Autophagy and Mitochondrial Permeability in Aging and Longevity

自噬是所有真核细胞消除缺陷细胞器和分子的保守过程， 并且通常被认为是促进健康和长寿的。自噬机制中的突变 人类疾病如自身免疫、代谢、炎症、肿瘤和神经变性 疾病，以及与过早衰老相一致的迅速变化。相反，几乎所有的基因和 延长寿命的环境操作以依赖于自噬的方式进行。但我们 已经确定，自噬对健康有负面影响时，它发生在设置 线粒体通透性增加。自噬的净后果是， 线粒体渗透性缩短寿命并增加对缺血/再灌注损伤的易感性。 有一个关键的需要，了解细胞和分子机制，线粒体 渗透性受到管制，以制定下一代干预措施，减少 自噬在衰老和疾病中的作用这个项目的长期目标是确定线粒体如何 为了确定线粒体通透性增加对细胞的影响， 以及衰老过程中的器官功能障碍。我们在这个特定应用中的目标是定义上游如何 参与促进长寿和减少疾病的信号通路抑制线粒体通透性， 以及这对自噬、线粒体功能和寿命的影响。该项目将满足这一 目的通过研究线粒体通透性调节的详细机制， 这一规定的后果。我们已经确定mTOR复合物2中的信号缺陷 途径导致线粒体通透性增加和自噬，缩短寿命和增加 缺血/再灌注损伤这一提议的中心假设是，低线粒体通透性是一种 自噬对寿命和衰老相关疾病的影响的中心决定因素。的理由 这一建议是，更全面地了解其调节将使我们能够将线粒体渗透性靶向于 促进人类健康衰老。在初步数据的指导下，我们将在三个具体的实验中检验我们的假设。 目标。在目标1中，我们将定义线粒体通透性降低的机制， 长寿之路。在目标2中，我们将定义线粒体通透性和 mTOR复合物2信号传导的缺陷驱动自噬。目标3将决定欧盟的机制， 线粒体渗透性和自噬会缩短寿命。在这些研究结束时，我们将有 确定了线粒体通透性破坏细胞功能和缩短细胞周期的主要机制， 寿命所提出的研究是重要的，因为它将对合理设计的 下一代干预措施，通过操纵自噬促进健康老龄化， 线粒体通透性

Autophagy is a conserved process by which all eukaryotic cells eliminate defective organelles and molecules, and is generally regarded as health- and longevity-promoting. Mutations in the autophagy machinery contribute to human conditions such as autoimmune, metabolic, inflammatory, neoplastic, and neurodegenerative diseases, and prompt changes consistent with premature aging. Conversely, nearly all genetic and environmental manipulations that extend lifespan do so in a manner dependent upon autophagy. However, we have determined that autophagy has negative consequences on health when it occurs in the setting of increased mitochondrial permeability. The net consequence of autophagy in the setting of increased mitochondrial permeability is shortened lifespan and increased susceptibility to ischemia/reperfusion injury. There is a critical need to understand the cellular and molecular mechanisms by which mitochondrial permeability is regulated in order to develop the next generation of interventions to reduce negative impacts of autophagy in aging and disease. The long-term goal of this project is to determine how mitochondrial permeability is regulated and to define the consequences of increased mitochondrial permeability on cellular and organismal dysfunction in aging. Our objective in this particular application is to define how upstream signaling pathways involved in promoting longevity and reducing disease suppress mitochondrial permeability, and the consequences this has on autophagy, mitochondrial function, and lifespan. This project will meet this objective by studying the detailed mechanisms by which mitochondrial permeability is regulated and the consequences of this regulation. We have determined that defects in signaling in the mTOR complex 2 pathway lead to increases in mitochondrial permeability and autophagy, shortening lifespan and increasing ischemia/reperfusion injury. The central hypothesis of this proposal is that low mitochondrial permeability is a central determinant of the effects of autophagy on lifespan and aging-associated diseases. The rationale for this proposal is that fuller understanding its regulation will permit us to target mitochondrial permeability to promote healthy aging in humans. Guided by preliminary data, we will test our hypothesis in three specific aims. In Aim 1, we will define the mechanisms by which mitochondrial permeability is decreased by prolongevity pathways. In Aim 2 we will define the mechanisms by which mitochondrial permeability and defects in mTOR complex 2 signaling drive autophagy. Aim 3 will determine the mechanism by which the union of mitochondrial permeability and autophagy shorten lifespan. At the conclusion of these studies, we will have identified the major mechanisms by which mitochondrial permeability disrupts cellular function and shortens lifespan. The proposed research is significant because it will have broad implications for rational design of the next generation of interventions that promote healthy aging through manipulation of autophagy and mitochondrial permeability.