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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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![Figure 5 Strategies for senescence‐associated secretory phenotype (SASP) attenuation. SASP factors could be blocked by targeting its induction (e.g., nuclear factor‐κB [NF‐κB] inhibitor, mammalian target of rapamycin [mTOR] inhibitor, or bromo and extra terminal domain [BET] inhibitor) or its activity (e.g., interleukin [IL]‐1 receptor antagonist, anti‐IL‐6 receptor antibody, IL‐6 inhibitor, or tumor necrosis factor‐α inhibitor).](/paper-figures/730c811b8cf14d54838fac279ba35097/impact-of-senescence-associated-secretory-phenotype-and-its-potential-as-a-figure-5.jpg)
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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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“The SASP includes many immunological cytokines that are associated with specific immune phenotypes (20).”
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“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].”
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“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).”
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“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).”
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Natural Polyphenols Targeting Senescence: A Novel Prevention and Therapy Strategy for Cancer
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“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
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“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
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“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
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Senescent cells as promising targets to tackle age-related diseases
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Oxidative Stress-Driven Cellular Senescence: Mechanistic Crosstalk and Therapeutic Horizons
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“While suppressing chronic SASP is desirable, indiscriminate inhibition may interfere with its beneficial roles in wound healing and tumor surveillance [235].”
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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
Malavolta, M., Giacconi, R., Brunetti, D., Provinciali, M., & Maggi, F. (2020) · Cells · doi:10.3390/cells9040909 · Cited by 72
“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
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 75
“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
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
Khalil, R., Diab‐Assaf, M., & Lemaître, J.-M. (2023) · Cells · doi:10.3390/cells12060915 · Cited by 68
“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
Strickland, M., Yacoubi‐Loueslati, B., Bouhaouala‐Zahar, B., Pender, S. L. F., & Larbi, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00158 · Cited by 64
Organ reserve, excess metabolic capacity, and aging
Atamna, H., Tenore, A., Lui, F., & Dhahbi, J. M. (2018) · Biogerontology · doi:10.1007/s10522-018-9746-8 · Cited by 72
“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 47
“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].”
BackgroundThe Jekyll and Hyde of Cellular Senescence in Cancer
Demirci, D., Dayanc, B., Mazi, F. A., & Şentürk, Ş. (2021) · Cells · doi:10.3390/cells10020208 · Cited by 62
Tetraploidy in cancer and its possible link to aging
Tanaka, K., Goto, H., Nishimura, Y., Kasahara, K., Mizoguchi, A., & Inagaki, M. (2018) · Cancer Science · doi:10.1111/cas.13717 · Cited by 58
“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…”
BackgroundDong, Y., Chen, H., Gao, J., Liu, Y., Li, J., & Wang, J. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00515 · Cited by 56
“Cell senescence is the irreversible state in which cells undergo cycle arrest responding to various factors (Watanabe et al., 2017).”
BackgroundProbiotic bacteria as modulators of cellular senescence: emerging concepts and opportunities
Sharma, R., & Padwad, Y. S. (2019) · Gut Microbes · doi:10.1080/19490976.2019.1697148 · Cited by 56
“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
Santos‐Otte, P., Leysen, H., van Gastel, J., Hendrickx, J. O., Martin, B., & Maudsley, S. R. (2019) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2019.08.005 · Cited by 53
“These deleterious insults include DNA damage, mitochondrial dysfunction, activation of certain oncogenes and inflammatory responses [58,59], all of which are classically associated with the pathological aging process [48].”
BackgroundEl‐Far, A. H., Darwish, N. H. E., & Mousa, S. A. (2020) · Integrative Cancer Therapies · doi:10.1177/1534735419901160 · Cited by 57
Ohtani, N. (2019) · The Journal of Biochemistry · doi:10.1093/jb/mvz055 · Cited by 55
Self-citationAdem, Y., Galderisi, U., & Alessio, N. (2023) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2023.1148761 · Cited by 55
Current Trends in Anti-Aging Strategies
Rosén, R., & Yarmush, M. L. (2023) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-120122-123054 · Cited by 56
Liu, P., Tang, Q., Chen, M., Chen, W., Lu, Y., Liu, Z., & He, Z. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.589908 · Cited by 50
Lazzarini, E., Lodrini, A. M., Arici, M., Bolis, S., Vagni, S., Panella, S., Rendon-Angel, A., Saibene, M., Metallo, A., Torre, T., et al. (2022) · Theranostics · doi:10.7150/thno.70884 · Cited by 51
“Cardiomyocytes (CMs) enduring exogenous cellular insult may develop a stress-induced premature senescence (SIPS) phenotype, which recapitulates many cellular and molecular features as those undergoing natural aging process [10, 11].”
