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Senescence as a therapeutic target in cancer and age-related diseases
Abstract
Cellular senescence is a stress response that restrains the growth of aged, damaged or abnormal cells. Thus, senescence has a crucial role in development, tissue maintenance and cancer prevention. However, lingering senescent cells fuel chronic inflammation through the acquisition of a senescence-associated secretory phenotype (SASP), which contributes to cancer and age-related tissue dysfunction. Recent progress in understanding senescence has spurred interest in the development of approaches to target senescent cells, known as senotherapies. In this Review, we evaluate the status of various types of senotherapies, including senolytics that eliminate senescent cells, senomorphics that suppress the SASP, interventions that mitigate senescence and strategies that harness the immune system to clear senescent cells. We also summarize how these approaches can be combined with cancer therapies, and we discuss the challenges and opportunities in moving senotherapies into clinical practice. Such therapies have the potential to address root causes of age-related diseases and thus open new avenues for preventive therapies and treating multimorbidities.
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“resistance mechanisms such as MCL-1 upregulation, and negative outcomes in some models21”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [21]
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Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., et al. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0122-z · Cited by 359 · cited 7×
“Another class of senolytic drugs that target the aberrant ionic homeostasis of SnCs are cardiac glycosides (CGs) such as ouabain or digoxin 119,120 .”
InfluentialSelf-citationNKG2D ligands mediate immunosurveillance of senescent cells
Sagiv, A., Burton, D. G. A., Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., Golani, O., Polic, B., & Krizhanovsky, V. (2016) · Aging · doi:10.18632/aging.100897 · Cited by 345
The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
Xu, Q., Fu, Q., Li, Z., Liu, H., Wang, Y., Lin, X., He, R., Zhang, X., Ju, Z., Campisi, J., et al. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00491-8 · Cited by 341
A versatile drug delivery system targeting senescent cells
Muñoz‐Espín, D., Rovira, M., Galiana, I., Giménez, C., Lozano‐Torres, B., Paez‐Ribes, M., Llanos, S., Chaib, S., Muñoz‐Martín, M., Ucero, A. C., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809355 · Cited by 339
Pluquet, O., Pourtier, A., & Abbadie, C. (2015) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00334.2014 · Cited by 305
González‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson, J. R., González‐López, C., Ou, H., Mirón‐Barroso, S., Zhang, Z., Lérida‐Viso, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13142 · Cited by 303
Nambiar, A., Kellogg, D., Justice, J., Goros, M., Gelfond, J., Pascual, R., Hashmi, S., Masternak, M., Prata, L., LeBrasseur, N., et al. (2023) · eBioMedicine · doi:10.1016/j.ebiom.2023.104481 · Cited by 298 · cited 1×
“However, more recent results from a larger phase I, single-blind, randomized, placebo control trial, although underpowered, failed to unveil differences in frailty, pulmonary or physical function 192 .”
Discovery of piperlongumine as a potential novel lead for the development of senolytic agents
Wang, Y., Chang, J., Liu, X., Zhang, X., Zhang, S., Zhang, X., Zhou, D., & Zheng, G. (2016) · Aging · doi:10.18632/aging.101100 · Cited by 274
Identification of senescent cell surface targetable protein DPP4
Kim, K. M., Noh, J. H., Bodogai, M., Martindale, J. L., Yang, X., Indig, F. E., Basu, S. K., Ohnuma, K., Morimoto, C., Johnson, P. F., et al. (2017) · Genes & Development · doi:10.1101/gad.302570.117 · Cited by 270
Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261 · cited 1×
“Treatment with TGFβR1 small molecule inhibitors (AZ12601011 or SB525334) reduced senescence and facilitated liver regeneration in a mouse model of liver poisoning by acetaminophen overdose 159 .”
Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts
Laberge, R.-M., Awad, P., Campisi, J., & Desprez, P.-Y. (2012) · Cancer Microenvironment · doi:10.1007/s12307-011-0069-4 · Cited by 255
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer
Haston, S., Gonzalez-Gualda, E., Morsli, S., Ge, J., Reen, V., Calderwood, A., Moutsopoulos, I., Panousopoulos, L., Deletic, P., Carreno, G., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.05.004 · Cited by 251
Self-citationGeorgilis, A., Klotz, S., Hanley, C. J., Herranz, N., Weirich, B., Morancho, B., Leote, A. C., D'Artista, L., Gallage, S., Seehawer, M., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.06.007 · Cited by 237 · cited 1×
“For example, genetic screens identified polypyrimidine tract-binding protein 1 (PTBP1) as an SASP regulator, and knockdown of Ptbp1 specifically targets the inflammatory SASP, and results in the inhibition of liver cancer progression even if it decreases senescence surveillance 158 .”
Self-citationWang, L., Leite de Oliveira, R., Wang, C., Fernandes Neto, J. M., Mainardi, S., Evers, B., Lieftink, C., Morris, B., Jochems, F., Willemsen, L., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.09.085 · Cited by 224
Herdy, J. R., Traxler, L., Agarwal, R. K., Karbacher, L., Schlachetzki, J. C. M., Boehnke, L., Zangwill, D., Galasko, D., Glass, C. K., Mertens, J., et al. (2022) · Cell Stem Cell · doi:10.1016/j.stem.2022.11.010 · Cited by 208
A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
Wakita, M., Takahashi, A., Sano, O., Loo, T. M., Imai, Y., Narukawa, M., Iwata, H., Matsudaira, T., Kawamoto, S., Ohtani, N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15719-6 · Cited by 206
The Cancer SENESCopedia: A delineation of cancer cell senescence
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Vascular smooth muscle cell senescence in atherosclerosis
GORENNE, I., KAVURMA, M., SCOTT, S., & BENNETT, M. (2006) · Cardiovascular Research · doi:10.1016/j.cardiores.2006.06.004 · Cited by 196 · cited 1×
“…ageing but are also present in fibrotic 12,62 and many other diseased tissues and in diseases as diverse as type 2 diabetes 63 , atherosclerosis 64,65 , non-alcoholic fatty liver disease 66 , Alzheimer disease, retinopathy 67 , idiopathic pulmonary fibrosis (IPF) 62 or osteoarthritis 68,69…”
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 · cited 2×
“The development of mouse p16 INK4a reporter models has been key to confirming the accumulation of SnCs with age and identifying the nature of these SnCs 36,57,60 (Box 1).”
