Blood-hypothalamus barrier and metabolic impairment in advanced aging

老年时的血液-下丘脑屏障和代谢损伤

• 批准号: 10548160
• 负责人: Allison W Xu
• 金额: $ 46.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10548160
• 关键词: ART protein; Ablation; Acceleration; Adult; Affect; Age; Aging; Anatomy; Animals; Appetite Stimulants; Blood; Blood - brain barrier anatomy; Blood Vessels; Body Weight; Body Weight decreased; Brain region; Cell Line; Cellular Stress; Cessation of life; Chronic; Defect; Diffusion; Disease; Ensure; Environmental Risk Factor; Event; Exposure to; FGF2 gene; Failure; Genetic; Goals; Hippocampus; Hypothalamic structure; Impaired cognition; Impairment; Individual; Individuality; Injections; Injury; Lesion; Longevity; Metabolic; Metabolic Control; Morbidity - disease rate; Mus; Names; Neurons; Obesity; Organ; Population; Predisposition; Pro-Opiomelanocortin; Process; Proliferating; Radial; Rattus; Regulation; Reporting; Risk; Role; Signal Transduction; Sodium Glutamate; Structure of nucleus infundibularis hypothalami; Subcutaneous Injections; Testing; Toxin; Ventricular; age related; aged; blood-brain barrier permeabilization; coping; energy balance; experimental study; median eminence; mortality; neuronal excitability; normal aging; progenitor; repaired; response; response to injury; self-renewal; young adult

Project Summary/Abstract The world population is aging. Despite our advances in extending lifespan, there is tremendous individuality in age-related morbidity and mortality. It is recognized that the breakdown of the blood-brain barrier (BBB) in hippocampus marks an early event of cognitive impairment in aging. However, how aging affects BBB in the hypothalamus, and its ensuring metabolic consequences is not well understood. The goal of this study is to test whether the age-related decline of tanycyte number contributes to the weakening of the BBB in the hypothalamus and its impact on metabolic impairment and mortality. We will determine if proliferative capacity of tanycytes decreases with age, leading to age-dependent loss of tanycytes. We will explore if inadequate tanycyte proliferation leads to weakened BBB in the mediobasal hypothalamus and its consequences. We will evaluate if aging of the AgRP neurons outside the BBB marks the decline of AgRP neuronal function and metabolic derailment in advanced aging. Lifespan is influenced by both genetic and environmental factors. Given the essential roles of the AgRP neurons in metabolic control and their unique anatomical localization outside the BBB, information obtained from this study will establish the importance of the hypothalamic BBB in metabolic control and longevity in advanced aging.

项目概要/摘要 世界人口正在老龄化。尽管我们在延长寿命方面取得了进步，但仍有巨大的差距 与年龄相关的发病率和死亡率的个体性。人们认识到， 海马体中的血脑屏障（BBB）标志着认知障碍的早期事件 老化。然而，衰老如何影响下丘脑的 BBB 及其确保代谢 后果尚不清楚。本研究的目的是检验年龄是否与年龄相关 单细胞数量的减少导致下丘脑及其 BBB 的减弱 对代谢损伤和死亡率的影响。我们将确定是否具有增殖能力 tanycytes 随着年龄的增长而减少，导致年龄依赖性的 tanycytes 损失。我们将探讨是否 单细胞增殖不足会导致下丘脑内侧基底层 BBB 减弱， 它的后果。我们将评估 BBB 外部 AgRP 神经元的衰老是否标志着 AgRP 神经元功能下降和晚期衰老代谢脱轨。寿命为 受遗传和环境因素双重影响。鉴于 AgRP 的重要作用 代谢控制中的神经元及其在血脑屏障外的独特解剖定位， 从这项研究中获得的信息将确定下丘脑 BBB 在 晚期衰老中的代谢控制和长寿。