Role of Intestinal Homeostasis in Organismal Aging

项目摘要 衰老是阿尔茨海默病(AD)的主要危险因素，随着年龄的变化 神经系统在AD病理中起作用。这项提议的主要目标是发展 对抗神经元衰老表型、延长健康寿命和延迟的新方法 阿尔茨海默病的发生和发展。近年来，肠屏障的丧失 功能已经成为进化上保守的衰老的病理生理标志。 重要的是，对包括老鼠和果蝇在内的模式生物的研究表明， 直接针对肠道屏障的完整性可以在机体水平上调节健康寿命。 然而，有关肠道屏障之间的关系的基本问题仍然存在。 远端器官系统的功能障碍和老化。事实上，人们对其原因知之甚少。 肠屏障功能障碍、神经元老化与AD的关系。 肌动蛋白细丝网络的改变与阿尔茨海默病有关 以及相关的痴呆，但神经元肌动蛋白动力学在衰老和寿命中的作用 决心还没有得到体现。在前期工作中，我们发现衰老 和年龄起病的肠屏障功能障碍与积聚 老年人脑中的丝状肌动蛋白(F-肌动蛋白)和富含肌动蛋白的杆。此外，我们还发现 这种针对性的、神经元特异性的干预降低了F-肌动蛋白在脑内的超稳定作用 老化的大脑，改善衰老的细胞标志物，显著延长健康寿命。这些 这些发现为理解这种机制的相互作用提供了重要的第一步 衰老过程中神经元肌动蛋白动力学、AD相关神经毒性和机体健康之间的关系。 在这里，我们建议在这些开创性发现的基础上，探索三个广泛的 问题： 1)肠屏障功能障碍和肠道屏障功能障碍之间的机制关系是什么 衰老大脑中的肌动蛋白动力学？ 2)调节老年动物神经元肌动蛋白动力学是否能改善神经元功能， 健康长寿和/或对抗AD发病机制？ 3)衰老大脑中的肌动蛋白动力学和肌动蛋白之间的机制关系 衰老的其他细胞特征：蛋白平衡丧失和线粒体功能障碍？ 这里描述的工作将为我们带来基本的知识 了解衰老的机制和AD相关的病理。我们的发现也可能 引领新的治疗方法来对抗衰老、阿尔茨海默病和相关的痴呆症。

Project Summary Aging is the major risk factor for Alzheimer’s disease (AD), with changes in the aging nervous system contributing to AD pathology. The major goal of this proposal is to develop novel approaches to counteract neuronal aging phenotypes, prolong healthy lifespan and delay the onset and progression of Alzheimer’s disease. In recent years, loss of intestinal barrier function has emerged as an evolutionarily conserved pathophysiological hallmark of aging. Importantly, studies in model organisms, including mice and Drosophila, have revealed that directly targeting intestinal barrier integrity can mediate healthy lifespan at the organismal level. However, fundamental questions remain regarding the relationships between intestinal barrier dysfunction and aging of distal organ systems. Indeed, little is known regarding the causal relationships between intestinal barrier dysfunction, neuronal aging and AD. Alterations in the actin filament network have been implicated in Alzheimer’s disease and related dementias, but the role of neuronal actin dynamics in aging and lifespan determination has not been characterized. In preliminary work, we have discovered that aging and age-onset intestinal barrier dysfunction are associated with the accumulation of filamentous actin (F-actin) and actin-rich rods in aged brains. Furthermore, we have discovered that targeted, neuron-specific interventions that reduce the hyper stabilization of F-actin in the aging brain, improve cellular markers of aging and dramatically prolong healthy lifespan. These findings provide an important first step towards understanding the mechanistic interplay between neuronal actin dynamics, AD-related neurotoxicity and organismal health during aging. Here, we propose to build upon these groundbreaking findings by exploring three broad questions: 1) What are the mechanistic relationships between intestinal barrier dysfunction and actin dynamics in the aging brain? 2) Can modulating neuronal actin dynamics in aged animals improve neuronal function, healthy longevity and/or counteract AD pathogenesis? 3) What are the mechanistic relationships between actin dynamics in the aging brain and other cellular hallmarks of aging; loss of proteostasis and mitochondrial dysfunction? The work described herein will bring about fundamental knowledge towards our understanding of the mechanisms of aging and AD-related pathology. Our findings may also lead to novel therapeutic approaches to counteract aging, AD and related dementias.