This study was designed to investigate the change of expression level of G protein beta(4) subunit (Gbeta(4)) and the activity of PKB/Akt and ERK1/2 during aging process. Both mRNA and protein levels of Gbeta(4) and the induction of phosphorylation of PKB/Akt and ERK1/2 were examined in nine regions of brain (frontal cortex, striatum, hypothalamus, hippocampus, cerebellum, cerebral cortex, thalamic area, brainstem, and amygdala-septum-preoptic area) from weanling (3-week-old), young (12-week-old), adult (24-week-old), and aged (80- or 96-week-old) rats. Aging process (defined as the comparison of 12-week-old young rats with 96-week-old aged rats in this study) significantly reduced Gbeta(4) mRNA (in all testing regions except striatum and thalamic area) and protein expression (except hypothalamus and hippocampus). Aging process also caused a significant increase in the phosphorylation of both PKB/Akt in striatum, hippocampus, cerebellum and thalamic area, and ERK1/2 in all testing regions. Although the precise relationship between increased activities of PKB/Akt and ERK1/2 by aging and decreased expression of Gbeta(4) remains unknown, current data represent the first demonstration of a change in Gbeta(4) expression with age in rat brain and suggest that an age-related alteration in expression level of Gbeta(4) may, at least in part, play an important role in aging processes.