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Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status
Open accessAbstract
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 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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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
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 64
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 61
“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 58
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
“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
“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 53
“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
“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 43
“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 43
“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
Role of p53 in Regulating Radiation Responses
Okazaki, R. (2022) · Life · doi:10.3390/life12071099 · Cited by 40
“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 41
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
“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
“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
“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
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
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
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
“, 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
“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 32
“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 32
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 31
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
“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
Giardi, M. T., Touloupakis, E., Bertolotto, D., & Mascetti, G. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms140817168 · Cited by 30
“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
“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
Park, H.-R., & Jo, S. (2010) · Cellular Immunology · doi:10.1016/j.cellimm.2010.10.004 · Cited by 27
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 30
“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 26
“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 25
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
“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 25
Senescence and Aging: Does It Impact Cancer Immunotherapies?
Maggiorani, D., & Beausejour, C. M. (2021) · Cells · doi:10.3390/cells10071568 · Cited by 25
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
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 23
“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 20
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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