Strategies for targeting senescent cells in human disease
Open accessAbstract
Cellular senescence represents a distinct cell fate characterized by replicative arrest in response to a host of extrinsic and intrinsic stresses. Senescence provides programming during development and wound healing, while limiting tumorigenesis. However, pathologic accumulation of senescent cells is implicated in a range of diseases and age-associated morbidities across organ systems. Senescent cells produce distinct paracrine and endocrine signals, causing local tissue dysfunction and exerting deleterious systemic effects. Senescent cell removal by apoptosis-inducing "senolytic" agents or therapies that inhibit the senescence-associated secretory phenotype, SASP inhibitors, have demonstrated benefit in both pre-clinical and clinical models of geriatric decline and chronic diseases, suggesting senescent cells represent a pharmacologic target for alleviating effects of fundamental aging processes. However, senescent cell populations are heterogeneous in form, function, tissue distribution, and even differ among species, possibly explaining issues of bench-to-bedside translation in current clinical trials. Here, we review features of senescent cells and strategies for targeting them, including immunologic approaches, as well as key intracellular signaling pathways. Additionally, we survey current senolytic therapies in human trials. Collectively, there is demand for research to develop targeted senotherapeutics that address the needs of the aging and chronically-ill.
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Senescent cells with a proapoptotic SASP survive a cytotoxic environment by upregulating pro-survival and antiapoptotic pathways such as SRC kinases, PI3K-AKT, HSP, serpines, mitochondrial pathways, and BCL-2-related proteins.
“Through upregulation of pro-survival and antiapoptotic pathways such as SRC kinases, the PI3K-AKT signaling pathway, heat shock protein (HSP) pathways, serpines, mitochondrial pathways or apoptosis regulator BCL-2-related proteins, those senescent cells with a proapoptotic SASP can survive, despite the cytotoxic microenvironment they create6,7,14,34,35,54–58.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [58]
The Cellular Senescence section says senescent cells avoid apoptosis by upregulating pro-survival pathways. The Modulating SCAPs section discusses Src kinase inhibition, PI3K/Akt, BCL-2-family proteins, mitochondrial apoptotic signaling and HSP90. The cited copy does not identify serpines as one of these pathways or specifically describe survival of cells with a proapoptotic SASP in a cytotoxic microenvironment; the SASP section instead discusses inflammatory effects and resistance to immune-mediated clearance. Page numbers are unavailable in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSenescent cells in each pathological condition enhance the SASP autocrine loop.
“but also enhance SASP autocrine loop, as found in multiple previous studies,124,125,126,127”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [127]
The Senescence-Associated Secretory Phenotype section says the SASP reinforces senescence through autocrine signaling and describes a feed-forward cycle involving increased SASP signals. It does not establish that senescent cells enhance this loop in every pathological condition; the section also notes that SASP effects vary by context. Page numbers were not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredPersistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis.
“Persistent senescent cells are known to exert detrimental long-term effects on organ function and can promote tumorigenesis33,96,112,177,178.”
From COVID-19 and cellular senescence (2023) · cites this paper as [96]
Senescent cells are associated with aging and pathological conditions and can be targeted to slow the aging process.
“Senescent cells are highly associated with aging and pathological conditions and could be targeted to slow the aging process.”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
At the transcript level, p16 and p21 are the two most commonly used markers for senescent cells.
“At the transcript level, p16 and p21 are the two most commonly used markers for senescent cells [3,16].”
