Mitogen-activated protein kinases (MAPK), which include the extracellular signal-related kinases (ERK), the c-Jun N-terminal kinases (JNK), and the p38 MAPK, are important regulatory proteins by which a wide variety of extracellular signals are transduced into intracellular sites. Recent studies reported that mitogenic signal transduction in various cell types are exquisitely sensitive to reactive oxygen species (ROS) and the celluar redox status. In the present study, we investigated the activation of MAPK activity by aging and calorie restriction (CR) in rat kidneys isolated from Fischer 344 rats, ages 6, 12, 18, and 24 months fed ad libitum (AL) and CR diets. Results showed that the aging process strongly enhanced all three of the MAPK activities studied, ERK, JNK, and p38 MAPK, in parallel to increased ROS status. In contrast, we observed CR to markedly suppress the age-related activation of MAPKs. Based on these data, we concluded that an age-related increase in MAPK activity is associated with increased ROS, which was effectively suppressed by the anti-oxidative action of CR.