Aging Intervention Studies

衰老干预研究

基本信息

批准号：
10913049
负责人：
Julie Mattison
金额：
$ 273.61万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10913049
关键词：
Adjuvant Adult Age Aging Animal Model Attenuated Biological Biological Assay Biological Markers Blood specimen Cardiac Cardiovascular Physiology Clinical Clinical Treatment Complex DNA Methylation Diabetes Mellitus Diagnostic Disease Drug Compounding Environmental Risk Factor Epigenetic Process Exercise FDA approved Gene Expression Genetic Goals Health Status Human Immune response Incidence Inflammatory Inflammatory Response Intervention Intervention Studies Intervention Trial Learning Link Longevity Macaca mulatta Memory Metabolism Monkeys Muscle Muscle Proteins Muscle function Myocardial dysfunction Non-Insulin-Dependent Diabetes Mellitus Outcome Measure Pathogenesis Pathway interactions Pharmaceutical Preparations Physical activity Physiological Population Post-Translational Protein Processing Prediabetes syndrome Probability Process Protein Biosynthesis Proteins RNA RNA Splicing Research Resources Rhesus Role Running T cell response Testing Time Tissues Training Vaccines Virus Vulnerable Populations age related antibody test biomarker development diabetes management effectiveness evaluation experimental study gut microbiome heart function heart rhythm high risk immunogenicity improved influenza virus strain influenza virus vaccine methylation pattern mortality risk multiple omics muscle strength nonhuman primate novel novel therapeutics preservation programs rapid growth seasonal influenza sedentary therapeutic target translational model treadmill

项目摘要

Within this program several studies are on-going 1. Muscle protein remodeling with exercise Muscle strength and function decline with age and lead to loss of mobility. Physical activity is known to attenuate the decline, but mechanisms are not clear. Muscle from sedentary older humans is associated with an imbalance in energetic metabolism, a pro-inflammatory profile, and a breakdown of protein. RNA functions to control synthesis of proteins and as it carries the message, it can be changed by a process of splicing, leading to changes in proteins. Studies in older sedentary humans shows that their muscles have more of this splicing while active age-matched subjects maintain a protein profile more consistent with younger subjects. The mechanisms for this activity induced preservation of muscle protein are unclear. Certainly, the inflammatory response may play a role and the gut microbiome provides a window into these changes. Rhesus monkeys, which are 95% genetically similar to humans, provide an excellent opportunity to more closely examine the time course of changes in RNA splicing, protein modifications and the role of the inflammatory pathways. Although largely sedentary, monkeys can be trained to run on treadmills and therefore, we can assess the effects of physical activity. 2. Multi-omics across the lifespan Omics-based assays can be used to study the complex interactions between multiple genetic and environmental factors that occur during aging and the pathogenesis of disease. These approaches can be used to develop diagnostic and therapeutic targets for treatment. The Core rhesus colony spans the average lifespan and provides a unique resource for a multi-omics approach to generate a multi-tissue profile associated with health status and biomarker development. This project will improve our understanding of the connectivity of the various omics components and will help identify important biological connections to disease and aging. 3. Treating pre-diabetes in NHPs Type II diabetes mellitus occurs spontaneously in aging rhesus monkey colonies at rates approximating those of the human population. An increasing incidence of diabetes among humans has led to rapid growth in the number of FDA approved treatments available for clinical use. However, managing diabetes in the research setting has not been expanded to include newer clinical treatments. We will evaluate outcome measures to compare some of the more commonly used human medications to improve long-term management for monkeys. 4. Immunogenicity of novel adjuvant to flu vaccine Seasonal influenza vaccines often provide suboptimal immune responses to current circulating influenza strains because of virus drift and the lack of adjuvants, added ingredients which boost the immune response. Aging populations are at high risk of death due to the seasonal flu; thus, more effective vaccine treatments are needed to protect this vulnerable population. The objective of this study is to test the antibody and T cell response to a novel computationally derived vaccine with and without an adjuvant. 5. Cardiovascular function in aging NHPs The objective of this project is to evaluate age-dependent changes in cardiac function (systolic and diastolic), the probability of developing cardiac rhythm abnormalities, and cardiac gene expression in nonhuman primates. These experiments will help to establish potential links between changes in gene expression and age-dependent cardiac dysfunction. 6. Epigenetic Clock DNA methylation is now widely used as an indicator of biological age and a marker of to evaluate the effectiveness of age-related interventions. Rhesus monkeys are an important translational model for aging studies with a 93% genetic homology with humans. Characterization of the epigenetic clock representing the lifespan will provide valuable information in an animal model that is widely used in translational aging research. In a cross-sectional approach, we have collected blood samples from of rhesus monkeys covering the adult lifespan to describe the DNA methylation pattern and generated rhesus specific clocks as well as comparisons to other nonhuman primates.

