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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 aging12,13.”
From Spatial mapping of cellular senescence: emerging challenges and opportunities (2023) · cites this paper as [12]
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“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]
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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 23
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 27
“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
“…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 23
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
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 21
“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 17
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
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 19
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
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
“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
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 17
“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 18
“(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
Contreras, O., & Harvey, R. P. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1017660 · Cited by 13
“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
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
“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 13
“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 13
“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
“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 14
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 18
Self-citationZampieri, S., Narici, M. V., Gargiulo, P., & Carraro, U. (2023) · European Journal of Translational Myology · doi:10.4081/ejtm.2023.11247 · Cited by 13
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
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
Hung, Y., Sato, A., Takino, Y., Ishigami, A., & Machida, S. (2024) · GeroScience · doi:10.1007/s11357-024-01338-2 · Cited by 13
“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 11
Oyabu, M., Ohira, Y., Fujita, M., Yoshioka, K., Kawaguchi, R., Kubo, A., Hatazawa, Y., Yukitoshi, H., Quiroga, H. P. O., Horii, N., et al. (2025) · iScience · doi:10.1016/j.isci.2025.112144 · Cited by 10
“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 11
Shen, Z.-L., Chen, W., Liu, Z., Yu, D., Chen, W., Zang, W., Zhang, P., Yan, X., & Yu, Z. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112244 · Cited by 9
Human myofiber‐enriched aging‐induced lncRNA FRAIL1 promotes loss of skeletal muscle function
Miller, M. J., Gries, K. J., Marcotte, G. R., Ryan, Z., Strub, M. D., Kunz, H., Arendt, B. K., Dasari, S., Ebert, S. M., Adams, C. M., et al. (2024) · Aging Cell · doi:10.1111/acel.14097 · Cited by 8
“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
“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 10
“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
Xiong, J., Guo, Q., & Luo, X. (2025) · Frontiers of Medicine · doi:10.1007/s11684-025-1125-7 · Cited by 10
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 9
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 10
“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
“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
Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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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