Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status
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Exposure to IR has been shown to induce the formation of senescence markers, a phenotype that coincides with lifelong delayed repair and regeneration of irradiated tissues. We hypothesized that IR-induced senescence markers could persist long-term in vivo, possibly contributing to the permanent reduction in tissue functionality. Here, we show that mouse tissues exposed to a sublethal dose of IR display persistent (up to 45 weeks, the maximum time analyzed) DNA damage foci and increased p16(INK4a) expression, two hallmarks of cellular senescence and aging. BrdU-labeling experiments revealed that IR-induced damaged cells are preferentially eliminated, at least partially, in a tissue-dependent manner. Unexpectedly, the accumulation of damaged cells was found to occur independent from the DNA damage response modulator p53, and from an intact immune system, as their levels were similar in wild-type and Rag2(-/-) gammaC(-/-) mice, the latter being deficient in T, B, and NK cells. Together, our results provide compelling evidence that exposure to IR induces long-term expression of senescence markers in vivo, an effect that may contribute to the reduced tissue functionality observed in cancer survivors.
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Ageing and genotoxic stress induce cellular senescence of haematopoietic stem cells and osteoprogenitor cells, with subsequent decline in their functions in both mice and humans.
“Ageing and genotoxic stress induce cellular senescence of these stem cells 96,97 and osteoprogenitor cells, 98,99 with subsequent decline in the functions of these cells in both mice and humans.100”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [97]
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Rodier, F., Muñoz, D. P., Teachenor, R., Chu, V., Le, O., Bhaumik, D., Coppé, J.-P., Campeau, E., Beauséjour, C. M., Kim, S.-H., et al. (2011) · Journal of Cell Science · doi:10.1242/jcs.071340 · Cited by 535 · see citing works
Self-citationSenescent Cells in Cancer Therapy: Friends or Foes?
Wang, B., Kohli, J., & Demaria, M. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.05.004 · Cited by 508 · see citing works
“Total-body γ-irradiation of mice also induces senescence and an upregulated SASP in various tissues [49,51].”
Backgroundp53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
Davalos, A. R., Kawahara, M., Malhotra, G. K., Schaum, N., Huang, J., Ved, U., Beausejour, C. M., Coppe, J.-P., Rodier, F., & Campisi, J. (2013) · Journal of Cell Biology · doi:10.1083/jcb.201206006 · Cited by 439 · see citing works
“Although the SASP does not require p53 activity, it requires DDR signaling (Coppé et al., 2008; Bhaumik et al., 2009; Rodier et al., 2009, 2011; Le et al., 2010), and cells lacking ATM, a key DDR component, senesce with much reduced cytokine secretion (Rodier et al., 2009).”
InfluentialSelf-citationHall, B. M., Balan, V., Gleiberman, A. S., Strom, E., Krasnov, P., Virtuoso, L. P., Rydkina, E., Vujcic, S., Balan, K., Gitlin, I. I., et al. (2017) · Aging · doi:10.18632/aging.101268 · Cited by 407 · see citing works
“β-galactosidase activity evaluated via enzymatic 4-MUG hydrolysis and SAβG staining was unaffected by p53 deficiency (Figures 1A,D&E), consistent with previous reports of SAβG-positive macrophages in p53-deficient mice [48,49].”
ResultMechanisms 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
FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence
Fouillade, C., Curras-Alonso, S., Giuranno, L., Quelennec, E., Heinrich, S., Bonnet-Boissinot, S., Beddok, A., Leboucher, S., Karakurt, H. U., Bohec, M., et al. (2019) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1440 · Cited by 311 · see citing works
“FLASH elicits less persistent nuclear 53bp1 foci than CONV irradiation in lung Persisting focal accumulation of the adaptor protein 53bp1 at sites of chromosomal damage has been observed in liver, brain, and lung tissues long after exposure to a sublethal dose of radiation (20).”