Crespo-Garcia, S., Tsuruda, P. R., Dejda, A., Ryan, R. D., Fournier, F., Chaney, S. Y., Pilon, F., Dogan, T., Cagnone, G., Patel, P., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.01.011 · Cited by 182
Sentinel p16 INK4a+ cells in the basement membrane form a reparative niche in the lung
Reyes, N. S., Krasilnikov, M., Allen, N. C., Lee, J. Y., Hyams, B., Zhou, M., Ravishankar, S., Cassandras, M., Wang, C., Khan, I., et al. (2022) · Science · doi:10.1126/science.abf3326 · Cited by 181
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Elimination of p19ARF-expressing cells enhances pulmonary function in mice
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COVID-19 and cellular senescence
Schmitt, C. A., Tchkonia, T., Niedernhofer, L. J., Robbins, P. D., Kirkland, J. L., & Lee, S. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-022-00785-2 · Cited by 153
Senescent cell turnover slows with age providing an explanation for the Gompertz law
Karin, O., Agrawal, A., Porat, Z., Krizhanovsky, V., & Alon, U. (2019) · Nature Communications · doi:10.1038/s41467-019-13192-4 · Cited by 151
Anti-senescent drug screening by deep learning-based morphology senescence scoring
Kusumoto, D., Seki, T., Sawada, H., Kunitomi, A., Katsuki, T., Kimura, M., Ito, S., Komuro, J., Hashimoto, H., Fukuda, K., et al. (2021) · Nature Communications · doi:10.1038/s41467-020-20213-0 · Cited by 143
Mariette, X., Hermine, O., Tharaux, P.-L., Resche-Rigon, M., Steg, P. G., Porcher, R., & Ravaud, P. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2021.2209 · Cited by 140
Discovery of senolytics using machine learning
Smer-Barreto, V., Quintanilla, A., Elliott, R. J. R., Dawson, J. C., Sun, J., Campa, V. M., Lorente-Macías, Á., Unciti-Broceta, A., Carragher, N. O., Acosta, J. C., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-39120-1 · Cited by 139
Gonzalez-Meljem, J. M., Haston, S., Carreno, G., Apps, J. R., Pozzi, S., Stache, C., Kaushal, G., Virasami, A., Panousopoulos, L., Mousavy-Gharavy, S. N., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01992-5 · Cited by 130
Self-citationChandra, A., Lagnado, A. B., Farr, J. N., Doolittle, M., Tchkonia, T., Kirkland, J. L., LeBrasseur, N. K., Robbins, P. D., Niedernhofer, L. J., Ikeno, Y., et al. (2022) · Aging Cell · doi:10.1111/acel.13602 · Cited by 120
The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2
Chaib, S., López-Domínguez, J. A., Lalinde-Gutiérrez, M., Prats, N., Marin, I., Boix, O., García-Garijo, A., Meyer, K., Muñoz, M. I., Aguilera, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-023-00712-x · Cited by 114
Local senolysis in aged mice only partially replicates the benefits of systemic senolysis
Farr, J. N., Saul, D., Doolittle, M. L., Kaur, J., Rowsey, J. L., Vos, S. J., Froemming, M. N., Lagnado, A. B., Zhu, Y., Weivoda, M., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci162519 · Cited by 81
Invariant natural killer T cells coordinate removal of senescent cells
Arora, S., Thompson, P. J., Wang, Y., Bhattacharyya, A., Apostolopoulou, H., Hatano, R., Naikawadi, R. P., Shah, A., Wolters, P. J., Koliwad, S., et al. (2021) · Med · doi:10.1016/j.medj.2021.04.014 · Cited by 77
The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress
Anerillas, C., Mazan-Mamczarz, K., Herman, A. B., Munk, R., Lam, K.-W. G., Calvo-Rubio, M., Garrido, A., Tsitsipatis, D., Martindale, J. L., Altés, G., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00480-4 · Cited by 76 · cited 2×
“This vulnerability is further highlighted by a CRISPR screen that identified how signalling through the transcription factor axis YAP–TEAD is needed to maintain the viability of SnCs 117 .”
Taking advantage of drug resistance, a new approach in the war on cancer
Wang, L., & Bernards, R. (2018) · Frontiers of Medicine · doi:10.1007/s11684-018-0647-7 · Cited by 53
Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration
Yu, Q., Walters, H. E., Pasquini, G., Pal Singh, S., Lachnit, M., Oliveira, C. R., León-Periñán, D., Petzold, A., Kesavan, P., Subiran Adrados, C., et al. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.09.009 · Cited by 52
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Cited by
Sorted by citations
Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming
Zhang, W., Song, S., Zhang, Y., Pan, Y., Hu, D., & Wang, Y. (2026) · npj Aging · doi:10.1038/s41514-026-00355-z · Cited by 6
Metadata
- Authors
- McHugh, D., Durán, I., & Gil, J.
- Venue
- Nature Reviews Drug Discovery
- Published
- 2024-11-15
- Volume
- 24
- Issue
- 1
- Pages
- 57-71
- ISSN
- 1474-1776
- 1474-1784
- Cited by
- 197
- References
- 103
- Language
- en
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