In humans, decreased intestinal motility, compromised nutritional status and increased risk of colon cancer are commonly associated with aging. Here, we used the cDNA microarray analysis to detect age-associated changes in duodenal and colonic gene expression in male Fischer 344 rats. The primary finding of this study is that the magnitude and direction of age-associated changes in gene expression differs in the colon and duodenum. In the colon, 56 genes showed altered expression, whereas expression of only 25 genes was altered in the duodenum. The magnitude of change was greater in the colon than in the duodenum. The direction of change also differed; in the aged colon, expression of 51 genes increased and only five genes decreased. In contrast, in the aged duodenum, only seven genes increased, whereas 18 genes decreased in expression. In the duodenum of aged rats, expression of genes involved in ATP-generating pathways is decreased. In contrast, in the colon of aged rats, expression of genes involved in energy generating pathways and in lipid oxidation is increased. In addition, in the aging colon, an increased expression of genes that show an aberrant regulation in colon cancer, including CD44, ras, and maspin is observed. Collectively, these findings provide clues to molecular events that may be related to compromised intestinal function and the high incidence of colon cancer in the aged population.