The essence of senescence: Figure 1.

Kuilman, Thomas; Michaloglou, Chrysiis; Mooi, Wolter J.; Peeper, Daniel S.

doi:10.1101/gad.1971610

Cited by 2,038Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

The essence of senescence: Figure 1.

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Kuilman, Thomas, Michaloglou, Chrysiis, Mooi, Wolter J., Peeper, Daniel S.·2010·Genes & Development

DOI 10.1101/gad.1971610PMC PMC2975923

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Abstract

Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of “cellular senescence” in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo.

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The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration.
“The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration”
From Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype (2016) · cites this paper as Kuilman et al., 2010
The ‘Replicative cellular senescence’ and ‘Cell cycle arrest’ sections describe senescence as a stable, long-term loss of proliferative capacity. Our copy does not say that this arrest depletes progenitor or stem cell pools or consequently compromises tissue repair and regeneration. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Senescent cells communicate with their microenvironment through juxtacrine NOTCH/JAG1 signaling, release of ROS, cytoplasmic bridges, and extracellular vesicles, such as exosomes.
“Senescent cells also communicate with their microenvironment through juxtacrine NOTCH/JAG1 signaling (Ito et al., 2017), release of ROS (Kuilman et al., 2010), cytoplasmic bridges (Video S1) (Biran et al., 2015), and extracellular vesicles, such as exosomes”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Kuilman et al., 2010
The ROS section (page unavailable) says ROS levels increase during replicative and oncogene-induced senescence. The Secreted factors in senescence section (page unavailable) describes communication with neighboring cells through secreted factors, but does not identify released ROS as one of those signals. The Kuilman citation is attached specifically to the ROS part of the sentence, not the other listed mechanisms. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Increased lysosomal GLB1 and p16 are commonly used immunohistological biomarkers of senescence.
“Increased lysosomal β-galactosidase (GLB1) and the DNA damage repair protein p16INK4A (p16, encoded by CDKN2A) are commonly used immunohistological biomarkers of senescence [41].”
From Characterisation of premature cell senescence in Alzheimer's disease using single nuclear transcriptomics (2024) · cites this paper as [41]
The sections “Induction of SA-b-GAL activity” and “Identifying senescent cells” describe GLB1-derived β-galactosidase activity and p16INK4A as commonly used senescence markers. But the paper describes an activity assay for SA-β-GAL, not immunohistological detection of GLB1, and identifies p16INK4A as a cell-cycle inhibitor rather than a DNA-damage repair protein. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Cellular senescence halts proliferation of damaged or dysfunctional cells and constrains malignant progression of tumour cells.
“Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells1,2.”
From Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011) · cites this paper as [2]
Activated oncogenes can induce senescence (OIS) as a tumor-suppressive response, restricting the uncontrolled proliferation of potentially oncogenic cells.
“Moreover, activated oncogenes can induce senescence (known as OIS) as a tumor-suppressive response, restricting the uncontrolled proliferation of potentially oncogenic cells.”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Kuilman et al., 2010
Experimental — accuracy not yet measured

OIS is often mediated by the tumor suppressors p16 INK4A and ARF, both encoded by the CDKN2A locus, imposing a cell-cycle arrest.
“OIS is often mediated by the tumor suppressors p16 INK4A and ARF, both encoded by the C DKN2A locus, imposing a cell-cycle arrest (Kuilman et al., 2010; Serrano et al., 1997).”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Kuilman et al., 2010
Oncogene-induced senescence (OIS) is crucial for tumour suppression.
“Oncogene-induced senescence (OIS) is crucial for tumour suppression.”
From A complex secretory program orchestrated by the inflammasome controls paracrine senescence (2013) · cites this paper as [1]
Both normal and tumor cells undergo senescence in response to various insults that cause persistent DNA damage.
“Both normal and tumor cells undergo senescence in response to various insults that cause persistent DNA damage (Kuilman et al., 2010; Rodier and Campisi, 2011; Sikora et al., 2011; Ohtani and Hara, 2013)”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Kuilman et al., 2010
Cellular senescence is a state of stable cell cycle arrest in response to diverse stresses.
