Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    cGAS catalyzes production of the second messenger cGMP that binds STING, resulting in phosphorylation of IRF3 and NF-κB and stimulating production of type I interferons and inflammatory cytokines.

    “cGAS catalyzes the production of the second messenger cGMP that binds to stimulator of interferon genes (STING). This results in the phosphorylation of both interferon-regulatory factor 3 (IRF3) and of NF-κB transcription factors, thereby stimulating respectively the production of type I interferons and inflammatory cytokines [171,172,173,174].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [171] Dou, 2017, Cytoplasmic chromatin triggers inflammation in senescence and cancer, Nature source

      Not checked in the free run.

    • cites [172] Guey, 2017, Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [173] Yang, 2017, cGAS is essential for cellular senescence, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [174] Ablasser, 2019, cGAS in action: Expanding roles in immunity and inflammation, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HMGB2 remodels chromatin architecture and binds to loci of key SASP genes, preventing their incorporation into transcriptionally repressive heterochromatin regions and facilitating their expression.

    “Among the high mobility group (HMG) family members, HMGB2 is a non-histone chromatin-binding protein that remodels the chromatin architecture and binds to the loci of key SASP genes. Then, HMGB2 prevents their incorporation into transcriptionally repressive heterochromatin regions, facilitating their expression [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Aird, 2016, HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci, J. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of the SASP program requires a sustained DDR signal but is independent of p53, p21, and p16.

    “Activation of the SASP program requires a sustained DDR signal but is independent of p53, p21, and p16 (the mediators of cell cycle arrest in senescent cells) [147,148].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [147] Coppé, J.-P., Patil, C.K., Rodier, F., Sun, Y., Muñoz, D.P., Goldstein, J.N., Nelson, P.S., Desprez, P.-Y., and Campisi, J. (2008). Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor. PLoS Biol., 6. source

      Not checked in the free run.

    • cites [148] Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM signaling is required for the secretion of IL-6 and IL-8, the most conserved and robustly expressed inflammatory cytokines, but does not regulate the entire production of SASP factors.

    “ATM signaling does not regulate the entire production of SASP factors, although it is required for the secretion of IL-6 and IL-8, the most conserved and robustly expressed inflammatory cytokines [148].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [148] Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    At later stages of senescence, NOTCH1 expression decreases, entailing activation of C/EBPβ and subsequent production of the inflammatory SASP.

    “This inhibition is transient, and at later stages of senescence, NOTCH1 expression decreases, entailing the activation of C/EBPβ and the subsequent production of the inflammatory SASP [150].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [150] Hoare, 2016, NOTCH1 mediates a switch between two distinct secretomes during senescence, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The nuclear envelope of micronuclei is unstable and can rupture, leading to exposure of micronuclear DNA that induces a cellular immune response via cGAS.

    “The nuclear envelope of these micronuclei is unstable and can rupture, leading to the exposure of micronuclear DNA that induces a cellular immune response via cGAS [171,172,173].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [171] Dou, 2017, Cytoplasmic chromatin triggers inflammation in senescence and cancer, Nature source

      Not checked in the free run.

    • cites [172] Guey, 2017, Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [173] Yang, 2017, cGAS is essential for cellular senescence, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The mass and number of mitochondria are increased in senescent fibroblasts.

    “Due to their functional defects, the mass and number of mitochondria are increased in senescent fibroblasts [212].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [212] Passos, J.F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Wappler, I., Birket, M.J., Harold, G., and Schaeuble, K. (2007). Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence. PLoS Biol., 5. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    miRNAs are differentially expressed during senescence and regulate key nodes of senescence signaling pathways through direct binding to mRNAs of p53, p16, SASP factors, and other senescence-regulatory proteins.

    “Importantly, miRNAs are differentially expressed during senescence and regulate key nodes of the senescence signaling pathways through direct binding to the mRNAs of p53, p16, SASP factors, and other senescence-regulatory proteins [193].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [193] Ma, 2020, Regulation of cellular senescence by microRNAs, Mech. Ageing Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other splicing regulators such as PTBP1 regulate alternative splicing of genes involved in intracellular trafficking and are required for the pro-inflammatory SASP.

