Impact of senescence-associated secretory phenotype and its potential as a therapeutic target for senescence-associated diseases
Open accessAbstract
"Cellular senescence" is a state in which cells undergo irreversible cell cycle arrest in response to a variety of cellular stresses. Once cells senesce, they are strongly resistant to any mitogens, including oncogenic stimuli. Therefore, cellular senescence has been assumed to be a potent anticancer mechanism. Although irreversible cell-cycle arrest is traditionally considered the major characteristic of senescent cells, recent studies have revealed some additional functions. Most noteworthy is the increased secretion of various secretory proteins, such as inflammatory cytokines, chemokines, growth factors, and MMPs, into the surrounding extracellular fluid. These newly recognized senescent phenotypes, termed senescence-associated secretory phenotypes (SASPs), reportedly contribute to tumor suppression, wound healing, embryonic development, and even tumorigenesis promotion. Thus, SASPs appear to be beneficial or deleterious, depending on the biological context. As senescent cells are known to accumulate during the aging process in vivo, it is quite possible that their accumulation in aged tissues promotes age-associated functional decline and various diseases, including cancers, at least to some extent. Here, we focus on and discuss the functional and regulatory network of SASPs toward opening up new possibilities for controlling aging and aging-associated diseases.
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Senescent cells accumulate with age in the dermis and epidermis, which can be accelerated by various harmful factors, such as DNA-damaging agents and mitochondrial dysfunction.
“Senescent cells accumulate with age in the dermis and epidermis, which can be accelerated by various harmful factors, such as DNA-damaging agents (eg, x-rays, ultraviolet radiation, and cigarette smoke) and mitochondrial dysfunction.56”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [56]
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Denkinger, M. D., Leins, H., Schirmbeck, R., Florian, M. C., & Geiger, H. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.10.008 · Cited by 105 · see citing works
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Crosstalk between the Rb pathway and AKT signaling forms a quiescence-senescence switch.
Imai, Y., Takahashi, A., Hanyu, A., Hori, S., Sato, S., Naka, K., Hirao, A., Ohtani, N., & Hara, E. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.03.006 · Cited by 84 · see citing works
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Self-citationAge-related changes in collagenase expression in cultured embryonic and fetal human skin fibroblasts
Bauer, E. A., Kronberger, A., Stricklin, G. P., Smith, L. T., & Holbrook, K. A. (1985) · Experimental Cell Research · doi:10.1016/0014-4827(85)90103-x · Cited by 20 · see citing works
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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
“They can influence neighboring proliferating cells and the recruitment and activation of immune cells in aging tissues and tumors (92, 339), as is detailed in sect.”
BackgroundAge and Age-Related Diseases: Role of Inflammation Triggers and Cytokines
Rea, I. M., Gibson, D. S., McGilligan, V., McNerlan, S. E., Alexander, H. D., & Ross, O. A. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00586 · Cited by 1,267 · see citing works
“There appears to be multi-level control of senescence and the SASP secretome, which includes the tumor suppressor pathways involved in the cell cycle arrest and the NF-κB and persistent damage response (DAMP) pathway, involved in triggering transcription of the SASP-related factors (115).”
BackgroundExploiting senescence for the treatment of cancer
Wang, L., Lankhorst, L., & Bernards, R. (2022) · Nature Reviews Cancer · doi:10.1038/s41568-022-00450-9 · Cited by 867 · see citing works
Unmasking senescence: context-dependent effects of SASP in cancer
Faget, D. V., Ren, Q., & Stewart, S. A. (2019) · Nature Reviews Cancer · doi:10.1038/s41568-019-0156-2 · Cited by 863 · see citing works
Skeletal Muscle as Potential Central Link between Sarcopenia and Immune Senescence
Nelke, C., Dziewas, R., Minnerup, J., Meuth, S. G., & Ruck, T. (2019) · eBioMedicine · doi:10.1016/j.ebiom.2019.10.034 · Cited by 437 · see citing works
TGF-β Signaling in Cellular Senescence and Aging-Related Pathology
Tominaga, K., & Suzuki, H. I. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20205002 · Cited by 393 · see citing works
“The SASP appears to participate in age-related pathological processes [15].”
