Mechanisms and Regulation of Cellular Senescence

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

“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

• Not checked yetcites [60] Baus, 2003, Permanent cell cycle exit in G2 phase after DNA damage in normal human fibroblasts, EMBO J. source
• Not checked yetcites [61] Gire, 2004, p21-Mediated Nuclear Retention of Cyclin B1-Cdk1 in Response to Genotoxic Stress, Mol. Biol. Cell source

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

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

What the sources say

• Not checked yetcites [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

“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

“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
• Not checked yetcites [11] Gire, 2004, DNA damage checkpoint kinase Chk2 triggers replicative senescence, EMBO J. source
• Not checked yetcites [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 yetcites [48] Krtolica, 2003, Reversal of human cellular senescence: Roles of the p53 and p16 pathways, EMBO J. source

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

In the paper

“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].”

What the sources say

• Not checked yetcites [239] Harding, 1999, Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase, Nature source
• Not checked yetcites [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 yetcites [241] Jarosch, 2000, A regulatory link between ER-associated protein degradation and the unfolded-protein response, Nat. Cell Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [244] Young, 2009, Autophagy mediates the mitotic senescence transition, Genes Dev. source

In the paper

“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].”

What the sources say

• Not checked yetcites [168] Chen, 2015, MacroH2A1 and ATM Play Opposing Roles in Paracrine Senescence and the Senescence-Associated Secretory Phenotype, Mol. Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [258] Catz, 2001, Transcriptional Regulation of Bcl-2 by Nuclear Factor KB and Its Signicance in Prostate Cancer, Oncogene source

In the paper

“Indeed, induction of senescence appears protective against p53-dependent apoptosis [146] and high oxidative stress [254,255].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [255] Sanders, 2013, Histone Modifications in Senescence-Associated Resistance to Apoptosis by Oxidative Stress, Redox Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [256] Gartel, 2002, The role of the cyclin-dependent kinase inhibitor p21 in apoptosis, Mol. Cancer Ther.
• Not checked yetcites [257] Xia, 2011, p21 does not protect cancer cells from apoptosis induced by nongenotoxic p53 activation, Oncogene source
• Not checked yetcites [144] Yosef, 2017, p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling, EMBO J. source

In the paper

“Conversely, culturing cells in low oxygen or in the presence of antioxidants delays senescence onset [111,212,267,268].”

What the sources say

• Not checked yetcites [111] Parrinello, 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, Nat. Cell Biol. source
• Not checked yetcites [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 yetcites [267] Saretzki, 2003, MitoQ counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress, Aging Cell source
• Not checked yetcites [268] Takahashi, 2006, Mitogenic signalling and the p16INK4a–Rb pathway cooperate to enforce irreversible cellular senescence, Nat. Cell Biol. source

In the paper

“Conversely, restoring autophagy activity in old satellite cells clears protein aggregates and reverses senescence [262].”

What the sources say

• Not checked yetcites [262] Perdiguero, 2016, Autophagy maintains stemness by preventing senescence, Nature source

In the paper

“These chromatin rearrangements affect the transcriptional program of senescent cells and contribute to their transcriptome diversity [133,136,275].”

What the sources say

• Not checked yetcites [133] Melov, 2017, Unmasking Transcriptional Heterogeneity in Senescent Cells, Curr. Biol. source
• Not checked yetcites [136] Shelton, 1999, Microarray analysis of replicative senescence, Curr. Biol. source
• Not checked yetcites [275] Shah, 2013, Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape, Genes Dev. source

In the paper

“Indeed, β-interferons increase ROS production, leading to DNA damage and p53 activation [273,274].”

What the sources say

• Not checked yetcites [273] Takaoka, 2003, Integration of Interferon-a/b Signalling to P53 Responses in Tumour Suppression and Antiviral Defence, Nature source
• Not checked yetcites [274] Moiseeva, 2006, DNA Damage Signaling and P53-Dependent Senescence after Prolonged b-Interferon Stimulation, Mol. Biol. Cell source

In the paper

“Senescence induction following CXCR2 engagement is mediated by p53 and RB activation because CXCR2 depletion is sufficient for bypassing senescence [153].”