    “Other splicing regulators such as the RNA-binding protein polypyrimidine tract binding protein 1 (PTBP1), regulate the alternative splicing of genes involved in intracellular trafficking and are required for the pro-inflammatory SASP [203].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Georgilis, 2018, PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells, Cancer Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53β is required for senescence induction, possibly through transcriptional repression.

    “Functionally, p53β is required for senescence induction, possibly through transcriptional repression [202].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [202] Chen, 2017, Identification of a DNA Damage–Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers, Cancer Discov. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The level of splicing factor SRSF3 decreases in replicatively senescent human fibroblasts, and its knockdown promotes p53-mediated senescence by directly upregulating p53β.

    “For example, the level of the splicing factor SRSF3 decreases in replicatively senescent human fibroblasts, and its knockdown promotes p53-mediated senescence by directly upregulating p53β, an alternatively spliced p53 isoform [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [201] Tang, 2013, Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Damaged mitochondria are insensitive to mitophagy, and consequently mitochondrial number and size are not properly regulated in senescent cells.

    “Moreover, damaged mitochondria are insensitive to mitophagy (i.e., selective autophagy of mitochondria), and consequently, mitochondrial number and size are not properly regulated in senescent cells [214].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Kurz, 2008, Lysosomes and oxidative stress in aging and apoptosis, Biochim. Biophys. Acta BBA-Gen. Subj. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells display a very active but altered metabolism, with increased glycolysis and mTOR activity.

    “Although senescent cells do not divide, they display a very active but altered metabolism, with increased glycolysis and mTOR activity [204].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [204] Wiley, 2016, From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During OIS, fatty acid metabolism is altered, glucose consumption is enhanced, and utilization of pyruvate in the tricarboxylic acid cycle and nucleotide deficiency are increased.

    “Moreover, during OIS, fatty acid metabolism is altered, glucose consumption is enhanced, and the utilization of pyruvate in the tricarboxylic acid cycle and nucleotide deficiency are increased [119,216,217,218,219].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [119] Aird, 2013, Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence, Cell Rep. source

      Not checked in the free run.

    • cites [216] Quijano, 2012, Oncogene-induced senescence results in marked metabolic and bioenergetic alterations, Cell Cycle source

      Not checked in the free run.

    • cites [217] Li, 2013, Oncogene-induced cellular senescence elicits an anti-Warburg effect, Proteomics source

      Not checked in the free run.

    • cites [218] Aird, 2014, Metabolic alterations accompanying oncogene-induced senescence, Mol. Cell. Oncol. source

      Not checked in the free run.

    • cites [219] Aird, 2015, Nucleotide metabolism, oncogene-induced senescence and cancer, Cancer Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence induced by nucleotide deficiency causes aberrant DNA replication but can be overcome by ATM inactivation through restoration of glucose and glutamine consumption.

    “Senescence induced by nucleotide deficiency causes aberrant DNA replication but can be overcome by ATM inactivation through restoration of glucose and glutamine consumption [220].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [220] Aird, 2015, ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence, Cell Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mitochondrial dysfunction, initiated by pathways different from DNA damage, can determine SASP quality because local extracellular factors such as pyruvate can modify the SASP in senescent cells.

    “Therefore, mitochondrial dysfunction, initiated by pathways different from DNA damage, can determine the SASP quality because local extracellular factors, such as pyruvate, can modify the SASP in senescent cells [225].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [225] Wiley, 2016, Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p53 restricts glycolysis activity of senescent cells through several mechanisms, while RB upregulates glycolytic genes, resulting in high glycolytic activity.

    “In addition to stopping senescent cell proliferation, p53 and RB mediate senescence-related metabolic changes by balancing their effects on glycolysis: p53 restricts the glycolysis activity of senescent cells through several mechanisms [226], while RB upregulates glycolytic genes, resulting in high glycolytic activity [227].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [226] 2011, The Role of p53 in Metabolic Regulation, Genes Cancer source

      Not checked in the free run.

    • cites [227] Takebayashi, 2015, Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In senescent cells, activity of lysosomal β-galactosidase is significantly increased as a consequence of increased lysosomal mass and becomes detectable experimentally at pH 6.0.

