Moderate-Intensity Exercise Induces Neurogenesis and Improves Cognition in Old Mice by Upregulating Hippocampal Hippocalcin, Otub1, and Spectrin-α.

Exercise increases the levels of neurogenic factors and enhances neurogenesis, memory, and learning. However, the molecular link between exercise and neurogenesis is not clear. The purpose of this study was to examine the effects of exercise intensity on cognitive function and protein expression in the hippocampus of old mice. To compare the effects of aerobic exercise intensity on cognition in old mice, we exposed 18-month-old mice to low- and moderate-intensity treadmill exercise for 4 weeks. Moderate-intensity exercise improved cognitive function in the old mice, while low-intensity exercise did not. To investigate the underlying mechanisms, two-dimensional electrophoresis was used to examine protein expression. Using peptide fingerprinting mass spectrometry, we identified 19 proteins that were upregulated in the hippocampus following exercise training, and seven of these proteins were normalized by the control value. Among them, the levels of 14-3-3 zeta and heat shock protein 70, which have been shown to be induced by exercise training and related to neurogenesis, were dramatically increased by moderate exercise. Hippocalcin, α-spectrin, ovarian tumor domain-containing ubiquitin aldehyde-binding protein 1 (otub1), mu-crystallin, serine racemase, and rho GDP dissociation inhibitor 1, which are related to neurogenesis, neuroprotection, and synaptic strength, were upregulated in the hippocampus by moderate exercise. In addition, we confirmed that neurogenic markers, including doublecortin and the neuronal nuclei antigen, and hippocalcin, otub1, and spectrin-α are potential molecular links between hippocampal neurogenesis and exercise in the elderly. Thus, these results showed that steady moderate-intensity exercise delayed the declines in cognitive function in the elderly through the activation of multiple factors.