Characterization of cellular senescence in aging skeletal muscle
Open accessAbstract
Senescence is a cell fate that contributes to multiple aging-related pathologies. Despite profound age-associated changes in skeletal muscle (SkM), whether its constituent cells are prone to senesce has not been methodically examined. Herein, using single cell and bulk RNA-sequencing and complementary imaging methods on SkM of young and old mice, we demonstrate that a subpopulation of old fibroadipogenic progenitors highly expresses p16 Ink4a together with multiple senescence-related genes and, concomitantly, exhibits DNA damage and chromatin reorganization. Through analysis of isolated myofibers, we also detail a senescence phenotype within a subset of old cells, governed instead by p2 Cip1 . Administration of a senotherapeutic intervention to old mice countered age-related molecular and morphological changes and improved SkM strength. Finally, we found that the senescence phenotype is conserved in SkM from older humans. Collectively, our data provide compelling evidence for cellular senescence as a hallmark and potentially tractable mediator of SkM aging.
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Several studies have used single-cell technologies to successfully identify senescence-associated signatures in the context of aging.
“Several studies have used single-cell technologies to successfully identify senescence-associated signatures in the context of aging12,13.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [12]
γ-H2A.X is formed by post-translational modifications triggered by double-strand breaks, while 53BP1 is recruited to damage sites through RNA-mediated condensation.
“γ-H2A.X is formed by post-translational modifications triggered by DSBs, while 53BP1 is recruited to DSBs in response to damage undergoing RNA-mediated condensation21.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [21]
The Results section on p16-expressing FAPs describes γH2A.X-positive nuclei as a mark of DNA damage, and the Methods section describes staining for γH2A.X. Neither passage explains how γH2A.X forms. Searches for double-strand-break-triggered modification and RNA-mediated recruitment of 53BP1 found no passage addressing either mechanism. (LLM, conf=0.76)
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“During aging, the expression of p21 and p16 increases in mouse muscle tissues, and high expression of p21 is predominantly found in muscle fibres (36).”
Backgroundp21 induces a senescence program and skeletal muscle dysfunction
Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., Zeidler, J. D., Warner, G. M., McNinch, C., White, T. A., et al. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101652 · Cited by 90 · see citing works
“Moreover, we uncovered an inverse association between levels of p21 in skeletal muscle and measures of strength and function, that was conserved across species [7].”
BackgroundInfluentialSelf-citationLiu, B., Peng, Z., Zhang, H., Zhang, N., Liu, Z., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02284-z · Cited by 82 · see citing works
“Furthermore, senescent cells secrete pro-inflammatory cytokines, chemokines, and proteases, collectively termed the senescence-associated secretory phenotype (SASP) (9) tumor proliferative activity and the onset of senescence [117, 118].”
Fielding, R. A., Atkinson, E. J., Aversa, Z., White, T. A., Heeren, A. A., Achenbach, S. J., Mielke, M. M., Cummings, S. R., Pahor, M., Leeuwenburgh, C., et al. (2022) · GeroScience · doi:10.1007/s11357-022-00685-2 · Cited by 75 · see citing works
“Finally, we have recently identified distinct subpopulations of fibroadipogenic progenitors and postmitotic myofibers that are localized in aging skeletal muscle and express features of cellular senescence [33].”
BackgroundSelf-citationCalcium’s Role and Signaling in Aging Muscle, Cellular Senescence, and Mineral Interactions
Terrell, K., Choi, S., & Choi, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242317034 · Cited by 80 · see citing works
“Some studies on aged SkM have reported increased senescent markers, such as up-regulated gene and protein expressions of p16, p21, or p53 in various organisms, while others have shown no detection of p16 or SA-β -gal [60–63].”
BackgroundXiang, W., Zhang, T., Li, B., Li, S., Zhang, B., Fang, S., Chen, L., Gong, Y., Huang, B., Feng, D., et al. (2025) · Nature Aging · doi:10.1038/s43587-025-00907-0 · Cited by 79 · see citing works
“Recent data from high-throughput sequencing have identified a typical signature of cellular senescence in aging skeletal muscle 7–9 .”