BackgroundResurrection of endogenous retroviruses during aging reinforces senescence
Liu, X., Liu, Z., Wu, Z., Ren, J., Fan, Y., Sun, L., Cao, G., Niu, Y., Zhang, B., Ji, Q., et al. (2023) · Cell · doi:10.1016/j.cell.2022.12.017 · Cited by 390 · see citing works
Targeted Elimination of Senescent Beta Cells Prevents Type 1 Diabetes
Thompson, P. J., Shah, A., Ntranos, V., Van Gool, F., Atkinson, M., & Bhushan, A. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.021 · Cited by 353 · see citing works
Hallmarks of senescence and aging
Dodig, S., Čepelak, I., & Pavić, I. (2019) · Biochemia Medica · doi:10.11613/bm.2019.030501 · Cited by 347 · see citing works
“kinase inhibitor 2A, multiple tumour suppressor 1), p53, p21, p15 (p15INK4b, protein kinase; cyclin-dependent protein serine/threonine kinase inhibitor, multiple tumour suppressor), p27 (cyclin-dependent kinases regulator), ADP-ribosylation factor (ARF), hypophosphorylated retinoblastoma protein (7,11).”
BackgroundSenescence mechanisms and targets in the heart
Chen, M. S., Lee, R. T., & Garbern, J. C. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab161 · Cited by 336 · see citing works
Aging Atlas: a multi-omics database for aging biology
Liu, G., Bào, Y., Qu, J. T., Zhang, W., Zhāng, T., Kang, W., Yang, F., Ji, Q., Jiang, X., Ma, Y., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa894 · Cited by 325 · see citing works
Mechanisms of melanocyte death in vitiligo
Chen, J., Li, S., & Li, C. (2020) · Medicinal Research Reviews · doi:10.1002/med.21754 · Cited by 312 · see citing works
“After that, the cell might be orchestrated into cellular senescence featuring irreversible cell proliferation arrest.(42,43) The process is governed by a strong cell cycle checkpoint mechanism wherein activation of p53, p16, and p21 are indispensable,(44) and extensive melanocyte cell‐cycle arrest might accentuate the…”
BackgroundOhtani, N. (2022) · Inflammation and Regeneration · doi:10.1186/s41232-022-00197-8 · Cited by 306 · see citing works
Self-citationCellular Senescence in Neurodegenerative Diseases
Martínez‐Cué, C., & Rueda, N. (2020) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.00016 · Cited by 285 · see citing works
“While, chronic senescence, induced by prolonged exposure to stress (Salama et al., 2014; van Deursen, 2014; Childs et al., 2015; Velarde and Menon, 2016; Watanabe et al., 2017; Ogrodnik et al., 2019), produces cellular and tissue alterations.”
BackgroundRoles of extracellular vesicles in the aging microenvironment and age‐related diseases
Yin, Y., Chen, H., Wang, Y., Zhang, L., & Wang, X. (2021) · Journal of Extracellular Vesicles · doi:10.1002/jev2.12154 · Cited by 199 · see citing works
Oncogene-induced senescence: a double edged sword in cancer
Liu, X., Ding, J., & Meng, L. (2018) · Acta Pharmacologica Sinica · doi:10.1038/aps.2017.198 · Cited by 191 · see citing works
Chung, L., Maestas, D. R., Lebid, A., Mageau, A., Rosson, G. D., Wu, X., Wolf, M. T., Tam, A. J., Vanderzee, I., Wang, X., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aax3799 · Cited by 172 · see citing works
“The SASP includes many immunological cytokines that are associated with specific immune phenotypes (20).”
BackgroundMesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges
Xueke, Z., Hong, Y., Zhang, H., & Li, X. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00364 · Cited by 166 · see citing works
“The senescent features of MSCs include enlarged and more granular morphology, and a deficient capacity for proliferation (Haynesworth, 1997) and differentiation, and secretion of a variety molecules, referred to as a “senescence-associated secretory phenotype (SASP)” (Watanabe, 2017).”
