The signals and pathways activating cellular senescence

Ben-Porath, Ittai; Weinberg, Robert A.

doi:10.1016/j.biocel.2004.10.013

Cited by 1,046Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

The signals and pathways activating cellular senescence

Ben-Porath, Ittai, Weinberg, Robert A.·2005·The International Journal of Biochemistry & Cell Biology

DOI 10.1016/j.biocel.2004.10.013

Open this paper in CoChat — free account

Abstract

Cellular senescence is a program activated by normal cells in response to various types of stress. These include telomere uncapping, DNA damage, oxidative stress, oncogene activity and others. Senescence can occur following a period of cellular proliferation or in a rapid manner in response to acute stress. Once cells have entered senescence, they cease to divide and undergo a series of dramatic morphologic and metabolic changes. Cellular senescence is thought to play an important role in tumor suppression and to contribute to organismal aging, but a detailed description of its physiologic occurrence in vivo is lacking. Recent studies have provided important insights regarding the manner by which different stresses and stimuli activate the signaling pathways leading to senescence. These studies reveal that a population of growing cells may suffer from a combination of different physiologic stresses acting simultaneously. The signaling pathways activated by these stresses are funneled to the p53 and Rb proteins, whose combined levels of activity determine whether cells enter senescence. Here we review recent advances in our understanding of the stimuli that trigger senescence, the molecular pathways activated by these stimuli, and the manner by which these signals determine the entry of a population of cells into senescence.

Integrity signals

Registry

Crossref · 10.1016/j.biocel.2004.10.013

Cites

37 of 37 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

The proliferative arrest imposed by cellular senescence represents an early barrier against cancer initiation by preventing the propagation of damaged DNA to the next generation of cells.
“The proliferative arrest imposed by cellular senescence represents an early barrier against cancer initiation by preventing the propagation of damaged DNA to the next generation of cells [18,20].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [20]
pksC E. coli-infected cells exhibited accumulation of phospho-p53, p21 Cip, and Retinoblastoma protein and decreased E2F-1 expression at day 5 post-infection.
“pksC E. coli-infected cells exhibited an accumulation of phospho-p53, p21 Cip , and Retinoblastoma protein as well as a decrease in E2F-1 expression at day 5 post-infection, which correspond to a protein expression profile characteristic of senescent cells.12”
From The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment (2014) · cites this paper as [12]

