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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 (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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“Aging BMSCs are known to develop a senescence-associated secretory phenotype (SASP); SASP factors have been shown to propagatesenescenceinneighboring non-senescentcellsthroughparacrine signaling or cell-cell contact, thereby affecting the homeostasis of multiple systems within bone 24 – 26 .”
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“Glioma driver genes upregulate SASP signature factors via epigenetic mechanisms Since senescence has been linked to tumorigenesis by non–cellautonomous mechanisms such as SASP (14, 15), we examined the expression of a subset of SASP factors as we did with U87 cells.”
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Chang, Y., He, F., Wang, T., & Aisa, H. A. (2022) · Journal of Food Processing and Preservation · doi:10.1111/jfpp.16789 · Cited by 9
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Antioxidant Senotherapy by Natural Compounds: A Beneficial Partner in Cancer Treatment
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Karnam, S., Girish, H., & Nayak, V. N. (2022) · Journal of Oral and Maxillofacial Pathology · doi:10.4103/jomfp.jomfp_115_21 · Cited by 7
“The effect of senescent cells and its SASP varies in different biological scenarios.[5] The present study explores the role of SFs in fibrosis and malignant transformation of OSMF.”
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Bazi Bushen alleviates reproductive aging in aged male mice
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“…secretory phenotype (SASP) is a phenotype associated with senescent cells that secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases These include interleukin 1 β (IL1 β ), IL6, IL8, and plasminogen activator inhibitor 1 (PAI-1), among others [14,32,33].”
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“Oncogene‐ induced senescence has been linked to the release of SASPs including multiple cytokines that play an effector role in the process.(23) Cyto-”
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“This ultimately leads to the upregulation of SASPrelated proteins, promotes chronic inflammation, and accelerates age-related functional decline and disease [67].”
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Zheng, H., Li, T., Hu, Z., Zheng, Q., & Wang, J. (2024) · Biogerontology · doi:10.1007/s10522-024-10141-7 · Cited by 6
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“…chronic low-grade inflammation is associated with the incidence of multiple age-dependent diseases (Howcroft et al. 2013; Camell et al. 2019; Messerschmidt et al. 2019), primarily characterized by the accumulation of immune cells and production of proinflammatory cytokines (Watanabe et al. 2017).”
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“In response to oxidative stress or chronic DNA damage, SASP first aids in tissue healing and encourages the immune system to eliminate damaged cells[21].”
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Li, H., Zheng, Y., Yuan, C., Wang, J., Zhao, X., Yang, M., Xiong, D., Yang, Y., Dai, Y., Gao, Y., et al. (2025) · Cell Discovery · doi:10.1038/s41421-025-00820-1 · Cited by 3
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“…factors can be both beneficial and detrimental: initially, the SASP can aid in tissue repair and immune surveillance, but prolonged SASP activity drives a pro-inflammatory environment that contributes to aging and various diseases, such as osteoarthritis, sarcopenia, and neurodegeneration [6].”
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“Depending on the cell type and cellular context, senescent cells will secrete a variety of pro-inflammatory cytokines, chemokines, growth modulators, proteases and other soluble signalling factors, collectively termed senescence-associated secretory-phenotype (SASP) factors [3].”
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“…excessive senescent cell accumulation can drive chronic in fl ammation in surrounding tissues through SASP, potentially contributing to functional decline and promoting the onset of various age-related diseases, including cancer (Chan and Narita, 2019; Lee and Schmitt, 2019; Watanabe et al, 2017).”
Self-citationSenescent Factors Suppress Innate Antiviral Immunity in Aged Mice via Two Distinct Mechanisms
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“…cells, which cease to divide in response to various stressors, secrete a complex mixture of growth factors, proteases, and pro-inflammatory cytokines, collectively referred to as the senescence-associated secretory phenotype (SASP) (Coppé et al. 2010; Watanabe et al. 2017; Gorgoulis et al. 2019).”
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“…secretory phenotype (SASP) (Acosta et al, 2008; Coppe et al, 2008; Kuilman et al, 2008), the excessive accumulation of senescent cells induces a variety of in fl ammatory symptoms depending on the biological context (Baz-Martinez et al, 2016; Chan and Narita, 2019, Watanabe et al, 2017).”
Self-citationZNF512B safeguards genome integrity at regulatory regions to repress the SASP and inflammation
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“Senescent cells secrete SASP, which disrupts the surrounding environment, promotes inflammation, and speeds up aging [21,22].”
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“Senescent cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases, which affect the function of neighbouring cells [22, 54].”