    “In senescent cells, the activity of lysosomal β-galactosidase is significantly increased as a consequence of the increased lysosomal mass and becomes detectable experimentally at pH 6.0 [232].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [232] Dimri, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SA-β Gal activity is one of the first and most used biomarkers of senescence, although it can be detected in non-senescent cells that are confluent or serum-starved.

    “Senescence-associated β-galactosidase (SA-β Gal) activity is one of the first and most used biomarkers of senescence, although it has limitations because it can be detected in non-senescent cells that are confluent or serum-starved [233].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [233] Severino, 2000, Is β-Galactosidase Staining a Marker of Senescence in Vitro and in Vivo?, Exp. Cell Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK prevents cytoplasmic translocation of HuR, thereby increasing p21 and p16 mRNA stability and enhancing RB activity.

    “AMPK also prevents cytoplasmic translocation of the mRNA-stabilization factor HuR, thereby increasing p21 and p16 mRNA stability and enhancing RB activity [224].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [224] Wang, 2003, Increased AMP:ATP Ratio and AMP-activated Protein Kinase Activity during Cellular Senescence Linked to Reduced HuR Function, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Lipofuscin accumulation reflects reduced lysosomal activity, altered metabolism, and autophagy dysfunction.

    “Lipofuscin accumulation reflects reduced lysosomal activity, altered metabolism, and autophagy dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    As p53 response efficiency declines during aging, aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling.

    “As the p53 response efficiency declines during aging [228], aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling [155].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [228] Feng, 2007, Declining p53 function in the aging process: A possible mechanism for the increased tumor incidence in older populations, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [155] Chien, 2011, Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    During senescence, mTORC1 activation due to sustained DDR promotes mitochondrial biogenesis, contributing to ROS-dependent DDR persistence and SASP regulation.

    “Similarly, during senescence, mTORC1 activation due to sustained DDR does not favor growth but promotes mitochondrial biogenesis, thus contributing to the ROS-dependent DDR persistence and to SASP regulation [215].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [215] Marques, 2016, Mitochondria are required for pro-ageing features of the senescent phenotype, EMBO J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OIS relies on autophagic turnover of cytoplasmic material and specific autophagic degradation of nuclear lamin B1 in lysosomes, delivered by nucleus-to-cytoplasm transport.

    “OIS relies not only on the autophagic turnover of cytoplasmic material but also on the specific autophagic degradation of nuclear lamin B1 in lysosomes, where it is delivered by nucleus-to-cytoplasm transport [247].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [247] Dou, 2015, Autophagy mediates degradation of nuclear lamina, Nature source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Progressive protein misfolding/aggregation or massive SASP protein synthesis in senescent cells causes loss of proteostasis and activation of the unfolded protein response.

    “As a consequence, progressive protein misfolding/aggregation or massive SASP protein synthesis in senescent cells cause the loss of the protein quality control homeostasis (or proteostasis) and activation of the unfolded protein response (UPR).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Continuous DNA damage signaling is essential for maintenance of cell cycle arrest in senescence because inactivation of checkpoint kinases ATM, CHK2, and p53 results in escape from arrest.

    “Continuous DNA damage signaling is essential for cell cycle arrest maintenance because inactivation of checkpoint kinases, such as ATM [10,12], CHK2 [11], and p53 [47,48], results in escape from this arrest.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source

      Not checked in the free run.

    • cites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source

      Not checked in the free run.

    • cites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source

      Not checked in the free run.

    • cites [47] Gire, 1998, Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies, Mol. Cell. Biol. source

      Not checked in the free run.

    • cites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Under basal conditions, SQSTM1/p62 interacts with GATA4 and mediates its degradation by selective autophagy.

    “Under basal conditions, the autophagic adaptor SQSTM1/p62 interacts with GATA4 and mediates its degradation by selective autophagy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Kang, 2015, The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The TASCC, close to the nucleus, is highly enriched in mTOR and keeps mTOR away from the autophagy machinery to avoid its inactivation.