Telomeres shorten during ageing of human fibroblasts
Harley, C. B., Futcher, A. B., & Greider, C. W. (1990) · Nature · doi:10.1038/345458a0 · Cited by 5,750 · see citing works
Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a
Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D., & Lowe, S. W. (1997) · Cell · doi:10.1016/s0092-8674(00)81902-9 · Cited by 5,178 · see citing works
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975 · see citing works
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,855 · cited 2× · see citing works
“These foci contain multiple DNA damage-response proteins, such as -H2AX, 53BP1, MDC1, NBS1, MRE11 and RAD17 (d’Adda di Fagagna et al., 2003; Herbig, Jobling, Chen, Chen, & Sedivy, 2004).”
Background
Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence
Narita, M., Nuñez, S., Heard, E., Narita, M., Lin, A. W., Hearn, S. A., Spector, D. L., Hannon, G. J., & Lowe, S. W. (2003) · Cell · doi:10.1016/s0092-8674(03)00401-x · Cited by 2,278 · see citing works
Atmospheric carbon dioxide concentrations over the past 60 million years
Pearson, P. N., & Palmer, M. R. (2000) · Nature · doi:10.1038/35021000 · Cited by 1,771 · see citing works
High frequency of BRAF mutations in nevi
Pollock, P. M., Harper, U. L., Hansen, K. S., Yudt, L. M., Stark, M., Robbins, C. M., Moses, T. Y., Hostetter, G., Wagner, U., Kakareka, J., et al. (2003) · Nature Genetics · doi:10.1038/ng1054 · Cited by 1,730 · see citing works
TRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709 · see citing works
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566 · see citing works
Reversal of human cellular senescence: roles of the p53 and p16 pathways
Beauséjour, C. M., Krtolica, A., Galimi, F., Narita, M., Lowe, S. W., Yaswen, P., & Campisi, J. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg417 · Cited by 1,457 · see citing works
Telomere Shortening Triggers Senescence of Human Cells through a Pathway Involving ATM, p53, and p21CIP1, but Not p16INK4a
Herbig, U., Jobling, W. A., Chen, B. P. C., Chen, D. J., & Sedivy, J. M. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00256-4 · Cited by 1,344 · see citing works
Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells
Kiyono, T., Foster, S. A., Koop, J. I., McDougall, J. K., Galloway, D. A., & Klingelhutz, A. J. (1998) · Nature · doi:10.1038/23962 · Cited by 1,206 · cited 1× · see citing works
“…in human epithelial cells, specifically mammary epithelial cells and keratinocytes. p16 is solely responsible for the induction of an early, stress-induced, senescence stage in these cell types, often termed M0 (Foster, Wong, Barrett, & Galloway, 1998; Kiyono et al., 1998; Rheinwald et al., 2002).”
Background
Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts
Alcorta, D. A., Xiong, Y., Phelps, D., Hannon, G., Beach, D., & Barrett, J. C. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13742 · Cited by 1,008 · see citing works
Mild hyperoxia shortens telomeres and inhibits proliferation of fibroblasts: a model for senescence?
von Zglinicki, T., Saretzki, G., Döcke, W., & Lotze, C. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1305 · Cited by 856 · see citing works
Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis
Sharpless, N. E., Bardeesy, N., Lee, K.-H., Carrasco, D., Castrillon, D. H., Aguirre, A. J., Wu, E. A., Horner, J. W., & DePinho, R. A. (2001) · Nature · doi:10.1038/35092592 · Cited by 848 · see citing works
Bypass of Senescence After Disruption of p21 CIP1/WAF1 Gene in Normal Diploid Human Fibroblasts
Brown, J. P., Wei, W., & Sedivy, J. M. (1997) · Science · doi:10.1126/science.277.5327.831 · Cited by 804 · see citing works
Endogenous oncogenic K-rasG12D stimulates proliferation and widespread neoplastic and developmental defects
Tuveson, D. A., Shaw, A. T., Willis, N. A., Silver, D. P., Jackson, E. L., Chang, S., Mercer, K. L., Grochow, R., Hock, H., Crowley, D., et al. (2004) · Cancer Cell · doi:10.1016/s1535-6108(04)00085-6 · Cited by 798 · see citing works
Senescence Induced by Altered Telomere State, Not Telomere Loss
Karlseder, J., Smogorzewska, A., & de Lange, T. (2002) · Science · doi:10.1126/science.1069523 · Cited by 796 · see citing works
Oxidative DNA damage and senescence of human diploid fibroblast cells.
Chen, Q., Fischer, A., Reagan, J. D., Yan, L. J., & Ames, B. N. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.10.4337 · Cited by 720 · see citing works
Tumor suppression by Ink4a-Arf: progress and puzzles.
Lowe, S. W., & Sherr, C. J. (2003) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(02)00013-8 · Cited by 699 · cited 4× · see citing works
