CELL AGING OF HUMAN-DIPLOID FIBROBLASTS IS ASSOCIATED WITH CHANGES INRESPONSIVENESS TO EPIDERMAL GROWTH-FACTOR AND CHANGES IN HER-2 EXPRESSION

The limited replicative life span of diploid human cells in vitro (cel lular senescence) serves as a cellular model of aging. We examined the proliferative response of 2BS cells of different population doubling levels to epidermal growth factor (EGF). DNA synthesis was measured by thymidine incorporation. As the cells aged, there was a significant d ecrease both in the baseline level of DNA synthesis and in the stimula tion of DNA synthesis by EGF addition. The effective concentration of EGF and the latent period prior to DNA synthesis did not change. EGF r eceptor mRNA expression also remained unchanged as the cells aged, in the absence or presence of EGF, suggesting that the defect in old cell s lies downstream in the EGF signaling pathway. As the cells reached 1 00% of their life span, however, there was a 70% decrease in EGF recep tor mRNA. Expression of the EGF receptor homologue HER-2 was also exam ined. The HER-2 mRNA level was significantly reduced in old cells. Mor eover, HER-2 expression was stimulated by EGF addition in young cells but not in old cells. The results suggest that cell aging is associate d with a progressive loss in the ability of cells to respond to growth factors.