BackgroundCellular senescence in development, regeneration and disease
Rhinn, M., Ritschka, B., & Keyes, W. M. (2019) · Development · doi:10.1242/dev.151837 · Cited by 296 · see citing works
Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases
Naylor, R. M., Baker, D. J., & van Deursen, J. M. (2012) · Clinical Pharmacology & Therapeutics · doi:10.1038/clpt.2012.193 · Cited by 280 · see citing works
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Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Wang, Z., Chen, Z., Jiang, Z., Luo, P., Liu, L., Huang, Y., Wang, H., Wang, Y., Long, L., Tan, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10386-8 · Cited by 219 · see citing works
Therapeutic Implications for Overcoming Radiation Resistance in Cancer Therapy
Kim, B. M., Hong, Y., Lee, S., Liu, P., Lim, J. Y., Lee, Y. C., Lee, T., Chang, K. T., & Hong, Y. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161125991 · Cited by 235 · see citing works
“Although p53-independent mechanisms have also been described in IR-induced senescence [55,56], a genetically regulated response to IR-induced DNA damage is usually seen in solid tumor-derived cell lines, especially those with wild-type p53 [57].”
BackgroundRadiobiology of the FLASH effect
Friedl, A. A., Prise, K. M., Butterworth, K. T., Montay‐Gruel, P., & Favaudon, V. (2021) · Medical Physics · doi:10.1002/mp.15184 · Cited by 205 · see citing works
Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
Omori, S., Wang, T.-W., Johmura, Y., Kanai, T., Nakano, Y., Kido, T., Susaki, E. A., Nakajima, T., Shichino, S., Ueha, S., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.006 · Cited by 194 · see citing works
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Self-citationCellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
Kudlová, N., Sanctis, J. B. D., & Hajdúch, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084168 · Cited by 176 · see citing works
Clinical strategies and animal models for developing senolytic agents
Kirkland, J. L., & Tchkonia, T. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2014.10.012 · Cited by 168 · see citing works
“…many years after chemotherapy or radiation, delayed recovery after elective surgery or acute events such as myocardial infarction (Kirkland, 2013a; Le et al., 2010; Marcoux et al., 2013; Roninson, 2003; Tchkonia et al., 2013)), 6) neurodegenerative diseases (Alzheimer's disease and…”
BackgroundMuñoz, D. P., Yannone, S. M., Daemen, A., Sun, Y., Vakar-Lopez, F., Kawahara, M., Freund, A. M., Rodier, F., Wu, J. D., Desprez, P.-Y., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.124716 · Cited by 162 · see citing works
Self-citationAge‐associated increase in heterochromatic marks in murine and primate tissues
Kreiling, J. A., Tamamori‐Adachi, M., Sexton, A. N., Jeyapalan, J. C., Munoz‐Najar, U., Peterson, A. L., Manivannan, J., Rogers, E. S., Pchelintsev, N. A., Adams, P. D., et al. (2011) · Aging Cell · doi:10.1111/j.1474-9726.2010.00666.x · Cited by 152 · see citing works
“Another method to determine the frequency of senescent cells is to score cells that stain positive for DNA damage foci-associated proteins c-H2AX or 53BP1 (Bartkova et al., 2006; Di Micco et al., 2006; Herbig et al., 2006; Jeyapalan et al., 2007; Sedelnikova et al., 2008; Wang et al., 2009; Le et al., 2010).”
BackgroundMethodDissecting Aging and Senescence—Current Concepts and Open Lessons
Schmeer, C. W., Kretz, A., Wengerodt, D., Stojiljkovic, M. R., & Witte, O. W. (2019) · Cells · doi:10.3390/cells8111446 · Cited by 148 · see citing works
“, via human leukocyte antigen (HLA)-E-mediated natural killer (NK) and CD8+ cell inhibition [7,71] that is stimulated by paracrine release of pro-inflammatory cytokines.”