BackgroundSenescence and senotherapeutics: a new field in cancer therapy
Myrianthopoulos, V., Evangelou, K., Vasileiou, P. V. S., Cooks, T., Vassilakopoulos, T. P., Pangalis, G. A., Kouloukoussa, M., Kittas, C., Georgakilas, A. G., & Gorgoulis, V. G. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2018.08.006 · Cited by 160 · see citing works
Notch Signaling Mediates Secondary Senescence
Teo, Y. V., Rattanavirotkul, N., Olova, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Müller, M., Green, A. R., Adams, P. D., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.104 · Cited by 149 · see citing works
“SASP has been implicated in cancer initiation (Watanabe et al., 2017) by creating an inflammatory pro-tumorigenic microenvironment.”
BackgroundCellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases
Ji, S., Xiong, M., Chen, H., Liu, Y., Zhou, L., Hong, Y., Wang, M., Wang, C., Fu, X., & Sun, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01343-5 · Cited by 166 · see citing works
“Meanwhile, SASP can contribute to angiogenesis to facilitate tumor development and an EMT in neighboring cancer cells and induce ECM degradation further resulting in the migration and metastasis of cancer cells.(454) To overcome this obstacle, a sequential therapy regimen consisting of TIS followed by a second compoun…”
MethodSpatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging
Ma, S., Ji, Z., Zhang, B., Geng, L., Cai, Y., Nie, C., Li, J., Zuo, Y., Sun, Y., Xu, G., et al. (2024) · Cell · doi:10.1016/j.cell.2024.10.019 · Cited by 162 · see citing works
Lee, K. S., Lin, S., Copland, D. A., Dick, A. D., & Liu, J. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02088-0 · Cited by 150 · see citing works
Cellular senescence in musculoskeletal homeostasis, diseases, and regeneration
Wan, M., Gray-Gaillard, E. F., & Elisseeff, J. H. (2021) · Bone Research · doi:10.1038/s41413-021-00164-y · Cited by 150 · see citing works
Dissecting 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
“The SASP acts as a tumor suppressor [82], however, it is also connected to tumor induction by generating a pro-inflammatory tumor-favoring microenvironment [83].”
BackgroundOxylipin-PPARγ-initiated adipocyte senescence propagates secondary senescence in the bone marrow
Liu, X., Gu, Y., Kumar, S., Amin, S., Guo, Q., Wang, J., Fang, C.-L., Cao, X., & Wan, M. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.03.005 · Cited by 137 · see citing works
Mechanisms of NLRP3 priming in inflammaging and age related diseases
Gritsenko, A., Green, J., Brough, D., & López‐Castejón, G. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.08.003 · Cited by 143 · see citing works
“Stopping cell division after a certain number of cycles plays an important role in preventing malignant transformation [47].”
BackgroundThe 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
Flavonoids in Skin Senescence Prevention and Treatment
Domaszewska-Szostek, A., Puzianowska‐Kuźnicka, M., & Kuryłowicz, A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136814 · Cited by 138 · see citing works
“This accumulation can be induced and accelerated by various cellular perturbations, including DNA damage and mitochondrial dysfunction [17].”
BackgroundCellular Interactions in the Tumor Microenvironment: The Role of Secretome
da Cunha, B. R., Domingos, C., Stefanini, A. C. B., Henrique, T., Polachini, G. M., Castelo‐Branco, P., & Tajara, E. H. (2019) · Journal of Cancer · doi:10.7150/jca.21780 · Cited by 128 · see citing works
“This mechanism is a response to stress, which blocks cell proliferation and is often associated with expression of the tumor suppressor protein p16INK4a and accompanied by a secretory phenotype (senescence-associated secretory phenotype - SASP) with stress-type–dependent profile [62-64].”
