Functional Consequences of Impaired Autophagy in Aging

描述（由申请人提供）：这是一个计划项目（PP）的第一个竞争性更新的修订版本，重点是研究自噬中与年龄相关的变化在功能改变和对免疫挑战和老年生物体应激的无效反应中的作用。自噬是维持细胞内环境稳定、调节细胞能量平衡和应激反应的一个重要组成部分。PP的组成部分是四个项目，涉及来自5个学术部门的6名教师和三个核心，为四个项目的研究活动提供支持。这些项目分享想法、技术和实验模型。目标的完成需要来自几个项目的成员的参与。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整体假设，即自噬损伤介导功能恶化，无法协调对应激源和老年生物体免疫挑战的有效反应。基于前一时期的新发现，我们现在提出以下具体目标：1）表征不同自噬途径，包括内体微自噬（eMI），在细胞应激反应中的参与，现在重点关注蛋白毒性，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应答（P2，P3）、脂肪组织稳态和重塑（P4）以及生物体对应激的抗性（P1）的影响; 3）分析调节不同自噬途径活性的不同干预对与衰老相关的代谢变化（P1，P4）和对两种基本免疫功能失效的影响，抗原加工和呈递（P2）和T细胞活化（P3）。这些研究将需要具有以下专门知识的团体的协同合作： 自噬、树突状细胞功能、T细胞生物学、脂质代谢、药物化学和氧化性细胞损伤。相关性：本PP探讨了以下新概念：1。有缺陷的自噬功能是老年生物体对压力源的更高脆弱性的背后，2.旨在恢复或增强自噬的干预措施可以作为延长健康寿命的抗衰老策略来实施。我们的研究可能最终导致理解，治疗或预防老年人的代谢改变和认知和免疫功能下降，通过操纵自噬系统的基本见解。

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.