We investigated the age-related alterations of calcineurin and Akt1/protein kinase Bα (Akt1/PKBα) immunoreactivity in the mouse hippocampal CA1 sector using immunohistochemistry. Calcineurin and Akt1/PKBα immunoreactivity was measured in 2-, 8-, 18-, 40–42- and 50–59-weeks-old animals. Diffuse calcineurin immunoreactivity was evident in pyramidal neurons of the hippocampal CA1 sector of 8-weeks-old mice. Densities of calcineurin immunoreactivity were lowered significantly in the hippocampal CA1 neurons of 2-weeks-old mice. In contrast, densities of calcineurin immunoreactivity were unchanged in the hippocampal CA1 neurons up to 40–42-weeks-old mice. However, densities of calcineurin immunoreactivity were increased significantly in the dendrites and plasma membranes of the hippocampal CA1 neurons of 50–59-weeks-old mice compared to 8-weeks old animals. Akt1/PKBα immunoreactivity was slightly detectable in the hippocampal CA1 sector of 8-weeks-old mice. A weak Akt1/PKBα immunoreactivity was found in cytoplasm of the hippocampal CA1 neurons and glial cells. Densities of Akt1/PKBα immunoreactivity were unchanged in the hippocampal CA1 neurons and glial cells of 2-weeks-old mice. In contrast, densities of Akt1/PKBα immunoreactivity were increased significantly in cytoplasm of neurons and glial cells of the hippocampal CA1 sector from 40–42 to 50–59 weeks after birth. The present study indicates that densities of calcineurin immunoreactivity and number of Akt1/PKBα immunoreactive cells were increased significantly in the hippocampal CA1 sector during aging processes. Our study also demonstrates that the activation of Akt1/PKBα signaling pathway may act defense mechanism against the neuronal dysfunction of the hippocampal CA1 sector caused by the activation of calcineurin signaling pathway during aging processes. These findings suggest that the calcineurin and Akt1/PKBα signaling pathway may be important targets for the development of novel therapeutic strategies for protection against age-related neurodegeneration.