BackgroundCellular Senescence Promotes Skin Carcinogenesis through p38MAPK and p44/42MAPK Signaling
Alimirah, F., Pulido, T., Valdovinos, A., Alptekin, S., Chang, E., Jones, E., Diaz, D. A., Flores, J., Velarde, M. C., Demaria, M., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0108 · Cited by 128 · see citing works
“For example, childhood cancer survivors treated with radiation, which induces senescence (18), had a higher incidence of nonmelanoma skin cancer years after treatment for their original cancer (17).”
BackgroundSelf-citationAlibhai, F. J., Lim, F., Yeganeh, A., DiStefano, P. V., Marvasti, T. B., Belfiore, A., Wlodarek, L., Gustafson, D., Millar, S., Li, S., et al. (2020) · Aging Cell · doi:10.1111/acel.13103 · Cited by 139 · see citing works
“Therefore, using sub-lethal total body irradiation (TBI) as an in vivo model of global senescence (Le et al., 2010), we investigated whether senescent cells have an effect on plasma EVs.”
The costs and benefits of senotherapeutics for human health
Raffaele, M., & Vinciguerra, M. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00300-7 · Cited by 140 · see citing works
Senescence and the tumor-immune landscape: Implications for cancer immunotherapy
Chibaya, L., Snyder, J. T., & Ruscetti, M. A. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.02.005 · Cited by 138 · see citing works
Cellular senescence links aging and diabetes in cardiovascular disease
Shakeri, H., Lemmens, K., Gevaert, A. B., De Meyer, G. R. Y., & Segers, V. F. M. (2018) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00287.2018 · Cited by 134 · see citing works
“For instance, chronic exposure to oxidative stress, toxins, hyperglycemia, inflammation, and ultraviolet radiation can cause stress-induced premature senescence (SIPS) (103, 110, 124).”
BackgroundExtranuclear DNA accumulates in aged cells and contributes to senescence and inflammation
Lan, Y. Y., Heather, J. M., Eisenhaure, T., Garris, C. S., Lieb, D., Raychowdhury, R., & Hacohen, N. (2019) · Aging Cell · doi:10.1111/acel.12901 · Cited by 130 · see citing works
“Unrepaired or persistent double‐stranded breaks (DSBs) can be found in senescing cells and aging human and animal tissues (Rube et al., 2011; Sedelnikova et al., 2004; Wang et al., 2009), and cells are known to senesce upon DNA damage (Le et al., 2010).”
BackgroundParamos-de-Carvalho, D., Jacinto, A., & Saúde, L. (2021) · eLife · doi:10.7554/elife.72449 · Cited by 111 · see citing works
Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment
Maggiorani, D., Lê, O., Lisi, V., Landais, S., Moquin‐Beaudry, G., Lavallée, V., Decaluwe, H., & Beausejour, C. M. (2024) · Nature Communications · doi:10.1038/s41467-024-46769-9 · Cited by 123 · see citing works
“However, several significant concerns/suggestions exist in this study that need to be addressed to improve this manuscript.”
Cellular Senescence - its role in cancer and the response to ionizing radiation
Sabin, R. J., & Anderson, R. M. (2011) · Genome Integrity · doi:10.1186/2041-9414-2-7 · Cited by 116 · see citing works
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Role of cellular senescence in inflammation and regeneration
Saito, Y., Yamamoto, S., & Chikenji, T. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00342-5 · Cited by 117 · see citing works
FLASH radiotherapy: A new milestone in the field of cancer radiotherapy
Tang, R., Yin, J., Liu, Y., & Xue, J. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216651 · Cited by 84 · see citing works
Mitochondrial DNA damage induces apoptosis in senescent cells
Laberge, R.-M., Adler, D., DeMaria, M., Mechtouf, N., Teachenor, R., Cardin, G. B., Desprez, P.-Y., Campisi, J., & Rodier, F. (2013) · Cell Death & Disease · doi:10.1038/cddis.2013.199 · Cited by 82 · see citing works
Self-citationEfficacy and limitations of senolysis in atherosclerosis
Garrido, A. M., Kaistha, A., Uryga, A. K., Oc, S., Foote, K., Shah, A., Finigan, A., Figg, N., Dobnikar, L., Jørgensen, H., et al. (2022) · Cardiovascular Research · doi:10.1093/cvr/cvab208 · Cited by 83 · see citing works
Radiation-induced liver injury and hepatocyte senescence
Zhu, W., Zhang, X., Yu, M., Lin, B., & Yu, C. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00634-6 · Cited by 83 · see citing works
Causes and Mechanisms of Hematopoietic Stem Cell Aging
Lee, J., Yoon, S. R., Choi, I., & Jung, H. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20061272 · Cited by 76 · see citing works
“Aging and genotoxic stress induce cellular senescence of HSCs [72,73].”
