Mitochondrial action of metformin in aging and longevity

越来越多的证据表明，二甲双胍对线粒体的作用是导致其能够 降血糖，减少癌症的生长和发病率。在模型系统中，二甲双胍延长了 寿命，而对人类的观察研究也同样表明，服用 二甲双胍。尽管二甲双胍的生物学作用最近取得了进展，但二甲双胍的作用机制 对长寿和衰老的有利影响仍未完全确定。我们最近的工作提供了 有证据表明，二甲双胍针对衰老过程的多个基本方面。特别是，我们有 研究表明，二甲双胍介导的线粒体能量学抑制抑制了通过核的运输 孔道复合体(NPC)。受抑制的NPC转运将促衰老激酶mTORC1锁定在非活动状态。它是 我们知道，随着年龄的增长，许多细胞都会出现核泄漏，而我们的工作首次表明二甲双胍 可以通过对线粒体的作用来针对这种泄漏。我们的初步数据和发表的研究表明 二甲双胍还可以针对与衰老有机械联系的线粒体泄漏。这些令人兴奋的东西 观察表明，二甲双胍可以逆转发生的多种病理性细胞病变 随着年龄的增长。在这样做的过程中，该药物准备好满足老年科学原则：通过逆转基本方面 在衰老过程中，二甲双胍可能不是同时针对一种，而是许多与衰老相关的疾病。在……里面 尽管存在这种诱人的可能性，但我们知识中的关键差距仍然阻碍着我们充分认识到 二甲双胍的治疗潜力。二甲双胍需要在哪些组织中发挥作用才能延长寿命？你好吗？ 线粒体上的二甲双胍效应转导到介导药物的牙齿保护作用的效应器？什么 在衰老过程中，二甲双胍效应是否需要全谱的分子事件？这样做的总体目标是 应用是为了确定二甲双胍在衰老过程中的作用部位和机制。的中心假说 这项建议是，二甲双胍通过靶向特定组织中的线粒体能量来促进健康衰老， 它通过下游的效应器通路发出信号来延长寿命。这项工作的基本原理是 该项目的完成将阐明药物的特定效应部位和药物的意想不到的元素 二甲双胍反应通路。在目标1中，我们将定义二甲双胍靶向线粒体的机制 促进长寿。目标2将描述二甲双胍降低线粒体通透性的机制 在衰老过程中。在目标3中，我们将探索更大范围的二甲双胍反应基因，以了解完整的 二甲双胍在衰老过程中的直接和间接细胞作用的光谱。这个项目意义重大，因为它将 阐明双胍类化合物调节其对寿命的积极作用的分子机制。我们把 四是概念和技术创新，这将使我们能够发现 对二甲双胍的反应。该项目的圆满完成将为新一代 能够促进健康老龄化并减少与老龄化相关的疾病的发病和严重程度的战略。

A growing body of evidence suggests that metformin effects on mitochondria are responsible for its ability to lower blood glucose and reduce the growth and incidence of cancer. In model systems, metformin prolongs lifespan, and observational studies in humans similarly suggest a longevity benefit for patients who take metformin. In spite of recent progress in the biology of metformin action, the mechanisms by which metformin exacts favorable effects on longevity and aging remain incompletely characterized. Our recent work provides evidence that metformin targets multiple, fundamental aspects of the aging process. In particular, we have shown that metformin-mediated inhibition of mitochondrial energetics restrains transport through the nuclear pore complex (NPC). Restrained NPC transport locks the pro-aging kinase mTORC1 in the inactive state. It is known that many cells obtain a “leaky” nucleus as they age, and our work is the first suggestion that metformin can target this leakiness through action on mitochondria. Our preliminary data and published studies indicate that metformin can also target mitochondrial leakiness that is mechanistically linked to aging. These exciting observations suggest that metformin is positioned to reverse multiple, pathological cellular changes that occur with aging. In doing so, the drug is poised to fulfill the geroscience principle: by reversing fundamental aspects of the aging process, metformin may target not one but many aging-associated diseases simultaneously. In spite of this tantalizing possibility, critical gaps in our knowledge remain that prevent us from fully realizing the therapeutic potential of metformin. In which tissues is metformin action needed to promote longevity? How are metformin effects at mitochondria transduced to effectors that mediate the drug’s geroprotective effects? What is the full spectrum of molecular events required for metformin effects in aging? The overall objective of this application is to determine the sites and mechanisms of metformin action in aging. The central hypothesis of this proposal is that metformin promotes healthy aging by targeting mitochondrial energetics in specific tissues, which signals through downstream effector pathways to promote longevity. The rationale for this work is that completion of the project will illuminate both specific effector sites of the drug and unexpected elements of the metformin response pathway. In Aim 1 we will define mechanisms by which metformin targets mitochondria to promote longevity. Aim 2 will characterize mechanisms by which metformin reduces mitochondrial permeability in aging. In Aim 3, we will probe a larger landscape of metformin response genes in order to understand the full spectrum of metformin’s direct and indirect cellular effects in aging. This project is significant because it will elucidate the molecular mechanisms by which biguanides mediate their positive effects on lifespan. We put forth conceptual and technical innovations that will allow discovery of the most important aspects of the response to metformin. Successful completion of this project will pave the way for a new generation of strategies that can promote healthy aging and reduce the onset and severity of aging-related diseases.