Self-citationPetrocelli, J. J., McKenzie, A. I., de Hart, N. M. M. P., Reidy, P. T., Mahmassani, Z. S., Keeble, A. R., Kaput, K. L., Wahl, M., Rondina, M. T., Marcus, R. L., et al. (2023) · Aging Cell · doi:10.1111/acel.13936 · Cited by 71 · see citing works
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Therapeutic targeting of senescent cells in the CNS
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“…9 , AD-associated amyloid-β accumulation 45 , frailty 65 , osteoporosis 65 , vasomotor dysregulation 65,73 , hepatic steatosis 74 , insulin resistance 75 , pulmonary fibrosis 76 , adipose tissue inflammation 77 , intervertebral disc degeneration 78 and skeletal muscle debility 79 .”
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Telomeres, cellular senescence, and aging: past and future
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Self-citationMechanisms of Muscle Cells Alterations and Regeneration Decline During Aging.
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Self-citationRoadmap for alleviating the manifestations of ageing in the cardiovascular system
Liberale, L., Tual-Chalot, S., Sedej, S., Ministrini, S., Georgiopoulos, G., Grunewald, M., Bäck, M., Bochaton-Piallat, M.-L., Boon, R. A., Ramos, G. C., et al. (2025) · Nature Reviews Cardiology · doi:10.1038/s41569-025-01130-5 · Cited by 59 · see citing works
“This stress-induced senescence is not unique to cardiomyocytes and might affect other postmitotic cell types, such as skeletal muscle, neurons or osteocytes 66–68 .”
Self-citationTelomere function and regulation from mouse models to human ageing and disease
Jones-Weinert, C. W., Mainz, L., & Karlseder, J. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00800-5 · Cited by 57 · see citing works
“Moreover, age-dependent accumulation of telomeric DNA damage has been observed in terminally differentiated postmitotic tissues and non-dividing cells such as cardiomyocytes 27 , adipocytes 121 , neurons 235,236 , osteoclasts and osteo-cytes 124 , and skeletal muscle fibres 237 in mice.”
Age-associated inflammation and implications for skeletal muscle responses to exercise
Kunz, H. E., & Lanza, I. R. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112177 · Cited by 56 · see citing works
“nucleated fiber and improvements in grip strength (Zhang et al., 2022).”
BackgroundSelf-citationYang, L., Ng, Y. E., Sun, H., Li, Y., Chini, L., LeBrasseur, N. K., Chen, J., & Zhang, X. (2023) · BMC Biology · doi:10.1186/s12915-023-01728-6 · Cited by 52 · see citing works
“Moreover, scMayoMap was used in multiple different tissues, including mouse skeletal muscle [29], brain [30], and kidney [31], in datasets generated in our lab and provided perfect cell annotation accuracy.”
MethodSelf-citationJones, R. G., Dimet‐Wiley, A., Haghani, A., da Silva, F. M., Brightwell, C. R., Lim, S., Khadgi, S., Wen, Y., Dungan, C. M., Brooke, R. T., et al. (2022) · The Journal of Physiology · doi:10.1113/jp283836 · Cited by 47 · see citing works
Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions
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Macrophage Involvement in Aging-Associated Skeletal Muscle Regeneration
Cui, C., Ferrucci, L., & Gorospe, M. (2023) · Cells · doi:10.3390/cells12091214 · Cited by 47 · see citing works
“A recent study identified an increase in a p16+ FAP subpopulation in old skeletal muscle in mice and humans [20], suggesting that senescent FAPs accumulate during aging.”
BackgroundInfluentialBiomarkers of ageing of humans and non-human primates
Wu, Z., Qu, J. T., Zhang, W., Bao, Z., Bi, Y., Cai, J.-P., Cai, S.-Q., Cao, C.-M., Cao, F., Cao, Z., et al. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00883-8 · Cited by 49 · see citing works
“Caution is warranted as some biomarkers, such as SA-β-gal, may not accurately reflect the status of cell senescence in primate skeletal muscles 322 .”
