The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein (APP) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR. Although the hippocampus displayed significant alterations in APP mRNA and protein expression and no significant changes in PS-1 expression, an opposite pattern was observed in the cortex. DR counteracted the age-related changes in APP mRNA expression in both structures of old animals. The observed DR-induced increase in mRNA levels in the hippocampus was accompanied by an increase in the level of full-length protein APP. These results indicate that although both structures are very sensitive to aging, a specific spatial pattern of changes in APP and PS-1 occurs during aging. Furthermore, these findings provide evidence that DR can affect APP and PS-1 expression in a manner consistent with its proposed 'antiaging' effect.