“2). p16 is an inhibitor of cyclin D/Cdk4, omplexes and is not normally expressed in adul ues (Lowe & Sherr, 2003; Zindy, Quelle, Roussel, herr, 1997).”
BackgroundInfluential
Ras Proteins Induce Senescence by Altering the Intracellular Levels of Reactive Oxygen Species
Lee, A. C., Fenster, B. E., Ito, H., Takeda, K., Bae, N. S., Hirai, T., Yu, Z.-X., Ferrans, V. J., Howard, B. H., & Finkel, T. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.7936 · Cited by 691 · see citing works
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice
Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A., & Berns, A. (2001) · Nature · doi:10.1038/35092584 · Cited by 568 · see citing works
Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts
von Zglinicki, T., Pilger, R., & Sitte, N. (2000) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(99)00207-5 · Cited by 546 · cited 1× · see citing works
“It has been shown that the rate of telomere shortening is accelerated in fibroblasts grown in high oxygen conditions (von Zglinicki et al., 1995; Forsyth et al., 2003).”
Background
Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibroblasts
Robles, S. J., & Adami, G. R. (1998) · Oncogene · doi:10.1038/sj.onc.1201862 · Cited by 498 · see citing works
Different telomere damage signaling pathways in human and mouse cells
Smogorzewska, A., & de Lange, T. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf433 · Cited by 482 · see citing works
Control of the replicative life span of human fibroblasts by p16 and the polycomb protein Bmi-1
Itahana, K., Zou, Y., Itahana, Y., Martinez, J.-L., Beausejour, C., Jacobs, J. J. L., van Lohuizen, M., Band, V., Campisi, J., & Dimri, G. P. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.389-401.2003 · Cited by 438 · see citing works
Ablation of the Retinoblastoma gene family deregulates G1 control causing immortalization and increased cell turnover under growth-restricting conditions
Dannenberg, J.-H., van Rossum, A., Schuijff, L., & te Riele, H. (2000) · Genes & Development · doi:10.1101/gad.847700 · Cited by 413 · see citing works
A Two-Stage, p16 INK4A - and p53-Dependent Keratinocyte Senescence Mechanism That Limits Replicative Potential Independent of Telomere Status
Rheinwald, J. G., Hahn, W. C., Ramsey, M. R., Wu, J. Y., Guo, Z., Tsao, H., De Luca, M., Catricalà, C., & O'Toole, K. M. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.14.5157-5172.2002 · Cited by 338 · see citing works
Erosion of the telomeric single-strand overhang at replicative senescence
Stewart, S. A., Ben-Porath, I., Carey, V. J., O'Connor, B. F., Hahn, W. C., & Weinberg, R. A. (2003) · Nature Genetics · doi:10.1038/ng1127 · Cited by 335 · see citing works
Self-citation
Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice
Liu, G., Parant, J. M., Lang, G., Chau, P., Chavez-Reyes, A., El-Naggar, A. K., Multani, A., Chang, S., & Lozano, G. (2004) · Nature Genetics · doi:10.1038/ng1282 · Cited by 325 · see citing works
Accumulation of Short Telomeres in Human Fibroblasts Prior to Replicative Senescence
Martens, U. M., Chavez, E. A., Poon, S. S. S., Schmoor, C., & Lansdorp, P. M. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4823 · Cited by 263 · see citing works
The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis
Sharpless, N. E., Ramsey, M. R., Balasubramanian, P., Castrillon, D. H., & DePinho, R. A. (2004) · Oncogene · doi:10.1038/sj.onc.1207074 · Cited by 224 · see citing works
Murine fibroblasts lacking p21 undergo senescence and are resistant to transformation by oncogenic Ras.
Pantoja, C., & Serrano, M. (1999) · Oncogene · doi:10.1038/sj.onc.1202880 · Cited by 201 · see citing works
Superoxide Dismutase 1 Knock-down Induces Senescence in Human Fibroblasts
Blander, G., de Oliveira, R. M., Conboy, C. M., Haigis, M., & Guarente, L. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307146200 · Cited by 183 · see citing works
Reinitiation of DNA Synthesis and Cell Division in Senescent Human Fibroblasts by Microinjection of Anti-p53 Antibodies
Gire, V., & Wynford-Thomas, D. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.3.1611 · Cited by 161 · see citing works
Increased p53 Protein Associated with Aging in Human Diploid Fibroblasts
Kulju, K. S., & Lehman, J. M. (1995) · Experimental Cell Research · doi:10.1006/excr.1995.1095 · Cited by 155 · cited 1× · see citing works
“The p53 protein is stabilized and proceeds to activate its transcriptional targets, such as p21CIP1/WAF1 (Kulju & Lehman, 1995).”
Background
Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion
Khan, S. H., Moritsugu, J., & Wahl, G. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.7.3266 · Cited by 103 · see citing works