Huang, Y., Wang, C., Cui, H., Sun, G., Qi, X., & Yao, X. (2025) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1590524 · Cited by 45 · see citing works
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
“In this Article, we showed that p21 high cells are distinct from p16 high cells in skin wounds, similar to other tissues 5,6,8 .”
Livshits, G., & Kalinkovich, A. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102267 · Cited by 42 · see citing works
Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues
Saul, D., Jurk, D., Doolittle, M. L., Kosinsky, R. L., Han, Y., Zhang, X., Franco, A. C., Kim, S. Y., Wyles, S. P., Prakash, Y. S., et al. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00601-2 · Cited by 45 · see citing works
“…on skeletal muscle, bone, and liver, as previous research had indicated age-dependent increases in senescence-associated markers and demonstrated the bene fi ts of eliminating senescent cells for the functional outcomes of these organs (Farr et al, 2017; Ogrodnik et al, 2017; Zhang et al, 2022).”
Self-citationZhang, X., Ng, Y. E., Chini, L., Heeren, A. A., White, T. A., Li, H., Huang, H., Doolittle, M. L., Khosla, S., & LeBrasseur, N. K. (2023) · Aging Cell · doi:10.1111/acel.14069 · Cited by 38 · see citing works
Self-citationMeng, F., He, J., Zhang, X., Lyu, W., Wei, R., Wang, S., Du, Z., Wang, H., Bi, J., Hua, X., et al. (2025) · Advanced Science · doi:10.1002/advs.202412747 · Cited by 38 · see citing works
Self-citationIL-23R is a senescence-linked circulating and tissue biomarker of aging
Carver, C. M., Rodriguez, S. L., Atkinson, E. J., Dosch, A. J., Asmussen, N. C., Gomez, P. T., Leitschuh, E. A., Espíndola‐Netto, J. M., Jeganathan, K. B., Whaley, M. G., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00752-7 · Cited by 39 · see citing works
Self-citationAdvancing biological understanding of cellular senescence with computational multiomics
Li, S., Agudelo Garcia, P. A., Aliferis, C., Becich, M. J., Calyeca, J., Cosgrove, B. D., Elisseeff, J., Farzad, N., Fertig, E. J., Glass, C., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02314-y · Cited by 40 · see citing works
Self-citationSenotherapeutic drug treatment ameliorates chemotherapy-induced cachexia
Englund, D. A., Jolliffe, A. M., Hanson, G. J., Aversa, Z., Zhang, X., Jiang, X., White, T. A., Zhang, L. J., Monroe, D. G., Robbins, P. D., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.169512 · Cited by 39 · see citing works
“Previous work has shown that treatment with senolytics can improve skeletal muscle strength, regeneration, and growth in old mice (32, 34, 39).”
BackgroundInfluentialSelf-citationImmunoengineering Biomaterials for Musculoskeletal Tissue Repair across Lifespan
Han, J., Rindone, A. N., & Elisseeff, J. H. (2024) · Advanced Materials · doi:10.1002/adma.202311646 · Cited by 35 · see citing works
Barbera, M. C., Guarrera, L., Cecconi, A. D. R., Cassanmagnago, G. A., Vallerga, A., Lunardi, M., Checchi, F., Rito, L. D., Romeo, M., Mapelli, S. N., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56918-3 · Cited by 34 · see citing works
“For the Zhang et al. dataset 15 , a standard UMAP representationwasused,basedonprincipalcomponentanalysis(PCA) without additional batch correction.”
InfluentialExploring cellular senescence in the musculoskeletal system: Any insights for biomarkers discovery?
Gerosa, L., Malvandi, A. M., Malavolta, M., Provinciali, M., & Lombardi, G. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101943 · Cited by 32 · see citing works
Senescent fibro-adipogenic progenitors are potential drivers of pathology in inclusion body myositis
Nelke, C., Schroeter, C. B., Theissen, L., Preuße, C., Pawlitzki, M., Räuber, S. J., Dobelmann, V., Cengiz, D., Kleefeld, F., Roos, A., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-023-02637-2 · Cited by 33 · see citing works
“This choice was motivated by several recent studies in murine and human tissues demonstrating that p21 governs a senescent program in skeletal muscle and serves as a marker for muscle cell senescence [12, 50, 64].”
