Bioenergetics of Metformin Action and Aging

抽象的。 二甲双胍已被用作治疗糖尿病的药物约70年 年除了糖尿病，双胍类药物还具有许多其他有益作用 预防/治疗癌症、心血管疾病、神经退行性疾病和体重 损失二甲双胍也被证明可以增加健康寿命和延长寿命。尽管 这些广泛的多效性效应，主要的分子作用机制仍然是 悬而未决衰老可以说是大多数疾病的最大风险因素。本申请 是基于这样的前提，即破译二甲双胍的分子作用机制将 更好地了解衰老过程和与衰老有关的疾病可能是如何 更有针对性。基于大量的初步数据和基本面，但往往 被低估的，热力学和生物能原理，这一中心假设 线粒体生物能量效率的轻度降低是 二甲双胍和其他有机阳离子延长健康寿命和/或寿命的机制。 进一步假设二甲双胍对健康跨度的疗效取决于慢性 代谢状态-在热量过剩的情况下是有益的，但在热量不足的情况下是有害的。 将使用最先进的体内和体外方法：建立老化的相互作用 和二甲双胍（和其他有机阳离子）对线粒体生物能量效率的影响 从心脏、骨骼肌、肝、肾、肠和脑分离的线粒体来自3，12， 和24月龄Fischer 344大鼠（目的1）;确定二甲双胍和 12月龄大鼠体内代谢状态（低或高脂肪饮食，进食或禁食）（目的2）;以及 确定二甲双胍对男性健康寿命和寿命的特定环境影响， 雌性大鼠本项目的结果预计将证明二甲双胍，类似于 其他有机阳离子，剂量依赖性地降低线粒体生物能量效率， 揭示了一个主要的机制，可以解释许多下游细胞， 生理作用，包括防止衰老相关疾病。

Abstract. Metformin has been used as a medication for the treatment of diabetes for approximately 70 years. Besides diabetes, biguanides are associated with a number of other beneficial effects prevention/treatment of cancer, cardiovascular disease, neurodegenerative disease, and weight loss. Metformin has also been shown to increase health span and prolong life span. Despite these wide-ranging pleotropic effects, the primary molecular mechanism of action is still unresolved. Aging is arguably the single greatest risk factor for most diseases. This application is based on the premise that deciphering metformin's molecular mechanism of action will provide a better understanding of how the aging process and aging-related diseases may be more effectively targeted. Based on extensive preliminary data and fundamental, yet often underappreciated, thermodynamic and bioenergetic principles, the central hypothesis of this project is that a mild reduction in mitochondrial bioenergetic efficiency is the primary molecular mechanism by which metformin, and other organic cations, extend health span and/or lifespan. It is further hypothesized that the efficacy of metformin on health span depends on the chronic metabolic state – beneficial under caloric surplus but detrimental under caloric deficit conditions. State-of-the-art in vivo and in vitro approaches will be used: to establish the interaction of aging and metformin (and other organic cations) on mitochondrial bioenergetic efficiency in mitochondria isolated from heart, skeletal muscle, liver, kidney, intestine and brain from 3, 12, and 24 month old Fischer 344 rats (Aim 1); to establish the acute interaction of metformin and metabolic state (low or high fat diet, fed or fasted) in vivo in 12 month old rats (Aim 2); and to determine the context specific impact of metformin on health span and lifespan in male and female rats. The outcomes of this project are expected to demonstrate that metformin, similar to other organic cations, dose-dependently decreases mitochondrial bioenergetic efficiency, revealing a primary mechanism that can account for the numerous downstream cellular and physiological effects, including protection from aging-related diseases.