Does Metformin Modulate the Pillars of Aging in Older Adults?

根据流行病学数据和无脊椎动物和啮齿动物的干预性研究，二甲双胍是一种 是调节衰老的最佳人选。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短，并且应用的二甲双胍剂量远高于使用的剂量 在人类身上。因此，二甲双胍对以衰老为重点的结局的影响和机制是 二甲双胍可促进老年人健康寿命延长的机制尚不清楚。 本基金申请的目标是RFA-AG-20-044“代谢物对衰老影响的生物学机制” 和长寿”来检验二甲双胍调节老年人衰老的关键支柱， healthspan.我们将利用我们正在进行的由国家免疫局资助的二甲双胍随机、安慰剂对照试验， 预防老年人虚弱（R 01 AG 052697）。母试验（n=120）正在测试二甲双胍是否 给药24个月可预防或延迟老年人（≥ 65岁）虚弱的发作。深度老化- 重点表型包括虚弱（Fried表型评分和罗克伍德缺陷累积）的变化 指数）、身体功能（短期身体表现组合和6分钟步行）、肌肉力量/质量、葡萄糖 代谢（胰岛素钳夹和葡萄糖耐量）和认知（简易精神状态检查）。母试验 还收集了几个生物标本，包括血液，骨骼肌和脂肪组织之前和期间 二甲双胍/安慰剂给药，用于测量代谢（AMPK和胰岛素信号传导）和炎症 (NFκB和MAPK）途径。 通过应用创新的代谢组学、蛋白质组学、分子和生物统计学方法， 这些丰富的表型数据和生物样本的优势，以评价二甲双胍对1） 线粒体功能; 2）细胞衰老; 3）表观遗传学（DNA甲基化），这将是除了 衰老的支柱研究在父母补助金（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修饰与变化之间的联系 在以衰老为中心的表型结果中。 我们在三个机构（UTHSCSA，马约，加州大学洛杉矶分校）组建了一个跨学科小组， 有望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.