BackgroundUnraveling aging from transcriptomics
Huang, Y., Zhu, S., Yao, S., Zhai, H., Liu, C., & Han, J. J. (2024) · Trends in Genetics · doi:10.1016/j.tig.2024.09.006 · Cited by 33 · see citing works
Current cutting-edge omics techniques on musculoskeletal tissues and diseases
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STING signaling in inflammaging: a new target against musculoskeletal diseases
Song, C., Hu, Z., Xu, D., Bian, H., Lv, J., Xuanxuan, Z., Zhang, Q., Su, L., Yin, H., Lu, T., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1227364 · Cited by 31 · see citing works
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Distinct secretomes in p16- and p21- positive senescent cells across tissues
Saul, D., Jurk, D., Doolittle, M. L., Kosinsky, R. L., Monroe, D. G., LeBrasseur, N. K., Robbins, P. D., Niedernhofer, L. J., Khosla, S., & Passos, J. F. (2023) · doi:10.1101/2023.12.05.569858 · Cited by 28 · see citing works
Self-citationLim, J., & Frontera, W. R. (2023) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2023.111559 · Cited by 27 · see citing works
Nolt, G. L., Keeble, A. R., Wen, Y., Strong, A. C., Thomas, N. T., Valentino, T. R., Brightwell, C. R., Murach, K. A., Patrizia, S., Weinstabl, H., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00976-2 · Cited by 27 · see citing works
“Removal of senescent cells using senolytics, such as the cocktail of dasatinib and quercetin (D + Q), augments regeneration, facilitates muscle hypertrophy, and improves physical and muscle function in aged mice [9, 10, 12–14].”
BackgroundYao, C., Sun, J., Luo, W., Chen, H., Chen, T., Chen, C., Zhang, B., & Zhang, Y. (2024) · Bone and Joint Research · doi:10.1302/2046-3758.132.bjr-2023-0146.r2 · Cited by 27 · see citing works
Cellular senescence and frailty: a comprehensive insight into the causal links
Marcozzi, S., Bigossi, G., Giuliani, M. E., Giacconi, R., Piacenza, F., Cardelli, M., Brunetti, D., Segala, A., Valerio, A., Nisoli, E., et al. (2023) · GeroScience · doi:10.1007/s11357-023-00960-w · Cited by 24 · see citing works
Ginkgolide B increases healthspan and lifespan of female mice
Lee, C., Wang, B. Y., Wong, S. H., Chen, Y., Cao, Q., Hsiao, A. W., Fung, S.-H., Chen, Y.-F., Wu, H.-H., Cheng, P.-Y., et al. (2025) · Nature Aging · doi:10.1038/s43587-024-00802-0 · Cited by 25 · see citing works
“Current senotherapeutics, such as dasatinib plus quercetin 80 , MSC-derived extracellular vesicles 60 and metformin 81 , cannot resolve sarcopenia, a condition critical to human healthspan 82 .”