Investigation on ABCC6-Deficient Human Hepatocytes Generated by CRISPR–Cas9 Genome Editing
Plümers, R., Jelinek, S., Lindenkamp, C., Osterhage, M. R., Knabbe, C., & Hendig, D. (2025) · Cells · doi:10.3390/cells14080576 · Cited by 1
“This secretome includes the proinflammatory cytokines interleukin 6 (IL6) and interleukin 1 β (IL1B) [25,26].”
Accelerated senescence of bone marrow erythrocyte precursors in myelodysplastic syndrome
Liu, M., Yang, L., Liu, Y., Niu, H., Zhang, M., Shao, Z., Xing, L., & Wang, H. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2494676 · Cited by 1
“Another hallmark of cells entering senescence is the secretion of numerous cytokines through autocrine or paracrine pathways, collectively known as the Senescence-Associated Secretory Phenotype (SASP) [28,29].”
Coppola, H., Al-Khalidi, K., Gremlich, S., Viertl, D., Siméoni, U., Armengaud, J.-B., & Yzydorczyk, C. (2025) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2025.110096 · Cited by 3
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Macrophage repolarization by epigallocatechin-3-gallate via NF-κB and CREB1/HO-1
Ida, T., Edanami, N., Gomez-Kasimoto, S., Sotozono, M., Takenaka, S., Ohkura, N., & Noiri, Y. (2026) · Archives of Oral Biology · doi:10.1016/j.archoralbio.2026.106592 · Cited by 1
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Aging and Malignant Hemopathies: A Complex Multistep Process
Chi, V. L. D., Sibille, C., Willard-Gallo, K. E., & Bron, D. (2018) · Springer eBooks · doi:10.1007/978-3-319-64597-1_142-1 · Cited by 1
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Antioxidant properties and applications of Ophiopogon japonicus root for age-related disease
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Therapy Induced Senescence Promote Expression of Death Receptors in Breast Cancer Cells
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Aging and Malignant Hemopathies: A Complex Multistep Process
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Evaluation of TGF-β isoforms based on selected clinical parameters in asthmatic patients
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Predictive modeling of co-evolving growing populationsPreprint
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Notch signalling mediates secondary senescencePreprint
Teo, Y. V., Rattanavirotkul, N., Salzano, A., Quintanilla, A., Tarrats, N., Kiourtis, C., Mueller, M., Green, A. R., Adams, P. D., Acosta, J. C., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/554741
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Ablation of Arf -expressing cells ameliorates cigarette smoke-induced lung dysfunction in micePreprint
Mikawa, R., Sato, T., Suzuki, Y., Baskoro, H., & Sugimoto, M. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/809160
“These are collectively called SASP (the senescence-associated secretory phenotype), and increasing evidence suggests that SASP mediates the deleterious effects of cellular senescence and is involved in a number of pathologies in both humans and mice [11].”
BackgroundMitochondria: Potential Targets for Interventions to Counteract Senescence
Lagnado, A. B., Victorelli, S. G., & Passos, J. F. (2020) · Healthy ageing and longevity · doi:10.1007/978-3-030-44903-2_11
Analysis of cellular senescence in gingival tissues and gingival fibroblast culturesPreprint
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Dissecting the molecular mechanism and spatiotemporal dynamics controlling senescence entry
Sofiadis, K. (2021) · eDiss (Georg-August-Universität Göttingen) · doi:10.53846/goediss-8409
Sharoni, E. Y. (2021) · Digital Access to Scholarship at Harvard (DASH) (Harvard University)
DEVELOPMENT OF A NOVEL METABOLIC GLYCO-SENSING APPROACH WITH ANTI-AGING POTENTIAL
AlSadek, D. M. M., Badr, H. A., & Ahmed, H. (2018) · Mansoura Veterinary Medical Journal · doi:10.21608/mvmj.2018.198486
“Depending on the biological context, the SASP appears to be beneficial such as early in life or in an acute wound healing (Demaria et al., 2014) or”
BackgroundInfluentialCellular senescence in the ageing brain
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Faculty Opinions recommendation of Hallmarks of senescence and aging.
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A novel in vitro senescent model of intervertebral disc degeneration induced by D-galactosePreprint
Zhang, S., Ma, Z., Sheng, W., & Wang, H. (2022) · Research Square · doi:10.21203/rs.3.rs-2151159/v1
Esmat, M., Shahein, M. H., Khashab, S., & Ali, A. Y. (2023) · The Egyptian Journal of Hospital Medicine · doi:10.21608/ejhm.2023.284353
Stem Cell Therapy and Rejuvenation, and Their Impact on Society
Ibarretxe, G. (2023) · Bioengineering · doi:10.3390/bioengineering10060694
“In addition, senescent cells show an altered secretome, which can have deleterious effects on tissues [16].”
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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