“senescence can be described as a state of stable cell cycle arrest in response to diverse stresses”
From Cellular senescence and its effector programs (2014) · cites this paper as Kuilman et al. 2010
Senescent cells can communicate with surroundings through juxtacrine NOTCH/JAG1 signaling or ROS secretion or cargo transfer by cytoplasmic bridges or release of extracellular vesicles such as exosomes.
“Senescent cells can communicate with the surroundings through juxtacrine NOTCH/JAG1 signaling (Hoare et al., 2016; Ito et al., 2017) or ROS secretion (Kuilman et al., 2010; Nelson et al., 2012, 2018) or cargo transfer by formation of cytoplasmic bridges (Biran et al., 2015) or release of extracellular vesicles such exosomes (Lehmann et al., 2008; Takasugi et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Kuilman et al., 2010
Senescence is a protective mechanism that induces cell cycle arrest to prevent transmission of defects to progeny cells, particularly to stop malignant transformation.
“Senescence is a protective mechanism that induces cell cycle arrest to prevent transmission of defects to progeny cells, particularly to stop malignant transformation 72-74 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [74]
A persistent DNA damage response (DDR) is the most unified pathway leading to senescence, with sensing by ATM leading to p53 phosphorylation and upregulation of cell cycle inhibitors.
“A persistent DNA damage response (DDR) is the most unified pathway leading to senescence, with sensing by the Ataxia Telangiectasia Mutated (ATM) protein leading to p53 phosphorylation and upregulation of cell cycle inhibitors 72-74 .”
From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [74]
Telomere shortening, persistent DNA damage response, autophagy, metabolic alterations, altered protein secretion, and epigenetic gene regulation are senescence effector programs.
“These include telomere shortening and a persistent DNA damage response, autophagy and other metabolic alterations, altered protein secretion, and epigenetic gene regulation [2][3][4] .”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [3]
Cellular senescence is a permanent cell cycle arrest with distinct metabolic activity and marked morphological changes.
“Cellular senescence is a state of permanent cell cycle arrest characterized by distinct metabolic activity and dramatic changes in cell morphology.1,2”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [1]
The distribution of senescent cells is consistent with the idea that senescence limits early tumor progression and that malignancy involves escaping senescence.
“This is consistent with the hypothesis that senescence restricts tumor progression during the early stages of tumorigenesis, whereas progression to malignancy would involve evading senescence. 1”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [1]
ROS can mediate the deleterious effects of radiation and contribute to DNA damage and activation of senescence pathways in cells.
“reactive oxygen species (ROS) can mediate the deleterious effects of radiation and contribute to DNA damage and the activation of senescence pathways in cells (Diehn et al., 2009; Kuilman et al., 2010; Sonis, 2009; Spitz et al., 2004).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Kuilman et al., 2010
Activation of the DNA damage response is one of the main mediators of cell senescence, resulting in irreversible growth arrest.
“The activation of the DNA damage response is one of the main mediators of cell senescence, which results in irreversible growth arrest (Kuilman et al., 2010; Rodier and Campisi, 2011).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Kuilman et al., 2010
Activation of the RB tumor suppressive pathway by accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes.
“The activation of the RB tumor suppressive pathway by the accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes (Kuilman et al., 2010; Luis et al., 2011).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Kuilman et al., 2010
Senescence can be triggered by multiple mechanisms, including ROS production and oxidative stress.
“Senescence can be triggered by multiple mechanisms, including those resulting in ROS production and oxidative stress (Kuilman et al., 2010; Rodier and Campisi, 2011).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Kuilman et al., 2010
NanoString gene expression analysis of cases without apparent DNA damage by γH2AX revealed up-regulation of pathways involved in cellular senescence.