BackgroundEmerging roles of and therapeutic strategies targeting BRD4 in cancer
White, M. E., Fenger, J. M., & Carson, W. E. (2019) · Cellular Immunology · doi:10.1016/j.cellimm.2019.02.001 · Cited by 124 · see citing works
The roles of osteocytes in alveolar bone destruction in periodontitis
Huang, X., Xie, M.-R., Xie, Y.-L., Mei, F., Lu, X., Li, X.-S., & Chen, L.-L. (2020) · Journal of Translational Medicine · doi:10.1186/s12967-020-02664-7 · Cited by 110 · see citing works
“SASP, which is comprised of a variety of secretory proteins, including inflammatory cytokines, chemokines, extracellular matrix remodeling factors, and growth factors, is an important characteristic of senescent cells and has benefits, such as tumor suppression [84], but typically, it promotes chronic inflammation and…”
BackgroundPolyphenols as Caloric-Restriction Mimetics and Autophagy Inducers in Aging Research
Yessenkyzy, A., Saliev, T. M., Zhanaliyeva, M., Masoud, A., Umbayev, B. A., Sergazy, S., Кривых, Е. А., Gulyayev, A., & Nurgozhin, T. S. (2020) · Nutrients · doi:10.3390/nu12051344 · Cited by 115 · see citing works
Osteoclasts protect bone blood vessels against senescence through the angiogenin/plexin-B2 axis
Liu, X., Chai, Y., Liu, G., Su, W., Guo, Q., Lv, X., Gao, P., Yu, B., Ferbeyre, G., Cao, X., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22131-1 · Cited by 116 · see citing works
Functional Role of Taurine in Aging and Cardiovascular Health: An Updated Overview
Santulli, G., Kansakar, U., Varzideh, F., Mone, P., Jankauskas, S. S., & Lombardi, A. (2023) · Nutrients · doi:10.3390/nu15194236 · Cited by 115 · see citing works
“Senescent cells are characterized by the cell cycle arrest, decreased susceptibility to apoptosis, and release of a particular set of cytokines, known as senescence-associated secretory phenotype (SASP) [176–178].”
BackgroundSenescent cells and macrophages: key players for regeneration?
Elder, S. S., & Emmerson, E. (2020) · Open Biology · doi:10.1098/rsob.200309 · Cited by 109 · see citing works
“To date the SASP is known to have important roles in embryonic development, wound healing and tumour growth, indicating that the SASP has more complex physiological roles than we currently understand (reviewed in [81,82]).”
BackgroundDestabilizing heterochromatin by APOE mediates senescence
Zhao, H., Ji, Q., Wu, Z., Wang, S., Ren, J., Yan, K., Wang, Z., Hu, J., Chu, Q., Hu, H., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00186-z · Cited by 104 · see citing works
Impact of Klebsiella pneumoniae in lower gastrointestinal tract diseases
Kaur, C. P., Vadivelu, J., & Chandramathi, S. (2018) · Journal of Digestive Diseases · doi:10.1111/1751-2980.12595 · Cited by 90 · see citing works
Biomarkers of Physical Frailty and Sarcopenia: Coming up to the Place?
Picca, A., Calvani, R., Cesari, M., Landi, F., Bernabei, R., Coelho‐Júnior, H. J., & Marzetti, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165635 · Cited by 101 · see citing works
Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease
Picca, A., Guerra, F., Calvani, R., Coelho‐Júnior, H. J., Bossola, M., Landi, F., Bernabei, R., Bucci, C., & Marzetti, E. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9051440 · Cited by 98 · see citing works
The Histone Code of Senescence
Paluvai, H., Giorgio, E. D., & Brancolini, C. (2020) · Cells · doi:10.3390/cells9020466 · Cited by 94 · see citing works
“Moreover, SASP loci are localized in newly formed super-enhancers that require the binding of BRD4 to promote their transcription [105,106].”
BackgroundLim, S., An, S. B., Jung, M., Joshi, H. P., Kumar, H., Kim, C., Song, S. Y., Lee, J., Kang, M., Han, I., et al. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202101483 · Cited by 94 · see citing works
Senescence-Associated Metabolomic Phenotype in Primary and iPSC-Derived Mesenchymal Stromal Cells
Fernández‐Rebollo, E., Franzen, J., Goetzke, R., Hollmann, J., Ostrowska, A., Oliverio, M., Sieben, T., Rath, B., Kornfeld, J., & Wagner, W. (2020) · Stem Cell Reports · doi:10.1016/j.stemcr.2019.12.012 · Cited by 91 · see citing works
“The SASP was meanwhile observed across multiple cell types, and there is evidence that this secretory function of senescent cells has an impact on wound healing, embryonic development, and tumorigenesis (Watanabe et al., 2017).”
