Mitochondrial action of metformin in aging and longevity

二甲双胍在衰老和长寿中的线粒体作用

• 批准号: 10264030
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 42万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10264030
• 关键词: Adenosine Monophosphate; Age; Aging; Animal Model; Biguanides; Biological Models; Biology; Blood Glucose; Caenorhabditis elegans; Cell Nucleus; Cells; Complex; Data; Diabetes Mellitus; Disease; Elements; Event; FRAP1 gene; Gene Expression; Generations; Genes; Genetic; Genomics; Geroscience; Goals; Growth; Health; Health Benefit; Health Promotion; Human; Hypoglycemic Agents; Incidence; Knowledge; Laboratories; Link; Longevity; Malignant Neoplasms; Mediating; Metformin; Mitochondria; Molecular; Morbidity - disease rate; Mus; Nuclear Pore Complex; Observational Study; Oral; Pathologic; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phosphotransferases; Positioning Attribute; Process; Protein Kinase; Proteomics; Publishing; Response Elements; Severities; Signal Transduction; Site; Suggestion; Therapeutic; Tissues; Translating; Work; cancer cell; cellular targeting; combat; functional genomics; gene function; genetic approach; genome editing; genome wide screen; healthspan; healthy aging; human data; innovation; interest; mTOR inhibition; member; molecular imaging; mortality; prevent; prospective; response; therapeutic target

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.

越来越多的证据表明，二甲双胍对线粒体的影响是其能力的原因， 降低血糖，减少癌症的生长和发病率。在模型系统中，二甲双胍延长 寿命，对人类的观察性研究也同样表明服用该药物的患者可以获得长寿益处 二甲双胍。尽管最近在二甲双胍作用的生物学方面取得了进展，但二甲双胍的作用机制仍不清楚。 对寿命和衰老的确切有利影响仍然没有完全表征。我们最近的工作提供了 二甲双胍靶向衰老过程的多个基本方面的证据。我们特别 显示二甲双胍介导的线粒体能量学抑制抑制了通过核的转运， 孔复合体（NPC）。受抑制的NPC转运将促衰老激酶mTORC 1锁定在非活性状态。是 我们知道许多细胞随着年龄的增长会有一个“渗漏”的细胞核，我们的工作是第一次提出二甲双胍 可以通过对线粒体的作用来靶向这种泄漏。我们的初步数据和已发表的研究表明 二甲双胍也可以靶向与衰老机制相关的线粒体泄漏。这些令人兴奋 观察表明，二甲双胍可以逆转发生的多种病理性细胞变化 随着年龄的增长。在这样做的过程中，药物准备履行老年科学的原则：通过扭转基本方面 在衰老过程中，二甲双胍可能同时针对多种而不是一种衰老相关疾病。在 尽管有这种诱人的可能性，我们的知识中仍然存在着严重的差距，使我们无法充分认识到 二甲双胍的治疗潜力。在哪些组织中二甲双胍的作用是促进长寿所必需的？好吗 二甲双胍对线粒体的作用被转导为介导药物老年保护作用的效应物？什么 二甲双胍对衰老的影响是否需要全谱的分子事件？本报告的总体目标 应用是确定二甲双胍在衰老中的作用部位和机制。的中心假设 该建议是二甲双胍通过靶向特定组织中的线粒体能量学来促进健康衰老， 其通过下游效应子途径发出信号以促进长寿。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位点和药物的意外因素。 二甲双胍反应途径。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。在目标3中，我们将探索二甲双胍反应基因的更大范围，以了解二甲双胍反应基因的完整表达。 二甲双胍在衰老中的直接和间接细胞效应谱。这个项目意义重大，因为它将 阐明双胍介导其对寿命的积极影响的分子机制。我们把 第四，概念和技术创新，这将使发现的最重要的方面， 对二甲双胍的反应。该项目的成功完成将为新一代 促进健康老龄化和减少与老龄化有关的疾病的发生和严重程度的战略。