From The heterogeneity of cellular senescence: insights at the single-cell level (2023) · cites this paper as [3]
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DNA Ligase IV-Dependent NHEJ of Deprotected Mammalian Telomeres in G1 and G2
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Cardiac glycosides are broad-spectrum senolytics
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Transcriptome signature of cellular senescence
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Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice
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Self-citationRole of immune cells in the removal of deleterious senescent cells
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A versatile drug delivery system targeting senescent cells
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Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span
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Senolytics reduce coronavirus-related mortality in old mice
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Cellular Senescence in the Kidney
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Influence of immune aging on vaccine responses
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Cellular Senescence in Neurodegenerative Diseases
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The Dual Role of Cellular Senescence in Developing Tumors and Their Response to Cancer Therapy
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Morphologic changes accompanying senescence of cultured human diploid cells
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Essential role for premature senescence of myofibroblasts in myocardial fibrosis
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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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Generation of a p16 Reporter Mouse and Its Use to Characterize and Target p16high Cells In Vivo
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Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
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Chemical screening identifies ATM as a target for alleviating senescence
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Detection of Senescence-Associated Heterochromatin Foci (SAHF)
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SIRT1 suppresses the senescence-associated secretory phenotype through epigenetic gene regulation
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Paracrine cellular senescence exacerbates biliary injury and impairs regeneration
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A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence
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Senescent fibroblasts resist apoptosis by downregulating caspase-3.
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Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy
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The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype
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Notch Signaling Mediates Secondary Senescence
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Self-citationHeterogeneity of Aging: Individual Risk Factors, Mechanisms, Patient Priorities, and Outcomes
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Self-citationCurcumin and o-Vanillin Exhibit Evidence of Senolytic Activity in Human IVD Cells In Vitro
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Self-citationSnapShot: Cellular Senescence Pathways
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Self-citationCell senescence contributes to tissue regeneration in zebrafish
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Conserved and novel functions of programmed cellular senescence during vertebrate development
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Cellular Senescence and the Immune System in Cancer
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Senescent Keratinocytes Die by Autophagic Programmed Cell Death
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CCN1-Induced Cellular Senescence Promotes Heart Regeneration
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C/EBPγ Suppresses Senescence and Inflammatory Gene Expression by Heterodimerizing with C/EBPβ
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Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction
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Self-citationCellular senescence in gastrointestinal diseases: from pathogenesis to therapeutics
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Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice
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Self-citationSenescence-Associated Metabolomic Phenotype in Primary and iPSC-Derived Mesenchymal Stromal Cells
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Cellular Senescence in the Lung: The Central Role of Senescent Epithelial Cells
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Musculoskeletal senescence: a moving target ready to be eliminated
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Transcriptome signature of cellular senescence
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Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression
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Transplanting cells from old but not young donors causes physical dysfunction in older recipients
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Self-citationDynamic Modeling of the Interaction Between Autophagy and Apoptosis in Mammalian Cells
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Epigenetic Basis of Cellular Senescence and Its Implications in Aging
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Apoptosis during embryonic tissue remodeling is accompanied by cell senescence
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Self-citationSenescence and the Aging Immune System as Major Drivers of Chronic Kidney Disease
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Induction and Validation of Cellular Senescence in Primary Human Cells
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Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria
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Insights into replicative senescence of human testicular peritubular cells
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Senolytics alleviate the degenerative disorders of temporomandibular joint in old age
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Self-citationThe mTORC1-autophagy pathway is a target for senescent cell elimination
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Cellular senescence and liver disease: Mechanisms and therapeutic strategies
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Cellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,105 · see citing works
Self-citationCAR T therapy beyond cancer: the evolution of a living drug
Baker, D. J., Arany, Z., Baur, J. A., Epstein, J. A., & June, C. (2023) · Nature · doi:10.1038/s41586-023-06243-w · Cited by 467 · see citing works
“Identifying senoantigens will be both difficult and important as senescent cells are notoriously heterogeneous 58,59 .”
Mechanisms and consequences of endothelial cell senescence
Bloom, S. I., Islam, M. T., Lesniewski, L. A., & Donato, A. J. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00739-0 · Cited by 512 · see citing works
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SenNet recommendations for detecting senescent cells in different tissues
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Metabolic changes in aging humans: current evidence and therapeutic strategies
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“Senescent cells have emerged as an attractive therapeutic target in the prevention and treatment of age-related and metabolic disease (119).”
BackgroundMolecular mechanisms of aging and anti-aging strategies
Li, Y., Tian, X., Luo, J., Bao, T., Wang, S., & Wu, X. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01663-1 · Cited by 333 · see citing works
“In addition, DNA damage, telomere depletion, epigenetic changes, protein damage, lipid damage, dysfunction of mitochondria and lysosomes, ROS and inflammation are all important inducers of cell senescence [199].”
