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Common mechanisms for declines in oxidative stress tolerance and proliferation with aging

Ji Li1, Nikki J Holbrook

  • 1Department of Internal Medicine, Section of Geriatrics, Yale University School of Medicine, New Haven, CT 06511, USA. nikki.holbrook@yale.edu

Free Radical Biology & Medicine
|July 30, 2003
PubMed

Insights

Aging impairs hepatocyte proliferation and stress tolerance due to reduced epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK) signaling. An imbalance in ERK and p38 activity contributes to age-related oxidative stress sensitivity.

Area of Science:

  • Cell Biology
  • Gerontology
  • Molecular Biology

Background:

  • Aging is associated with decreased stress tolerance and proliferation.
  • Epidermal growth factor receptor (EGFR) signaling and extracellular signal-regulated kinase (ERK) activation are crucial for these cellular responses.
  • Previous studies suggest impairments in EGFR/ERK signaling contribute to age-related effects in rat hepatocytes.

Purpose of the Study:

  • To investigate the impact of aging on mouse hepatocyte responsiveness to proliferative and oxidative stress signals.
  • To examine the role of EGFR and ERK signaling pathways in age-related changes in hepatocyte function.
  • To determine the involvement of ERK and p38 signaling in oxidative stress tolerance in aged hepatocytes.

Main Methods:

  • Primary hepatocytes were isolated from young (4-5 months) and aged (24-29 months) mice.
  • Hepatocytes were stimulated with low concentrations of hydrogen peroxide (H2O2) or epidermal growth factor (EGF) to assess proliferation.
  • Hepatocytes were treated with high concentrations of H2O2 to evaluate oxidative stress tolerance.
  • EGFR and ERK signaling pathway activation (phosphorylation) was measured.
  • Pharmacological inhibitors of ERK and p38 were used to assess their roles in H2O2-induced cell death.

Main Results:

  • Aged hepatocytes exhibited reduced DNA synthesis in response to EGF and low H2O2 concentrations compared to young hepatocytes.
  • Old hepatocytes showed decreased survival rates when exposed to high H2O2 concentrations.
  • Reduced ERK activation and EGFR phosphorylation at tyrosine 1173 were observed in aged hepatocytes.
  • While p38 was activated by H2O2 in both age groups, its activation was more pronounced in old cells.
  • Inhibition of ERK increased H2O2 sensitivity in young hepatocytes, whereas p38 inhibition decreased H2O2 sensitivity in aged hepatocytes.

Conclusions:

  • Age-related declines in hepatocyte proliferative capacity and oxidative stress tolerance are linked to impairments in common signaling pathways.
  • Reduced EGFR and ERK signaling contribute to diminished proliferative capacity in aged hepatocytes.
  • An imbalance between ERK and p38 signaling pathways exacerbates the sensitivity of aged hepatocytes to oxidative stress.

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