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

二甲双胍作为2型糖尿病的一线治疗药物而闻名，也有无数的健康益处，包括 延长模型系统的寿命，降低癌症发病率和死亡率。虽然它被广泛接受 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 线粒体的下游还没有很好的理解。我们最近的工作提供了一个重要的线索， 二甲双胍在衰老和癌症中的作用机制。我们已经证明，双胍类药物， 包括二甲双胍和相关药物苯丙氨酸，抑制线粒体呼吸能力， RagA/RagC异二聚体通过核孔复合物（NPC）的转运。因此，RagC被锁定在 “关闭”状态，无法激活mTORC 1。在这种情况下，mTORC 1活性的缺乏激活了酰基辅酶A 脱氢酶家族成员10（ACAD 10），这是必要的和足够的二甲双胍延长 并阻止人类癌细胞的生长。然而，我们的知识仍然存在重大差距， 我们充分认识到二甲双胍的治疗潜力。二甲双胍如何影响线粒体 调节NPC活动？二甲双胍对NPC的全谱效应是什么？如何使用ACAD 10 调节寿命和控制生长我们迫切需要了解二甲双胍的全系列 分子效应，以便能够对癌症和与衰老相关的疾病进行更智能的治疗。的 本申请的总体目的是确定二甲双胍作用的转化机制 对健康产生积极影响。该建议的中心假设是二甲双胍对线粒体的影响 通过大规模改变核转运和诱导ACAD 10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非预期因素 作为衰老和癌症的治疗靶点。在目标1中，我们将通过以下方式确定机制： 二甲双胍在线粒体中的作用增强，从而改变NPC转运。目标2将完全 描述二甲双胍对核转运的影响及其在衰老和癌症中的意义。在目标3中，我们 确定ACAD 10对双胍类药物产生积极健康效应的分子机制。 该项目意义重大，因为它将阐明双胍介导的分子机制 它们对寿命和阻止癌细胞生长的积极影响。我们提出了概念和技术 创新，将允许无偏见的基因发现的最重要的方面的反应， 二甲双胍。该项目将利用跨模型系统的简易遗传发现，并最终验证我们的 动物和人类癌细胞的主要假设。该项目的成功完成将通知 获得双胍的健康促进益处而没有不良影响的替代方法， 对于新一代癌症治疗剂和药剂，其可以减少与衰老相关的疾病的发作或严重程度， 疾病

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.