Aging and Senescence of Dental Pulp and Hard Tissues of the Tooth
Maeda, H. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.605996 · Cited by 91 · see citing works
ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin
Hu, H., Ji, Q., Song, M., Ren, J., Liu, Z., Wang, Z., Liu, X., Yan, K., Hu, J., Jing, Y., et al. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa425 · Cited by 87 · see citing works
“In addition, ZKSCAN3-deficiency activated senescence-associated secretory phenotype (SASP) and upregulated the expression of senescence markers in hMSCs (Figure 1L and M) (74).”
BackgroundmTOR Activity and Autophagy in Senescent Cells, a Complex Partnership
Cayo, Á., Segovia, R., Venturini, W., Moore‐Carrasco, R., Valenzuela, C. A., & Brown, N. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158149 · Cited by 92 · see citing works
“Of note, due to the trophic and pro-inflammatory actions of many SASP components [11], senescent cells arising in tissues can promote an inflammatory microenvironment that, in the long run, could facilitate tumorigenesis [45,46].”
BackgroundNon-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
Saleh, T., Tyutynuk-Massey, L., Cudjoe, E. K., Idowu, M. O., Landry, J. W., & Gewirtz, D. A. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00164 · Cited by 85 · see citing works
“For example, tocilizumab (IL-6 receptor antibody) and anakinra (IL-1 receptor antagonist) are used as immunomodulating therapy in the treatment of inflammatory diseases and can be readily investigated as regulators of the SASP in combination with conventional cancer treatment (50).”
BackgroundInfluentialAlqahtani, S., Alqahtani, T., Venkatesan, K., Sivadasan, D., Ahmed, R., Sirag, N., Elfadil, H., Mohamed, H. A., A, H., Ahmed, R. E., et al. (2025) · Cells · doi:10.3390/cells14080608 · Cited by 87 · see citing works
Wang, S., Wang, X., Cheng, Y., Ouyang, W., Sang, X., Liu, J., Su, Y., Liu, Y., Li, C., Yang, L., et al. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3632169 · Cited by 83 · see citing works
“ABT-737 BCL-W, BCL-Xl MEFs, IMR-90 cells, HUVECs [27, 28, 53]”
BackgroundInfluentialThe immunomodulatory effects of endocrine therapy in breast cancer
Huang, H., Zhou, J., Chen, H., Li, J., Zhang, C., Jiang, X., & Ni, C. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-01788-4 · Cited by 83 · see citing works
“to promote the recruitment of immune cells, including T cells and macrophages [130, 131].”
BackgroundPreininger, M. K., & Kaufer, D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116217 · Cited by 83 · see citing works
Khanh, V. C., Zulkifli, A. F., Tokunaga, C., Yamashita, T., Hiramatsu, Y., & Ohneda, O. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.04.136 · Cited by 81 · see citing works
Borrelli, C., Ricci, B., Vulpis, E., Fionda, C., Ricciardi, M. R., Petrucci, M. T., Masuelli, L., Peri, A., Cippitelli, M., Zingoni, A., et al. (2018) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-17-0604 · Cited by 83 · see citing works
“Discussion Senescent cells show numerous changes in gene expression, leading to an increased expression of many proteins that can promote or repress tumor progression (33,34).”
BackgroundCardiomyocytes Cellular Phenotypes After Myocardial Infarction
Lodrini, A. M., & Goumans, M. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.750510 · Cited by 81 · see citing works
“Furthermore, many senescent cells acquire a senescenceassociated secretory phenotype (SASP) that mediates non-cell autonomous effects of senescence, contributing to inflammation, and promoting tissue remodelling and repair or apoptosis (53).”
