Mechanisms and Regulation of Cellular Senescence

In the paper

“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].”

What the sources say

• Partly supported

  The Results section on p21 association with G2/M Cdks (page unavailable) reports that p21 binds some cyclin B1–CDK1 complexes and that their activity is blocked after drug treatment. It says their inactivation appears predominantly due to inhibition of Cdc25 and that p21’s role remains under investigation. It does not establish that the complexes are nuclear or cannot be activated after dephosphorylation by CDC25C. (LLM, conf=0.85)

  cites [60] Baus, 2003, Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts, EMBO J. sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘p21 Binds to Inactive Cyclin B1-Cdk1 Complexes’ section reports that p21-bound complexes are inactive and retained in the nucleus. The ‘P21 Blocks Activation of Cyclin B1-Cdk1 by Cdc25’ section reports that they resisted dephosphorylation and activation in the Figure 7 assay, but the phosphatase tested was Cdc25B, not the specifically named Cdc25C. Page numbers were not supplied in our copy. (LLM, conf=0.89)

  cites [61] Gire, 2004, p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress, Mol. Biol. Cell sourceExperimental — accuracy not yet measured

In the paper

“Due to their functional defects, the mass and number of mitochondria are increased in senescent fibroblasts [212].”

What the sources say

• Supported

  The Results section, under “Retrograde Response in Senescent Fibroblasts,” explicitly reports increased mitochondrial mass and number. The same section links mitochondrial dysfunction to increased biogenesis through the retrograde response, supporting the sentence’s framing, although it does not establish that link as a direct cause in these cells. (LLM, conf=0.93)

  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

In the paper

“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.”

What the sources say

• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source
• Supported

  The citation to this paper is attached to CHK2, not ATM or p53. In the Results (page unavailable), knocking down Chk2 in senescent human fibroblasts increased DNA synthesis, and the cells returned to a senescent phenotype after the knockdown wore off. The Discussion explicitly describes this as a temporary escape from senescence. (LLM, conf=0.94)

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

  The Abstract reports that blocking p53 in senescent human fibroblasts induced reentry into S phase and subsequent cell division. The Discussion concludes that p53 makes an essential contribution to maintaining their growth arrest. This supports the p53 portion of the citing sentence, to which this source is attached; ATM and CHK2 have separate citations. (LLM, conf=0.92)

  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
• Partly supported

  The Results report that p53 inactivation reversed the senescence arrest in BJ fibroblasts, supporting the p53 portion of the cited sentence. The Discussion and Results also say this reversal depends on p16 status: p53 inactivation did not restore proliferation in cells with an established p16-associated arrest. The paper therefore does not support an unqualified claim that p53 inactivation causes escape from senescence arrest. (LLM, conf=0.88)

  cites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. sourceExperimental — accuracy not yet measured

In the paper

“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].”

What the sources say

• Partly supported

  The Results section ('Senescent stellate cells are selectively targeted by NK cells'; page unavailable) reports NK-cell killing of senescent cells, and the Discussion identifies NK-cell cytotoxicity as a mechanism for clearing senescent activated stellate cells in fibrotic liver. The paper does not establish that T-cell recruitment or altered macrophage polarization promotes clearance, nor does its liver-fibrosis study establish those mechanisms in a tumor microenvironment. (LLM, conf=0.88)

  cites [29] Krizhanovsky, 2008, Senescence of Activated Stellate Cells Limits Liver Fibrosis, Cell sourceExperimental — accuracy not yet measured
• Partly supported

