Functional Consequences of Impaired Autophagy in Aging

描述(由申请人提供)：这是第一个竞争性更新计划项目(PP)的修订版，重点研究自噬中与年龄相关的变化在免疫挑战和应激反应低效的老生物体中所起的作用。自噬是维持细胞内稳态、调节细胞能量平衡所必需的一种基本的分解代谢途径，也是应激反应的重要组成部分。PP的组成部分是四个项目，涉及来自5个学术部门的6名教职员工，以及为这四个项目的研究活动提供支持的三个核心。这些项目分享了想法、技术和实验模型。AIMS的完成需要几个项目的成员参与。由6名成员组成的科学咨询委员会定期审查PPG活动。PP的长期目标仍然是测试总体假设，即自噬功能受损会调节老年生物体的功能恶化和无法协调对应激源和免疫挑战的有效反应。基于前一阶段的新发现，我们现在提出以下具体目标：1)表征不同的自噬途径，包括内体-微型自噬(Emi)，参与细胞对应激的反应，现在的重点是蛋白毒性、脂毒性和遗传毒性。 在肝脏、脑(P1)、脂肪组织(P4)和免疫系统(P2、P3)中；2)确定不同自噬途径中与年龄相关的变化对免疫反应(P2、P3)、脂肪组织动态平衡和重塑(P4)和机体对应激的抵抗力(P1)的影响；3)分析不同干预措施对与衰老相关的代谢变化(P1、P4)以及对两种基本免疫功能--抗原处理和呈递(P2)和T细胞激活(P3)的影响。这些研究将需要具有以下专业知识的小组的协同合作 自噬，树突状细胞功能，T细胞生物学，脂代谢，药物化学和氧化细胞损伤。相关性：这一PP探索了新的概念：1.自噬功能缺陷是老生物体对应激源更容易受到伤害的背后原因，2.旨在恢复或增强自噬的干预措施可以作为抗衰老战略来实施，以延长健康寿命。我们的研究最终可能在理解、治疗或预防老年人通过自噬系统的操作而导致的新陈代谢改变和认知和免疫功能下降方面获得基本的见解。

DESCRIPTION (provided by applicant): This is the revised version of the first competing renewal of a Program Project (PP) focused on investigating the role that age-related changes in autophagy play in the functional alterations and inefficient response to immunological challenges and to stress of old organisms. Autophagy is a basic catabolic pathway essential for the maintenance of cellular homeostasis, regulation of the cellular energetic balance and an integral part of the response to stress. The components of the PP are four Projects involving 6 faculty members from 5 academic departments and three Cores that provide support to the research activities of the four projects. The projects share ideas, techniques and experimental models. Completion of aims requires participation of members from several of the projects. The PPG activities are reviewed periodically by a 6-member Scientific Advisory Committee. The long-term goal of the PP remains testing the overall hypothesis that impairment in autophagy mediates the functional deterioration and the inability to orchestrate an efficient response to stressors and to immunological challenges in old organisms. Building on the novel findings of the previous period, we propose now the following specific aims: 1) to characterize the involvement of different autophagic pathways, including endosomal-microautophagy (eMI), in the cellular response to stress with the focus now on proteotoxicity, lipotoxicity and genotoxicity in liver, brain (P1), adipose tissue (P4) and immune system (P2, P3); 2) to determine the impact of age-related changes in the different autophagic pathways on the immune response (P2, P3), adipose tissue homeostasis and remodeling (P4) and in the organismal resistance to stress (P1); 3) to analyze the effect of different interventions that modulate the activity of different autophagic pathways on the metabolic changes associated with aging (P1, P4) and on the failure of two essential immune functions, antigen processing and presentation (P2) and T cell activation (P3). These studies will require the synergistic cooperation of groups with expertise in autophagy, dendritic cell function, T cell biology, lipid metabolism, medicinal chemistry and oxidative cellular injury. Relevance: This PP explores the novel concepts that: 1. defective autophagic function is behind the higher vulnerability to stressors of old organisms and that 2. interventions aimed at restoring or enhancing autophagy could be implemented as anti-aging strategies to prolong health-span. Our studies may ultimately lead to fundamental insights in understanding, treating or preventing the metabolic alterations and declined cognitive and immune function of elders through manipulations of the autophagic system.