BackgroundThe heterogeneity of cellular senescence: insights at the single-cell level
Cohn, R. L., Gasek, N. S., Kuchel, G. A., & Xu, M. (2023) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.04.011 · Cited by 294 · see citing works
Self-citationHallmarks of cardiovascular ageing
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Senescent alveolar macrophages promote early-stage lung tumorigenesis
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NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates
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PDK4-dependent hypercatabolism and lactate production of senescent cells promotes cancer malignancy
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“Cellular senescence represents a primary risk factor for initiation and development of age-related conditions, such as cancers, diabetes, cardiovascular disorders and neurodegenerative diseases 4,54 .”
Lipids and lipid metabolism in cellular senescence: Emerging targets for age-related diseases
Zeng, Q., Gong, Y., Zhu, N., Shi, Y., Zhang, C., & Li, Q. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102294 · Cited by 188 · see citing works
The role of p21 in cellular senescence and aging-related diseases
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“However, a universal marker for identifying senescent cells remains elusive. p21 has emerged as a promising candidate for this purpose (Gasek et al., 2021; Gorgoulis et al., 2019).”
Targeting p21Cip1 highly expressing cells in adipose tissue alleviates insulin resistance in obesity
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Self-citationMechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders
Huang, Y., Liu, B., Sinha, S. C., Amin, S., & Gan, L. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00672-x · Cited by 164 · see citing works
“Another characteristic of senescent cells is the resistance to programmed cell death through senescent cell anti-apoptotic pathways (SCAPs) [73, 74], which necessitates active clearance of senescent cells by the immune system.”
BackgroundThe Senescence Markers p16INK4A, p14ARF/p19ARF, and p21 in Organ Development and Homeostasis
Wagner, K., & Wagner, N. (2022) · Cells · doi:10.3390/cells11121966 · Cited by 156 · see citing works
“Also in the p21– ATTAC model, the clearance of p21- but not p16INK4A-positive senescent cells prevented radiation-induced osteoporosis and bone marrow adiposity [226], supporting the view that p16INK4A- and p21-dependent senescence comprise different and independent pathways [3,5,22,273].”
BackgroundCOVID-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 · see citing works
Self-citationMolecular Characterization of Acquired Resistance to KRASG12C–EGFR Inhibition in Colorectal Cancer
Yaeger, R., Mezzadra, R., Sinopoli, J., Bian, Y., Marasco, M., Kaplun, E., Gao, Y., Zhao, H., Paula, A. D. C., Zhu, Y., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-22-0405 · Cited by 144 · see citing works
Cellular senescence in brain aging and neurodegeneration
dos Santos, L. M., Trombetta-Lima, M., Eggen, B. J. L., & Demaria, M. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.102141 · Cited by 158 · see citing works
“Nevertheless, their effectiveness and safety require thorough evaluation in pre-clinical models and clinical trials (Gasek et al., 2021) (Table 1).”
BackgroundSingle-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
Tao, W., Yu, Z., & Han, J.-D. J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.03.009 · Cited by 147 · see citing works
Emerging role of senescent microglia in brain aging-related neurodegenerative diseases
Rim, C., You, M., Nahm, M., & Kwon, M. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00402-3 · Cited by 147 · see citing works
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 135 · see citing works
“The high potency of oleandrin could potentially bene fi t senolytic therapies administered locally on the site of damage; clinical trials are currently assessing such local administration of senolytics for osteoarthritis 10,77 .”
Hou, J., Chen, K., He, C., Li, X., Huang, M., Jiang, Y.-Z., Jiao, Y.-R., Xiao, Q., He, W., Liu, L., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00694-0 · Cited by 136 · see citing works
“Elimination of senescent cells 8,43,44 has emerged as a plausible therapeutic approach for preventing, delaying or alleviating multiple diseases and age-related dysfunction 3,45–49 .”
Flavonoids—Natural Gifts to Promote Health and Longevity
Fan, X., Fan, Z., Yang, Z., Huang, T., Tong, Y., Yang, D., Mao, X., & Yang, M. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042176 · Cited by 127 · see citing works
““Senolytic” compounds an k ll senescen cells [75].”