  The passages labeled Abstract report macrophage and natural killer cell infiltration after p53 reactivation and show that suppressing either cell type delayed clearance of senescent liver tumours. They do not establish macrophage polarization or T-cell recruitment and activation; the mice in the clearance experiment lacked functional T cells. (LLM, conf=0.88)

  cites [358] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('Neutralization of CCL2 prevents NK cell recruitment in vivo and diminishes tumor cell rejection'; page not supplied) supports NK-cell recruitment and elimination of senescent tumor cells. The paper does not establish that T-cell recruitment or activation, or altered macrophage polarization, promotes their removal. (LLM, conf=0.88)

  cites [359] Iannello, 2013, p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells, J. Exp. Med. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Discussion (page numbers unavailable) say senescent cells can attract NK cells and show that NK cells kill senescent cells. The Discussion also reports a role for CD4 T cells and macrophages in clearing premalignant senescent hepatocytes, but does not establish T-cell recruitment and activation in the tumor microenvironment or clearance through altered macrophage polarization. (LLM, conf=0.85)

  cites [360] Sagiv, 2012, Granule exocytosis mediates immune surveillance of senescent cells, Oncogene sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Not checked yetcites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source
• Not checked yetcites [2] Childs, 2014, Senescence and apoptosis: Dueling or complementary cell fates?, EMBO Rep. source
• Not checked yetcites [3] Zhu, 2015, The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs, Aging Cell source
• Not checked yetcites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

In the paper

“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.”

In the paper

“These cells display high metabolic activities [1], remain viable, and actively suppress apoptosis [2,3].”

What the sources say

• Not checked yetcites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source
• Not checked yetcites [2] Childs, 2014, Senescence and apoptosis: Dueling or complementary cell fates?, EMBO Rep. source
• Not checked yetcites [3] Zhu, 2015, The Achilles’ heel of senescent cells: From transcriptome to senolytic drugs, Aging Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source
• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [12] Herbig, 2004, Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a, Mol. Cell source

In the paper

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

In the paper

“Importantly, elimination of senescent cells can promote stem cell proliferation and delay the appearance of aging features [13,14,15].”

What the sources say

• Not checked yetcites [13] Baker, 2016, Naturally occurring p16Ink4a-positive cells shorten healthy lifespan, Nature source
• Not checked yetcites [14] Chang, 2016, Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice, Nat. Med. source
• Not checked yetcites [15] Yosef, 2016, Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL, Nat. Commun. source

In the paper

“All these factors can induce DNA damage and senescence in normal and cancer cells (in some contexts) [6].”

What the sources say

• Not checked yetcites [6] 2008, Living on a break: Cellular senescence as a DNA-damage response, Nat. Rev. Cancer source

In the paper

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

What the sources say

• Not checked yetcites [1] Yu, 2013, Synthetic lethal metabolic targeting of cellular senescence in cancer therapy, Nature source

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source

In the paper

“Therefore, it has been proposed that senescence escape is required for tumor progression to overt malignancy [18,21].”

What the sources say

• Not checked yetcites [18] Collado, 2005, Senescence in premalignant tumours, Nature source
• Not checked yetcites [21] Collado, 2010, Senescence in tumours: Evidence from mice and humans, Nat. Rev. Cancer source

In the paper

“Senescent cells are heterogeneous and perform various biological functions.”

In the paper

“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.”

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [41] Brown, 1997, Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts, Science source
• Not checked yetcites [42] Reyes, 2018, Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest, Mol. Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [44] Ma, 1999, Microinjection of anti-p21 antibodies induces senescent Hs68 human fibroblasts to synthesize DNA but not to divide, Cancer Res.

In the paper

“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.”

In the paper

“However, senescent cells are not effectively removed in aging tissues and this might reflect the age-related decline in immune functions [26].”

What the sources say

• Not checked yetcites [26] Serrano, 2014, Cellular senescence: From physiology to pathology, Nat. Rev. Mol. Cell Biol. source

In the paper

“Replicative senescence is bypassed upon loss of p21 [41] but not upon loss of p16 function [45,46].”

What the sources say

• Not checked yetcites [41] Brown, 1997, Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts, Science source
• Not checked yetcites [45] Wei, 2003, Loss of retinoblastoma but not p16 function allows bypass of replicative senescence in human fibroblasts, EMBOJ source
• Not checked yetcites [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

In the paper

“It has been proposed that active p16 signaling can compensate for p53 activity decline after full senescence establishment [49,50].”

