Aging, CRH Stress Pathways and Atherogenic Processes

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Age associated changes in the cardiovascular system are responsible for 50% of morbidity and mortality in the elderly. In fact, atherogenesis, a condition in which blood floc is blocked by fatty deposits in the arterial walls, increases dramatically when individuals are forty to fifty years old. It is no surprise, therefore, that clinical manifestations of atherosclerosis, such as myocardial infarction also increases with age. Furthermore, chronic stress is reported to propagate atherogenic processes in animals as well as humans. Stress in advanced age has severe consequences, where mortality rates increase by over 50% under chronic or extreme stress such as Alzheimer's caregiving and death of a spouse compare to a less stress cohort. The elderly experience a variety of chronic stressors, such as economic, health, spousal care-giving, relocation and social isolation. Stress mediates central synthesis and release of corticotropin- releasing hormone (CRH), which in turn has been observed to affect many neurohormonal, autonomic, immune and behavioral activities. CRH stress pathways appear to be altered with aging, for example. CRH injections in aged rats produced exaggerated immune and hormonal responses compared with younger rats. Hormonal and immune activities, in turn, have been linked with atherogenesis. Pro-inflammatory cytokines chemokines and cellular adhesion molecules (CAMs) on leukocytes are involved in adherence and migration of immune cells into the walls of blood vessels. Once within the intima macrophages can engulf oxidized LDLs, causing fatty streaks and atherogenic lesions. The present proposal is designed to explore the interaction between aging and CRH stress pathways on atherogenic processes. The overall hypothesis being tested is that aged rats are more sensitive to prolonged stress due to altered CRH stress pathways. More specifically it is hypothesized again will be associated with exaggerated immune responses to central CRH infections after 24 days of isolation stress, increasing pro-inflammatory cytokines, cellular adhesion molecules (CAMs) and chemotaxis of macrophages to chemokines. The results generated from these studies may provide a key to understanding a relationship between aging, CRH mediated stress responses and factors associated with atherogenesis. This knowledge may ultimately contribute to the development of novel drug therapies.