Extracellular Vesicle Analyses to Develop Aging and Resilience Biomarkers

摘要 细胞外囊泡是从几乎所有类型的细胞释放到所有体液中的膜状颗粒 包括血清和血浆。取决于组织来源、健康状况和生物体 随着年龄的增长，它们携带各种复杂的货物，包括核酸，蛋白质和代谢物。虽然 组织水平的恢复能力在很大程度上归功于干细胞，最近的证据越来越多地指出， 生产EV作为其显著再生能力的介质。小型电动汽车的快速释放是 身体活动引起的，并认为有助于长期有益的影响，定期锻炼， 肌肉代谢、心血管系统以及免疫调节。该项目的目标是 通过对电动汽车的分析，开发衰老和恢复力的生物标志物。由于它们的协调调节， 通过微小RNA和蛋白质货物的细胞间运输的组织稳态和生物过程， EV对于该项目特别有吸引力，因为它们可以潜在地用作以下的直接生物标志物： 老化和恢复力，即老化过程和对压力源的反应的指标和介质。我们将 使用我们新开发的18通道高分辨率流式细胞术方法，并通过 纳米粒子跟踪视频显微镜，和荧光激活的颗粒分选，我们已经建立在 实验室评估我们现有的大量人类样本集（n=4213个来自EPESE的个体， 帕尔斯、STRRIDE、BHS和杜克1 KP（1000例患者）队列），具有相关的去识别数据， 纵向随访6个月~ 23年。我们有初步的数据显示 在特定的循环EV亚群中。我们还发现，电动汽车的一个子集，包括其中一些 随着年龄的增长而下降，是由运动训练引起的，并预测对运动的有益代谢反应。 这些数据，以及我们这个项目的合作者，汇集了老龄化方面的广泛专业知识， 在整个生命周期（18至102岁）的弹性，运动和身体表现。这些资源 和能力为我们提供了一个独特的机会，使电动汽车沿着生物标志物管道 并确定健康衰老和恢复力的影响因素。为此，我们对资助作出回应， 机会公告PA-17-088，邀请采用现有数据二次分析的应用程序 以解决影响整个国家健康的衰老变化的临床相关问题 寿命

Abstract Extracellular vesicles (EVs) are membranous particles released from nearly all cell types into all bodily fluids evaluated to date — including serum and plasma. Depending on tissue of origin, health state and organism age, they carry a variety of complex cargo consisting of nucleic acids, proteins and metabolites. Although resilience at a tissue level has largely been attributed to stem cells, recent evidence increasingly points to their production of EVs as mediators of their remarkable regenerative capacity. The rapid release of small EVs is induced by physical activity and believed to contribute to the long-term beneficial effects of regular exercise on muscle metabolism, the cardiovascular system as well as immune modulation. The goal of this project is to develop biomarkers of aging and resilience through analyses of EVs. Due to their coordinate regulation of tissue homeostasis and biological processes through intercellular trafficking of microRNA and protein cargo, EVs are particularly attractive for this project because they can potentially serve as DIRECT biomarkers of aging and resilience, namely indicators AND mediators of the aging process and response to stressors. We will use our newly developed 18-channel-high-resolution flow cytometric methodology with validation by nanoparticle tracking video microscopy, and fluorescence-activated particle sorting that we have established in the laboratory to evaluate our large existing extensive human sample sets (n=4213 individuals from EPESE, PALS, STRRIDE, BHS and the Duke 1KP (1000 Patient) cohort) with associated deidentified data and longitudinal follow-up (6 months to 23 years). We have preliminary data demonstrating an age-related decline in specific subsets of circulating EVs. We also have identified that a subset of EVs, including some of those declining with age, are induced with exercise training and predict a beneficial metabolic response to exercise. These data, together with our collaborators for this project, bring together extensive expertise in aging, resilience, exercise, and physical performance across the lifespan (ages 18 to 102 years). These resources and capabilities provide a unique opportunity for us to significantly advance EVs along a biomarker pipeline and to identify effectors of heathy aging and resilience. For this reason, we are responding to the funding Opportunity Announcement PA-17-088 that invites applications that employ secondary analysis of existing data sets or stored biospecimens to address clinically related issues on aging changes influencing health across the lifespan.