BackgroundInfluentialLocal H2 release remodels senescence microenvironment for improved repair of injured bone
Chen, S., Yu, Y., Xie, S., Liang, D., Shi, W. K., Chen, S., Li, G., Tang, W., Liu, C., & He, Q. (2023) · Nature Communications · doi:10.1038/s41467-023-43618-z · Cited by 126 · see citing works
“The past decade has witnessed an explosion of understanding cellular senescence in aged organisms and the relationship between cellular senescence and various aging-related pathologies 1,35 .”
Major depression and the biological hallmarks of aging
Lorenzo, E. C., Kuchel, G. A., Kuo, C., Moffitt, T. E., & Diniz, B. S. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101805 · Cited by 128 · see citing works
“dase, and lipofuscin in the cytoplasm (Gasek et al., 2021; Hernandez-Segura et al., 2018; Ogrodnik, 2021).”
BackgroundSelf-citationThe Role of Oxidative Stress in Tumorigenesis and Progression
Li, K., Deng, Z., Lei, C., Ding, X., Li, J., & Wang, C. (2024) · Cells · doi:10.3390/cells13050441 · Cited by 126 · see citing works
“Then, senescent cells are cleared via apoptosis or phagocytosis mediated by SASP and the innate immune system, such as NK cells [124,125].”
BackgroundMacrophage senescence in health and diseases
Wang, L., Hong, W., Zhu, H., He, Q., Yang, B., Wang, J., & Weng, Q. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.01.008 · Cited by 115 · see citing works
“Generally, some therapeutic methods to avert the morbigenous effects of senescence are senolytics and senomorphics 2,178,179 .”
BackgroundSenescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis
Schloesser, D., Lindenthal, L., Sauer, J., Chung, K., Chavakis, T., Griesser, E., Baskaran, P., Maier-Habelsberger, U., Fundel‐Clemens, K., Schlotthauer, I., et al. (2022) · The Journal of Cell Biology · doi:10.1083/jcb.202207097 · Cited by 113 · see citing works
“Genetic and pharmacological approaches in modeled in vivo systems to reduce the number of senescent cells in aging have shown positive effects on lifespan and “ healthspan ” (Childs et al., 2017; Gasek et al., 2021).”
Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies
D’Ambrosio, M., & Gil, J. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.05.010 · Cited by 106 · see citing works
Role of cellular senescence in inflammation and regeneration
Saito, Y., Yamamoto, S., & Chikenji, T. (2024) · Inflammation and Regeneration · doi:10.1186/s41232-024-00342-5 · Cited by 117 · see citing works
Targeting senescent cells for a healthier longevity: the roadmap for an era of global aging
Sun, Y., Li, Q., & Kirkland, J. L. (2022) · Life Medicine · doi:10.1093/lifemedi/lnac030 · Cited by 105 · see citing works
Self-citationCellular Senescence and Ageing: Mechanisms and Interventions
Mylonas, A., & O’Loghlen, A. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.866718 · Cited by 111 · see citing works
“Furthermore, there is a group of drugs called “senomorphics” that act by targeting SASP factors, neutralising or inhibiting their actions (Gasek et al., 2021).”
BackgroundPotential Role of Quercetin Glycosides as Anti-Atherosclerotic Food-Derived Factors for Human Health
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Exosomal miR-302b rejuvenates aging mice by reversing the proliferative arrest of senescent cells
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Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota
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Senescence of alveolar epithelial progenitor cells: a critical driver of lung fibrosis
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Pun, F. W., Leung, G. H. D., Leung, H.-W., Liu, B. H. M., Long, X., Ozerov, I. V., Wang, J., Ren, F., Aliper, A. M., Izumchenko, E., et al. (2022) · Aging · doi:10.18632/aging.203960 · Cited by 86 · see citing works
“For example, cellular senescence has been associated with pathologies such as cancer, type 2 diabetes, and atherosclerosis [12], as well as pulmonary, neurological, renal, hepatic, infectious, musculoskeletal, and endocrine diseases [13].”
