Genetic mechanisms of metformin's pro-longevity and anti-cancer effects

二甲双胍延年益寿和抗癌作用的遗传机制

• 批准号: 9906124
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 14.28万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9906124
• 关键词: Adverse effects; Aging; Animal Model; Animals; Antidiabetic Drugs; Biguanides; Biochemical; Biogenesis; Biological; Biological Models; Caenorhabditis elegans; Cancer Cell Growth; Cell Aging; Cell model; Cells; Cessation of life; Data; Diabetes Mellitus; Disease; Dose; Elements; Family member; Functional disorder; Generations; Genes; Genetic; Genetic Engineering; Genetic Transcription; Goals; Growth; Health; Health Benefit; Health Promotion; Human; Hydrolase; Hypersensitivity; Incidence; Intelligence; Knowledge; Laboratories; Lipids; Longevity; Lysosomes; Malignant Neoplasms; Mediating; Metformin; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Pore Complex; Organelles; Pathway interactions; Pharmaceutical Preparations; Phenformin; Proteins; Proteomics; Regulation; Research; Risk; Role; Severities; Site; Therapeutic; Therapeutic Agents; Translating; Up-Regulation; Work; acyl-CoA dehydrogenase; age effect; anti aging; anti-cancer; cancer cell; cancer therapy; cell growth; combat; genome editing; healthy aging; in vivo; inducible gene expression; innovation; interest; member; metabolomics; mortality; novel; nucleocytoplasmic transport; prevent; respiratory; response; side effect; therapeutic target

Metformin, best known as first line therapy for type 2 diabetes, also has myriad health benefits, including prolonging lifespan in model systems, and reducing cancer incidence and death. Although it is widely accepted that mitochondria are a primary site of metformin action, the mechanisms by which metformin promotes health downstream of mitochondria are not well understood. Our recent work provides an important clue about the mechanism of action of metformin in aging and cancer. We have shown that biguanides, the class of drug that includes metformin and the related drug phenformin, inhibit mitochondrial respiratory capacity, which restrains transit of the RagA/RagC heterodimer through the nuclear pore complex (NPC). RagC is thereby locked in the “off” state and is unable to activate mTORC1. The lack of mTORC1 activity in this context activates acyl-CoA dehydrogenase family member 10 (ACAD10), which is necessary and sufficient for metformin to extend lifespan and block growth in human cancer cells. However, critical gaps in our knowledge remain that prevent us from fully realizing the therapeutic potential of metformin. How do metformin effects on the mitochondria modulate NPC activity? What is the full spectrum of metformin effects on the NPC? How does ACAD10 modulate lifespan and control growth? There is a critical need to understand the full range of metformin's molecular effects in order to enable more intelligent therapies for cancer and aging-related diseases. The overall objective of this application is to determine the mechanisms by which metformin effects are translated into positive effects on health. The central hypothesis of this proposal is that metformin effects on mitochondria promote health by large-scale alteration of nuclear transport and induction of ACAD10-dependent metabolites. The rationale for this work is that completion of the project will illuminate unexpected elements of the metformin response pathway as therapeutic targets in aging and cancer. In Aim 1 we will determine the mechanisms by which metformin action are enhanced at mitochondria to enact changes in NPC transport. Aim 2 will fully characterize metformin effects on nuclear transport and their significance in aging and cancer. In Aim 3, we will identify the molecular mechanism by which ACAD10 drives positive health effects in response to biguanides. This project is significant because it will elucidate the molecular mechanisms by which biguanides mediate their positive effects on lifespan and on blocking cancer cell growth. We put forth conceptual and technical innovations that will allow unbiased genetic discovery of the most important aspects of the response to metformin. This project will leverage facile genetic discovery across model systems and ultimately validate our main hypothesis in animals and human cancer cells. Successful completion of this project will inform alternative ways to derive the health promoting benefits of biguanides without untoward effects, paving the way for a new generation of cancer therapeutics and agents that can reduce the onset or severity of aging related diseases.

二甲双胍，作为治疗2型糖尿病的一线疗法，也有许多健康益处，包括 延长模型系统的寿命，降低癌症发病率和死亡率。尽管它被广泛接受 线粒体是二甲双胍作用的主要部位，也是二甲双胍促进健康的机制 对线粒体下游的研究还不是很清楚。我们最近的工作提供了一条关于 二甲双胍在衰老和癌症中的作用机制。我们已经证明了双胍类药物 包括二甲双胍和相关药物苯福明，抑制线粒体呼吸能力，从而抑制 RAGA/RagC异源二聚体通过核孔复合体(NPC)的运输。因此，RagC被锁定在 “关”状态，无法激活mTORC1。在这种情况下，mTORC1活性的缺乏激活了酰基辅酶A 脱氢酶家族成员10(ACAD10)，这是二甲双胍延伸的必要条件和充分条件 延长人类癌细胞的寿命并阻止其生长。然而，我们知识中的关键差距仍然存在，这阻碍了 我们无法充分认识到二甲双胍的治疗潜力。二甲双胍对线粒体的作用 调节鼻咽癌活动？二甲双胍对鼻咽癌的作用全谱是什么？ACAD10如何 调节寿命和控制增长？迫切需要了解二甲双胍的全部范围 分子效应，以便能够对癌症和衰老相关疾病进行更智能的治疗。这个 本申请的总体目标是确定二甲双胍效应的翻译机制 对健康产生积极影响。这一提议的中心假设是二甲双胍对线粒体的作用 通过大规模改变核运输和诱导依赖ACAD10的代谢物来促进健康。 这项工作的基本原理是，项目的完成将照亮制造过程中意想不到的因素 作为衰老和癌症治疗靶点的反应通路。在目标1中，我们将通过以下方式确定机制 在线粒体上，二甲双胍的作用增强，从而改变鼻咽癌的运输。目标2将全面 描述二甲双胍对核运输的影响及其在衰老和癌症中的意义。在《目标3》中，我们将 确定ACAD10对双胍类化合物的积极健康效应的分子机制。 这个项目很有意义，因为它将阐明双胍类化合物的分子调节机制。 它们对延长寿命和阻止癌细胞生长有积极作用。我们提出了概念和技术上的 创新将使无偏见的基因发现反应的最重要方面 二甲双胍。该项目将在模型系统中利用便捷的基因发现，并最终验证我们的 主要假设存在于动物和人类癌细胞中。该项目的成功完成将通知 以其他方式获得双胍促进健康的益处，而不会产生不良影响，为 新一代癌症疗法和药物可以降低与衰老有关的发病或严重程度 疾病。