Molecular interception and immunological characterization of age-associated disease

项目摘要 在发达国家，癌症、心血管疾病、慢性呼吸道疾病等非传染性疾病 疾病和糖尿病是70岁及以上老年人死亡的主要原因。全球经济 照顾非传染性疾病患者的负担是天文数字。2010年，估计花费了47 在2010-2030年期间，将投入2000亿美元，相当于2010年全球国内生产总值的75%， 对于慢性病患者。显然，我们需要一个更好的策略来识别风险最大的患者， 我们可以预防疾病发展或提供早期干预。我们最近的研究表明， 免疫功能下降是心血管疾病发展的一个主要的、潜在的、可改变的危险因素。 疾病然而，目前还不清楚患者的免疫系统在生命周期的哪个阶段老化， 有助于疾病，遗传和环境因素如何影响免疫年龄，以及免疫力是否下降， 功能也与其他非传染性疾病的发展有关， 时间老化项目2旨在了解免疫衰老（其 加深了对我们在项目1）中评估的流感应对的理解和关系， 与时间老化相关的疾病-我们假设这种关联始于中年， 贯穿个人的一生。在项目2中，首先，我们添加了一个中年双胞胎队列（MAT-SELA） 在人口统计学上与SELA队列相似，不仅扩大了待分析患者的年龄范围，而且 解开遗传和环境对免疫衰老的影响。为了进一步隔离环境 影响免疫年龄，我们还将比较一个超级适合老年队列（AL-SELA）的免疫年龄与 SELA队列，他们是正常的，老年患者，生活方式久坐不动。第二，我们深入 分析免疫年龄如何影响心血管疾病的发展，建立在我们以前的工作， 通过连续分析处于发展动脉粥样硬化最大风险的患者的免疫年龄（例如， 斑块积聚、心脏病发作或中风），通过非侵入性成像监测这些患者， 和/或心血管疾病进展，并记录任何主要不良临床事件。此外，委员会认为， 我们应用我们实验室开发的先进的基于免疫的测定来询问分子和细胞， 动脉粥样硬化斑块的组成部分，扩展了我们最近的发现，即流感特异性T细胞在动脉粥样硬化斑块中发现。 动脉粥样硬化斑块，为了更好地了解最近临床 观察发现，患流感会增加心脏病发作和中风的风险。最后，我们将确定是否免疫 年龄有助于其他非传染性疾病，通过比较与 在我们的队列中使用公开可用的数据库将免疫状态与疾病联系起来， 可能性、严重性和预后。

PROJECT SUMMARY In developed countries, noncommunicable diseases such as cancer, cardiovascular disease, chronic respiratory illness, and diabetes account for the majority of deaths among people aged 70 and older. The global economic burden to care for patients with noncommunicable diseases is astronomical. In 2010, it cost an estimated 47 trillion dollars in 2010-2030, which is equivalent to 75% of global gross domestic product in 2010, to provide care for patients with chronic disease. Clearly, we need a better strategy to identify patients at greatest risk so that we can prevent disease development or provide earlier intervention. Our recent work has suggested that a decline in immune function is a major, potentially modifiable, risk factor for the development of cardiovascular disease. It remains unclear, however, at what point in the patient’s lifespan does the immune system age and contribute to disease, how genetic and environmental factors affect immune age, and whether decline in immune function is also associated with the development of other noncommunicable diseases associated with chronological aging. Project 2 is designed to understand the relationship between immune-aging (whose deepened understanding and relationship to flu response we assess in Project 1) and the development of diseases associated with chronological aging - an association that we hypothesize begins in middle-age but extends throughout the individual’s life span. In Project 2, first, we add a middle age cohort of twins (MAT-SELA) demographically similar to the SELA cohort, to not only expand the age range of patients to be profiled, but also to disentangle the effects of genetics and the environment to immune aging. To further isolate the environmental effects on immune age, we will also compare the immune age of a super fit older cohort (AL-SELA) with that of the SELA cohort, who are normal, older patients leading sedentary lifestyles. Second, we perform an in-depth analysis of how immune age affects the development of cardiovascular disease, building from our previous work, by serially profiling the immune age of patients who are at greatest risk for developing atherosclerosis (e.g., plaque build-up, heart attack or stroke), monitoring these patients by non-invasive imaging for the development and/or progression of cardiovascular disease, and documenting any major adverse clinical events. Furthermore, we apply advanced immune-based assays developed by our lab to interrogate the molecular and cellular components of the atherosclerotic plaque, extending our recent finding that flu specific T cells are found in the atherosclerotic plaque, in order to better understand the underlying mechanisms behind recent clinical observations that having the flu increases the risk of heart attack and stroke. Lastly, we will determine if immune age contributes to other non-communicable diseases by comparing the immune gene signatures associated with advanced aging in our cohorts with publicly available databases to associate the immune state with disease likelihood, severity, and prognosis.