BackgroundLi, X., & Ma, L. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102175 · Cited by 83 · see citing works
Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer
Bian, Y., Wei, J., Zhao, C., & Li, G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020684 · Cited by 80 · see citing works
“CXCR2: C-X-C motif chemokine receptor 2; DDR: DNA damage response; ROS: reactive oxygen species; DLC1: deleted in liver cancer1; SASP: senescence-associated secretory phenotype; Pokemon: POK erythroid myeloid ontogenic factor; SIRT1: silent information regulator 1; Rictor: rapamycin-insensitive companion of mammalian…”
BackgroundInfluentialGlomerular endothelial cell senescence drives age‐related kidney disease through PAI‐1
Cohen, C., Le Goff, O., Soysouvanh, F., Vasseur, F., Tanou, M., Nguyen, C., Amrouche, L., Le Guen, J., Saltel‐Fulero, O., Meunier, T., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114146 · Cited by 79 · see citing works
“SASP includes pro-inflammatory cytokines, growth factors, proteases, and extracellular matrix components (Kuilman et al, 2008; Salama et al, 2014; Watanabe et al, 2017).”
BackgroundCellular Senescence in Lung Fibrosis
Hernández‐González, F., Faner, R., Rojas, M. M., Agustí, A. G. N., Serrano, M., & Sellarés, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137012 · Cited by 78 · see citing works
“Alterations in the secretome of senescent cells with a chronic increment of production of several inflammatory secretory proteins, including plasminogen activator inhibitor-1 (PAI-1), matrix remodelling proteins (MMPs), growth factors such as TGFβ1, as well as other initial inflammatory stimuli, including IL-6, IL-8 a…”
BackgroundThe twilight of the immune system: The impact of immunosenescence in aging
Feehan, J., Tripodi, N., & Apostolopoulos, V. (2021) · Maturitas · doi:10.1016/j.maturitas.2021.02.006 · Cited by 76 · see citing works
Khavinson, V., Linkova, N. S., Dyatlova, A., Кантемирова, Р. К., & Kozlov, K. L. (2022) · Cells · doi:10.3390/cells12010106 · Cited by 78 · see citing works
Senescent cells as promising targets to tackle age-related diseases
Prašnikar, E., Borišek, J., & Perdih, A. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101251 · Cited by 74 · see citing works
Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons
Stojanović, B., Jovanovic, I., Stojanovic, M. D., Stojanović, B., Kovačević, V., Radosavljević, I., Jovanović, D., Kovačević, M. M., Zornić, N., Arsić, A. A., et al. (2025) · Antioxidants · doi:10.3390/antiox14080987 · Cited by 83 · see citing works
“While suppressing chronic SASP is desirable, indiscriminate inhibition may interfere with its beneficial roles in wound healing and tumor surveillance [235].”
Acklin, S., Zhang, M., Du, W., Zhao, X., Plotkin, M. D., Chang, J., Campisi, J., Zhou, D., & Xia, F. (2020) · Scientific Reports · doi:10.1038/s41598-020-71042-6 · Cited by 76 · see citing works
Senescence in polyploid giant cancer cells: A road that leads to chemoresistance
Bharadwaj, D., & Mandal, M. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.11.002 · Cited by 64 · see citing works
Malavolta, M., Giacconi, R., Brunetti, D., Provinciali, M., & Maggi, F. (2020) · Cells · doi:10.3390/cells9040909 · Cited by 72 · see citing works
“Drugs targeting IL-6 have been included among the potential strategies to inhibit the deleterious consequences of the senescence-associated secretory phenotype (SASP), the secretome produced by senescent cells [31,32].”
BackgroundTherapeutic Potential of Senolytics in Cardiovascular Disease
Dookun, E., Passos, J. F., Arthur, H. M., & Richardson, G. D. (2022) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-020-07075-w · Cited by 69 · see citing works
Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG
Balakrishnan, I., Danis, E. P., Pierce, A. M., Madhavan, K. P. C., Wang, D., Dahl, N. A., Sanford, B. L., Birks, D. K., Davidson, N., Metselaar, D. S., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108286 · Cited by 67 · see citing works
“We also found that BMI1 inhibition showed a moderate increase in the release of several SASP factors (interleukin [IL]-6, IL-8, VEGF [Vascular Endothelial Growth Factor], and CXCLs [Chemokine C-X-C motif Ligands]) in both PTC028-treated cells and BMI1 knockdown cells (Figures 6E– 6G).”
