Does Metformin Modulate the Pillars of Aging in Older Adults?

二甲双胍能否调节老年人的衰老支柱？

基本信息

批准号：
10087333
负责人：
Sara Elyse Espinoza
金额：
$ 41.05万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10087333
关键词：
Adipose tissue Adult Age Aging Animals Applications Grants Biological Biological Markers Biometry Blood Cell Aging Clinical Trials Cognition DNA Methylation Disease Dose Elderly Epigenetic Process Fluorescent Antibody Technique Funding Geroscience Goals Human Inflammation Institution Intervention Intervention Studies Invertebrates Life Extension Link Longevity MAP Kinase Gene Mass Spectrum Analysis Measures Mediation Metabolic Metabolism Metformin Methodology Mitochondria Modeling Modification Molecular Muscle Outcome Parents Pathway interactions Pharmacology Phenotype Physical Function Physical Performance Placebos Process Proteomics Reactive Oxygen Species Research Resolution Respiration Rodent Skeletal Muscle Specimen Testing Time Tissue imaging Tissues Urine Walking base clinically relevant epidemiologic data frailty glucose and insulin clamps glucose metabolism glucose tolerance healthspan human subject improved improved functioning indexing innovation insulin signaling mental state metabolomics muscle form muscle strength novel parent grant phenotypic data prevent randomized placebo controlled trial randomized placebo-controlled clinical trial senescence transcriptomics

项目摘要

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.

根据流行病学数据和无脊椎动物和啮齿动物的介入研究，二甲双胍是一种然而，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，并且使用的二甲双胍剂量远高于实际使用的剂量因此，二甲双胍对衰老结果的影响及其机制哪种二甲双胍可以促进老年受试者的健康寿命延长尚不清楚。该拨款申请针对 RFA-AG-20-044“二甲双胍对衰老影响的生物机制” 和长寿”来检验二甲双胍调节老年人衰老的关键支柱以改善这一假设我们将利用 NIA 资助的正在进行的二甲双胍随机、安慰剂对照试验来预防老年人虚弱 (R01AG052697) 母试验 (n=120) 正在测试二甲双胍是否有效。连续服用 24 个月可以预防或延缓老年人（≥ 65 岁）的衰弱发生。重点表型分析包括虚弱的变化（Fried 表型评分和 Rockwood 赤字累积指数）、身体机能（短时间身体表现电池和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）。还在之前和期间收集了一些生物样本，包括血液、骨骼肌和脂肪组织二甲双胍/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，我们将采取利用这些丰富的表型数据和生物样本来评估二甲双胍对 1) 的影响线粒体功能；2) 细胞衰老；3) 表观遗传学（DNA 甲基化）父母资助中研究的衰老支柱（代谢和炎症）我们的目标是：目标 1) 确定二甲双胍对老年人衰老支柱的影响。目标 2) 确定二甲双胍引起的衰老支柱修饰与变化之间的联系以衰老为中心的表型结果。我们在三个机构（UTHSCSA、梅奥大学、加州大学洛杉矶分校）组建了一个跨学科小组，该小组非常擅长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。