Immune and metabolic dysfunction during aging in human cohorts

人类衰老过程中的免疫和代谢功能障碍

基本信息

批准号：
10673299
负责人：
BLANCA I RESTREPO
金额：
$ 57.45万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10673299
关键词：
Adult Affect Age Aging Anti-Inflammatory Agents Autoimmune Diseases Biological Biological Markers Blood Brain Cells Clinical Communities Complement Containment Cross-Sectional Studies Defect Diabetes Mellitus Diagnosis Elderly Enrollment Event Exposure to Failure Foundations Functional disorder Future Genetic Goals Growth HIV Health Health system High Prevalence Hispanic Homeostasis Human Immune Immune System Diseases Immunologics Impairment Individual Infection Inflammation Intervention Joints Lead Longitudinal Studies Lung Lung infections Measures Metabolic Metabolic dysfunction Metabolism Mexico Mitochondria Modeling Molecular Morbidity - disease rate Mus Mycobacterium tuberculosis Non-Insulin-Dependent Diabetes Mellitus Organ failure Outcome Oxidative Stress Oxidative Stress Pathway Participant Pathway interactions Patients Persons Phenotype Plasma Premature aging syndrome Process Proteins Pulmonary Tuberculosis Research Personnel Role Sampling Site Skeletal Muscle Specimen Testing Texas Time Tuberculosis Waste Management age effect age group body system chemokine cohort cytokine functional decline healthspan high risk human old age (65+)immune function in vivo monitoring monocyte mortality novel older patient oxidation pathogen prevent research clinical testing response restoration therapy development tuberculosis treatment

项目摘要

Old age is associated with a high prevalence of metabolic alterations like type 2 diabetes mellitus (DM) and preOM 0ointly 'dysglycemia'), and with an immunologic decline associated with higher risk of developing and dying from lung infections like pulmonary tuberculosis (PTB). These immune-metabolic alterations are accompanied by failure in other organ systems (lung, brain, skeletal muscle), leading to increased morbidity and mortality. Understanding these interactions and detecting them early is critical for delaying, preventing or restoring an individual's organ system health. The underlying mechanisms for immunometabolic alterations are unknown, but our joint studies in humans and mice with and without Mycobacterium tuberculosis (M.tb) infection provide support for the role of oxidative stress and associated inflammation as a driver. Accordingly, in our Hispanic human cohort, we find that systemic oxidative stress is higher in TB or DM patients, and exacerbates age effects. We hypothesize that aging-related immunometabolic changes that drive organ failure are largely originated from impaired mitochondria-driven oxidative stress pathways. We will test these hypotheses, conducting snap-shot and longitudinal studies in humans. We will identify the age at which these changes initiate and the most affected pathway, focusing on monocytes attained from relatively non-invasive specimens. i.e., blood. These studies will take advantage of a well-defined Hispanic clinical cohort at the Texas-Mexico border and our established team of field investigators. In Aim 1, we will determine: i) when altered measures of mitochondria-induced oxidative stress and immune dysfunction are first detected in blood and monocytes during the process of aging, to identify the most effective age for interventions. In Aim 2, we will determine the impact of host biological perturbations (dysglycemia and PTB) on these outcomes. We will further evaluate if PTB may serve as a new model of accelerated aging, given its association with inflammation and oxidative stress. Overall, results will provide the foundation for future clinical testing selected interventions in-vivo and monitoring individualized responsiveness with simple biomarker testing, to promote extended cellular health and organ system healthspan.

老年与 2 型糖尿病 (DM) 和 preOM 0（即“血糖异常”）等代谢改变的高发生率相关，并且与免疫功能下降相关，而免疫功能下降则与较高的发病和死亡风险相关肺部感染，如肺结核 (PTB)。这些免疫代谢改变伴随着其他器官系统（肺、脑、骨骼肌）衰竭，导致发病率和死亡率增加。了解这些相互作用并及早发现它们对于延迟、预防或恢复疾病至关重要个人器官系统的健康。免疫代谢改变的潜在机制尚不清楚，但我们对感染或未感染结核分枝杆菌 (M.tb) 的人类和小鼠进行的联合研究提供了支持氧化应激和相关炎症作为驱动因素的作用。因此，在我们的西班牙裔在人类队列中，我们发现结核病或糖尿病患者的全身氧化应激更高，并加剧了年龄效应。我们假设导致器官衰竭的衰老相关免疫代谢变化很大程度上源于线粒体驱动的氧化应激途径受损。我们将测试这些假设，进行快照和人类纵向研究。我们将确定这些变化开始的年龄以及受影响最严重的人途径，重点关注从相对非侵入性标本中获得的单核细胞。即血液。这些研究将利用德克萨斯州-墨西哥边境明确的西班牙裔临床队列和我们现有的团队的实地调查员。在目标 1 中，我们将确定：i) 何时改变线粒体诱导的氧化测量在衰老过程中，首先在血液和单核细胞中检测到压力和免疫功能障碍，以识别干预措施最有效的年龄。在目标 2 中，我们将确定宿主生物扰动的影响（血糖异常和 PTB）对这些结果的影响。我们将进一步评估PTB是否可以作为新的模式鉴于其与炎症和氧化应激的相关性，加速衰老。总体而言，结果将提供为未来临床测试选定的体内干预措施和监测个体化反应奠定基础通过简单的生物标志物测试，促进延长细胞健康和器官系统健康寿命。