Hepatic aging may involve alterations in redox status, resulting in enhanced oxidant production and changes in specific signaling pathways that lead to a pro-inflammatory response. The authors investigated whether mild calorie restriction and long-term voluntary exercise could attenuate these changes. Four groups of male Fischer 344 rats were compared: young (6 mo), old (24 mo), old calorie restricted (8% CR, 24 mo) and old CR with daily voluntary wheel running (Exercise; 8% CR, 24 mo). Levels of endogenous reactive oxygen species (ROS), nitric oxide (NO*), and peroxynitrite (ONOO-) were significantly higher in the old ad libitum fed group compared to the young group. Sulfhydryl (-SH) content was significantly reduced and glutathione (GSH) content tended to be lower in the old animals. Old rats had significantly increased nuclear presence of NF-kappaB and in connection, increased levels of regulatory cytosolic phosphorylated I-kappaBalpha and decreased dephosphorylated I-kappaBalpha, suggesting an increased inflammatory response. Interestingly, a significant increase in liver RNA oxidation (8-oxo-7,8-dihydroguanosine) in the old ad libitum fed rats was detected and DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine) tended to be increased. The age-associated increase in oxidative stress and upregulation of pro-inflammatory proteins was attenuated in the livers from both the CR and the exercise + CR groups.