Flagged first, then by citations

Sorted by citations

The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206 · 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
The essence of senescence: Figure 1.
Kuilman, T., Michaloglou, C., Mooi, W. J., & Peeper, D. S. (2010) · Genes & Development · doi:10.1101/gad.1971610 · Cited by 2,038 · see citing works
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354 · see citing works
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4.
Kang, C., Xu, Q., Martin, T. D., Li, M. Z., Demaria, M., Aron, L., Lu, T., Yankner, B. A., Campisi, J., & Elledge, S. J. (2015) · Science · doi:10.1126/science.aaa5612 · Cited by 982 · see citing works
Senescence-messaging secretome: SMS-ing cellular stress
Kuilman, T., & Peeper, D. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2560 · Cited by 909 · see citing works
Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7
Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M., & Green, M. R. (2008) · Cell · doi:10.1016/j.cell.2007.12.032 · Cited by 903 · see citing works
Therapy-induced senescence in cancer.
Ewald, J. A., Desotelle, J. A., Wilding, G., & Jarrard, D. F. (2010) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djq364 · Cited by 824 · see citing works
DNA damage response and cellular senescence in tissues of aging mice
Wang, C., Jurk, D., Maddick, M., Nelson, G., Martin‐Ruiz, C., & Von Zglinicki, T. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2009.00481.x · Cited by 696 · see citing works
Stem cells, ageing and the quest for immortality
Rando, T. A. (2006) · Nature · doi:10.1038/nature04958 · Cited by 695 · see citing works
A guide to assessing cellular senescence in vitro and in vivo
González‐Gualda, E., Baker, A. G., Fruk, L., & Muñoz‐Espín, D. (2021) · The FEBS Journal · doi:10.1111/febs.15570 · Cited by 645 · see citing works
Senescent cells as a source of inflammatory factors for tumor progression
Davalos, A. R., Coppe, J.-P., Campisi, J., & Desprez, P.-Y. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9220-9 · Cited by 636 · see citing works
Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence
Jiang, P., Du, W., Mancuso, A., Wellen, K. E., & Yang, X. (2013) · Nature · doi:10.1038/nature11776 · Cited by 491 · see citing works
Bacterial genotoxin colibactin promotes colon tumour growth by inducing a senescence-associated secretory phenotype
Cougnoux, A., Dalmasso, G., Martinez, R., Buc, E., Delmas, J., Gibold, L., Sauvanet, P., Darcha, C., Déchelotte, P., Bonnet, M., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-305257 · Cited by 486 · see citing works
The Gene Expression Program of Prostate Fibroblast Senescence Modulates Neoplastic Epithelial Cell Proliferation through Paracrine Mechanisms
Bavik, C., Coleman, I., Dean, J. P., Knudsen, B., Plymate, S., & Nelson, P. S. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-1716 · Cited by 453 · see citing works
Mechanisms and Regulation of Cellular Senescence
Roger, L., Tomas, F., & Gire, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222313173 · Cited by 395 · see citing works
Cellular senescence in renal ageing and disease
Sturmlechner, I., Durik, M., Sieben, C. J., Baker, D. J., & van Deursen, J. M. (2017) · Nature Reviews Nephrology · doi:10.1038/nrneph.2016.183 · Cited by 345 · see citing works
Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease
Aravinthan, A., Scarpini, C., Tachtatzis, P., Verma, S., Penrhyn-Lowe, S., Harvey, R., Davies, S. E., Allison, M., Coleman, N., & Alexander, G. (2013) · Journal of Hepatology · doi:10.1016/j.jhep.2012.10.031 · Cited by 326 · see citing works
The unfolded protein response and cellular senescence. A Review in the Theme: Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease
Pluquet, O., Pourtier, A., & Abbadie, C. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00334.2014 · Cited by 305 · see citing works
The bacterial genotoxin colibactin promotes colon tumor growth by modifying the tumor microenvironment
Dalmasso, G., Cougnoux, A., Delmas, J., Darfeuille-Michaud, A., & Bonnet, R. (2014) · Gut Microbes · doi:10.4161/19490976.2014.969989 · Cited by 296 · see citing works
Cellular senescence and the aging brain
Chinta, S. J., Woods, G., Rane, A., Demaria, M., Campisi, J., & Andersen, J. K. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2014.09.018 · Cited by 282 · see citing works
Microglial dystrophy in the aged and Alzheimer's disease brain is associated with ferritin immunoreactivity
Lopes, K. O., Sparks, D. L., & Streit, W. J. (2008) · Glia · doi:10.1002/glia.20678 · Cited by 262 · see citing works
Human lipodystrophies linked to mutations in A-type lamins and to HIV protease inhibitor therapy are both associated with prelamin A accumulation, oxidative stress and premature cellular senescence
Caron, M., Auclair, M., Donadille, B., Béréziat, V, Guerci, B., Laville, M., Narbonne, H., Bodemer, C., Lascols, O., Capeau, J., et al. (2007) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402197 · Cited by 226 · see citing works
Senescence‐associated β‐galactosidase reveals the abundance of senescent CD8+ T cells in aging humans