Huang, N., Ge, M., Liu, X., Tian, X., Yin, P., Bao, Z., Cao, F., Shyh‐Chang, N., Dong, B., Dai, L., et al. (2024) · Life Medicine · doi:10.1093/lifemedi/lnaf001 · Cited by 24 · see citing works
Single-cell morphology encodes functional subtypes of senescence in aging human dermal fibroblasts
Kamat, P., Macaluso, N. C., Li, Y., Agrawal, A., Winston, A., Pan, L., Stewart, T., Starich, B., Milcik, N., Min, C., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads1875 · Cited by 24 · see citing works
New Horizons in cellular senescence for clinicians
Witham, M. D., Granic, A., Miwa, S., Passos, J. F., Richardson, G. D., & Sayer, A. A. (2023) · Age and Ageing · doi:10.1093/ageing/afad127 · Cited by 25 · see citing works
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Dungan, C. M., Wells, J. M., & Murach, K. A. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00553.2022 · Cited by 21 · see citing works
Propagation of senescent phenotypes by extracellular HMGB1 is dependent on its redox state
Shin, J.-W., Jang, D., Kim, S. Y., Lee, J., Gil, T., Shim, E., Kim, J. Y., Kim, H. S., Conboy, M. J., Conboy, I. M., et al. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156259 · Cited by 21 · see citing works
The roles of miRNAs in adult skeletal muscle satellite cells
Koopmans, P. J., Ismaeel, A., Goljanek‐Whysall, K., & Murach, K. A. (2023) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2023.10.403 · Cited by 22 · see citing works
Ectodysplasin A2 receptor signaling in skeletal muscle pathophysiology
Özen, S. D., & Kır, S. (2024) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2024.02.002 · Cited by 21 · see citing works
Molecular and Structural Alterations of Skeletal Muscle Tissue Nuclei during Aging
Cisterna, B., & Malatesta, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031833 · Cited by 21 · see citing works
“A subpopulation of myonuclei with a senescent phenotype has been identified [125] in isolated single myofibers from the extensor digitorum longus muscle of aged mice.”
BackgroundMethodBiomarkers of cellular senescence and major health outcomes in older adults
Cummings, S. R., Lui, L., Aversa, Z., Mau, T., Fielding, R. A., Atkinson, E. J., Patel, S., & LeBrasseur, N. K. (2024) · GeroScience · doi:10.1007/s11357-024-01474-9 · Cited by 22 · see citing works
“…research is needed to test this premise, the data from the current study complement mechanistic studies of senolytic and senomor-phic interventions in a wide range of diseases modeled in mice that demonstrate therapeutic benefit of clearance of senescent cells and suppression of the SASP [4–10].”
Self-citationMurray, K. O., Mahoney, S. A., Ludwig, K. R., Miyamoto-Ditmon, J., VanDongen, N. S., Banskota, N., Herman, A. B., Seals, D. R., Mankowski, R. T., Rossman, M. J., et al. (2025) · Aging Cell · doi:10.1111/acel.70114 · Cited by 19 · see citing works
Collao, N., D’Souza, D. M., Messeiller, L., Pilon, E., Lloyd, J. C., Larkin, J., Ngu, M., Cuillerier, A., Green, A. E., Menzies, K. J., et al. (2023) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13320 · Cited by 19 · see citing works
Ruff, Z. D. V., Miller, M. J., Moro, T., Reidy, P. T., Ebert, S. M., Volpi, E., Adams, C. M., & Rasmussen, B. B. (2025) · GeroScience · doi:10.1007/s11357-025-01564-2 · Cited by 19 · see citing works
“Furthermore, cellular senescence and the SASP have emerged as a hallmark of multiple aging-related pathologies, including sarcopenia [81, 82].”
Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease
Nicholson, T. A., Dhaliwal, A., Quinlan, J. I., Allen, S., Williams, F. R., Hazeldine, J., McGee, K. C., Sullivan, J., Breen, L., Elsharkawy, A. M., et al. (2024) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01287-y · Cited by 16 · see citing works
Fu, L., Wang, S., Zhang, N., Lin, Y., Zhang, S., Mao, Y., & Zhou, P. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.158540 · Cited by 17 · see citing works
Rehabilitation of Older Adults with Sarcopenia: From Cell to Functioning
Frontera, W. R. (2022) · Progress in Rehabilitation Medicine · doi:10.2490/prm.20220044 · Cited by 17 · see citing works
Han, J., Cherry, C., Mejías, J. C., Krishnan, K., Ruta, A., Maestas, D. R., Peña, A. N., Nguyen, H. H., Nagaraj, S., Yang, B., et al. (2024) · Advanced Materials · doi:10.1002/adma.202310476 · Cited by 17 · see citing works
Translatability of mouse muscle-aging for humans: the role of sex
de Jong, J. C. B. C., Caspers, M. P. M., Worms, N., Keijzer, N., Kleemann, R., Menke, A. L., Nieuwenhuizen, A. G., Keijer, J., Verschuren, L., & van den Hoek, A. M. (2024) · GeroScience · doi:10.1007/s11357-024-01082-7 · Cited by 17 · see citing works
“For example, cellular senescence, which is a state of irreversible growth arrest due to various aging-related stressors, has been shown to occur in aged skeletal muscle of both humans and mice [13].”