Backgroundp53/MDM2 signaling pathway in aging, senescence and tumorigenesis
Huang, Y., Che, X., Wang, P., & Qu, X. (2024) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2024.05.001 · Cited by 92 · see citing works
Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology
Aguado, J., Amarilla, A. A., Taherian Fard, A., Albornoz, E. A., Tyshkovskiy, A., Schwabenland, M., Chaggar, H. K., Modhiran, N., Gómez-Inclán, C., Javed, I., et al. (2023) · Nature Aging · doi:10.1038/s43587-023-00519-6 · Cited by 80 · see citing works
Jang, D. S., Shin, J., Shim, E., Ohtani, N., & Jeon, O. H. (2024) · Aging Cell · doi:10.1111/acel.14315 · Cited by 84 · see citing works
“Developing senotherapeutic drugs that selectively inhibit SASPs or prevent the triggers of cellular senescence may offer a more nuanced approach to extending the health span and minimizing the side effects (Gasek et al., 2021 ; Zhang, Pitcher, et al., 2023 ) ( Figure 1 ).”
BackgroundSharma, R. (2022) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-021-09903-3 · Cited by 80 · see citing works
“burden with age disrupts tissue structure and function and is emerging as a critical factor for increased risk of disease and mortality in the elderly [22, 23].”
BackgroundSalerno, N., Marino, F., Scalise, M., Salerno, L., Molinaro, C., Filardo, A., Chiefalo, A., Panuccio, G., Angelis, A. D., Urbanek, K., et al. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111740 · Cited by 78 · see citing works
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 · see citing works
The pancreatic β-cell in ageing: Implications in age-related diabetes
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“used in mouse models can be efficiently implemented in humans (Gasek et al., 2021).”
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“21,37,38 Because BCL-X L /BCL-2 are key anti-apoptotic proteins in many types of senescent cells, we hypothesized that 753B may eliminate senescent cells before escaping from senescence.”
BackgroundMuthamil, S., Kim, H., Jang, H., Lyu, J., Shin, U. C., Go, Y., Park, S., Lee, H. G., & Park, J. H. (2024) · Advanced Biology · doi:10.1002/adbi.202400079 · Cited by 79 · see citing works
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Targeting senescent cells with NKG2D-CAR T cells
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“The SASP factors produced by senescent joint cells include pro-inflammatory cytokines IL-1, IL-6, IL-8, TNFα, chemokines (C–C motif ligand 2, CCL2, CCL4), proteases (MMP-1, 3, 12, 13, and ADAMTS), growth factors, smallmolecule metabolites [140, 143, 144], and microRNAs.”
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Cellular senescence in Alzheimer’s disease: from physiology to pathology
Zhu, J., Wu, C., & Yang, L. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00447-4 · Cited by 70 · see citing works
Targeting aging and age-related diseases with vaccines
Wu, R., Sun, F., Zhang, W., Ren, J., & Liu, G.-H. (2024) · Nature Aging · doi:10.1038/s43587-024-00597-0 · Cited by 66 · see citing works
“Additionally, it is important to consider the limitations of immune aging on vaccine response, especially in older adults 190 .”
Tackling the glial scar in spinal cord regeneration: new discoveries and future directions
Shafqat, A., Albalkhi, I., Magableh, H. M., Saleh, T., AlKattan, K. M., & Yaqinuddin, A. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1180825 · Cited by 67 · see citing works
“Cellular senescence, a state of irreversible cell cycle arrest accompanied by characteristic molecular, morphological, and functional alterations, has emerged as a key therapeutic target in aging and chronic diseases, including neurodegenerative diseases (Kirkland et al., 2017; Kirkland and Tchkonia, 2017, 2020; Herna…”
BackgroundStress-induced β cell early senescence confers protection against type 1 diabetes
Lee, H., Sahin, G. S., Chen, C.-W., Sonthalia, S., Cañas, S. M., Oktay, H. Z., Duckworth, A. T., Brawerman, G. M., Thompson, P. J., Hatzoglou, M., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.10.014 · Cited by 65 · see citing works
Zorina, A. I., Zorin, V. L., Kudlay, D. A., & Kopnin, P. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126655 · Cited by 66 · see citing works
Biomaterial design for regenerating aged bone: materiobiological advances and paradigmatic shifts
Dai, K., Geng, Z., Zhang, W., Xue, W., Wang, J., Nie, G., & Liu, C. (2024) · National Science Review · doi:10.1093/nsr/nwae076 · Cited by 63 · see citing works
“Strategies to eliminate senescent cells have been employed to alleviate age-related symptoms [86 ].”
