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Updated: Jun 2, 2025
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Induction and Validation of Cellular Senescence in Primary Human Cells
Published on: June 20, 2018
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Centromere inactivation during aging can be rescued in human cells
Sweta Sikder1, Songjoon Baek1, Truman McNeil2
1Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892, USA.
Molecular Cell
|January 14, 2025
Summary
Aging cells lose centromeric proteins like CENP-A due to epigenetic changes. Inhibiting p53 and LSD1/KDM1A rejuvenates these cells by restoring centromeric function.
Area of Science:
- Cellular senescence
- Epigenetics
- Molecular biology
Background:
- Aging is characterized by genetic, epigenetic, and physiological changes.
- Aged cells exhibit loss of heterochromatin and reduced histone levels.
- Centromeric integrity is crucial for genomic stability.
Purpose of the Study:
- To investigate the fate of centromeres in aged cells.
- To identify mechanisms regulating centromeric function during aging.
- To explore strategies for mitotic rejuvenation of aged cells.
Main Methods:
- Tracking centromere dynamics in aged human fibroblasts, tissues, and senescent models.
- Analyzing CENP-A levels and centromeric transcription.
- Investigating the role of p53 and lysine-specific demethylase 1 (LSD1/KDM1A).
- Employing dual inhibition of p53 and LSD1/KDM1A.
Main Results:
- CENP-A is downregulated in aged cells in a p53-dependent manner.
- Epigenetic repression of centromeric noncoding transcription occurs via LSD1/KDM1A recruitment.
- This repression impairs de novo CENP-A loading at aging centromeres.
- Dual inhibition of p53 and LSD1/KDM1A restores centromeric proteins and transcripts, leading to mitotic rejuvenation.
Conclusions:
- Aging involves p53-dependent downregulation of CENP-A and epigenetic silencing of centromeric transcription.
- LSD1/KDM1A plays a key role in centromeric inactivation during aging.
- Targeting p53 and LSD1/KDM1A offers a therapeutic strategy for age-related cellular dysfunction.
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