BackgroundA cellular identity crisis? Plasticity changes during aging and rejuvenationPreprint
Gorelov, R. A., & Hochedlinger, K. (2024) · Genes & Development · doi:10.1101/gad.351728.124 · Cited by 18 · see citing works
Physical training reduces cell senescence and associated insulin resistance in skeletal muscle
Podraza-Farhanieh, A., Spinelli, R., Zatterale, F., Nerstedt, A., Gogg, S., Blüher, M., & Smith, U. (2025) · Molecular Metabolism · doi:10.1016/j.molmet.2025.102130 · Cited by 16 · see citing works
“In SkM, accumulation of senescent cells affects both muscle fi bers and satellite cells [49].”
Exercise as a Therapy to Maintain Telomere Function and Prevent Cellular Senescence
Kim, J., Ahn, A., Ying, J. Y., Hickman, E., & Ludlow, A. T. (2023) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000324 · Cited by 17 · see citing works
“(57) demonstrated the presence of TERT transcript isoforms (via alternative RNA splicing (AS)) in normal fibroblasts, thus, challenging the common thought paradigm thatTERT is only regulated by transcription.”
BackgroundFibroblasts in heterotopic ossification: mechanisms and therapeutic targets
Li, J., Dang, Y.-M., Liu, M., Gao, L., & Lin, H. (2024) · International Journal of Biological Sciences · doi:10.7150/ijbs.102297 · Cited by 15 · see citing works
Contreras, O., & Harvey, R. P. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1017660 · Cited by 14 · see citing works
“Single cell cross-validation of the Enpp2-Lpar-Plpp axis in skeletal muscle cells We next aimed to validate our previous single-cell transcriptomics findings using three public scRNAseq datasets (McKellar et al., 2021; Yang et al., 2022; Zhang et al., 2022).”
MethodChambers, T. L., Wells, J. M., Koopmans, P. J., da Silva, F. M., Malik, Z. B., Greene, N. P., Filareto, A., Franti, M., Sini, P., Weinstabl, H., et al. (2025) · Aging Cell · doi:10.1111/acel.70068 · Cited by 14 · see citing works
Kim, S., Gu, B., So, C., Mantik, K. E. K., Jung, S.-H., Moon, S., Park, D., Kwak, H., Cho, J., Cho, E., et al. (2025) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-025-00731-9 · Cited by 14 · see citing works
“Clearing these cells can alleviate pathologies linked to aging [44, 45], and senolytic drugs such as dasatinib and quercetin (D + Q) have shown promise in enhancing physical function and muscle recovery in aged mice [17, 20, 46, 47].”
InfluentialKamal, M. J., Joanisse, S., & Parise, G. (2023) · GeroScience · doi:10.1007/s11357-023-00929-9 · Cited by 12 · see citing works
“Recent evidence implicates cellular senescence as a potential contributor to the decline in human skeletal muscle health during advanced age [38].”
Bi, W., Yang, M., Shi, M., Hou, M., Jiang, C. Q., Fan, G., & Guo, W. (2024) · Scientific Reports · doi:10.1038/s41598-024-69284-9 · Cited by 12 · see citing works
“Samples in each dataset were filtered based on original studies 16–19 , then merged using the “merge” function in the Seurat package, and the batch effect was removed using the “Harmony” method.”
