Molecular aging and rejuvenation of human muscle stem cells
Open accessAbstract
Very little remains known about the regulation of human organ stem cells (in general, and during the aging process), and most previous data were collected in short-lived rodents. We examined whether stem cell aging in rodents could be extrapolated to genetically and environmentally variable humans. Our findings establish key evolutionarily conserved mechanisms of human stem cell aging. We find that satellite cells are maintained in aged human skeletal muscle, but fail to activate in response to muscle attrition, due to diminished activation of Notch compounded by elevated transforming growth factor beta (TGF-beta)/phospho Smad3 (pSmad3). Furthermore, this work reveals that mitogen-activated protein kinase (MAPK)/phosphate extracellular signal-regulated kinase (pERK) signalling declines in human muscle with age, and is important for activating Notch in human muscle stem cells. This molecular understanding, combined with data that human satellite cells remain intrinsically young, introduced novel therapeutic targets. Indeed, activation of MAPK/Notch restored 'youthful' myogenic responses to satellite cells from 70-year-old humans, rendering them similar to cells from 20-year-old humans. These findings strongly suggest that aging of human muscle maintenance and repair can be reversed by 'youthful' calibration of specific molecular pathways.
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Advancing age is associated with loss of skeletal muscle regenerative potential.
“Advancing age is associated with a loss of regenerative potential.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Carlson et al., 2009
The age-related loss of regenerative potential is partly due to reduced satellite cell content in old mice and humans but primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.
“This is partly due to reduced satellite cell content in old mice (20–24-months) (Brack et al., 2007; Chakkalakal et al., 2012) and humans (Carlson et al., 2009) but is primarily driven by impaired activation and proliferation in response to damage-inducing stimuli.”
From Skeletal muscle aging, cellular senescence, and senotherapeutics: current knowledge and future directions (2021) · cites this paper as Carlson et al., 2009
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References 28 · Cited by 245
- Authors
- Carlson, M. E., Suetta, C., Conboy, M. J., Aagaard, P., Mackey, A., Kjaer, M., & Conboy, I.
- Affiliations
- University of California, Berkeley (US)
- University of Copenhagen (DK)
- University of Southern Denmark (DK)
- Corresponding author
- Conboy, Irina
- Venue
- EMBO Molecular Medicine
- Published
- 2009-11-26
- Volume
- 1
- Issue
- 8-9
- Pages
- 381-391
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC2875071
- OpenAlex
- W2159524128
- Cited by
- 245
- References
- 28
- Citations by year
- 2026: 11 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 11 · 2021: 18 · 2020: 8 · 2019: 9 · 2018: 16 · 2017: 12 · 2016: 24 · 2015: 18 · 2014: 19 · 2013: 25 · 2012: 20
- FWCI
- 7.37
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Funders
- Glenn Research Foundation
- CIRM
- Danish National Research Council
- Topics
- 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
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- stem cell aging, muscle stem cells, satellite cells, skeletal muscle aging, Notch signaling, ERK signaling, muscle regeneration, rejuvenation, myogenesis
- MeSH terms
- Adult, Aged, Aging, Cells, Cultured, Humans, Male, Rejuvenation, Transforming Growth Factor beta, Cellular Senescence, Muscle, Skeletal, Mitogen-Activated Protein Kinases, Myoblasts, Satellite Cells, Skeletal Muscle, Extracellular Signal-Regulated MAP Kinases, Receptors, Notch, Young Adult
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