Aging is often characterized by reduced stress tolerance and decreased proliferative capacity, but little is known about the effects of aging on signaling pathways important in regulating these responses. Recent studies from our laboratory have implicated impairments in epidermal growth factor receptor (EGFR) signaling and extracellular signal-regulated kinase (ERK) activation to both effects in rat hepatocytes. Here we investigated the responsiveness of hepatocytes derived from young (4-5 months) and aged (24-29 months) mice to proliferative signals (low concentrations of H2O2 and epidermal growth factor [EGF] stimulation), and oxidant injury (high H2O2 concentrations). Old hepatocytes displayed lower levels of DNA synthesis in response to low H(2)O(2) concentrations (5-10 microM) and EGF stimulation, and reduced survival following treatment with high H2O2 concentrations (20-50 microM). Both effects were associated with reduced activation of ERK and diminished phosphorylation of EGFR tyrosine residue 1173. p38 was also activated by H2O2, but to a greater extent in old cells. Pharmacologic inhibition of ERK increased the sensitivity of young cells to H2O2-induced cell death, while inhibition of p38 decreased the sensitivity of old cells. Our findings suggest that impairments in common signaling events underlie age-related declines in proliferative capacity and oxidative stress tolerance in mouse hepatocytes, and that an imbalance in ERK and p38 activities contributes to the greater sensitivity of aged cells to H2O2.