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造成其能力的原因 降低血糖并减少癌症的生长和入射。在模型系统中，二甲双胍延长 人类的寿命和观察性研究同样表明对服用患者的寿命益处 二甲双胍。尽管二甲双胍作用的生物学最近取得了进步，但二甲双胍的机制 确切对寿命和衰老的有利影响仍然不完全表征。我们最近的工作提供 二甲双胍针对衰老过程的多个基本方面的证据。特别是，我们有 表明二甲双胍介导的线粒体能量抑制限制了通过核能的转运 孔复合物（NPC）。限制的NPC传输锁定了无活跃状态下的促血激酶MTORC1。这是 知道许多细胞随着年龄的增长而获得“漏水”核，而我们的工作是二甲双胍的第一个建议 可以通过对线粒体的作用来靶向这种泄漏。我们的初步数据和发表的研究表明 该二甲双胍还可以靶向与衰老有关的线粒体泄漏。这些令人兴奋 观察结果表明，二甲双胍定位可逆转多种发生的病理细胞变化 随着衰老。这样，该药物被毒死以实现Geroscience原则：通过逆转基本方面 在衰老过程中，二甲双胍可能仅针对一种而是靶向许多与衰老相关的疾病。 有这种诱人的可能性，我们知识的关键差距仍然使我们无法完全意识到 二甲双胍的治疗潜力。在哪些组织中，二甲双胍作用需要促进寿命？怎样 线粒体对线粒体的作用转导至介导该药物的凝胶保护作用的作用？什么 二甲双胍效应在衰老中是否需要全部分子事件？总体目标 应用是在衰老中确定二甲双胍作用的位点和机制。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来促进健康的衰老， 通过下游效应器途径发出信号以促进寿命。这项工作的理由是 该项目的完成将阐明药物的特定效应部位和意外元素 二甲双胍反应途径。在AIM 1中，我们将定义二甲双胍将线粒体靶向的机制 促进寿命。 AIM 2将表征二甲双胍可降低线粒体渗透性的机制 在AIM 3中，我们将探测较大的二甲双胍反应基因的景观，以了解完整 二甲双胍在衰老中的直接和间接细胞效应的光谱。这个项目很重要，因为它将 阐明了Biguanides介导其对寿命的积极影响的分子机制。我们放了 概念和技术创新将允许发现最重要的方面 对二甲双胍的反应。成功完成该项目将为新一代的道路铺平道路 可以促进健康衰老并减少与衰老相关疾病的发作和严重程度的策略。