在该计划中，一些研究正在进行 1。锻炼肌肉蛋白重塑肌肉力量和功能随着年龄的增长而下降，导致流动性丧失。已知体育锻炼会减少下降，但机制尚不清楚。久坐的老年人的肌肉与能量新陈代谢的失衡，促炎性概况和蛋白质分解有关。 RNA功能可以控制蛋白质的合成并随附消息时，可以通过剪接过程更改它，从而导致蛋白质的变化。对年长久坐的人类的研究表明，他们的肌肉具有更多的剪接，而活跃的年龄匹配受试者则保持蛋白质谱与年轻受试者更一致。该活性诱导的肌肉蛋白保存的机制尚不清楚。当然，炎症反应可能起作用，肠道微生物组为这些变化提供了一个窗口。恒河猴在遗传上与人类相似95％，为更仔细地研究RNA剪接，蛋白质修饰和炎症途径的作用的时间过程提供了一个绝佳的机会。尽管在很大程度上久坐不动，但可以训练猴子在跑步机上运行，因此，我们可以评估体育活动的影响。 2。整个生命周期基于OMICS的测定方法可用于研究衰老过程中多种遗传因素和疾病发病机理的复杂相互作用。这些方法可用于开发治疗的诊断和治疗靶标。核心的恒河殖民地涵盖了平均寿命，并为多摩斯方法提供了独特的资源，以生成与健康状况和生物标志物开发相关的多组织配置文件。该项目将提高我们对各种OMIC组件的连通性的理解，并有助于确定与疾病和衰老的重要生物学联系。 3。在NHP中治疗糖尿病前期 II型糖尿病以近似于人口的晶状体菌落自发发生。人类糖尿病的发生率的越来越多，导致可用于临床使用的FDA批准治疗的数量迅速增长。但是，在研究环境中管理糖尿病尚未扩展，以包括新的临床治疗方法。我们将评估结果指标，以比较一些更常用的人类药物，以改善猴子的长期管理。 4。新型辅助对流感疫苗的免疫原性季节性流感疫苗通常由于病毒漂移和缺乏佐剂而对当前循环流感菌株的免疫反应提供次优的免疫反应，并添加了增强免疫反应的成分。由于季节性流感，衰老的人口处于高死亡风险。因此，需要更有效的疫苗治疗来保护这一脆弱人群。这项研究的目的是测试具有和没有佐剂的新型计算疫苗的抗体和T细胞反应。 5。衰老NHP的心血管功能该项目的目的是评估心脏功能（收缩期和舒张压）的年龄依赖性变化，发展心律异常的可能性以及在非人类灵长类动物中的心脏基因表达。这些实验将有助于建立基因表达变化与年龄依赖性心脏功能障碍之间的潜在联系。 6。表观遗传钟现在，DNA甲基化被广泛用作生物年龄的指标，并且是评估与年龄相关干预措施有效性的标志物。恒河猴是与人类遗传同源性为93％的衰老研究的重要翻译模型。代表寿命的表观遗传时钟的表征将在动物模型中提供有价值的信息，该信息广泛用于转化衰老研究。在横截面方法中，我们从涵盖成人寿命的恒河猴中收集了血液样本，以描述DNA甲基化模式并产生了恒河猴的特定时钟，并与其他非人类灵长类动物进行了比较。