What the sources say

• Not checked yetcites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [58] Krenning, 2014, Transient Activation of p53 in G2 Phase Is Sufficient to Induce Senescence, Mol. Cell source
• Not checked yetcites [62] Cascales, 2014, Nuclear translocation of Cyclin B1 marks the restriction point for terminal cell cycle exit in G2 phase, Cell Cycle source
• Not checked yetcites [63] Cascales, 2017, Residual Cdk1/2 activity after DNA damage promotes senescence, Aging Cell source

In the paper

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

In the paper

“Moreover, cells with low baseline p16 levels do not undergo OIS but show anchorage-independent growth (a feature of cell transformation) [54].”

What the sources say

• Not checked yetcites [54] Benanti, 2004, Normal Human Fibroblasts Are Resistant to RAS-Induced Senescence, Mol. Cell. Biol. source

In the paper

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

What the sources say

• Not checked yetcites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source
• Not checked yetcites [49] Jacobs, 2004, Significant Role for p16INK4a in p53-Independent Telomere-Directed Senescence, Curr. Biol. source

In the paper

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

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [65] Macedo, 2018, FoxM1 repression during human aging leads to mitotic decline and aneuploidy-driven full senescence, Nat. Commun. source

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [67] Jones, 2008, Many roads lead to oncogene-induced senescence, Oncogene source

In the paper

“However, neither p53 nor p16 are implicated in human mammary epithelial cells [77] or melanocytes [78] undergoing Ras-induced senescence.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [78] Denoyelle, 2006, Anti-oncogenic role of the endoplasmic reticulum differentially activated by mutations in the MAPK pathway, Nat. Cell Biol. source

In the paper

“Overexpression of BMI1 [80], CBX7 [81], or CBX8 [82] results in the direct repression of p16 and senescence delay in human and mouse cells.”

What the sources say

• Not checked yetcites [80] Jacobs, 1999, The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus, Nature source
• Not checked yetcites [81] Gil, 2004, Polycomb CBX7 has a unifying role in cellular lifespan, Nat. Cell Biol. source
• Not checked yetcites [82] Dietrich, 2007, Bypass of senescence by the polycomb group protein CBX8 through direct binding to the INK4A-ARF locus, EMBO J. source

In the paper

“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].”

What the sources say

• Not checked yetcites [8] Hayflick, 1961, The serial cultivation of human diploid cell strains, Exp. Cell Res. source
• Not checked yetcites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

In the paper

“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].”

What the sources say

• Not checked yetcites [71] Takai, 2003, DNA Damage Foci at Dysfunctional Telomeres, Curr. Biol. source
• Not checked yetcites [95] Celli, 2005, DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [94] Baird, 2003, Extensive allelic variation and ultrashort telomeres in senescent human cells, Nat. Genet. source
• Not checked yetcites [10] Reaper, 2003, A DNA Damage Checkpoint Response in Telomere-Initiated Senescence, Nature source
• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“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.”

What the sources say

• Not checked yetcites [83] Bracken, 2007, The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells, Genes Dev. source
• Not checked yetcites [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 yetcites [85] Barradas, 2009, Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS, Genes Dev. source

In the paper

“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.”

What the sources say

• Not checked yetcites [101] Karlseder, 2002, Senescence Induced by Altered Telomere State, Not Telomere Loss, Science source
• Not checked yetcites [88] Doksani, 2013, Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-loop Formation, Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“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.”

What the sources say

• Not checked yetcites [86] 2005, Shelterin: The protein complex that shapes and safeguards human telomeres, Genes Dev. source
• Not checked yetcites [87] Griffith, 1999, Mammalian Telomeres End in a Large Duplex Loop, Cell source
• Not checked yetcites [88] Doksani, 2013, Super-Resolution Fluorescence Imaging of Telomeres Reveals TRF2-Dependent T-loop Formation, Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“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].”