“Indeed, gene expression analysis with NanoString of cases without apparent DNA damage as shown by γH2AX revealed up-regulation of pathways involved in cellular senescence [82]”
From DNA repair deficiency and senescence in concussed professional athletes involved in contact sports (2019) · cites this paper as [82]

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Gruis, N. A., van der Velden, P. A., Sandkuijl, L. A., Prins, D. E. M., Weaver-Feldhaus, J., Kamb, A., Bergman, W., & Frants, R. R. (1995) · Nature Genetics · doi:10.1038/ng0795-351 · Cited by 309 · see citing works
Increased activity of p53 in senescing fibroblasts
Atadja, P., Wong, H., Garkavtsev, I., Veillette, C., & Riabowol, K. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.18.8348 · Cited by 308 · see citing works
Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302 · cited 5× · see citing works
“Subsequent work from various laboratories has revealed that cells undergoing either replicative or premature senescence display profound changes in their secretome, termed the senescence-associated secretory phenotype (SASP) (Coppé et al. 2008; Rodier et al. 2009).”
BackgroundInfluential
BRAFE600 in benign and malignant human tumours
Michaloglou, C., Vredeveld, L. C. W., Mooi, W. J., & Peeper, D. S. (2007) · Oncogene · doi:10.1038/sj.onc.1210704 · Cited by 275 · see citing works
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Replicative senescence: a critical review
Cristofalo, V. J., Lorenzini, A., Allen, R. G., Torres, C. A., & Tresini, M. (2004) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2004.07.010 · Cited by 275 · see citing works
The promises and perils of p53
Krizhanovsky, V., & Lowe, S. W. (2009) · Nature · doi:10.1038/4601085a · Cited by 274 · see citing works
Reversal of Senescence in Mouse Fibroblasts through Lentiviral Suppression of p53
Dirac, A. M. G., & Bernards, R. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300023200 · Cited by 254 · see citing works
DNA Damage Signaling and p53-dependent Senescence after Prolonged β-Interferon Stimulation
Moiseeva, O., Mallette, F. A., Mukhopadhyay, U. K., Moores, A., & Ferbeyre, G. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-09-0858 · Cited by 252 · see citing works
Cdk2 suppresses cellular senescence induced by the c-myc oncogene
Campaner, S., Doni, M., Hydbring, P., Verrecchia, A., Bianchi, L., Sardella, D., Schleker, T., Perna, D., Tronnersjö, S., Murga, M., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb2004 · Cited by 251 · see citing works
The limitations and validities of senescence associated-β-galactosidase activity as an aging marker for human foreskin fibroblast Hs68 cells
YANG, N., & HU, M. (2005) · Experimental Gerontology · doi:10.1016/j.exger.2005.07.011 · Cited by 245 · see citing works
Age-Dependent Telomere Shortening Is Slowed down by Enrichment of Intracellular Vitamin C via Suppression of Oxidative Stress
Furumoto, K., Inoue, E., Nagao, N., Hiyama, E., & Miwa, N. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00351-8 · Cited by 240 · see citing works
VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400
Young, A. P., Schlisio, S., Minamishima, Y. A., Zhang, Q., Li, L., Grisanzio, C., Signoretti, S., & Kaelin, W. G. (2008) · Nature Cell Biology · doi:10.1038/ncb1699 · Cited by 239 · see citing works
Lack of Replicative Senescence in Cultured Rat Oligodendrocyte Precursor Cells
Tang, D. G., Tokumoto, Y. M., Apperly, J. A., Lloyd, A. C., & RAFF, M. C. (2001) · Science · doi:10.1126/science.1056780 · Cited by 228 · see citing works
Downregulation of Wnt Signaling Is a Trigger for Formation of Facultative Heterochromatin and Onset of Cell Senescence in Primary Human Cells
Ye, X., Zerlanko, B. J., Kennedy, A. L., Gowrishankar, B., Zhang, R., & Adams, P. D. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.05.034 · Cited by 227 · see citing works
The first molecular details of ALT in human tumor cells