BackgroundMethodResultInfluentialPCSK9 affects vascular senescence through the SIRT1 pathway
Wang, Y., Cao, S., Wang, Z., Li, C., Ye, J., Liu, Y., Jin, T., Zhou, Y., Su, W., & Zong, G. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112701 · Cited by 12 · see citing works
“Therefore, P53, p21, and p16 are expressed in senescent cells and are often used as senescence markers (Huang et al., 2022; Cohn et al., 2023; Zhang et al., 2022).”
Deciphering Osteosarcopenia through the hallmarks of aging
Franulic, F., Salech, F., Rivas, D., & Duque, G. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111997 · Cited by 13 · see citing works
Self-citationMitochondrial metabolism and epigenetic crosstalk drive SASP
Martini, H., Birch, J., Marques, F. M., Victorelli, S. G., Lagnado, A. B., Pirius, N., Franco, A. C., Lee, G., Han, Y., Rowsey, J. L., et al. (2026) · Nature · doi:10.1038/s41586-026-10791-2 · Cited by 11 · see citing works
Self-citationZampieri, S., Narici, M. V., Gargiulo, P., & Carraro, U. (2023) · European Journal of Translational Myology · doi:10.4081/ejtm.2023.11247 · Cited by 11 · see citing works
Multi-dimensional metabolomic remodeling under diverse muscle atrophic stimuli in vivo
Oyabu, M., Sato, T., Kawaguchi, R., Yoshioka, K., Ito, N., Eguchi, T., Gotoh, H., Yoshizawa, T., Ogawa, Y., Ono, Y., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116097 · Cited by 11 · see citing works
Gorelov, R. A., Weiner, A. I., Huebner, A. J., Yagi, M., Haghani, A., Brooke, R. T., Horvath, S., & Hochedlinger, K. (2024) · Stem Cell Reports · doi:10.1016/j.stemcr.2024.07.009 · Cited by 11 · see citing works
Hung, Y., Sato, A., Takino, Y., Ishigami, A., & Machida, S. (2024) · GeroScience · doi:10.1007/s11357-024-01338-2 · Cited by 10 · see citing works
“Zhang et al. [27] demonstrated that FAPs exhibit high cellular senescence among mitotically competent monocular cells (endothelial cells, macrophages, satellite cells, and FAPs) in aging skeletal muscle.”
Aging: A struggle for beneficial to overcome negative factors made by muscle and bone
Welc, S. S., Brotto, M., White, K. E., & Bonewald, L. F. (2025) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2025.112039 · Cited by 10 · see citing works
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“Indeed, we observed an increased number of central nuclei in myofibers in Dnmt3a-Tg muscle, which is also a hallmark of muscle degeneration with age, 45,73,74 suggesting that DNA methylation balance is important for maintaining muscle homeostasis.”
InfluentialWang, N., Zheng, A., Yan, Y., He, T., Wu, X., Xian, M., Luo, J., Li, C., Wei, J., Wang, Y., et al. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2025.07.004 · Cited by 10 · see citing works
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Human myofiber‐enriched aging‐induced lncRNA FRAIL1 promotes loss of skeletal muscle function
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“Kinase Inhibitor 1A ( Cdkn1a/p21 ), RUNX Family Transcription Factor 1 ( Runx1 ), Insulin-Like Growth Factor Binding Protein 7 ( Igfbp7 ), and CD55 (Avelar et al., 2020; Englund et al., 2023; Saul et al., 2022; Zhang et al., 2022) (Figure 5c,d).”
BackgroundSelf-citationRuple, B. A., Mattingly, M. L., Godwin, J. S., McIntosh, M. C., Kontos, N. J., Agyin-Birikorang, A., Michel, J. M., Plotkin, D. L., Chen, S., Ziegenfuss, T. N., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202302103rrr · Cited by 9 · see citing works
“Aging is positively 83 associated with senescent cell abundance in muscle tissue [24-26].”
BackgroundLiu, Z., Sun, C. J., Zhang, Z., Jiang, Y., & Zhao, C. (2025) · Biogerontology · doi:10.1007/s10522-025-10228-9 · Cited by 9 · see citing works
“As observed in cardiomyocytes (Anderson et al. 2019) and other post-mitotic tissues in mice (Fielder et al. 2020; X. Zhang et al. 2022), telomere-associated DNA damage occurs in a manner independent of telomere length.”
