Related Experiment Video
Updated: Jun 16, 2026
Isolation of Intermediate Filament Proteins from Multiple Mouse Tissues to Study Aging-associated Post-translational Modifications
Published on: May 18, 2017
GSK3beta and aging liver
Jingling Jin1, Guo-Li Wang, Lubov Timchenko
1Huffington Center on Aging and Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Abstract:
The loss of regenerative capacity of tissues is one of the major characteristics of aging. Liver represents a powerful system for investigations of mechanisms by which aging reduces regenerative capacity of tissues. The studies within last five years revealed critical role of epigenetic silencing in the inhibition of liver proliferation in old mice. These studies have shown that a number of cell cycle proteins are silenced in livers of old mice by C/EBPalpha-HDAC1-Brm complex and that old liver fails to reduce the complex and activate these genes in response to proliferative stimulus such as partial hepatectomy. The complex modifies histone H3 on the promoters of c-myc and FoxM1B in the manner which prevents expression of these genes. Despite this progress, little is known about mechanisms by which aging causes this epigenetic silencing. We have recently discovered signal transduction pathways which operate upstream of the C/EBPalpha-HDAC1-Brm complex. These pathways involve communications of growth hormone, GSK3beta and cyclin D3. In addition to the liver, GH-GSK3beta-cyclin D3 pathway is also changed with age in lung, brain and adipose tissues. We suggest that other age-associated alterations in these tissues might be mediated by the reduced levels of GSK3beta and by elevation of cyclin D3. In this review, we summarize these new data and discuss the role of such alterations in the development of aging phenotype in the liver and in other tissues.
Insights
Aging reduces tissue regeneration by epigenetically silencing cell cycle genes in the liver. New research identifies upstream pathways involving growth hormone, GSK3beta, and cyclin D3, offering insights into aging mechanisms.
Area of Science:
- Gerontology
- Molecular Biology
- Epigenetics
Background:
- Tissue regenerative capacity declines with age, a key aging characteristic.
- Liver regeneration is impaired in aged mice due to epigenetic silencing of cell cycle proteins.
- The C/EBPalpha-HDAC1-Brm complex silences genes like c-myc and FoxM1B in aged livers.
Purpose of the Study:
- To investigate the upstream mechanisms driving age-associated epigenetic silencing in liver regeneration.
- To explore the role of growth hormone (GH), GSK3beta, and cyclin D3 in regulating the C/EBPalpha-HDAC1-Brm complex.
- To examine if these pathways are altered in other aging tissues.
Main Methods:
- Review of recent studies on epigenetic regulation of liver proliferation in aging mice.
- Analysis of signal transduction pathways involving GH, GSK3beta, and cyclin D3.
- Comparison of pathway alterations in liver, lung, brain, and adipose tissues.
Main Results:
- Aging causes epigenetic silencing of cell cycle genes in the liver via the C/EBPalpha-HDAC1-Brm complex.
- Novel upstream pathways involving GH, GSK3beta, and cyclin D3 regulate this complex.
- These GH-GSK3beta-cyclin D3 pathway alterations are also observed in lung, brain, and adipose tissues with age.
Conclusions:
- Age-related decline in liver regeneration is linked to epigenetic silencing mediated by the C/EBPalpha-HDAC1-Brm complex.
- The GH-GSK3beta-cyclin D3 pathway represents a critical upstream regulator of this silencing.
- Dysregulation of this pathway may contribute to the aging phenotype in multiple tissues.
Related Concept Videos
01:24Liver Regeneration
Cells of Liver
The liver comprises four major types of cells— hepatocytes, stellate, Kupffer, and sinusoidal endothelial cells. The hepatocytes are large...
01:24Cirrhosis II: Pathophysiology
01:18Pharmacokinetics in Geriatric Patients: Effect of Age on Drug Metabolism