Growing evidence suggests that exercise can provide neuroprotection by improving mitochondrial quality control (MQC) on the aged brain. Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling responsiveness declines with aging. However, whether AMPK plays a role in the exercise-mediated improvement of memory and MQC in the aged hippocampus remains to be established. AICAR (5-Aminoimidazole 4-carboxamide ribonucleoside), a pharmacological agonist of AMPK, has been proposed to be an exercise mimetic recently. However, it has not been clarified whether AICAR could mimic the effects of exercise on the aged hippocampus through improvement of MQC. In this study, AICAR (AMPK agonist) and Compound C (AMPK inhibitor) were used to investigate if AMPK plays a key role in exercise-induced improvement of MQC and if AICAR could act as an exercise mimetic through improvement of MQC in aged hippocampus. Both exercise and AICAR improved the memory of aged mice and increased AMPK phosphorylation in the aged hippocampus. Exercise, but not AICAR, improved mitochondrial respiratory function in the aged hippocampus and increased the Microtubule associated protein 1 light chain 3 (LC3) II/LC3 I ratio and the protein expression of LC3 II and Autophagy Related Protein 7 (ATG7) in the lysate of whole hippocampal tissue. Both exercise and AICAR increased the ratio of LC3 II/LC3 I and the protein expression of LC3 II in the mitochondrial fractions of the hippocampus. Regarding mitochondrial dynamics, neither exercise training nor AICAR changed the protein level of Mitofusin2 (Mfn2). Exercise, but not AICAR, increased the protein level of Dynamin-related protein 1 (Drp1). Furthermore, both exercise training and AICAR increased the protein level of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a modulator of mitochondrial biogenesis. Compound C abolished the exercise-induced effects on memory in aged mice (Fig. 1), AMPK phosphorylation, autophagy, mitophagy, and mitochondrial fission in the aged hippocampus. However, Compound C did not reverse the exercise-induced increase in PGC-1α protein levels in the aged hippocampus. Our data provide evidence that AMPK plays an important role in the exercise-induced improvement of memory and MQC in the hippocampus of aged mice. Importantly, we demonstrated for the first time that AICAR could partially mimetic the beneficial effects of endurance exercise on memory and MQC in the hippocampus of aged mice, and thus may be a promising exercise mimetic for counteracting brain aging. 

Exercise is recognized as an effective strategy to delay brain aging, which is related to the activation of autophagy. Trehalose is a natural compound that can activate autophagy and exert beneficial effects in delaying brain aging. In this study, we investigated whether trehalose may exert neuroprotection similar to those of exercise in delaying age-related cognitive decline. Fifteen-month-old male C57BL/6 mice underwent swim exercise and/or were treated with 2% trehalose for 12 weeks. Trehalose, exercise and the combination of exercise and trehalose intervention improved the learning and memory of aged mice. They also improved the ratio of LC3-II/LC3-I, the protein level of LC3-II, Bnip3L, and Parkin respectively. Additionally, both exercise and trehalose increased the phosphorylation of AMPK. Exercise decreased cortical phosphorylation of mTOR and S6k, whereas trehalose did not change these cortical levels. These data indicated that exercise and trehalose might modulate autophagy through mTOR-dependent or mTOR-independent pathways, respectively. However, a combination of exercise and trehalose did not play a synergistic role in improving cognitive function and modulation of autophagy. Taken together, our findings suggest that trehalose exerts similar effects to those of exercise in delaying age-related cognitive decline and that it may thus represent an exercise mimetic to delay brain aging.