MethodPancreatic Cancer and Cellular Senescence: Tumor Microenvironment under the Spotlight
Cortesi, M., Zanoni, M., Pirini, F., Tumedei, M. M., Ravaioli, S., Rapposelli, I. G., Frassineti, G. L., & Bravaccini, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms23010254 · Cited by 61 · see citing works
“Additionally, SASP signaling has been shown to affect the regenerative potential of non-senescent cells [131].”
BackgroundAgeing, cellular senescence and chronic kidney disease: experimental evidence
Tan, H., Xu, J., & Liu, Y. (2022) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000782 · Cited by 61 · see citing works
“right © 2022 Wolters Kluwe Cellular senescence plays a critical role in regulating diverse biological events under different circumstances [6,7].”
BackgroundLathigara, D., Kaushal, D., & Wilson, R. B. (2023) · Metabolites · doi:10.3390/metabo13050675 · Cited by 62 · see citing works
“This elicits an immune response via damage-associated molecular patterns (DAMPS), Toll-like receptors (TLR-4) and chemokines [66].”
BackgroundSenolysis Enabled by Senescent Cell‐Sensitive Bioorthogonal Tetrazine Ligation
Chang, M., Dong, Y., Xu, H., Cruickshank‐Taylor, A. B., Kozora, J. S., Behpour, B., & Wang, W. (2024) · Angewandte Chemie International Edition · doi:10.1002/anie.202315425 · Cited by 60 · see citing works
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Targeting Cellular Senescence for Healthy Aging: Advances in Senolytics and Senomorphics
Alum, E. U., Izah, S. C., Uti, D. E., Ugwu, O. P.-C., Betiang, P. A., Basajja, M., & Ejemot-Nwadiaro, R. I. (2025) · Drug Design Development and Therapy · doi:10.2147/dddt.s543211 · Cited by 59 · see citing works
“140”
Ribierre, T., Bacq, A., Donneger, F., Doladilhe, M., Maletic, M., Roussel, D., Roux, I. L., Chassoux, F., Devaux, B. C., Adle‐Biassette, H., et al. (2024) · Nature Neuroscience · doi:10.1038/s41593-024-01634-2 · Cited by 62 · see citing works
“Altogether, these findings support the rationale of using the combination of dasat-inib and quercetin (DQ cocktail), which has been shown to decrease the senescent cell burden and the SASP in vitro, in mouse models of age-related diseases 32,35 and glioblastoma 36 and in human tissues 29,32,37,38 .”
The Naked Mole-Rat as a Model for Healthy Aging
Oka, K., Yamakawa, M., Kawamura, Y., Kutsukake, N., & Miura, K. (2022) · Annual Review of Animal Biosciences · doi:10.1146/annurev-animal-050322-074744 · Cited by 57 · see citing works
Liu, Y., Dou, Y., Sun, X., & Yang, Q. (2024) · Journal of Orthopaedic Translation · doi:10.1016/j.jot.2024.02.003 · Cited by 57 · see citing works
“Cellular senescence denotes the enduring arrest of the cell cycle subsequent to exposure to various stresses, concomitantly giving rise to a secretory ensemble termed the “ senescence-related secretory phenotype" (SASP) [11].”
BackgroundKandhaya‐Pillai, R., Miró‐Mur, F., Alijotas‐Reig, J., Tchkonia, T., Schwartz, S., Kirkland, J. L., & Oshima, J. (2023) · Aging · doi:10.18632/aging.204743 · Cited by 53 · see citing works
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“This, coupled with the dysfunction of the immune system in eliminating SCs and reinstating the balance between proliferative and SCs, is influenced by immunosenescence [23,24].”