BackgroundDormant cancer cells: programmed quiescence, senescence, or both?
Truskowski, K., Amend, S. R., & Pienta, K. J. (2023) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10073-z · Cited by 79 · see citing works
“1 3 replicative stress, or direct DNA damaging agents in replicative, oncogene-induced, and therapy-induced senescence, respectively (Table 1) [25, 30, 32, 33].”
BackgroundFielder, E., Wan, T., Alimohammadiha, G., Ishaq, A., Low, E., Weigand, B. M., Kelly, G., Parker, C., Griffin, B., Jurk, D., et al. (2022) · eLife · doi:10.7554/elife.75492 · Cited by 75 · see citing works
Liakou, E., Mavrogonatou, E., Pratsinis, H., Rizou, S. V., Evangelou, K., Panagiotou, P. N., Karamanos, N. K., Gorgoulis, V. G., & Kletsas, D. (2016) · Aging · doi:10.18632/aging.100989 · Cited by 72 · see citing works
“On the other hand, it has been shown that ionizing radiation can induce senescence in murine cells in vivo several weeks after treatment [48].”
InfluentialYu, Y.-C., Yang, P., Chuah, Q.-Y., Huang, Y.-H., Peng, C.-W., Lee, Y., & Chiu, S.-J. (2013) · Scientific Reports · doi:10.1038/srep01675 · Cited by 71 · see citing works
Uwineza, A., Kalligeraki, A., Hamada, N., Jarrín, M., & Quinlan, R. (2019) · Mutation research · doi:10.1016/j.mrrev.2019.02.004 · Cited by 68 · see citing works
Wang, Y., Liu, L., & Zhou, D. (2011) · Radiation Research · doi:10.1667/rr2727.1 · Cited by 67 · see citing works
Carbonneau, C. L., Despars, G., Rojas-Sutterlin, S., Fortin, A., Le, O., Hoang, T., & Beauséjour, C. M. (2012) · Blood · doi:10.1182/blood-2011-06-361626 · Cited by 59 · see citing works
Ionizing Radiation-Induced Brain Cell Aging and the Potential Underlying Molecular Mechanisms
Wang, Q., Yin, G., Huang, J., Xi, S.-J., Qian, F., Lee, R.-X., Peng, X., & Tang, F. R. (2021) · Cells · doi:10.3390/cells10123570 · Cited by 58 · see citing works
Restored immune cell functions upon clearance of senescence in the irradiated splenic environment
Palacio, L., Goyer, M., Maggiorani, D., Espinosa, A., Villeneuve, N., Bourbonnais, S., Moquin‐Beaudry, G., Le, O., Demaria, M., Davalos, A. R., et al. (2019) · Aging Cell · doi:10.1111/acel.12971 · Cited by 54 · see citing works
“Alternatively, perhaps only a small fraction of cells express higher level of p16INK4a (Liu et al., 2019).”
BackgroundKlein, D., Schmetter, A., Imsak, R., Wirsdörfer, F., Unger, K., Jastrow, H., Stuschke, M., & Jendrossek, V. (2015) · Antioxidants and Redox Signaling · doi:10.1089/ars.2014.6183 · Cited by 56 · see citing works
“These findings corroborate observations made by Le and coworkers about the induction of senescence markers in murine brain, lung, and liver tissue exposed to a sublethal dose of IR in vivo (43).”