InfluentialNagesh, P. K. B., Chowdhury, P., Hatami, E., Kumari, S., Kashyap, V. K., Tripathi, M. K., Wagh, S., Meibohm, B., Chauhan, S. C., Jaggi, M., et al. (2019) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.9b14738 · Cited by 48
Astrocyte senescence contributes to cognitive decline
Csípő, T., Lipécz, Á., Ashpole, N. M., Balasubramanian, P., & Tarantini, S. (2019) · GeroScience · doi:10.1007/s11357-019-00140-9 · Cited by 50
Resolution of inflammation and mood disorders
Chistyakov, D. V., Astakhova, A. A., & Sergeeva, M. G. (2018) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2018.08.002 · Cited by 48
Chanda, F., Lin, K.-X., Chaurembo, A. I., Huang, J.-Y., Zhang, H., Deng, W., Xu, Y.-J., Li, Y., Fu, L.-D., Cui, H., et al. (2024) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2024.176255 · Cited by 49
Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice
Mikawa, R., Suzuki, Y., Baskoro, H., Kanayama, K., Sugimoto, K., Sato, T., & Sugimoto, M. (2018) · Aging Cell · doi:10.1111/acel.12827 · Cited by 44
“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.”
BackgroundA tale of the good and bad: Cell senescence in bone homeostasis and disease
Liu, X., & Wan, M. (2019) · International review of cytology · doi:10.1016/bs.ircmb.2019.03.005 · Cited by 45
Liu, D., Richardson, G. D., Benli, F. M., Park, C., de Souza, J. V. B., Bronowska, A. K., & Spyridopoulos, I. (2020) · Clinical Science · doi:10.1042/cs20191213 · Cited by 47
The Senolytic Drug Fisetin Attenuates Bone Degeneration in the Zmpste24−/− Progeria Mouse Model
Hambright, W. S., Mu, X., Gao, X., Guo, P., Kawakami, Y., Mitchell, J., Mullen, M., Nelson, A.-L., Bahney, C., Nishimura, H., et al. (2023) · Journal of Osteoporosis · doi:10.1155/2023/5572754 · Cited by 44
The role of vitamin D on redox regulation and cellular senescence
Sosa-Díaz, E., Cruz, E. Y. H., & Pedraza‐Chaverrí, J. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.10.003 · Cited by 43
Functional genomics of inflamm-aging and immunosenescence
Lu, R. J., Wang, E. K., & Benayoun, B. A. (2021) · Briefings in Functional Genomics · doi:10.1093/bfgp/elab009 · Cited by 43
“Importantly, a decreased ability to clear senescent cells through efferocytosis could also indirectly drive increased inflammation due to an increasing burden of cells producing SASP factors [52,53].”
BackgroundLife and death of microglia: Mechanisms governing microglial states and fates
Matsudaira, T., & Prinz, M. (2022) · Immunology Letters · doi:10.1016/j.imlet.2022.04.001 · Cited by 47
Möller, P., Wils, R. S., Jensen, D. M., Andersen, M. H. G., & Roursgaard, M. (2018) · Critical Reviews in Toxicology · doi:10.1080/10408444.2018.1538201 · Cited by 42
“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).”
BackgroundDifferent sensitivities of senescent breast cancer cells to immune cell‐mediated cytotoxicity
Inao, T., Kotani, H., Iida, Y., Kartika, I. D., Okimoto, T., Tanino, R., Shiba, E., & Harada, M. (2019) · Cancer Science · doi:10.1111/cas.14116 · Cited by 41
Picca, A., Calvani, R., Coelho‐Júnior, H. J., Landi, F., Bernabei, R., & Marzetti, E. (2020) · Cells · doi:10.3390/cells9030598 · Cited by 41
Converging Paths of Pulmonary Arterial Hypertension and Cellular Senescence
van der Feen, D. E., Berger, R. M. F., & Bartelds, B. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2018-0329tr · Cited by 38
Oridonin inhibits SASP by blocking p38 and NF-κB pathways in senescent cells
Yasuda, S., Horinaka, M., Iizumi, Y., Goi, W., Sukeno, M., & Sakai, T. (2021) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2021.12.098 · Cited by 39
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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