Beneficial effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) on the development and function of the central nervous system are well documented. In spite of primary deficiency of GH and secondary IGF-1 deficiency, Ames dwarf mice live considerably longer than normal animals, exhibit apparently normal cognitive functions and maintain them into advanced age. In an attempt to reconcile these findings, we have examined local expression of GH and IGF-1 in the hippocampus of normal and Ames dwarf mice. We found that both hippocampal GH and IGF-1 protein levels are increased and the corresponding mRNAs are normal in Ames dwarf as compared with normal mice. Increased phosphorylation of Akt and cyclic AMP responsive element-binding protein (CREB) were detected in the hippocampus of Ames dwarf mice. Our results suggest that increase in hippocampal GH and IGF-1 protein expression and subsequent activation of PI3K/Akt-CREB signal transduction cascade might contribute to the maintenance of cognitive function and is likely to be responsible for the integrity of neuronal structure, and maintenance of youthful levels of cognitive function in these long-lived mice during aging. © 2004 Elsevier Inc. All rights reserved.