The Immune Response Against Human Cytomegalovirus Links Cellular to Systemic Senescence
Heath, J., & Grant, M. D. (2020) · Cells · doi:10.3390/cells9030766 · Cited by 56 · see citing works
Ruysscher, D. D., Wauters, E., Jendrossek, V., Filippi, A. R., Revel, M., Finn, C. F., Naidoo, J., Ramella, S., Gückenberger, M., Ricardi, U., et al. (2025) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2025.110837 · Cited by 59 · see citing works
Induction and Validation of Cellular Senescence in Primary Human Cells
Hernandez‐Segura, A., Brandenburg, S. M., & Demaria, M. (2018) · Journal of Visualized Experiments · doi:10.3791/57782 · Cited by 58 · see citing works
Luo, J., Sun, T., Liu, Z., Liu, Y., Liu, J., Wang, S., Shi, X., & Zhou, H. (2025) · International Journal of Oral Science · doi:10.1038/s41368-025-00380-w · Cited by 56 · see citing works
“IR can also induce the expression of p16 INK4a and maintain DNA damage in both human and mouse models for several months, 45 indicating the long-term existence of TIS under real-world conditions.”
Verreet, T., Verslegers, M., Quintens, R., Baatout, S., & Benotmane, M. A. (2016) · Neural Plasticity · doi:10.1155/2016/1243527 · Cited by 52 · see citing works
Radiation-induced liver disease: beyond DNA damage
Zhou, Y. J., Tang, Y., Liu, S. J., Zeng, P. H., Qu, L., Jing, Q., & Yin, W. J. (2022) · Cell Cycle · doi:10.1080/15384101.2022.2131163 · Cited by 50 · see citing works
“Senescence has been proven to be independent of p53 and the intact immune system [63].”
BackgroundMarcoux, S., Lê, O., Langlois-Pelletier, C., Laverdière, C., Hatami, A., Robaey, P., & Beausejour, C. M. (2013) · Radiation Oncology · doi:10.1186/1748-717x-8-252 · Cited by 49 · see citing works
“Surprisingly, and in opposite to what we observed previously in irradiated mouse tissues [5], p21 and p14 (a tumor suppressor gene expressed from the same locus as p16) were also generally increased in the scalp biopsies, although not reaching statistical significance (Additional file 1: Figure S1); p = 0.”
InfluentialSelf-citationDiverse Roles of Cellular Senescence in Skeletal Muscle Inflammation, Regeneration, and Therapeutics
Saito, Y., & Chikenji, T. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.739510 · Cited by 48 · see citing works
“Similarly, cellular senescence can arise due to DNA damage from various stresses, including radiation (Le et al., 2010), oncogene activation (Di Micco et al., 2006), high levels of reactive oxygen species (ROS) (von Zglinicki, 2002), mitochondrial dysfunction (Chapman et al., 2019), mechanical…”
BackgroundMcRobb, L. S., McKay, M. J., Gamble, J. R., Grace, M., Moutrie, V., Santos, E. D., Lee, V. S., Zhao, Z., Molloy, M. P., & Stoodley, M. A. (2017) · Aging · doi:10.18632/aging.101225 · Cited by 47 · see citing works
“Radiation has been shown to stimulate a stress-induced premature senescence-like phenotype in ECs both in vitro and in vivo [19-21].”
BackgroundModeling DNA damage-induced pneumopathy in mice: insight from danger signaling cascades
Wirsdörfer, F., & Jendrossek, V. (2017) · Radiation Oncology · doi:10.1186/s13014-017-0865-1 · Cited by 42 · see citing works
“Depending on the radiation dose and the irradiated volume damage to resident cells with induction of senescence or cell death [12, 19, 20] initiates an acute damage response with release of danger signals, that are recognized by specialized receptors and culminate in the creation of a multifaceted pro-inflammatory and…”
Senescence and Host–Pathogen Interactions
Humphreys, D., ElGhazaly, M., & Frisan, T. (2020) · Cells · doi:10.3390/cells9071747 · Cited by 40 · see citing works
“This is exemplified by acute OIS [7,10] and chronic senescence caused by cells experiencing mild and persistent genotoxic stress [8,11].”