    “The mTOR–autophagy spatial coupling compartment (TASCC), which is close to the nucleus, is highly enriched in mTOR and keeps mTOR away from the autophagy machinery, located away from the TASCC, to avoid its inactivation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [246] Narita, 2011, Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UPR signaling limits ER abnormal protein load and reduces ER stress by inhibiting protein translation, upregulating ER chaperones, and degrading misfolded proteins via the proteasome through ER-associated degradation.

    “The UPR signaling seeks to limit ER abnormal protein load and to reduce ER stress by inhibiting protein translation [239], by upregulating various ER chaperones that contribute to the correct organization of misfolded proteins [240], and by degrading misfolded proteins via the proteasome through an ER-associated degradation process [241].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [239] Harding, 1999, Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase, Nature source

      Not checked in the free run.

    • cites [240] Yoshida, 2000, ATF6 Activated by Proteolysis Binds in the Presence of NF-Y (CBF) Directly to the cis -Acting Element Responsible for the Mammalian Unfolded Protein Response, Mol. Cell. Biol. source

      Not checked in the free run.

    • cites [241] Jarosch, 2000, A regulatory link between ER-associated protein degradation and the unfolded-protein response, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In oncogenic Ras-induced senescence, protein synthesis and autophagic degradation are simultaneously activated, and the same cell displays high autophagic activity and activated mTOR.

    “In senescence induced by oncogenic Ras, protein synthesis and autophagic degradation are simultaneous activated, and the same cell displays high autophagic activity and activated mTOR, the autophagy inhibitor [244].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [244] Young, 2009, Autophagy mediates the mitotic senescence transition, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Active ATM triggers removal from SASP genes of the histone variant macroH2A1, leading to inhibition of their transcription and reduction in ER stress.

    “Active ATM triggers the removal from SASP genes of the histone variant macroH2A1, leading to inhibition of their transcription and reduction in ER stress [168].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [168] Chen, 2015, MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype, Mol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IL-6 facilitates maintenance of the senescent phenotype by inhibiting mitochondrial-mediated apoptosis and stimulating pro-survival activity of NF-κB in senescent cells.

    “IL-6 also facilitates the senescent phenotype maintenance by inhibiting mitochondrial-mediated apoptosis and by stimulating the pro-survival activity of NF-κB in senescent cells [258].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Catz, 2001, Transcriptional Regulation of Bcl-2 by Nuclear Factor KB and Its Signicance in Prostate Cancer, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Induction of senescence appears protective against p53-dependent apoptosis and high oxidative stress.

    “Indeed, induction of senescence appears protective against p53-dependent apoptosis [146] and high oxidative stress [254,255].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [146] Seluanov, 2001, Change of the Death Pathway in Senescent Human Fibroblasts in Response to DNA Damage Is Caused by an Inability to Stabilize p53, Mol. Cell. Biol. source

      Not checked in the free run.

    • cites [254] Chen, 2000, Apoptosis or Senescence-like Growth Arrest: Influence of Cell-Cycle Position, P53, P21 and Bax in H2O2 Response of Normal Human FIbroblasts, Biochem. J. source

      Not checked in the free run.

    • cites [255] Sanders, 2013, Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress, Redox Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upregulation of p21 contributes to apoptosis resistance by inhibiting p53-mediated apoptosis after DNA damage and by preventing cleavage of caspase-3 and activation of the JNK pathway.

    “Upregulation of the cell cycle inhibitor p21 contributes to apoptosis resistance, for example, by inhibiting p53-mediated apoptosis after DNA damage [256,257] and by preventing the cleavage of the apoptosis effector caspase-3 and the activation of the JNK pathway (both required for apoptosis) [144].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [256] Gartel, 2002, The role of the cyclin-dependent kinase inhibitor p21 in apoptosis, Mol. Cancer Ther.

      Not checked in the free run.

    • cites [257] Xia, 2011, p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation, Oncogene source

      Not checked in the free run.

    • cites [144] Yosef, 2017, p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling, EMBO J. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Culturing cells in low oxygen or in the presence of antioxidants delays senescence onset.

    “Conversely, culturing cells in low oxygen or in the presence of antioxidants delays senescence onset [111,212,267,268].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [111] Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol. source

      Not checked in the free run.

