Age-dependent agonist-specific dysregulation of membrane-mediated signal transduction: emergence of the gate theory of aging

Although a general mechanism for the limited responsiveness of senescent cells has yet to be established, reduced responsiveness may in part be ascribed to deficits in the apparatus required for cell surface receptor-mediated signal transduction. Age-related changes of receptor-mediated signal transduction occur at many levels, and are known to include quantitative and qualitative changes in growth factor receptors, G-protein coupled receptors, and many other downstream signaling molecules. Here, we emphasize the prime role of the cellular surface in the perception and transmission of external stimuli in response to the aging process. As major means of cellular signal transduction, the receptor tyrosine kinase (RTK) system and the G protein-coupled receptor (GPCR) system of senescent cells were investigated. We observed that the RTK system was severely damaged, while the GPCR system was only partially inactivated by aging. These results suggest that the agonist-dependent dysregulation of and imbalance of signal transduction pathways might be responsible for the functional deterioration of senescent cells, and indicate a possibility of the functional recovery of senescent cells through agonist-specific signal system activation. Moreover, those data evoke the emerging concept that the senescent phenotype may be modulated by the membrane-associated signal system, implying the gate theory of aging. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.