Muntoni, A., & Reddel, R. R. (2005) · Human Molecular Genetics · doi:10.1093/hmg/ddi266 · Cited by 226 · see citing works
Extended Culture of Mouse Embryo Cells Without Senescence: Inhibition by Serum
Loo, D. T., Fuquay, J. I., Rawson, C. L., & Barnes, D. W. (1987) · Science · doi:10.1126/science.3494308 · Cited by 219 · see citing works
Role of p14ARF in Replicative and Induced Senescence of Human Fibroblasts
Wei, W., Hemmer, R. M., & Sedivy, J. M. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.20.6748-6757.2001 · Cited by 217 · see citing works
Human melanocyte senescence and melanoma susceptibility genes
Bennett, D. C. (2003) · Oncogene · doi:10.1038/sj.onc.1206446 · Cited by 210 · see citing works
Telomere dysfunction suppresses spontaneous tumorigenesis in vivo by initiating p53‐dependent cellular senescence
Cosme‐Blanco, W., Shen, M., Lazar, A. J. F., Pathak, S., Lozano, G., Multani, A. S., & Chang, S. (2007) · The EMBO Reports · doi:10.1038/sj.embor.7400937 · Cited by 205 · see citing works
Deregulated E2F Activity Induces Hyperplasia and Senescence-Like Features in the Mouse Pituitary Gland
Denchi, E. L., Attwooll, C., Pasini, D., & Helin, K. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2660-2672.2005 · Cited by 195 · see citing works
High Intensity ras Signaling Induces Premature Senescence by Activating p38 Pathway in Primary Human Fibroblasts*
Deng, Q.-D., Liao, R., Wu, B.-L., & Sun, P. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m308644200 · Cited by 188 · see citing works
Uncoupling the Senescent Phenotype from Telomere Shortening in Hydrogen Peroxide-Treated Fibroblasts
Chen, Q. M., Prowse, K. R., Tu, V. C., Purdom, S., & Linskens, M. H. K. (2001) · Experimental Cell Research · doi:10.1006/excr.2001.5182 · Cited by 186 · cited 1× · see citing works
“A flat cell phenotype is commonly seen in cells undergoing H-RASV12induced senescence (Serrano et al. 1997; Denoyelle et al. 2006), stress-induced senescence (Parrinello et al. 2003), or DNA damage-induced senescence (Chen and Ames 1994; Chen et al. 2001).”
Background
Ink4a/Arf and Oncogene-Induced Senescence Prevent Tumor Progression during Alternative Colorectal Tumorigenesis
Bennecke, M., Kriegl, L., Bajbouj, M., Retzlaff, K., Robine, S., Jung, A., Arkan, M. C., Kirchner, T., & Greten, F. R. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.06.013 · Cited by 186 · see citing works
Tumor Stroma-Derived TGF-β Limits Myc-Driven Lymphomagenesis via Suv39h1-Dependent Senescence
Reimann, M., Lee, S., Loddenkemper, C., Dörr, J. R., Tabor, V., Aichele, P., Stein, H., Dörken, B., Jenuwein, T., & Schmitt, C. A. (2010) · Cancer Cell · doi:10.1016/j.ccr.2009.12.043 · Cited by 184 · see citing works
Lack of Replicative Senescence in Normal Rodent Glia
Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L., & Lloyd, A. C. (2001) · Science · doi:10.1126/science.1056782 · Cited by 180 · see citing works
Untitled work
(1996) · PubMed · Cited by 180 · see citing works
Remodeling of chromatin structure in senescent cells and its potential impact on tumor suppression and aging
Adams, P. D. (2007) · Gene · doi:10.1016/j.gene.2007.04.020 · Cited by 174 · see citing works
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53
Yamakoshi, K., Takahashi, A., Hirota, F., Nakayama, R., Ishimaru, N., Kubo, Y., Mann, D. J., Ohmura, M., Hirao, A., Saya, H., et al. (2009) · Journal of Cell Biology · doi:10.1083/jcb.200904105 · Cited by 172 · see citing works
Interleukin 6: a fibroblast-derived growth inhibitor of human melanoma cells from early but not advanced stages of tumor progression.
Lü, C., Vickers, M. F., & Kerbel, R. S. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.19.9215 · Cited by 170 · see citing works
Expression of catalytically active telomerase does not prevent premature senescence caused by overexpression of oncogenic Ha-Ras in normal human fibroblasts.
