Aging, CRH Stress Pathways and Atherogenic Processes

与年龄相关的心血管系统变化占老年人发病率和死亡率的50%。事实上，动脉粥样硬化，一种血液凝块被动脉壁上的脂肪沉积阻塞的情况，在人们40到50岁时急剧增加。因此，毫不奇怪，动脉粥样硬化的临床表现，如心肌梗死，也随着年龄的增长而增加。此外，据报道，慢性应激会在动物和人类中传播动脉粥样硬化过程。老年压力会带来严重后果，与压力较小的人群相比，在慢性或极端压力下（如老年痴呆症护理和配偶死亡），死亡率会增加50%以上。老年人经历各种慢性压力源，如经济、健康、配偶照顾、搬迁和社会孤立。应激介导促肾上腺皮质激素释放激素（CRH）的中枢合成和释放，而CRH反过来又影响许多神经激素、自主神经、免疫和行为活动。例如，CRH应激途径似乎随着年龄的增长而改变。与年轻的大鼠相比，老龄大鼠注射CRH产生了更大的免疫和激素反应。激素和免疫活动反过来又与动脉粥样硬化有关。白细胞上的促炎细胞因子趋化因子和细胞粘附分子（CAMs）参与免疫细胞粘附和迁移到血管壁上。一旦进入内膜，巨噬细胞可以吞噬氧化的ldl，造成脂肪条纹和动脉粥样硬化病变。本研究旨在探讨衰老和CRH应激途径在动脉粥样硬化过程中的相互作用。正在测试的总体假设是，由于CRH应激途径的改变，老年大鼠对长期应激更敏感。更具体地说，它再次被假设与隔离应激24天后对中央CRH感染的夸大免疫反应，促炎细胞因子，细胞粘附分子（CAMs）和巨噬细胞对趋化因子的趋化性增加有关。这些研究的结果可能为理解衰老、CRH介导的应激反应和动脉粥样硬化相关因素之间的关系提供了关键。这些知识可能最终有助于开发新的药物疗法。

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.