Cellular senescence in age-related musculoskeletal diseases
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Ageing of human myofibres in the Vastus Lateralis muscle: A narrative review
Granic, A., Simoes, D. C. M., Bowen, T. S., Almaghtuf, N., Richardson, G. D., & Sayer, A. A. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103022 · Cited by 8 · see citing works
Self-citationHabiballa, L., Hruby, A. J., Granic, A., Dodds, R. M., Hillman, S. J., Jurk, D., Passos, J. F., & Sayer, A. A. (2023) · GeroScience · doi:10.1007/s11357-023-00869-4 · Cited by 9 · see citing works
“First, only four senescence markers were used, and the study was unsuccessful to characterise the senescence burden with two other commonly used senescence markers, p21 and SA-β-Gal [30, 56].”
InfluentialSelf-citationGilad, N., Mohanam, M. P., Darlyuk‐Saadon, I., Heng, C. K. M., Plaschkes, I., Benyamini, H., Berezhnoy, N. V., & Engelberg, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031713 · Cited by 9 · see citing works
“Important in this regard is the study of Zhang et al., who found, through single cell RNA analysis, that p16 is expressed just in a subset of aged cells and that these particular cells possess damaged DNA [22].”
Background
- Authors
- Zhang, X., Habiballa, L., Aversa, Z., Ng, Y. E., Sakamoto, A. E., Englund, D. A., Pearsall, V. M., White, T. A., Robinson, M. M., Rivas, D. A., Dasari, S., Hruby, A. J., Lagnado, A. B., Jachim, S. K., Granic, A., Sayer, A. A., Jurk, D., Lanza, I. R., Khosla, S., Fielding, R. A., Nair, K. S., Schafer, M. J., Passos, J. F., & LeBrasseur, N. K.
- Affiliations
- Mayo Clinic (US)
- Oregon State University (US)
- Tufts University (US)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Corresponding author
- Passos, João F.
- LeBrasseur, Nathan K.
- ORCID
- Zhang, Xu
- Habiballa, Leena
- Ng, Yan Er
- Englund, Davis A.
- White, Thomas A.
- Robinson, Matthew M.
- Rivas, Donato A.
- Dasari, Surendra
- Hruby, Adam J.
- Lagnado, Anthony B.
- Jachim, Sarah K.
- Granic, Antoneta
- Sayer, Avan A.
- Jurk, Diana
- Lanza, Ian R.
- Khosla, Sundeep
- Fielding, Roger A.
- Nair, K. Sreekumaran
- Schafer, Marissa J.
- Passos, João F.
- LeBrasseur, Nathan K.
- Venue
- Nature Aging
- Published
- 2022-07-15
- Volume
- 2
- Issue
- 7
- Pages
- 601-615
- ISSN
- 2662-8465 (ISSN-L)
- PMC
- PMC9491365
- OpenAlex
- W4285490572
- Cited by
- 206
- References
- 64
- Citations by year
- 2026: 48 · 2025: 57 · 2024: 53 · 2023: 42 · 2022: 6
- FWCI
- 24.62
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Glenn Foundation for Medical Research
- Robert and Arlene Kogod Center on Aging Career Development Award
- NIHR Newcastle Biomedical Research Centre grant
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (T32 AG049672, P01 AG062413, 1P30AG031679, R00 AG058798, R01 AG068048, UG3CA 268103, R01 AG055529, R56 AG060907)
- U.S. Department of Agriculture
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, skeletal muscle aging, fibro-adipogenic progenitors, p16INK4a, p21, muscle fibers, DNA damage, chromatin reorganization, senotherapeutics, muscle strength, age-related decline, human skeletal muscle
- MeSH terms
- Aging, Animals, Humans, Phenotype, Cellular Senescence, Muscle, Skeletal, Cyclin-Dependent Kinase Inhibitor p16, Mice
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