What the sources say

• Not checked yetcites [9] Bodnar, 1998, Extension of Life-Span by Introduction of Telomerase into Normal Human Cells, Science source

In the paper

“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].”

What the sources say

• Not checked yetcites [57] Jullien, 2013, Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response, Nucleic Acids Res. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [116] Broccoli, 1997, Human telomeres contain two distinct Myb–related proteins, TRF1 and TRF2, Nat. Genet. source
• Not checked yetcites [109] Hewitt, 2012, Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence, Nat. Commun. source
• Not checked yetcites [115] Fumagalli, 2012, Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation, Nat. Cell Biol. source

In the paper

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

In the paper

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

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [111] Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [91] 2002, Oxidative stress shortens telomeres, Trends Biochem. Sci. source
• Not checked yetcites [110] Blackburn, 2005, Telomeres and telomerase: Their mechanisms of action and the effects of altering their functions, FEBS Lett. source

In the paper

“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.”

In the paper

“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].”

What the sources say

• Not checked yetcites [70] Fumagalli, 2006, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication, Nature source

In the paper

“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].”

What the sources say

• Not checked yetcites [124] Ortega, 2002, Cyclin D-dependent kinases, INK4 inhibitors and cancer, Biochim. Biophys. Acta BBA-Rev. Cancer

In the paper

“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].”

What the sources say

• Not checked yetcites [129] Evangelou, 2013, The DNA damage checkpoint precedes activation of ARF in response to escalating oncogenic stress during tumorigenesis, Cell Death Differ. source

In the paper

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

In the paper

“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].”

What the sources say

• Not checked yetcites [128] Krishnamurthy, 2004, Ink4a/Arf expression is a biomarker of aging, J. Clin. Investig. source
• Not checked yetcites [123] Kim, 2006, The Regulation of INK4/ARF in Cancer and Aging, Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [149] Desprez, 2010, The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression, Annu. Rev. Pathol. Mech. Dis. source

In the paper

“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].”

What the sources say

• Not checked yetcites [160] Kang, 2015, The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4, Science source

In the paper

“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].”

What the sources say

• Not checked yetcites [170] Tasdemir, 2016, BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance, Cancer Discov. source

In the paper

“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].”

What the sources say

• Not checked yetcites [171] Dou, 2017, Cytoplasmic chromatin triggers inflammation in senescence and cancer, Nature source
• Not checked yetcites [172] Guey, 2017, Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence, Nat. Cell Biol. source
• Not checked yetcites [173] Yang, 2017, cGAS is essential for cellular senescence, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [174] Ablasser, 2019, cGAS in action: Expanding roles in immunity and inflammation, Science source

In the paper

“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].”

What the sources say

• Not checked yetcites [169] Aird, 2016, HMGB2 orchestrates the chromatin landscape of senescence-associated secretory phenotype gene loci, J. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [148] Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [148] Rodier, 2009, Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [150] Hoare, 2016, NOTCH1 mediates a switch between two distinct secretomes during senescence, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [171] Dou, 2017, Cytoplasmic chromatin triggers inflammation in senescence and cancer, Nature source
• Not checked yetcites [172] Guey, 2017, Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence, Nat. Cell Biol. source
• Not checked yetcites [173] Yang, 2017, cGAS is essential for cellular senescence, Proc. Natl. Acad. Sci. USA source

In the paper

“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].”

What the sources say

• Not checked yetcites [193] Ma, 2020, Regulation of cellular senescence by microRNAs, Mech. Ageing Dev. source

In the paper

“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].”

What the sources say

• Not checked yetcites [203] Georgilis, 2018, PTBP1-Mediated Alternative Splicing Regulates the Inflammatory Secretome and the Pro-tumorigenic Effects of Senescent Cells, Cancer Cell source

In the paper

“Functionally, p53β is required for senescence induction, possibly through transcriptional repression [202].”

