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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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Self-citationHRasV12 induces apoptosis, not cellular senescence in mouse skeletal myoblasts
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Self-citationSenolytics improve muscle adaptation in old mice
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Anti-aging effect of TRF2 inhibition in skeletal myofibersPreprint
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Self-citationJames, E. L., Teh, M., Li, Y., Wagner-Bock, C., Al-Khateeb, Z. F. H., Karen‐Ng, L. P., Roberts, T., Synchyshyn, L., Lewis, A. L., O’Loghlen, A., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.30.609895
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Gene Expression Dynamics Underlying Muscle Aging in the Hawk Moth Manduca sexta
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Self-citationCharacterizing mitochondrial phenotypes and MERCS in aged human skeletal muscle myoblasts
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Regulation of Aging by the Epigenome
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“[180] In this study, the analysis of human skeletal muscle has revealed significant inverse associations between the enrichment of senescence-associated secretory phenotype (SASP)-related pathways and leg strength in older compared to younger skeletal muscle.”
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InfluentialCooper, R., Hurst, C., Syddall, H. E., Atkinson, H., Bunn, J. G., Carpinelli, D., Granic, A., Hillman, S. J., Lewis, E. G., McDonald, C., et al. (2026) · GeroScience · doi:10.1007/s11357-026-02341-5
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“Notably, D + Q treatment in old mice reverses the up‐regulation of chemokines and cytokines pathways specific to old muscle (X. Zhang et al. 2022).”
Senotherapeutics for Knee Osteoarthritis
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The senescence–immune axis as a target for combining immunotherapy and senotherapy
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Phase-transition failure in aged skeletal muscle regeneration
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“Indeed, aged muscle shows DNA damage, mitochondrial dysfunction, and SASP-like output coexisting in fibers without cell-cycle arrest, together with muscle pathology and functional decline (Zhang et al. 2022).”
The ageing microenvironment in sarcopenia: early alterations and targeted therapeutic strategies
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“Therefore, upregulation of p16 INK4a and p21 CIP1 should be interpreted as an early signal of senescence-like alterations in speci fi c cell populations, rather than evidence of terminal cellular senescence in all myo fi bers (66).”
Strengthening muscle for healthy ageing: innovative treatments for sarcopenia
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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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