Molecular interception and immunological characterization of age-associated disease

项目总结 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。在2010年，它的成本估计为47 2010-2030年的万亿美元，相当于2010年全球国内生产总值的75%，用于提供医疗服务 适用于慢性病患者。显然，我们需要一个更好的策略来识别风险最高的患者，以便 我们可以预防疾病发展或提供更早的干预。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，目前尚不清楚免疫系统在患者生命的哪个时间点老化和 导致疾病的因素，遗传和环境因素如何影响免疫年龄，以及免疫功能是否下降 功能也与其他非传染性疾病的发展有关，与 按时间顺序老化。项目2旨在了解免疫衰老(谁的 加深了对我们在项目1中评估的流感应对措施的理解和关系)以及 与慢性衰老相关的疾病--我们假设这种关联始于中年，但 它贯穿于个体的整个生命周期。在项目2中，首先，我们增加了一对中年双胞胎(Mat-Sela) 在人口统计上与SELA队列相似，不仅扩大了要分析的患者的年龄范围，而且还 理清遗传和环境对免疫衰老的影响。为了进一步隔离环境 关于免疫年龄的影响，我们还将比较超级健康的老年队列(AL-SELA)和 SELA是一群正常的老年患者，他们过着久坐的生活方式。第二，我们深入地进行了 分析免疫年龄如何影响心血管疾病的发展，建立在我们之前的工作基础上， 通过连续地描述具有发展为动脉粥样硬化最大风险的患者的免疫年龄(例如， 斑块堆积、心脏病发作或中风)，通过无创成像监测这些患者的发育 和/或心血管疾病的进展，并记录任何主要的不良临床事件。此外， 我们应用我们实验室开发的先进的基于免疫的分析方法来询问分子和细胞 动脉粥样硬化斑块的成分，延续了我们最近的发现，即在 动脉粥样硬化斑块，以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 年龄通过比较与非传染性疾病相关的免疫基因信号而导致其他非传染性疾病 通过公开可用的数据库将免疫状态与疾病联系起来，在我们的队列中提前老龄化 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.