BackgroundInfluentialLuo, 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 56 · see citing works
“162,163 Multiple pro-survival proteins and pathways have been explored as potential targets of senolytics (Table 2), most of which have shown promising results in preclinical trials.”
Elevated skin senescence in young mice causes delayed wound healing
Thanapaul, R. J. R. S., Shvedova, M., Shin, G. H., Crouch, J. D., & Roh, D. S. (2022) · GeroScience · doi:10.1007/s11357-022-00551-1 · Cited by 52 · see citing works
“The accumulation of pathologic senescent cells has been linked to a variety of diseases and age-related morbidity in various organ systems [19].”
BackgroundRole of Senescent Cells in Cutaneous Wound Healing
Andrade, A. M., Sun, M., Gasek, N. S., Hargis, G. R., Sharafieh, R., & Xu, M. (2022) · Biology · doi:10.3390/biology11121731 · Cited by 51 · see citing works
“In particular, chronologically aged and dysfunctional tissues are associated with the accumulation of senescent cells [2].”
BackgroundInfluentialSelf-citationCampellone, K. G., Lebek, N. M., & King, V. L. (2023) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2023.151301 · Cited by 50 · see citing works
Cellular Senescence as a Targetable Risk Factor for Cardiovascular Diseases
Kumar, M., Yan, P., Kuchel, G. A., & Xu, M. (2024) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2023.12.003 · Cited by 56 · see citing works
Self-citationNew insights into the role of cellular senescence and chronic wounds
Yang, H., Zhang, X., & Bo, X. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1400462 · Cited by 51 · see citing works
Emerging rejuvenation strategies—Reducing the biological age
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“…blood components Low DNAm age (a) (b) Differential damage clearance High biological age Low biological age and cardiovascular systems, and reduce the age- related mortality pertinent to coronavirus in mouse models (Camell et al., 2021; Gasek et al., 2021; Xu et al., 2018; Zhu et al., 2015).”
BackgroundTargeting cellular senescence as a novel treatment for osteoarthritis
Astrike‐Davis, E. M., Coryell, P., & Loeser, R. F. (2022) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2022.102213 · Cited by 51 · see citing works
Pancreatic β-cell senescence in diabetes: mechanisms, markers and therapies
Cha, J., Aguayo‐Mazzucato, C., & Thompson, P. J. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1212716 · Cited by 51 · see citing works
“Senescent cells activate anti-apoptotic pathways to resist normal programmed death signals [reviewed in (27)].”
BackgroundBeltzig, L., Christmann, M., & Kaina, B. (2022) · Cells · doi:10.3390/cells11162588 · Cited by 49 · see citing works
“Additionally, cellular senescence (CSEN) is characterized by the senescence associated secretory phenotype (SASP) [5], i.e., they secrete several inflammatory components, causing Cells 2022, 11, 2588. https://doi.org/10.3390/cells11162588 https://www.mdpi.com/journal/cells chemotherapy side effects and local inflammat…”
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“In 60 human studies, patients with idiopathic pulmonary fibrosis, a senescence associated disease, 61 improved 6-minute walk distance, walking speed, chair rise ability and short physical 62 performance battery after 9 doses of oral DQ over 3 weeks [24].”
BackgroundCellular Senescence and Periodontitis: Mechanisms and Therapeutics
Chen, S., Zhou, D., Liu, O., Chen, H., Wang, Y., & Zhou, Y. (2022) · Biology · doi:10.3390/biology11101419 · Cited by 49 · see citing works
“Cellular senescence is a fundamental mechanism of aging, which contributes to various age-related conditions [23].”
BackgroundSubcellular structure, heterogeneity, and plasticity of senescent cells
Bitencourt, T. C., Vargas, J. E., Silva, A. O., Fraga, L. R., & Filippi‐Chiela, E. C. (2024) · Aging Cell · doi:10.1111/acel.14154 · Cited by 46 · see citing works
“Conversely, the accumulation or dysfunction of senescent cells (SnCs) has been linked to the progression of diseases and the decline of tissue function in age-related conditions (Adams et al., 2020; Gasek et al., 2021 ; He & Sharpless, 2017 ; Kirkland & Tchkonia, 2020; Koenig et al., 2022 ).”