    • cites [212] Passos, J.F., Saretzki, G., Ahmed, S., Nelson, G., Richter, T., Peters, H., Wappler, I., Birket, M.J., Harold, G., and Schaeuble, K. (2007). Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence. PLoS Biol., 5. source

      Not checked in the free run.

    • cites [267] Saretzki, 2003, MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress, Aging Cell source

      Not checked in the free run.

    • cites [268] Takahashi, 2006, Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restoring autophagy activity in old satellite cells clears protein aggregates and reverses senescence.

    “Conversely, restoring autophagy activity in old satellite cells clears protein aggregates and reverses senescence [262].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [262] Perdiguero, 2016, Autophagy maintains stemness by preventing senescence, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromatin rearrangements affect the transcriptional program of senescent cells and contribute to their transcriptome diversity.

    “These chromatin rearrangements affect the transcriptional program of senescent cells and contribute to their transcriptome diversity [133,136,275].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [133] Melov, 2017, Unmasking Transcriptional Heterogeneity in Senescent Cells, Curr. Biol. source

      Not checked in the free run.

    • cites [136] Shelton, 1999, Microarray analysis of replicative senescence, Curr. Biol. source

      Not checked in the free run.

    • cites [275] Shah, 2013, Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape, Genes Dev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β-interferons increase ROS production, leading to DNA damage and p53 activation.

    “Indeed, β-interferons increase ROS production, leading to DNA damage and p53 activation [273,274].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [273] Takaoka, 2003, Integration of Interferon-a/b Signalling to P53 Responses in Tumour Suppression and Antiviral Defence, Nature source

      Not checked in the free run.

    • cites [274] Moiseeva, 2006, DNA Damage Signaling and P53-Dependent Senescence after Prolonged b-Interferon Stimulation, Mol. Biol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescence induction following CXCR2 engagement is mediated by p53 and RB activation because CXCR2 depletion is sufficient for bypassing senescence.

    “Senescence induction following CXCR2 engagement is mediated by p53 and RB activation because CXCR2 depletion is sufficient for bypassing senescence [153].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [153] Acosta, 2008, Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROS can be directly transferred between cells through gap junctions or released through hydrogen peroxide into the environment, where they can induce senescence in surrounding cells.

    “Moreover, ROS can be directly transferred between cells through gap junctions or released through hydrogen peroxide into the environment, where they can induce senescence in surrounding cells [270].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [270] Nelson, 2012, A senescent cell bystander effect: Senescence-induced senescence, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Damaged mitochondrial DNA alters oxidative phosphorylation reactions and can further enhance ROS production.

    “In turn, damaged mitochondrial DNA alters oxidative phosphorylation reactions and can further enhance ROS production [269].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [269] Passos, 2016, Demystifying the role of mitochondria in senescence, Mol. Cell. Oncol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IGFBP7 influences MAPK signaling and PAI-1 regulates PI3K pathway, and both contribute to senescence stabilization by inhibiting proliferative and mitogenic pathways.

    “Other secreted proteins, such as IGFBP7 that influences MAPK signaling [271] and PAI-1 [272] that regulates the phosphoinositide 3-kinase (PI3K) pathway, also contribute to senescence stabilization by inhibiting proliferative and mitogenic pathways.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [271] Wajapeyee, 2008, Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7, Cell source

      Not checked in the free run.

    • cites [272] Kortlever, 2006, Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence, Nat. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced lamin B1 levels are observed in many senescence models, and its depletion causes senescence.

    “Reduced lamin B1 levels are observed in many senescence models, and its depletion causes senescence [279,280,281].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [279] Sadaie, 2013, Redistribution of the Lamin B1 genomic binding profile affects rearrangement of heterochromatic domains and SAHF formation during senescence, Genes Dev. source

      Not checked in the free run.

    • cites [280] Shimi, 2011, The role of nuclear lamin B1 in cell proliferation and senescence, Genes Dev. source

      Not checked in the free run.