BackgroundInfluentialStigger, F. S., Zago Marcolino, M. A., Portela, K. M., & Plentz, R. D. M. (2019) · The Journals of Gerontology: Series A · doi:10.1093/gerona/gly173 · Cited by 68 · see citing works
Lee, J., Park, B., Park, J.-H., Lim, S., Kwon, S. P., Hwang, J., Kim, H., Park, H., & Kim, B. (2021) · Acta Biomaterialia · doi:10.1016/j.actbio.2021.08.028 · Cited by 66 · see citing works
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“1, which is a tumor suppressor histone variation, from SASP chromatin, resulting in SASP gene derepression and induction [98].”
BackgroundInfluentialRelationships Between Ion Channels, Mitochondrial Functions and Inflammation in Human Aging
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“Second, they adopt Senescence-Associated Secretory Phenotype (SASP), refers to the secretion of inflammatory cytokines, growth factors, and proteases from senescent cells (Watanabe et al. 2017).”
BackgroundMbara, K. C., Devnarain, N., & Owira, P. M. O. (2022) · Pharmaceutical Medicine · doi:10.1007/s40290-022-00444-w · Cited by 60 · see citing works
“In contrast to senescence and cell‐cycle arrest, SASP is independent of the ectopic expression of senescence factors such as p16Ink4a and p21Waf1/Cip1, suggesting that there are other signalling pathways in their induction [18, 19].”
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“In this regard, purging of senescent cells, termed senolysis, or inhibition of SASP induction, have now emerged as novel strategies for cancer treatment.(85) These approaches also show promise for suppressing aging‐related disorders(66) but, again, we have to bear in mind that senescence and SASP also have beneficial…”
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“Cell senescence is the irreversible state in which cells undergo cycle arrest responding to various factors (Watanabe et al., 2017).”
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“It is also pertinent to note here that senescent cells are not only characterized by the loss of proliferative capacity but also show several unique-associated features such as high metabolic activity,(22) activation of nutrient-sensing pathways such as mammalian target of rapamycin (mTOR),(23) and the development of…”
BackgroundG Protein-Coupled Receptor Systems and Their Role in Cellular Senescence
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Astrocyte senescence contributes to cognitive decline
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Resolution of inflammation and mood disorders
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Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice
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“SASP appears to elicit deleterious effects in several disease models (He & Sharpless, 2017; Watanabe et al., 2017), and its inhibition was shown to be sufficient for preventing senescence‐induced bone loss (Farr et al.”
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The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model
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“There is accumulating experimental evidence that show senescent cells secrete proteins such as inflammatory cytokines, chemokines and extracellular matrix remodeling factors (Watanabe et al. 2017).”
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Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence
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Oridonin inhibits SASP by blocking p38 and NF-κB pathways in senescent cells
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- Authors
- Watanabe, S., Kawamoto, S., Ohtani, N., & Hara, E.
- Affiliations
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Tokyo University of Science (JP)
- Japanese Foundation For Cancer Research (JP)
- Corresponding author
- Watanabe, Sugiko
- Venue
- Cancer Science
- Publisher
- Wiley
- Published
- 2017-04
- Volume
- 108
- Issue
- 4
- Pages
- 563-569
- ISSN
- 1347-9032 (ISSN-L)
- 1349-7006
- PMC
- PMC5406532
- OpenAlex
- W2587299332
- Cited by
- 321
- References
- 88
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 29 · 2023: 39 · 2022: 33 · 2021: 41 · 2020: 47 · 2019: 47 · 2018: 33 · 2017: 3
- FWCI
- 4.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancer Science (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Astellas Foundation for Research on Metabolic Disorders
- Naito Foundation
- Japan Agency for Medical Research and Development
- 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 › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- senescence-associated secretory phenotype, cellular senescence, aging, senolytics, secreted proteins, inflammatory cytokines, chemokines, matrix metalloproteinases, tumor suppression, carcinogenesis, cell cycle arrest, therapeutic target
- MeSH terms
- Aging, Animals, Cell Transformation, Neoplastic, Disease, Humans, Neoplasms, Phenotype, Cellular Senescence, Secretory Pathway, Cell Cycle Checkpoints
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