Dysregulation of tissue renin-angiotensin system (RAS) is involved in oxidative and inflammatory processes observed in major aging-related diseases, including neurodegenerative diseases such as Parkinson's disease (PD). Physical exercise has beneficial effects against aging-related changes, dopaminergic neuron vulnerability, and PD progression. The present study indicates that sedentary aged rats have an increase in activity of the nigral angiotensin (Ang) II/Ang type 1 receptor (AT1) axis (ie, the pro-oxidative pro-inflammatory arm), and a decrease in the activity of the RAS protective arm (ie, Ang II/AT2 and Ang 1-7/Mas receptor axis) in comparison with young rats. In addition, sedentary aged rats showed a decrease in levels of nigral IGF-1, SIRT1, SIRT3, and VEGF. Treadmill running induced a significant increase in levels of IGF-1, SIRT1, SIRT3, and VEGF, as well as an increase in expression of the protective Ang 1-7/Mas axis and inhibition of the Ang II/AT1 axis. The exercise-induced increase in IGF-1 and sirtuins may mediate the effects of exercise on the nigral RAS. However, exercise may induce the increase in VEGF and modulation of RAS activity by different pathways. Exercise, via RAS, contributes to inhibition of the pro-oxidative and proinflammatory state that increase dopaminergic neuron vulnerability and risk of PD with aging.