    • cites [281] Freund, 2012, Lamin B1 loss is a senescence-associated biomarker, Mol. Biol. Cell source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The extended proliferative period exacerbates telomere shortening and leads to chromosomal fusions and anaphase bridges.

    “This extended proliferative period exacerbates telomere shortening and leads to chromosomal fusions and anaphase bridges.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In other settings, senescent cells may facilitate cancer progression.

    “In other settings, senescent cells may facilitate cancer progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Critically short uncapped telomeres, oncogene stresses, and mitochondrial dysfunction result in proliferative stress and senescence induction, halting proliferation of cells with mutations or genomic instability.

    “Critically short, uncapped telomeres [9], oncogene stresses [51], and mitochondrial dysfunction [225] result in proliferative stress and senescence induction, thereby halting the proliferation of cells harboring mutations or genomic instability.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

      Not checked in the free run.

    • cites [51] Serrano, 1997, Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a, Cell source

      Not checked in the free run.

    • cites [225] Wiley, 2016, Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of p53 and RB bypassed senescence in cultured human fibroblasts and allowed entry into crisis, considered a second barrier to cancer formation.

    “Loss of p53 and RB bypassed senescence in cultured human fibroblasts, and allowed entry into crisis, which is considered as a second barrier to cancer formation [348].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [348] Shay, 1991, Defining the molecular mechanisms of human cell immortalization, Biochim. Biophys. Acta BBA-Rev. Cancer

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SASP factor expression by senescent cells can facilitate cancer progression by promoting growth of pre-neoplastic cells and modifying tumor microenvironment.

    “Paradoxically, SASP factor expression by senescent cells can also facilitate cancer progression by promoting growth of pre-neoplastic cells and by modifying the tumor microenvironment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Mechanisms to evade senescence are required for malignant progression of melanocytes and involve additional mutations to prevent or bypass OIS.

    “Mechanisms to evade senescence are required for malignant progression of melanocytes and involve additional mutations to prevent or bypass OIS, further underscoring the importance of senescence in counteracting tumor development.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    SASP composition and strength are context-dependent and highly heterogeneous.

    “The SASP composition and strength are context-dependent and highly heterogenous.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recruitment and activation of T cells and natural killer cells at senescent cells in tumor microenvironment or altered macrophage polarization promote removal of senescent or damaged cells.

    “Recruitment and activation of T cells and natural killer cells at the location of senescent cells in the tumor microenvironment or altered polarization of macrophages promote the removal of senescent or damaged cells [29,358,359,360].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [29] Krizhanovsky, 2008, Senescence of Activated Stellate Cells Limits Liver Fibrosis, Cell source

      Not checked in the free run.

    • cites [358] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source

      Not checked in the free run.

    • cites [359] Iannello, 2013, p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells, J. Exp. Med. source

      Not checked in the free run.

    • cites [360] Sagiv, 2012, Granule exocytosis mediates immune surveillance of senescent cells, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Telomere shortening may restrict and also promote tumor initiation.

    “Thus, telomere shortening may restrict and also promote tumor initiation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Persistence of senescent tumor cells can be a source of chronic inflammation and resistance to chemotherapy.

    “Consequently, persistence of senescent tumor cells can be a source of chronic inflammation and of resistance to chemotherapy [363].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [363] Ewald, 2010, Therapy-Induced Senescence in Cancer, JNCI J. Natl. Cancer Inst. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Senescence-inducing therapies rely on limiting cancer cell proliferation and also fibrosis formation during carcinogenesis.

    “Senescence-inducing therapies rely on limiting cancer cell proliferation and also fibrosis formation during carcinogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Cancer cells in which the molecular pathways leading to senescence are not affected respond to chemotherapy by entering senescence, which leads to tumor regression through immune clearance of senescent cells.

    “Cancer cells in which the molecular pathways leading to senescence are not affected respond to chemotherapy by entering senescence, which leads to tumor regression through immune clearance of senescent cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Following drug-induced DNA damage, tumor cells are forced into senescence, stop dividing, and cancer growth might be blocked.

    “Following drug-induced DNA damage, tumor cells are forced into senescence, they stop dividing, and cancer growth might be blocked.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tumor cells that escaped senescence after chemotherapy display stem cell characteristics and acquire higher tumor initiation potential in vivo.

