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: 10371988
• 负责人: ALEXANDER A SOUKAS
• 金额: $ 56.44万
• 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 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371988
• 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 2 型糖尿病的一线疗法而闻名，它还具有多种健康益处，包括 延长模型系统的寿命，并减少癌症发病率和死亡，尽管它已被广泛接受。 线粒体是二甲双胍作用的主要部位，二甲双胍促进健康的机制 我们最近的工作提供了有关线粒体下游的重要线索。 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乙双胍，抑制线粒体呼吸能力，从而抑制 RagA/RagC 异二聚体通过核孔复合物 (NPC) 的转运因此被锁定在 “关闭”状态并且无法激活 mTORC1 在这种情况下缺乏 mTORC1 活性会激活酰基辅酶 A。 脱氢酶家族成员 10 (ACAD10)，这对于二甲双胍延长时间是必要且充分的 然而，我们的知识仍然存在重大差距，无法阻止人类癌细胞的生长。 我们充分认识二甲双胍的治疗潜力。二甲双胍如何影响线粒体。 二甲双胍对 NPC 有何作用？ 调节寿命和控制生长？迫切需要了解二甲双胍的全部范围 分子效应，以便为癌症和衰老相关疾病提供更智能的治疗方法。 本申请的总体目标是确定二甲双胍作用的转化机制 该提案的中心假设是二甲双胍对线粒体的影响。 通过大规模改变核运输和诱导 ACAD10 依赖性代谢物来促进健康。 这项工作的基本原理是，该项目的完成将阐明二甲双胍的意外元素 在目标 1 中，我们将通过以下方式确定响应途径作为衰老和癌症的治疗靶点。 二甲双胍在线粒体中的作用得到增强，从而完全改变 NPC 的运输。 在目标 3 中，我们将描述二甲双胍对核转运的影响及其在衰老和癌症中的重要性。 确定 ACAD10 对双胍类药物产生积极健康影响的分子机制。 该项目意义重大，因为它将阐明双胍介导的分子机制 我们提出了它们对寿命和阻止癌细胞生长的积极影响。 创新将允许公正的基因发现反应的最重要方面 该项目将利用跨模型系统的简便遗传发现并最终验证我们的研究成果。 该项目的成功完成将为动物和人类癌细胞的主要假设提供信息。 获得双胍类药物促进健康的益处且不会产生不良影响的替代方法，为这一点铺平了道路 寻找可以减少衰老相关疾病的发生或严重程度的新一代癌症疗法和药物 疾病。