Early onset senescence occurs when fibroblasts lack the glutamate–cysteine ligase modifier subunit
Open accessAbstract
Cellular senescence is the irreversible entry of cells into growth arrest. Senescence of primary cells in culture has long been used as an in vitro model for aging. Glutamate-cysteine ligase (GCL) controls the synthetic rate of the important cellular antioxidant glutathione (GSH). The catalytic subunit of GCL, GCLC, is catalytically active and essential for life. By contrast the modifier subunit of GCL, GCLM, is dispensable in mice. Although it is recognized that GCLM increases the rate of GSH synthesis, its physiological role is unclear. Herein, we show that loss of Gclm leads to premature senescence of primary murine fibroblasts as characterized by: (a) diminished growth rate, (b) cell morphology consistent with senescence, (c) increases in senescence-associated beta-galactosidase activity, and (d) cell cycle arrest at the G(1)/S and G(2)/M boundaries. These changes are accompanied by increased intracellular ROS, accumulation of DNA damage, and induction of p53 and p21 proteins. We also found that N-acetylcysteine increases intracellular GSH and prevents premature senescence in Gclm(-/-) cells. These results suggest that the control of GCLM, which in turn controls aspects of the cellular redox environment via GSH, is important in determining the replicative capacity of the cell.
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The detrimental effects of decreased glutamate-cysteine ligase activity are reversed by N-acetylcysteine supplementation, which increases intracellular GSH levels.
“Of note, these detrimental effects are reversed by N-acetylcysteine supplementation, which is known to increase intracellular GSH levels [188].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [188]
Decreased activity of glutamate-cysteine ligase, involved in GSH synthesis, is linked to senescence, ROS production and DNA damage in primary mouse fibroblasts.
“Similarly, a decreased activity of the enzyme glutamate-cysteine ligase, which is involved in the synthesis of GSH, has been linked to senescence, ROS production and DNA damage in primary mouse fibroblasts [188].”
From The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence (2022) · cites this paper as [188]
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- Authors
- Chen, Y., Johansson, E., Fan, Y., Shertzer, H. G., Vasiliou, V., Nebert, D. W., & Dalton, T. P.
- Affiliations
- University of Cincinnati Medical Center (US)
- University of Colorado Denver (US)
- Corresponding author
- Chen, Ying
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 47
- Issue
- 4
- Pages
- 410-418
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2773044
- OpenAlex
- W1975589071
- Cited by
- 28
- References
- 71
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Eye Institute (R01EY017963)
- National Institute of Environmental Health Sciences (P30ES006096, R01ES012463)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- cellular senescence, GCLM, glutathione synthesis, fibroblasts, premature senescence, reactive oxygen species, DNA damage, p53, p21, cell cycle arrest, N-acetylcysteine, redox conditions, replicative capacity, aging
- MeSH terms
- Acetylcysteine, Animals, beta-Galactosidase, Cell Cycle, DNA Damage, Female, Fetus, Fibroblasts, Glutamate-Cysteine Ligase, Glutathione, Mice, Inbred C57BL, Pregnancy, Tumor Suppressor Protein p53, Free Radical Scavengers, Cellular Senescence, Reactive Oxygen Species, Mice, Knockout, Cell Culture Techniques, Protein Subunits, Cell Growth Processes, Cyclin-Dependent Kinase Inhibitor p21, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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