Martínez‐Zamudio, R. I., Dewald, H. K., Vasilopoulos, T., Gittens‐Williams, L., Fitzgerald‐Bocarsly, P., & Herbig, U. (2021) · Aging Cell · doi:10.1111/acel.13344 · Cited by 213 · see citing works
Induction of cellular senescence by insulin-like growth factor binding protein-5 through a p53-dependent mechanism
Kim, K. S., Seu, Y. B., Baek, S.-H., Kim, M. J., Kim, K. J., Kim, J. H., & Kim, J.-R. (2007) · Molecular Biology of the Cell · doi:10.1091/mbc.e07-03-0280 · Cited by 199 · see citing works
H2O2 Accelerates Cellular Senescence by Accumulation of Acetylated p53 via Decrease in the Function of SIRT1 by NAD+ Depletion
Furukawa, A., Tada-Oikawa, S., Kawanishi, S., & Oikawa, S. (2007) · Cellular Physiology and Biochemistry · doi:10.1159/000104152 · Cited by 184 · see citing works
Techniques to induce and quantify cellular senescence
Noren Hooten, N., & Evans, M. K. (2017) · Journal of Visualized Experiments · doi:10.3791/55533 · Cited by 178 · see citing works
Early aging–associated phenotypes in Bub3/Rae1 haploinsufficient mice
Baker, D. J., Jeganathan, K. B., Malureanu, L., Perez-Terzic, C., Terzic, A., & van Deursen, J. M. A. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507081 · Cited by 175 · see citing works
Macrophages in the Aging Liver and Age-Related Liver Disease
Stahl, E. C., Haschak, M. J., Popovic, B., & Brown, B. N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02795 · Cited by 171 · see citing works
Elimination of p19ARF-expressing cells enhances pulmonary function in mice
Hashimoto, M., Asai, A., Kawagishi, H., Mikawa, R., Iwashita, Y., Kanayama, K., Sugimoto, K., Sato, T., Maruyama, M., & Sugimoto, M. (2016) · JCI Insight · doi:10.1172/jci.insight.87732 · Cited by 162 · see citing works
MC1R Is a Potent Regulator of PTEN after UV Exposure in Melanocytes
Cao, J., Wan, L., Hacker, E., Dai, X., Lenna, S., Jimenez-Cervantes, C., Wang, Y., Leslie, N. R., Xu, G. X., Widlund, H. R., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.08.010 · Cited by 144 · see citing works
CPEB regulation of human cellular senescence, energy metabolism, and p53 mRNA translation
Burns, D. M., & Richter, J. D. (2008) · Genes & Development · doi:10.1101/gad.1697808 · Cited by 134 · see citing works
Microphthalmia-Associated Transcription Factor Controls the DNA Damage Response and a Lineage-Specific Senescence Program in Melanomas
Giuliano, S., Cheli, Y., Ohanna, M., Bonet, C., Beuret, L., Bille, K., Loubat, A., Hofman, V., Hofman, P., Ponzio, G., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-2913 · Cited by 135 · see citing works
Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cip1/Waf1 in opposite manners
Yu, H., Yuan, Y., Shen, H., & Cheng, T. (2006) · Blood · doi:10.1182/blood-2005-02-0685 · Cited by 127 · see citing works
Senescence-Induced Oxidative Stress Causes Endothelial Dysfunction
Bhayadia, R., Schmidt, B. M. W., Melk, A., & Hömme, M. (2016) · The Journals of Gerontology Series A: Biological Sciences and Medical Sciences · doi:10.1093/gerona/glv008 · Cited by 126 · see citing works
Systemic Regulation of the Age-Related Decline of Pancreatic β-Cell Replication
Salpeter, S. J., Khalaileh, A., Weinberg-Corem, N., Ziv, O., Glaser, B., & Dor, Y. (2013) · Diabetes · doi:10.2337/db13-0160 · Cited by 122 · see citing works
DNA repair and aging: The impact of the p53 family
Nicolai, S., Rossi, A., Di Daniele, N., Melino, G., Annicchiarico-Petruzzelli, M., & Raschellà, G. (2015) · Aging · doi:10.18632/aging.100858 · Cited by 118 · see citing works
Impact of er stress-regulated atf4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy
Liu, J., Yang, J.-R., Chen, X.-M., Cai, G.-Y., Lin, L.-R., & He, Y.-N. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00096.2014 · Cited by 117 · see citing works
Hepatocyte Expression of the Senescence Marker p21 Is Linked to Fibrosis and an Adverse Liver-Related Outcome in Alcohol-Related Liver Disease
Aravinthan, A., Pietrosi, G., Hoare, M., Jupp, J., Marshall, A., Verrill, C., Davies, S., Bateman, A., Sheron, N., Allison, M., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072904 · Cited by 117 · see citing works
Contribution of Mitochondrial Dysfunction and Oxidative Stress to Cellular Premature Senescence Induced by Antiretroviral Thymidine Analogues
Caron, M., Auclair, M., Vissian, A., Vigouroux, C., & Capeau, J. (2008) · Antiviral Therapy · doi:10.1177/135965350801300103 · Cited by 114 · see citing works
Cellular senescence in the lung across the age spectrum
Parikh, P., Wicher, S., Khandalavala, K., Pabelick, C. M., Britt, R. D., & Prakash, Y. S. (2019) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00424.2018 · Cited by 112 · see citing works
An intricate dance: life experience, multisystem resiliency, and rate of telomere decline throughout the lifespan
Puterman, E., & Epel, E. (2012) · Social and Personality Psychology Compass · doi:10.1111/j.1751-9004.2012.00465.x · Cited by 106 · see citing works
Hepatic senescence, the good and the bad
Huda, N., Liu, G., Hong, H., Yan, S., Khambu, B., & Yin, X.-M. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i34.5069 · Cited by 100 · see citing works
Conserved senescence associated genes and pathways in primary human fibroblasts detected by RNA-seq
