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.

二甲双胍是2型糖尿病的第一线治疗，也具有无数的健康益处 模型系统中延长寿命，并减少癌症的发病率和死亡。虽然被广泛接受 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 线粒体的下游尚不清楚。我们最近的工作为 二甲双胍在衰老和癌症中的作用机理。我们已经证明了Biguanides，这是一类药物 包括二甲双胍和相关的药物酚素，抑制线粒体呼吸能力，可限制 RAGA/RAGC异二聚体通过核孔复合物（NPC）的过境。因此，ragc被锁定在 “ OFF”状态，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），这是二甲双胍延伸的必要和足够的 寿命和阻断人类癌细胞的生长。但是，我们所知的关键差距仍然可以防止 我们是从充分意识到二甲双胍的治疗潜力的原因。二甲双胍对线粒体的影响如何 调节NPC活动？二甲双胍对NPC的全部影响是什么？ 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 分子作用以使对癌症和与衰老有关的疾病的更智能疗法。这 该应用的总体目的是确定二甲双胍效应翻译的机制 对健康产生积极影响。该提议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并诱导Acad10依赖性代谢产物来促进健康。 这项工作的理由是，该项目的完整将阐明二甲双胍的意外元素 反应途径是衰老和癌症的治疗靶标。在AIM 1中，我们将通过 线粒体在线粒体上增强了哪种二甲双胍作用，以实现NPC转运的变化。 AIM 2将完全 表征二甲双胍对核运输的影响及其在衰老和癌症中的重要性。在AIM 3中，我们将 确定ACAD10对BIGUANIDE响应阳性健康影响的分子机制。 该项目很重要，因为它将阐明Biguanides介导的分子机制 它们对寿命和阻断癌细胞生长的积极影响。我们提出了概念和技术 将允许对反应最重要方面的遗传发现无偏的创新 二甲双胍。该项目将利用跨模型系统的便捷遗传发现，并最终验证我们 动物和人类癌细胞中的主要假设。成功完成该项目将告知 获得促进健康益处的替代方法，而无需效果，铺平道路 对于新一代的癌症疗法和可以减少与衰老相关的发作或严重程度的药物 疾病。