Wei, S., Wei, S., & Sedivy, J. M. (1999) · PubMed · Cited by 166 · see citing works
In vitro establishment is not a sufficient prerequisite for transformation by activated Ras oncogenes
Franza, B. R., Maruyama, K., Garrels, J. I., & Ruley, H. E. (1986) · Cell · doi:10.1016/0092-8674(86)90462-9 · Cited by 166 · see citing works
Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice
Goel, V., Ibrahim, N., Jiang, G., Singhal, M., Fee, S., Flotte, T. J., Westmoreland, S. V., Haluska, F. S., Hinds, P. W., & Haluska, F. G. (2009) · Oncogene · doi:10.1038/onc.2009.95 · Cited by 165 · see citing works
Loss of Oncogenic H-ras-Induced Cell Cycle Arrest and p38 Mitogen-Activated Protein Kinase Activation by Disruption of Gadd45a
Bulavin, D. V., Kovalsky, O., Hollander, M. C., & Fornace, A. J. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.11.3859-3871.2003 · Cited by 161 · see citing works
Evidence of cisplatin-induced senescent-like growth arrest in nasopharyngeal carcinoma cells.
Wang, L., Wong, S. C., Pan, J., Tsao, S. W., Fung, K., Kwong, D., Sham, J. S. T., & Nicholls, J. M. (1998) · PubMed · Cited by 150 · see citing works
Arf tumor suppressor promoter monitors latent oncogenic signals in vivo
Zindy, F., Williams, R. T., Baudino, T. A., Rehg, J. E., Skapek, S. X., Cleveland, J. L., Roussel, M. F., & Sherr, C. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2536808100 · Cited by 150 · see citing works
Interferon-γ induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells
Kim, K. S., Kang, K. W., Seu, Y. B., Baek, S., & Kim, J.-R. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.11.004 · Cited by 146 · see citing works
The p400 E1A-associated protein is a novel component of the p53 → p21 senescence pathwayPreprint
Chan, H. M., Narita, M., Lowe, S. W., & Livingston, D. M. (2005) · Genes & Development · doi:10.1101/gad.1280205 · Cited by 144 · see citing works
SOCS1 Links Cytokine Signaling to p53 and Senescence
Calabrese, V., Mallette, F. A., Deschênes‐Simard, X., Ramanathan, S., Gagnon, J., Moores, A., Ilangumaran, S., & Ferbeyre, G. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.09.044 · Cited by 141 · see citing works
Rb Regulates DNA Damage Response and Cellular Senescence through E2F-Dependent Suppression of N-Ras Isoprenylation
Shamma, A., Takegami, Y., Miki, T., Kitajima, S., Noda, M., Obara, T., Okamoto, T., & Takahashi, C. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.03.001 · Cited by 140 · see citing works
Endogenous expression of Hras G12V induces developmental defects and neoplasms with copy number imbalances of the oncogene
Chen, X., Mitsutake, N., LaPerle, K., Akeno, N., ZANZONICO, P. B., Longo, V. A., Mitsutake, S., Kimura, E. T., Geiger, H., Santos, E., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900343106 · Cited by 139 · see citing works
Involvement of the Ink4 proteins p16 and p15 in T-lymphocyte senescence
Erickson, S., Sangfelt, O., Heyman, M. M., Castro, J., Einhorn, S., & Grandér, D. (1998) · Oncogene · doi:10.1038/sj.onc.1201965 · Cited by 125 · see citing works
Cellular senescence predicts treatment outcome in metastasised colorectal cancer
Haugstetter, A. M., Loddenkemper, C., Lenze, D., Gröne, J., Standfuß, C., Petersen, I., Dörken, B., & Schmitt, C. A. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605784 · Cited by 117 · see citing works
Predisposition to Neoplastic Transformation Caused by Gene Replacement of H- ras 1
Finney, R. E., & Bishop, J. M. (1993) · Science · doi:10.1126/science.8502998 · Cited by 116 · see citing works
Frequent p16-Independent Inactivation of p14ARF in Human Melanoma
Freedberg, D. E., Rigas, S. H., Russak, J. E., Gai, W., Kaplow, M., Osman, I., Turner, F., Randerson‐Moor, J. A., Houghton, A. N., BUSAM, K. J., et al. (2008) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djn157 · Cited by 110 · see citing works
Involvement of MINK, a Ste20 Family Kinase, in Ras Oncogene-Induced Growth Arrest in Human Ovarian Surface Epithelial Cells
Nicke, B., Bastien, J., Khanna, S. J., Warne, P. H., Cowling, V., Cook, S. J., Peters, G., Delpuech, O., Schulze, A., Berns, K., et al. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.038 · Cited by 108 · see citing works
Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells
Patschan, S., Chen, J., Polotskaia, A., Mendelev, N., Cheng, J., Patschan, D., & Goligorsky, M. S. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00713.2007 · Cited by 105 · see citing works
The interaction between Myc and Miz1 is required to antagonize TGFβ-dependent autocrine signaling during lymphoma formation and maintenancePreprint
van Riggelen, J., Müller, J., Otto, T., Beuger, V., Yetil, A., Choi, P. S., Kosan, C., Möröy, T., Felsher, D. W., & Eilers, M. (2010) · Genes & Development · doi:10.1101/gad.585710 · Cited by 105 · see citing works
Recurrent melanocytic nevi: Clinical and histologic review of 175 cases
Park, H. K., Leonard, D. D., Arlington, J. H., et al. (1987) · Journal of the American Academy of Dermatology · doi:10.1016/s0190-9622(87)70204-7 · Cited by 101 · see citing works
Raf-1-induced growth arrest in human mammary epithelial cells is p16-independent and is overcome in immortal cells during conversion
Olsen, C. L., Gardie, B., Yaswen, P., & Stampfer, M. R. (2002) · Oncogene · doi:10.1038/sj.onc.1205780 · Cited by 96 · see citing works
Molecular Regulation of Melanocyte Senescence
Bennett, D. C., & Medrano, E. E. (2002) · Pigment Cell Research · doi:10.1034/j.1600-0749.2002.02036.x · Cited by 95 · see citing works
Mechanisms of Cell-Cycle Arrest in Spitz Nevi with Constitutive Activation of the MAP-Kinase Pathway
Maldonado, J. L., Timmerman, L., Fridlyand, J., et al. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63736-4 · Cited by 93 · see citing works
p16INK4a expression begins early in human colon neoplasia and correlates inversely with markers of cell proliferation
Dai, C. Y., Furth, E. E., Mick, R., Koh, J., Takayama, T., Niitsu, Y., & Enders, G. H. (2000) · Gastroenterology · doi:10.1053/gast.2000.17952 · Cited by 92 · see citing works
Features of replicative senescence induced by direct addition of antennapedia‐p16INK4A fusion protein to human diploid fibroblasts
Kato, D., Miyazawa, K., Ruas, M., Starborg, M., Wada, I., Oka, T., Sakai, T., Peters, G. G., & Hara, E. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)00426-8 · Cited by 87 · see citing works
Expression of H-RASV12 in a zebrafish model of Costello syndrome causes cellular senescence in adult proliferating cells
Santoriello, C., Deflorian, G., Pezzimenti, F., Kawakami, K., Lanfrancone, L., di Fagagna, F. D., & Mione, M. (2008) · Disease Models & Mechanisms · doi:10.1242/dmm.001016 · Cited by 87 · see citing works
Superoxide generation in v-Ha-ras-transduced human keratinocyte HaCaT cells
Yang, J.-Q., Li, S., Domann, F. E., Buettner, G. R., & Oberley, L. W. (1999) · Molecular Carcinogenesis · doi:10.1002/(sici)1098-2744(199911)26:3 · Cited by 86 · see citing works
p16INK4a inactivation is not required to immortalize human mammary epithelial cells
Herbert, B., Wright, W. E., & Shay, J. W. (2002) · Oncogene · doi:10.1038/sj.onc.1205902 · Cited by 86 · see citing works
Molecular mechanisms of replicative senescence in endothelial cells
Foreman, K. E., & Tang, J. M. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.005 · Cited by 81 · see citing works
Oncogene-Induced Senescence Does Not Require the p16INK4a or p14ARF Melanoma Tumor Suppressors
Haferkamp, S., Scurr, L. L., Becker, T. M., Frausto, M., Kefford, R. F., & Rizos, H. (2009) · Journal of Investigative Dermatology · doi:10.1038/jid.2009.5 · Cited by 79 · see citing works
Real-time in vivo imaging of P16[INK]⁴[a] reveals cross talk with p53
Hara, E. (2010) · Medical Entomology and Zoology · Cited by 72 · see citing works
Novel mechanisms of sublethal oxidant toxicity: induction of premature senescence in human fibroblasts confers tumor promoter activity
Dilley, T. K., Bowden, G. T., & Chen, Q. M. (2003) · Experimental Cell Research · doi:10.1016/s0014-4827(03)00308-2 · Cited by 64 · cited 2× · see citing works
“In certain settings, pro-oncogenic effects result: The proliferative rate, migration, and invasion of premalignant cells are enhanced when they are cocultured with, or grown in medium conditioned by, senescent fibroblasts (Krtolica et al. 2001; Dilley et al. 2003; Parrinello et al. 2005; Yang et al. 2006).”