BackgroundPIWI-piRNA pathway: Setting the pace of aging by reducing DNA damage
Lenárt, P., Novák, J., & Vašků, J. B. (2018) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2018.03.009 · Cited by 42 · see citing works
Role of p53 in Regulating Radiation Responses
Okazaki, R. (2022) · Life · doi:10.3390/life12071099 · Cited by 39 · see citing works
“p16, with or without p53, causes senescence in mice after prolonged irradiation [145].”
BackgroundResidual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence
Putavet, D. A., & de Keizer, P. L. J. (2021) · Cancers · doi:10.3390/cancers13071560 · Cited by 39 · see citing works
Prolonged expression of senescence markers in mice exposed to gamma-irradiation
Seol, M.-A., Jung, U., Eom, H. S., Kim, S.-H., Park, H., & Jo, S. (2012) · Journal of Veterinary Science · doi:10.4142/jvs.2012.13.4.331 · Cited by 38 · see citing works
“Although the persistent elevation of DNA damage foci and p16 expression by IR has been previously reported [16], our study is the first to demonstrate that IR also elicits the long-term induction of mtDNA common deletion, p21 expression, and appearance of SA β-gal-positive cells.”
InfluentialCellular senescence and neurodegeneration
Holloway, K., Neherin, K., Dam, K. U., & Zhang, H. (2023) · Human Genetics · doi:10.1007/s00439-023-02565-x · Cited by 40 · see citing works
“Reduced expression of Lamin B1, a major component that maintains structural integrity of the nucleus, is often observed in senescent cells (Le et al. 2010; Freund et al. 2012).”
BackgroundKazakov, A., Müller, P., Jagoda, P., Semenov, A., Böhm, M., & Laufs, U. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr305 · Cited by 35 · see citing works
“This reduction is likely due to an enhancement of the anti-angiogenic effects of eNOS-deficiency by ionizing radiation accelerating senescence of mouse tissues.(31,32) Strain-mismatched transplantation of WT BM reduced pulmonary congestion and ameliorated cardiac fibrosis and capillarization, despite increased LV syst…”
BackgroundFrescas, D., Hall, B. M., Strom, E., Virtuoso, L. P., Gupta, M., Gleiberman, A. S., Rydkina, E., Balan, V., Vujcic, S., Chernova, O. B., et al. (2017) · Cell Cycle · doi:10.1080/15384101.2017.1339850 · Cited by 34 · see citing works
Wang, W., Hu, L., Chang, S., Ma, L., Li, X., Yang, Z. F., Du, C., Qu, X., Zhang, C., & Wang, S. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.05.002 · Cited by 32 · see citing works
Shachar, S. S., Deal, A. M., Reeder-Hayes, K. E., Nyrop, K. A., Mitin, N., Anders, C. K., Carey, L., Dees, E. C., Jolly, T. A., Kimmick, G. G., et al. (2020) · JNCI Cancer Spectrum · doi:10.1093/jncics/pkaa082 · Cited by 33 · see citing works
Manning, C. M., Johnston, C. J., Hernady, E., Miller, J. H., Reed, C. K., Lawrence, B. P., Williams, J. P., & Finkelstein, J. N. (2013) · Radiation Research · doi:10.1667/rr3279.1 · Cited by 33 · see citing works
“, p16, in tissues, including lung, and these markers are observed 12 weeks after exposure (46).”
El-Azime, A. S. A., Hussein, E. M., & Ashry, O. M. (2014) · International Journal of Radiation Biology · doi:10.3109/09553002.2014.926040 · Cited by 32 · see citing works
“Exposure to radiation has been shown to induce the formation of senescence markers possibly contributing to the permanent reduction in tissue functionality (Le et al. 2010).”
