Aging alters gastric mucosal responses to epidermal growth factor and transforming growth factor-alpha

Administration of pharmacological doses of epidermal growth factor (EGF) or transforming growth factor-alpha (TGF-alpha) in young rats stimulates gast ric mucosal proliferation, but, in aged rats, the same treatment inhibits p roliferation. This may be due to enhanced ligand-induced internalization of EGF receptor (EGFR). In support of this, we demonstrated that although a s ingle injection of EGF(10 mu g/kg) or TGF-alpha (5 mu g/kg) in young (4-6 m o old) rats greatly increased membrane-associated EGFR tyrosine kinase acti vity, the same treatment slightly inhibited the enzyme activity in aged (24 mo old) rats. This treatment also produced a greater abundance of punctate cytoplasmic EGFR staining in gastric epithelium of aged rats, consistent w ith EGFR internalization. In vitro analyses demonstrated that exposure of i solated gastric mucosal cells from aged but not young rats to 100 pM TGF-al pha resulted in marked increases in intracellular EGFR tyrosine kinase acti vity and that induction of EGFR tyrosine kinase activity in mucosal membran es from aged rats occurred at doses 1,000-fold less than those required in young rats. Our data suggest that aging enhances sensitivity of the gastric mucosa to EGFR ligands. This may partly explain EGFR-mediated inhibition o f gastric mucosal proliferation in aged rats.