The senescence-accelerated mouse (SAM) is an experimental model of aging, established through phenotypic selection from a common genetic pool of AKR/J mice. Here we use complementary DNA microarray, Western blot, and electrophoretic mobility shift assay to consider whether changes in liver gene expression observed in 5-month-old SAM-prone 8 (P8) mice, compared to SAM-R1 controls, are similar to those reported in aged rodents. Livers from SAM-P8 mice presented 88 differentially expressed transcripts, 59% of which were upregulated and 41% were downregulated. Of these, 14% were related to inflammatory/immunity processes, 10% were related to the xenobiotic metabolism (XM) and 3% to nervous system pathophysiology (NSP). Depressed expression and activity of genes related to XM, and altered expression of genes related to NSP, are similar to changes observed in aged rodents. Increased expression of heat shock protein 1 and Jun-B, reduced activity of activator protein 1 and absence of nuclear factor-kappaB activation indicate the lack of a strong liver inflammatory response in 5-month-old SAM-P8 mice.