Does Metformin Modulate the Pillars of Aging in Older Adults?

根据流行病学数据和对无脊椎动物和啮齿动物的干预研究，二甲双胍是一种 领先的候选人来调节衰老。然而，这些动物研究对人类受试者的适用性有限。 因为它们通常持续时间较短，并且使用的二甲双胍剂量比使用的剂量高得多 在人类身上。因此，二甲双胍对以衰老为重点的结果的影响和机制如下 目前尚不清楚哪种二甲双胍可以促进老年受试者的健康寿命延长。 本次资助申请针对的是RFA-AG-20-044《二甲双胍抗衰老的生物学机制》 和长寿“来验证这样的假设，即二甲双胍调节老年人衰老的关键支柱以改善 健康跨度。我们将利用我们正在进行的NIA资助的随机、安慰剂对照的二甲双胍试验来 预防老年人的虚弱(R01AG052697)。家长试验(n=120)正在测试二甲双胍 给药24个月可以预防或推迟老年(≥65岁)成年人的虚弱发作。深度老化- 重点表型包括脆弱的变化(油炸表型分数和洛克伍德缺陷积累 指数)、身体机能(短小的体能电池和6分钟步行)、肌肉力量/质量、血糖 代谢(胰岛素钳制和葡萄糖耐量)和认知(简易精神状态检查)。亲子试验 还收集了几种生物标本，包括血液、骨骼肌和脂肪组织 二甲双胍/安慰剂用于代谢(AMPK和胰岛素信号转导)和炎症的测量 (NF、κB和MAPK)途径。 通过应用创新的代谢组、蛋白质组、分子和生物统计学方法，我们将采取 利用这些丰富的表型数据和生物样品来评估二甲双胍对1)的影响 线粒体功能；2)细胞衰老；3)表观遗传学(DNA甲基化)，这将是 在父母补助金中研究了衰老的支柱(新陈代谢和炎症)。我们的目标是： 目的1)确定二甲双胍对老年人衰老支柱的影响。 目的2)确定二甲双胍诱导的衰老支柱的修饰和改变之间的联系 在以衰老为重点的表型结果中。 我们已经组建了一个跨三个机构的跨学科小组(UTHSCSA，Mayo，UCLA)，这是很好的 准备帮助阐明二甲双胍促进健康寿命延长的分子和细胞机制。

Based upon epidemiological data and interventional studies in invertebrates and rodents, metformin is a leading candidate to modulate aging. Yet, these animal studies have limited applicability to human subjects because they usually are of short duration and apply metformin doses that are much higher than the doses used in humans. Thus, the impact that metformin has on aging-focused outcomes and the mechanism by which metformin may promote healthy life extension in older human subjects is unknown. This grant application targets RFA-AG-20-044 “The Biological Mechanisms of Metformin Effects on Aging and Longevity” to test the hypothesis that metformin modulates critical pillars of aging in older adults to improve healthspan. We will leverage our ongoing NIA-funded randomized, placebo-controlled trial of metformin to prevent frailty in older adults (R01AG052697). The parent trial (n=120) is testing whether metformin administration for 24 months can prevent or delay the onset of frailty in older (≥ 65 years) adults. Deep aging- focused phenotyping includes changes in frailty (Fried phenotype score and Rockwood deficit accumulation index), physical function (short physical performance battery and 6-minute walk), muscle strength/mass, glucose metabolism (insulin clamping and glucose tolerance) and cognition (Mini-Mental State Exam). The parent trial also collects several biospecimens including blood, skeletal muscle and adipose tissue before and during metformin/placebo administration for measures of metabolic (AMPK and insulin signaling) and inflammation (NFκB and MAPKs) pathways. By applying innovative metabolomic, proteomic, molecular and biostatistical methodologies we will take advantage of these rich phenotypic data and biospecimens to evaluate the effect of metformin on 1) mitochondrial function; 2) cellular senescence; 3) epigenetics (DNA methylation), which will be in addition to the pillars of aging studied in the parent grant (metabolism and inflammation). Our objectives are: Aim 1) To determine the effect of metformin on pillars of aging in older adults. Aim 2) To determine the link between metformin-induced modifications in pillars of aging and changes in aging-focused phenotypic outcomes. We have assembled an interdisciplinary group across three institutions (UTHSCSA, Mayo, UCLA) that is well poised to help clarify the molecular and cellular mechanisms by which metformin promotes healthy life extension.