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

Abstract

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.

Exercise effects on physiological function during aging

“…Similar beneficial effects of regular exercise have been reported for young and old mice with ablation of PGC-1α, when hyper-fragmentation of mitochondrial networks was observed in aged relative to young animals, and exercise training normalized mitochondrial network structure in wild, but not in PGC-1α KO animals [50] or in human subjects [51]. The beneficial effects of exercise on mitochondrial dynamics is not limited to skeletal muscle, but also includes brains [29,52,53] and fetal hearts from exercised dams [54], while other organs have not been studied.…”

Short‐Duration Swimming Exercise after Myocardial Infarction Attenuates Cardiac Dysfunction and Regulates Mitochondrial Quality Control in Aged Mice

“…Mitochondrial quality control consists of a series of mechanisms, including reactive oxygen species (ROS) scavenging, mitochondrial dynamics, and mitophagy. Studies have revealed that exercise improves mitochondrial quality both in healthy [ 10 ] and in metabolic and neurodegenerative disorders as well as in aging [ 11 , 12 ].…”

Autophagy as a Physiological Response of the Body to Starvation

“…When cells are exposed to long-term nutrient deprivation and energy loss, an excess amount of lipolysis results in the production of ketone bodies, which are the end product of free fatty acid oxidation reaction and can be used as an energy source in muscle and neurons. Since not all cells have the ability to use ketone bodies as an energy source, the cells that cannot utilize these small molecules activate proteolysis as a response to starvation (Luo et al 2017;Lee et al 2017). Proteolysis can be activated in two different ways, depending on the tissue type and stress duration.…”