Lysosomal Proteolysis Is Associated with Exercise-Induced Improvement of Mitochondrial Quality Control in Aged Hippocampus

Exercise improves cognitive function in older adults, but the underlying mechanism is largely unknown. Both lysosomal degradation and mitochondrial quality control decline with age. We hypothesized that exercise ameliorates age-related cognitive decline through the improvement of mitochondrial quality control in aged hippocampus, and this effect is associated with lysosomal proteolysis. Sixteen to eighteen-month old male Sprague Dawley rats underwent swim exercise training for 10 weeks. The exercise regimen prevented cognitive decline in aged rats, reduced oxidative stress, and rejuvenated mitochondria in the aged hippocampus. Exercise training promoted mitochondrial biogenesis, increased mitochondrial fusion and fission, and activated autophagy/mitophagy in aged hippocampal neurons. Lysosomal inhibitor chloroquine partly blocked beneficial effects of exercise on cognitive function, oxidative stress, autophagy/mitophagy, and mitochondrial quality control in aged rats. These results suggest that preservation of cognitive function by long-term exercise is associated with improvement of mitochondrial quality control in aged hippocampus and that lysosomal degradation is required for this process. Our findings suggest that exercise training or pharmacological regulation of mitochondrial quality control and lysosomal degradation may be effective strategies for slowing down age-related cognitive decline.