BackgroundSelective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis
Admasu, T. D., Kim, K., Rae, M. J., Avelar, R. A., Gonciarz, R. L., Rebbaa, A., de Magalhães, J. P., Renslo, A. R., Stolzing, A., & Sharma, A. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112058 · Cited by 47 · see citing works
“17,18 Hence, more in-depth understanding of the molecular regulatory pathways of cellular senescence is still an ongoing endeavor.”
BackgroundCrosstalk between gut microbiota and cellular senescence: a vicious cycle leading to aging gut
Kawamoto, S., & Hara, E. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.12.004 · Cited by 47 · see citing works
Cell senescence in cardiometabolic diseases
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“This further leads to SASP ampli fi cation, creating an environment of chronic in fl ammation, driving a positive feed-back loop of senescent cell accumulation 18 .”
BackgroundLi, J., Wang, L., Luo, X., Xia, Y., Xie, Y., Liu, Y., & Tan, W. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.2c04223 · Cited by 47 · see citing works
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Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing
Gasek, N. S., Yan, P., Zhu, J., Purushothaman, K.-R., Kim, T., Wang, L., Wang, B., Flynn, W. F., Sun, M., Guo, C., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00755-4 · Cited by 43 · see citing works
“4a,b) and the transcriptomic signature (with elevated SASP in p21 high cells; Extended Data Fig.”
InfluentialSelf-citationTargeting Cellular Senescence for Age-Related Diseases: Path to Clinical Translation
Wyles, S. P., Tchkonia, T., & Kirkland, J. L. (2021) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000009669 · Cited by 42 · see citing works
Self-citationZheng, L., He, S., Wang, H., Li, J., Liu, Y., & Liu, S. (2024) · Aging and Disease · doi:10.14336/ad.2024.0206 · Cited by 44 · see citing works
Wang, J., Shao, F., Yu, Q., Ye, L., Wusiman, D., Wu, R., Tuo, Z., Wang, Z., Li, D., Cho, W. C. S., et al. (2025) · Research · doi:10.34133/research.0612 · Cited by 42 · see citing works
“These drugs achieve this by inducing apoptosis in senescent cells [ 388 , 389 ].”
Selective Elimination of Senescent Cancer Cells by Galacto-Modified PROTACs
Chang, M., Gao, F., Gnawali, G. R., Xu, H., Dong, Y., Meng, X., Li, W., Wang, Z., Lopez, B., Carew, J. S., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c00152 · Cited by 41 · see citing works
Recent Advances in Aging and Immunosenescence: Mechanisms and Therapeutic Strategies
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“On the other hand, given the notorious heterogeneity of SCs [140], universal senoantigens are unlikely to exist, and the number of identified anti-aging targets is very limited.”
Wong, G. C., & Chow, H. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220203 · Cited by 40 · see citing works
“Since then, multiple strategies have been identified, which can be classified into two major categories: senomorphics and senolytics [249].”
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- Authors
- Gasek, N. S., Kuchel, G. A., Kirkland, J. L., & Xu, M.
- Affiliations
- University of Connecticut (US)
- Mayo Clinic (US)
- Corresponding author
- Xu, Ming
- Venue
- Nature Aging
- Published
- 2021-10-07
- Volume
- 1
- Issue
- 10
- Pages
- 870-879
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC8612694
- OpenAlex
- W3202997660
- Cited by
- 501
- References
- 152
- Citations by year
- 2026: 78 · 2025: 120 · 2024: 141 · 2023: 95 · 2022: 63 · 2021: 4
- FWCI
- 10.10
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG063528,R33AG061456, R37AG013925, R01AG072301, P01AG062413, R21AG063528,R03AG072374,R01AG066679, R01AG068860)
- 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
- cellular senescence, senolytics, senescence-associated secretory phenotype, senolytic therapy, senotherapeutics, aging, age-related diseases, intracellular signaling, bench-to-bedside translation, chronic disease
- MeSH terms
- Senescence-Associated Secretory Phenotype, Aging, Cell Differentiation, Chronic Disease, Humans, Signal Transduction, Cellular Senescence
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