Marthandan, S., Baumgart, M., Priebe, S., Groth, M., Schaer, J., Kaether, C., Guthke, R., Cellerino, A., Platzer, M., Diekmann, S., et al. (2016) · PLOS ONE · doi:10.1371/journal.pone.0154531 · Cited by 91 · see citing works
“The results revealed significantly higher protein levels of p16, p15, p21 and p27 with age in all five fibroblast cell strains confirming earlier findings on the role of p16 [24, 44], p21 [21, 23, 43], p27 [18, 89–91] and p15 [18, 92] in senescence induction.”
Result
GDF15 contributes to radiation-induced senescence through the ROS-mediated p16 pathway in human endothelial cells
Park, H., Kim, C.-H., Jeong, J.-H., Park, M., & Kim, K. S. (2016) · Oncotarget · doi:10.18632/oncotarget.7457 · Cited by 92 · see citing works
Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene‐induced senescent cells
Takebayashi, S., Tanaka, H., Hino, S., Nakatsu, Y., Igata, T., Sakamoto, A., Narita, M., & Nakao, M. (2015) · Aging Cell · doi:10.1111/acel.12351 · Cited by 84 · see citing works
Is exercise a senolytic medicine? A systematic review
Chen, X., Yi, Z., Wong, G. T., Hasan, K. M. M., Kwan, J. S., Ma, A. C., & Chang, R. C. (2021) · Aging Cell · doi:10.1111/acel.13294 · Cited by 88 · see citing works
A common variant of the p16INK4a genetic region is associated with physical function in older people
Melzer, D., Frayling, T. M., Murray, A., Hurst, A. J., Harries, L. W., Song, H., Khaw, K., Luben, R., Surtees, P. G., Bandinelli, S. S., et al. (2007) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2007.03.005 · Cited by 84 · see citing works
Markers of cellular senescence.
Carnero, A. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-239-1_4 · Cited by 68 · see citing works
Senescence determines the fate of activated rat pancreatic stellate cells
Fitzner, B., Müller, S., Walther, M., Fischer, M., Engelmann, R., Müller‐Hilke, B., Pützer, B. M., Kreutzer, M., Nizze, H., & Jaster, R. (2012) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2012.01573.x · Cited by 66 · see citing works
Resveratrol Induced Premature Senescence Is Associated with DNA Damage Mediated SIRT1 and SIRT2 Down-Regulation
Kilic Eren, M., Kilincli, A., & Eren, Ö. (2015) · PLOS ONE · doi:10.1371/journal.pone.0124837 · Cited by 68 · see citing works
Evidence of oncogene-induced senescence in thyroid carcinogenesis
Vizioli, M. G., Possik, P. A., Tarantino, E., Meissl, K., Borrello, M. G., Miranda, C., Anania, M. C., Pagliardini, S., Seregni, E., Pierotti, M. A., et al. (2011) · Endocrine-Related Cancer · doi:10.1530/erc-11-0240 · Cited by 47 · see citing works
An RNA interference screen for identifying downstream effectors of the p53 and pRB tumour suppressor pathways involved in senescence.
Rovillain, E., Mansfield, L., Lord, C. J., Ashworth, A., & Jat, P. S. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-355 · Cited by 43 · see citing works
Endothelial senescence after high-cholesterol, high-fat diet challenge in baboons
Shi, Q., Hubbard, G. B., Kushwaha, R. S., Rainwater, D., Thomas, C. A., Leland, M. M., VandeBerg, J. L., & Wang, X. L. (2007) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01405.2006 · Cited by 43 · see citing works
Conserved genes and pathways in primary human fibroblast strains undergoing replicative and radiation induced senescence
Marthandan, S., Menzel, U., Priebe, S., Groth, M., Guthke, R., Platzer, M., Hemmerich, P., Kaether, C., & Diekmann, S. (2016) · Biological Research · doi:10.1186/s40659-016-0095-2 · Cited by 39 · see citing works
Quantitative model of cell cycle arrest and cellular senescence in primary human fibroblasts
Schäuble, S., Klement, K., Marthandan, S., Münch, S., Heiland, I., Schuster, S., Hemmerich, P., & Diekmann, S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0042150 · Cited by 35 · see citing works
XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence
Heo, J.-I., Kim, W., Choi, K. J., Bae, S., Jeong, J.-H., & Kim, K. S. (2016) · Oncotarget · doi:10.18632/oncotarget.6962 · Cited by 32 · see citing works
Early onset senescence occurs when fibroblasts lack the glutamate–cysteine ligase modifier subunit
Chen, Y., Johansson, E., Fan, Y., Shertzer, H. G., Vasiliou, V., Nebert, D. W., & Dalton, T. P. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.05.003 · Cited by 28 · see citing works
Effects of the renin angiotensin system on vasculogenesis-related progenitor cells
Roks, A. J., Rodgers, K., & Walther, T. (2011) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2011.01.002 · Cited by 26 · see citing works
Mitochondria can orchestrate sex differences in cell fate of vascular smooth muscle cells from rats
Straface, E., Vona, R., Campesi, I., & Franconi, F. (2015) · Biology of Sex Differences · doi:10.1186/s13293-015-0051-9 · Cited by 18 · see citing works
Continuous growth of telomerase-immortalised fibroblasts: How long do cells remain normal?
van Waarde-Verhagen, M. A. W. H., Kampinga, H. H., & Linskens, M. H. K. (2006) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2005.08.008 · Cited by 14 · see citing works
Moderate-vigorous physical activity attenuates premature senescence of immune cells in sedentary adults with obesity: a pilot randomized controlled trial
Chen, X.-K., Zheng, C., Wong, S. H.-S., & Ma, A. C.-H. (2022) · Aging · doi:10.18632/aging.204458 · Cited by 10 · see citing works

