二甲双胍分子的历史可以追溯到一个多世纪前，但其临床应用始于 20 世纪 50 年代。从那时起，它在糖尿病患者中的使用不断增长，目前用户数量已超过 1.5 亿。随着对新机制的理解不断加深，治疗方案也得到了扩展。二甲双胍通过作用于胰岛素受体和线粒体，很可能通过激活单磷酸腺苷激活激酶，对胰岛素抵抗具有主要活性。这些和相关机制导致显着的脂质降低和体重减轻。近年来出现了抗癌作用，其机制部分依赖于线粒体活性以及一些恶性肿瘤中发生的磷脂酰肌醇3激酶抗性。二甲双胍延长寿命的潜力是正在进行的大型研究以及多项基础和临床研究的目标。本文将尝试研究这些不同活动背后的基本机制以及潜在的临床益处。二甲双胍可能通过组蛋白修饰、DNA 甲基化和 miRNA 作用于转录活性。与年龄相关的炎症（炎症）可能通过核因子红细胞 2 相关因子的激活和肠道微生物群的变化而发生。衰老分解活性会导致具有衰老相关分泌表型的细胞减少，这对于延长寿命以及帕金森病等与年龄相关的疾病的辅助特性可能至关重要。端粒延长可能与线粒体呼吸因子 1 和过氧化物酶体 γ 增殖物辅激活因子 1-α 的活性有关。最近对治疗最严重的神经系统疾病（例如肌萎缩侧索硬化症和额颞叶痴呆）的潜力的观察给人们带来了很大的希望。版权所有 © 2024。由爱思唯尔有限公司出版。

The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.Copyright © 2024. Published by Elsevier Ltd.