Bioenergetics of Metformin Action and Aging

抽象的。 二甲双胍被用作治疗糖尿病的药物已有近70年的历史 好几年了。除糖尿病外，双胍类化合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。可以说，衰老是大多数疾病的最大风险因素。此应用程序 是基于这样一个前提，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相关的疾病 更有效的针对性。基于广泛的初步数据和基本数据，但通常 被低估的热力学和生物能量学原理，这一中心假设 项目是线粒体生物能效率的轻微下降是主要分子 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，二甲双胍对健康持续时间的疗效取决于慢性 代谢状态-在卡路里过剩的情况下有益，但在卡路里不足的情况下有害。 将使用最先进的体内和体外方法：建立衰老的相互作用 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、肠和脑中分离出线粒体3，12， 和24月龄Fischer 344只大鼠(目标1)；建立二甲双胍与Fischer 344大鼠的急性相互作用 12月龄大鼠体内代谢状态(低或高脂肪饮食，喂养或禁食)(目标2)； 确定二甲双胍对男性和女性健康寿命和寿命的具体影响 雌性老鼠。该项目的结果预计将证明二甲双胍，类似于 其他有机阳离子会剂量依赖性地降低线粒体的生物能量效率， 揭示了一种主要机制，可以解释众多下游细胞和 生理效应，包括对衰老相关疾病的保护。

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.