    “tumor cells that escaped senescence after chemotherapy display stem cell characteristics and acquire a higher tumor initiation potential in vivo [366].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [366] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    An important limitation in studying senescent cells is the lack of specific biomarkers to properly identify and follow them.

    “An important limitation in studying senescent cells is the lack of specific biomarkers to properly identify and follow them.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    Much of the current knowledge on the senescent cell state comes from work performed in cultured cells.

    “Much of the current knowledge on the senescent cell state comes from work performed in cultured cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Acute senescence induction contributes to adequate tissue patterning during embryogenesis, limits tissue damage, and facilitates tissue repair to ensure organismal fitness.

    “Acute senescence induction contributes to adequate tissue patterning during embryogenesis, limits tissue damage, and facilitates tissue repair to ensure organismal fitness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In cell xenografts, matrix metalloproteinases secreted by senescent human fibroblasts increase tumor growth, probably by disrupting immunosurveillance by paracrine action in the microenvironment.

    “In cell xenografts experiments, matrix metalloproteinases secreted by senescent human fibroblasts increase tumor growth [361], probably by disrupting the immunosurveillance by paracrine action in the microenvironment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [361] Liu, 2007, Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion, Cancer Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A major risk is that a population of post-chemotherapy senescent cancer cells may at some point re-enter the cell cycle, start to proliferate, become highly aggressive and chemo-resistant, and acquire stemness-like characteristics, leading to cancer relapse.

    “a major risk is that a population of post-chemotherapy senescent cancer cells may at some point re-enter the cell cycle, start to proliferate, become highly aggressive and chemo-resistant, and acquire stemness-like characteristics, leading to cancer relapse [366,368].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [366] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

      Not checked in the free run.

    • cites [368] Saleh, 2020, Acquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression, Semin. Cancer Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combining chemotherapeutic and anti-senescence agents (or senolytic drugs) allows selective elimination of senescent cells to restore tissue function, and potentially improve organ regeneration.

    “combining chemotherapeutic and anti-senescence agents (or senolytic drugs) allows the selective elimination of senescent cells to restore tissue function, and potentially improve organ regeneration [7,141].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

      Not checked in the free run.

    • cites [141] McHugh, 2018, Senescence and aging: Causes, consequences, and therapeutic avenues, J. Cell Biol. source

      Not checked in the free run.

123 of 123

  • The paper relies on this without support.

    The G2/M checkpoint only responds to 10–20 DNA breaks.

    “This threshold number is not a single DNA break because the G2/M checkpoint only responds to 10–20 DNA breaks.”

  • The paper relies on this without support.

    Endogenous expression levels of oncogenes are unlikely to cause OIS.

    “As the endogenous expression levels of oncogenes are unlikely to cause OIS, the stochastic accumulation of mutations might be needed for OIS induction [118].”

  • The paper relies on this without support.

    Cancer cells must replicate to produce a macroscopic tumor.

    “because cancer cells must replicate to produce a macroscopic tumor.”
3 of 3

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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • cGAS product conflicts with the enzyme name given

    Minor

    The text identifies cGAS as cyclic GMP-AMP synthase but then says it produces cGMP, a different molecule.

1 of 1

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Authors
Roger, L., Tomas, F., & Gire, V.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Gire, Véronique
ORCID
Gire, Véronique
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2021-12-06
Volume
22
Issue
23
Pages
13173
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms222313173
PMC
PMC8658264
OpenAlex
W4200606392
Cited by
395
References
375
Citations by year
2026: 65 · 2025: 139 · 2024: 90 · 2023: 69 · 2022: 31 · 2021: 1
FWCI
6.48
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
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 › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, senescence-associated secretory phenotype, DNA damage response, proliferative arrest, senescence induction, senescence heterogeneity, senescence-associated inflammation, heterochromatin, cellular metabolism, transcriptional programs, aging, cancer prevention
MeSH terms
Senescence-Associated Secretory Phenotype, Aging, Animals, DNA Damage, Humans, Inflammation, Signal Transduction, Cellular Senescence

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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