BackgroundKonstantonis, D., Papadopoulou, A., Makou, M., Eliades, T., Basdra, E. K., & Kletsas, D. (2013) · Biogerontology · doi:10.1007/s10522-013-9449-0 · Cited by 31 · see citing works
“In summary, senescent cells express an inflammatory phenotype and, as they accumulate in different tissues during ageing or after treatments like radiation (Jeyapalan and Sedivy 2008; Le et al. 2010), they affect tissue homeodynamics locally, and they play a role in age-related pathologies.”
BackgroundCellular Senescence in Mouse Hippocampus After Irradiation and the Role of p53 and p21
Cheng, Z., Zheng, Y. Z., Li, Y.-Q., & Wong, C. S. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlx006 · Cited by 31 · see citing works
Hyperoxia causes senescence and increases glycolysis in cultured lung epithelial cells
Scaffa, A., Peterson, A. L., Carr, J. F., Garcia, D., Yao, H., & Dennery, P. A. (2021) · Physiological Reports · doi:10.14814/phy2.14839 · Cited by 30 · see citing works
Noda, A., Mishima, S., Hirai, Y., Hamasaki, K., Landes, R. D., Mitani, H., Haga, K., Kiyono, T., Nakamura, N., & Kodama, Y. (2015) · Genes and Environment · doi:10.1186/s41021-015-0018-4 · Cited by 31 · see citing works
“Such accumulation of DSBs may cause premature aging by earlier onset of malfunction of affected tissues [1, 6].”
BackgroundElectron FLASH radiotherapy in vivo studies. A systematic review
Giannini, N., Gadducci, G., Fuentes, T., Gonnelli, A., Martino, F. D., Puccini, P., Naso, M., Pasqualetti, F., Capaccioli, S., & Paiar, F. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1373453 · Cited by 29 · see citing works
Giardi, M. T., Touloupakis, E., Bertolotto, D., & Mascetti, G. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140817168 · Cited by 30 · see citing works
“dysfunctional senescent cells in tissues, combined with a reduction in the proliferative potential of progenitor/stem cells (as a result of their apoptosis/senescence), may account for the development of long-term diseases [5,45].”
BackgroundBeach, T. A., Groves, A. M., Johnston, C. J., Williams, J. P., & Finkelstein, J. N. (2018) · International Journal of Radiation Biology · doi:10.1080/09553002.2018.1516907 · Cited by 27 · see citing works
“to do so in long-term irradiation experiments (Le et al. 2010).”
BackgroundMethodGuo, H., Chen, J., Yu, H., Dong, L., Yu, R., Li, Q., Song, J., Chen, H., Zhang, H., Pu, J., et al. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110864 · Cited by 28 · see citing works
Park, H.-R., & Jo, S. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.10.004 · Cited by 27 · see citing works
The dual role of cellular senescence in human tumor progression and therapy
Ma, L., Yu, J., Fu, Y., He, X., Ge, S., Jia, R., Zhuang, A., Yang, Z. H., & Fan, X. (2024) · MedComm · doi:10.1002/mco2.695 · Cited by 29 · see citing works
“151 We summarized the mechanisms by which several common oncogenes induce cellular senescence (Table 2).”
BackgroundINK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice
Lê, O., Palacio, L., Bernier, G., Batinic̈‐Haberle, I., Hickson, G. R. X., & Beausejour, C. M. (2018) · Stem Cell Reports · doi:10.1016/j.stemcr.2018.03.025 · Cited by 25 · see citing works
“Consistent with this hypothesis, we previously showed that irradiated brain tissues maintained an activated DNA damage response for several months following exposure to IR (Fumagalli et al., 2012; Le et al., 2010).”