Background
‘Senescence‐associated’ β‐galactosidase activity in the upper gastrointestinal tract
Going, J. J., Stuart, R. C., Downie, M., Fletcher‐Monaghan, A. J., & Keith, W. N. (2002) · The Journal of Pathology · doi:10.1002/path.1059 · Cited by 61 · see citing works
The Recurrence of Nevi After Incomplete Removal
Schoenfeld, R. J. (1958) · A M A Archives of Dermatology · doi:10.1001/archderm.1958.01560070032004 · Cited by 59 · see citing works
IGFBP7 Is Not Required for B-RAF-Induced Melanocyte Senescence
Scurr, L. L., Pupo, G. M., Becker, T. M., Lai, K., Schrama, D., Haferkamp, S., Irvine, M., Scolyer, R. A., Mann, G. J., Becker, J. C., et al. (2010) · Cell · doi:10.1016/j.cell.2010.04.021 · Cited by 59 · see citing works
Overexpression of plasminogen activator inhibitor type‐1 in senescent fibroblasts from normal subjects and those with Werner syndrome
Goldstein, S., Moerman, E. J., Fujii, S., & Sobel, B. E. (1994) · Journal of Cellular Physiology · doi:10.1002/jcp.1041610321 · Cited by 59 · see citing works

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The Hallmarks of Aging
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982 · see citing works
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670 · see citing works
Cellular Senescence: Defining a Path Forward
Gorgoulis, V., Adams, P. D., Alimonti, A., Bennett, D. C., Bischof, O., Bishop, C., Campisi, J., Collado, M., Evangelou, K., Ferbeyre, G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.10.005 · Cited by 3,225 · see citing works
Ageing as a risk factor for neurodegenerative disease
Hou, Y., Dan, X., Babbar, M., Wei, Y., Hasselbalch, S. G., Croteau, D. L., & Bohr, V. A. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0244-7 · Cited by 3,310 · see citing works
Cellular senescence: from physiology to pathology
Muñoz-Espín, D., & Serrano, M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3823 · Cited by 2,818 · see citing works
The role of senescent cells in ageing
van Deursen, J. M. (2014) · Nature · doi:10.1038/nature13193 · Cited by 2,623 · see citing works
A complex secretory program orchestrated by the inflammasome controls paracrine senescence
Acosta, J. C., Banito, A., Wuestefeld, T., Georgilis, A., Janich, P., Morton, J. P., Athineos, D., Kang, T.-W., Lasitschka, F., Andrulis, M., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2784 · Cited by 2,278 · see citing works
Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome
Yoshimoto, S., Loo, T. M., Atarashi, K., Kanda, H., Sato, S., Oyadomari, S., Iwakura, Y., Oshima, K., Morita, H., Hattori, M., et al. (2013) · Nature · doi:10.1038/nature12347 · Cited by 2,219 · see citing works
Sarcopenia: Aging-Related Loss of Muscle Mass and Function
Larsson, L., Degens, H., Li, M., Salviati, L., Lee, Y. I., Thompson, W., Kirkland, J. L., & Sandri, M. (2019) · Physiological Reviews · doi:10.1152/physrev.00061.2017 · Cited by 1,797 · see citing works
Cellular senescence and the senescent secretory phenotype: therapeutic opportunities
Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., & Kirkland, J. L. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64098 · Cited by 1,774 · see citing works
Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype
Kumari, R., & Jat, P. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.645593 · Cited by 1,622 · see citing works
Cellular Senescence: Aging, Cancer, and Injury
Calcinotto, A., Kohli, J., Zagato, E., Pellegrini, L., Demaria, M., & Alimonti, A. (2019) · Physiological Reviews · doi:10.1152/physrev.00020.2018 · Cited by 1,270 · see citing works
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Wiley, C. D., Velarde, M. C., Lecot, P., Liu, S., Sarnoski, E. A., Freund, A., Shirakawa, K., Lim, H. W., Davis, S. S., Ramanathan, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.11.011 · Cited by 1,275 · see citing works
“The permanent growth arrest can deplete progenitor or stem cell pools, thereby compromising tissue repair and regeneration (Kuilman et al., 2010; Sousa-Victor et al., 2014; Velarde et al., 2015).”