Authors: Ben-Porath, I., & Weinberg, R. A.
Affiliations: Whitehead Institute for Biomedical Research (US)
ORCID: Weinberg, Robert A.
Venue: The International Journal of Biochemistry & Cell Biology
Publisher: Elsevier BV
Published: 2005-05
Volume: 37
Issue: 5
Pages: 961-976
ISSN: 1357-2725 (ISSN-L)
DOI: 10.1016/j.biocel.2004.10.013
OpenAlex: W2110934787
Semantic Scholar: d1d033fcefc2538e5f278308a03e76a3963404a5
Cited by: 1,046
References: 37
Citations by year: 2026: 10 · 2025: 23 · 2024: 30 · 2023: 32 · 2022: 49 · 2021: 59 · 2020: 49 · 2019: 56 · 2018: 54 · 2017: 57 · 2016: 58 · 2015: 60 · 2014: 75 · 2013: 54 · 2012: 55
FWCI: 3.80
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: The International Journal of Biochemistry & Cell Biology (publishedVersion)
PubMed (publishedVersion)
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, telomere uncapping, DNA damage, oxidative stress, oncogene activation, p53, retinoblastoma protein, tumor suppression, aging, cellular stress response
MeSH terms: DNA Damage, Gene Expression Regulation, Humans, Oncogenes, Signal Transduction, Tumor Suppressor Protein p53, Retinoblastoma Protein, Telomere, Cellular Senescence, Oxidative Stress, Cyclin-Dependent Kinase Inhibitor p16

About these checks

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

The signals and pathways activating cellular senescence

Abstract

Integrity signals

Claims the paper makes

Claims other papers make about this one

Cites

Cited by

Record

About these checks