BackgroundMethodInfluentialYamamoto, Y., Minami, M., Yoshida, K., Nagata, M., Miyata, T., Yang, T., Takayama, N., Suzuki, K. W., Okawa, M., Yamada, K., et al. (2021) · Journal of the American Heart Association · doi:10.1161/jaha.120.020712 · Cited by 24 · see citing works
Mechanisms of Senescence and Anti-Senescence Strategies in the Skin
Konstantinou, E. K., Longange, E., & Kaya, G. (2024) · Biology · doi:10.3390/biology13090647 · Cited by 26 · see citing works
“Apart from different types of irradiation, chemotherapeutic drugs and crosslinking agents, such as doxorubicin, can also promote cellular senescence in vitro through the transcription and replication of DNA damage [142–144].”
BackgroundAccumulation of annexin A5 at the nuclear envelope is a biomarker of cellular aging
Klement, K., Melle, C., Murzik, U., Diekmann, S., Norgauer, J., & Hemmerich, P. H. (2012) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2012.06.003 · Cited by 24 · see citing works
Senescence and Aging: Does It Impact Cancer Immunotherapies?
Maggiorani, D., & Beausejour, C. M. (2021) · Cells · doi:10.3390/cells10071568 · Cited by 23 · see citing works
Farzipour, S., Amiri, F. T., Mihandoost, E., Shaki, F., Noaparast, Z., Ghasemi, A., & Hosseinimehr, S. J. (2019) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-019-09820-9 · Cited by 21 · see citing works
The impact of the senescent microenvironment on tumorigenesis: Insights for cancer therapy
Zhang, W., Zhang, K., Shi, J., Qiu, H., Kan, C., Ma, Y., Hou, N., Han, F., & Sun, X. (2024) · Aging Cell · doi:10.1111/acel.14182 · Cited by 21 · see citing works
“Over time, these senescent cells transition from a state of mild stress to a state of prolonged cell cycle arrest (Le et al., 2010; Roninson, 2003).”
BackgroundIdentification of a small molecule SR9009 that activates NRF2 to counteract cellular senescence
Gao, L., Wang, Y., Liu, Z., Sun, Y., Cai, P., & Jing, Q. (2021) · Aging Cell · doi:10.1111/acel.13483 · Cited by 19 · see citing works
- Authors
- Le, O. N. L., Rodier, F., Fontaine, F., Coppe, J., Campisi, J., DeGregori, J., Laverdière, C., Kokta, V., Haddad, E., & Beauséjour, C. M.
- Affiliations
- Buck Institute for Research on Aging (US)
- University of Colorado Anschutz (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Venue
- Aging Cell
- Publisher
- Wiley
- Published
- 2010-05-18
- Volume
- 9
- Issue
- 3
- Pages
- 398-409
- ISSN
- 1474-9718 (ISSN-L)
- 1474-9726
- PMC
- PMC2894262
- OpenAlex
- W1489456875
- Cited by
- 168
- References
- 60
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 14 · 2023: 9 · 2022: 9 · 2021: 22 · 2020: 11 · 2019: 14 · 2018: 8 · 2017: 12 · 2016: 7 · 2015: 10 · 2014: 11 · 2013: 10 · 2012: 6
- FWCI
- 5.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Aging Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Buck Institute for Research on Aging
- National Institutes of Health
- Canadian Institutes of Health Research (IAO-79317)
- National Institute on Aging (R56AG009909, AG017242, AG-09909, R37AG009909, P30AG025708, AG025708, P01AG017242)
- National Cancer Institute (CA12654, R01CA109657, U24CA126546, CA109657)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- ionizing radiation, cellular senescence, DNA damage foci, p16INK4a, immunodeficiency, Rag2 knockout mice, tissue regeneration, sublethal irradiation, cancer survivors, aging, DNA damage response
- MeSH terms
- Adolescent, Animals, B-Lymphocytes, Child, DNA Damage, Humans, Killer Cells, Natural, Mice, Inbred C57BL, Radiation, Ionizing, T-Lymphocytes, Time Factors, Biomarkers, Tumor Suppressor Protein p53, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16, Mice
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