What the sources say

• Not checked yetcites [202] Chen, 2017, Identification of a DNA Damage–Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers, Cancer Discov. source

In the paper

“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].”

What the sources say

• Not checked yetcites [201] Tang, 2013, Downregulation of splicing factor SRSF3 induces p53β, an alternatively spliced isoform of p53 that promotes cellular senescence, Oncogene source

In the paper

“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].”

What the sources say

• Not checked yetcites [214] Kurz, 2008, Lysosomes and oxidative stress in aging and apoptosis, Biochim. Biophys. Acta BBA-Gen. Subj. source

In the paper

“Although senescent cells do not divide, they display a very active but altered metabolism, with increased glycolysis and mTOR activity [204].”

What the sources say

• Not checked yetcites [204] Wiley, 2016, From Ancient Pathways to Aging Cells—Connecting Metabolism and Cellular Senescence, Cell Metab. source

In the paper

“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].”

What the sources say

• Not checked yetcites [119] Aird, 2013, Suppression of Nucleotide Metabolism Underlies the Establishment and Maintenance of Oncogene-Induced Senescence, Cell Rep. source
• Not checked yetcites [216] Quijano, 2012, Oncogene-induced senescence results in marked metabolic and bioenergetic alterations, Cell Cycle source
• Not checked yetcites [217] Li, 2013, Oncogene-induced cellular senescence elicits an anti-Warburg effect, Proteomics source
• Not checked yetcites [218] Aird, 2014, Metabolic alterations accompanying oncogene-induced senescence, Mol. Cell. Oncol. source
• Not checked yetcites [219] Aird, 2015, Nucleotide metabolism, oncogene-induced senescence and cancer, Cancer Lett. source

In the paper

“Senescence induced by nucleotide deficiency causes aberrant DNA replication but can be overcome by ATM inactivation through restoration of glucose and glutamine consumption [220].”

What the sources say

• Not checked yetcites [220] Aird, 2015, ATM Couples Replication Stress and Metabolic Reprogramming during Cellular Senescence, Cell Rep. source

In the paper

“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].”

What the sources say

• Not checked yetcites [225] Wiley, 2016, Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype, Cell Metab. source

In the paper

“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].”

What the sources say

• Not checked yetcites [226] 2011, The Role of p53 in Metabolic Regulation, Genes Cancer source
• Not checked yetcites [227] Takebayashi, 2015, Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells, Aging Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [232] Dimri, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc. Natl. Acad. Sci. USA source

In the paper

“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].”

What the sources say

• Not checked yetcites [233] Severino, 2000, Is β-Galactosidase Staining a Marker of Senescence in Vitro and in Vivo?, Exp. Cell Res. source

In the paper

“AMPK also prevents cytoplasmic translocation of the mRNA-stabilization factor HuR, thereby increasing p21 and p16 mRNA stability and enhancing RB activity [224].”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“As the p53 response efficiency declines during aging [228], aerobic glycolysis is increased as well as the proinflammatory SASP via NF-κB signaling [155].”

What the sources say

• Not checked yetcites [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 yetcites [155] Chien, 2011, Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity, Genes Dev. source

In the paper

“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].”

What the sources say

• Not checked yetcites [215] Marques, 2016, Mitochondria are required for pro-ageing features of the senescent phenotype, EMBO J. source

In the paper

“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].”

What the sources say

• Not checked yetcites [247] Dou, 2015, Autophagy mediates degradation of nuclear lamina, Nature source

In the paper

“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).”

In the paper

“Under basal conditions, the autophagic adaptor SQSTM1/p62 interacts with GATA4 and mediates its degradation by selective autophagy.”

What the sources say

• Not checked yetcites [160] Kang, 2015, The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4, Science source

In the paper

“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.”

What the sources say

• Not checked yetcites [246] Narita, 2011, Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes, Science source