What the sources say

• Not checked yetcites [153] Acosta, 2008, Chemokine Signaling via the CXCR2 Receptor Reinforces Senescence, Cell source

In the paper

“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].”

What the sources say

• Not checked yetcites [270] Nelson, 2012, A senescent cell bystander effect: Senescence-induced senescence, Aging Cell source

In the paper

“In turn, damaged mitochondrial DNA alters oxidative phosphorylation reactions and can further enhance ROS production [269].”

What the sources say

• Not checked yetcites [269] Passos, 2016, Demystifying the role of mitochondria in senescence, Mol. Cell. Oncol. source

In the paper

“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.”

What the sources say

• Not checked yetcites [271] Wajapeyee, 2008, Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7, Cell source
• Not checked yetcites [272] Kortlever, 2006, Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence, Nat. Cell Biol. source

In the paper

“Reduced lamin B1 levels are observed in many senescence models, and its depletion causes senescence [279,280,281].”

What the sources say

• Not checked yetcites [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 yetcites [280] Shimi, 2011, The role of nuclear lamin B1 in cell proliferation and senescence, Genes Dev. source
• Not checked yetcites [281] Freund, 2012, Lamin B1 loss is a senescence-associated biomarker, Mol. Biol. Cell source

In the paper

“This extended proliferative period exacerbates telomere shortening and leads to chromosomal fusions and anaphase bridges.”

In the paper

“In other settings, senescent cells may facilitate cancer progression.”

In the paper

“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.”

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 [51] Serrano, 1997, Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a, Cell source
• Not checked yetcites [225] Wiley, 2016, Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype, Cell Metab. source

In the paper

“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].”

What the sources say

• Not checked yetcites [348] Shay, 1991, Defining the molecular mechanisms of human cell immortalization, Biochim. Biophys. Acta BBA-Rev. Cancer

In the paper

“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.”

In the paper

“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.”

In the paper

“The SASP composition and strength are context-dependent and highly heterogenous.”

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

• Not checked yetcites [29] Krizhanovsky, 2008, Senescence of Activated Stellate Cells Limits Liver Fibrosis, Cell source
• Not checked yetcites [358] Xue, 2007, Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas, Nature source
• Not checked yetcites [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 yetcites [360] Sagiv, 2012, Granule exocytosis mediates immune surveillance of senescent cells, Oncogene source

In the paper

“Thus, telomere shortening may restrict and also promote tumor initiation.”

In the paper

“Consequently, persistence of senescent tumor cells can be a source of chronic inflammation and of resistance to chemotherapy [363].”

What the sources say

• Not checked yetcites [363] Ewald, 2010, Therapy-Induced Senescence in Cancer, JNCI J. Natl. Cancer Inst. source

In the paper

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

In the paper

“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.”

In the paper

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

In the paper

“tumor cells that escaped senescence after chemotherapy display stem cell characteristics and acquire a higher tumor initiation potential in vivo [366].”

What the sources say

• Not checked yetcites [366] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source

In the paper

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

In the paper

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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [361] Liu, 2007, Senescent Human Fibroblasts Increase the Early Growth of Xenograft Tumors via Matrix Metalloproteinase Secretion, Cancer Res. source

In the paper

“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].”

What the sources say

• Not checked yetcites [366] Milanovic, 2018, Senescence-associated reprogramming promotes cancer stemness, Nature source
• Not checked yetcites [368] Saleh, 2020, Acquired resistance to cancer immunotherapy: Role of tumor-mediated immunosuppression, Semin. Cancer Biol. source

In the paper

“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].”

What the sources say

• Not checked yetcites [7] Gorgoulis, 2019, Cellular Senescence: Defining a Path Forward, Cell source
• Not checked yetcites [141] McHugh, 2018, Senescence and aging: Causes, consequences, and therapeutic avenues, J. Cell Biol. source