Background
NAD + repletion improves mitochondrial and stem cell function and enhances life span in mice
Zhang, H., Ryu, D., Wu, Y., Gariani, K., Wang, X., Luan, P., D’Amico, D., Ropelle, E. R., Lutolf, M. P., Aebersold, R., et al. (2016) · Science · doi:10.1126/science.aaf2693 · Cited by 1,255 · see citing works
Senescence and aging: Causes, consequences, and therapeutic avenues
McHugh, D., & Gil, J. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201708092 · Cited by 1,233 · see citing works
Mechanisms and functions of cellular senescence
Herranz, N., & Gil, J. (2018) · Journal of Clinical Investigation · doi:10.1172/jci95148 · Cited by 1,232 · see citing works
Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence
Glück, S., Guey, B., Gulen, M. F., Wolter, K., Kang, T.-W., Schmacke, N. A., Bridgeman, A., Rehwinkel, J., Zender, L., & Ablasser, A. (2017) · Nature Cell Biology · doi:10.1038/ncb3586 · Cited by 1,196 · see citing works
Senescence is a developmental mechanism that contributes to embryonic growth and patterning
Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.10.041 · Cited by 1,186 · see citing works
Forging a signature of in vivo senescence
Sharpless, N. E., & Sherr, C. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc3960 · Cited by 1,104 · see citing works
ROS, Cell Senescence, and Novel Molecular Mechanisms in Aging and Age‐Related Diseases
Davalli, P., Mitic, T., Caporali, A., Lauriola, A., & D’Arca, D. (2016) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/3565127 · Cited by 1,059 · see citing works
Lamin B1 loss is a senescence-associated biomarker
Freund, A., Laberge, R.-M., Demaria, M., & Campisi, J. (2012) · Molecular Biology of the Cell · doi:10.1091/mbc.e11-10-0884 · Cited by 1,046 · see citing works
Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity
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Epigenetic Control in Cellular Senescence
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Authors: Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S.
Affiliations: The Netherlands Cancer Institute (NL)
Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
ORCID: Kuilman, Thomas
Peeper, Daniel S.
Venue: Genes & Development
Publisher: Cold Spring Harbor Laboratory
Published: 2010-11-15
Volume: 24
Issue: 22
Pages: 2463-2479
ISSN: 0890-9369 (ISSN-L)
1549-5477
DOI: 10.1101/gad.1971610
PMC: PMC2975923
OpenAlex: W2116437342
Cited by: 2,038
References: 212
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Type: posted content
Language: en
Open access: bronze
doi.org
Locations: Genes & Development (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
Pure Amsterdam UMC (submittedVersion)
Data Archiving and Networked Services (DANS) (submittedVersion)
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
KWF Kankerbestrijding
Topics: Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: cellular senescence, replicative senescence, tumor suppression, senescence biomarkers, primary cell culture
MeSH terms: Animals, Cells, Humans, Neoplasms, Biomarkers, Cellular Senescence

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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The essence of senescence: Figure 1.

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