AbstractAging is accompanied by a decline in memory and other brain functions. Physical exercise may mitigate this decline through the modulation of factors participating in the crosstalk between skeletal muscle and the brain, such as neurotrophins and oxidative stress parameters. We aimed to determine whether long term exercise training (35 ± 15 years) promotes memory maintenance in middle-aged men, and to characterize the changes in neurotrophic factors and lipid oxidation markers in peripheral blood samples in both middle-aged and young men. The neuropsychological analysis showed significant improvements in memory through the Free and Cued Immediate Recall tests, in the middle-aged trained individuals when compared to the sedentary ones. We found a significant decrease in the resting serum BDNF and plasma Cathepsin B (CTSB) levels in the trained groups at both middle and young ages. BDNF and CTSB levels were inversely correlated with weekly hours of exercise. We also found a significant decrease in plasma malondialdehyde, an index of lipid peroxidation, in middle-aged and young trained subjects. The positive impact of long-term exercise training by delaying the onset of physiological memory loss and the associated neurotrophic and redox peripheral modulation, suggests the effectiveness of exercise as preventive strategy against age-related memory loss and neurodegeneration.