The Human Life Course and the Biodemography of Aging

描述(申请人提供)：本申请的目标是测试一般假设：(1)早期和频繁地接触病原体会加速免疫系统的发展，并使免疫系统达到更高水平的基线免疫活动，以及2)这种贯穿一生的慢性免疫系统激活会导致更快的免疫衰老和对新病原体的防御能力下降。Tsimane人是玻利维亚的觅食园艺家，他们生活在没有电、没有自来水或垃圾处理的情况下，获得现代医学的机会极其有限。为了实现我们的目标，这次竞争性修订对现有的R01《人类生命历程和老龄化生物人口学》有五个具体目标。目的1测定血清中细胞因子、炎症生物标志物和免疫球蛋白的水平。目的2检测细菌、病毒和蠕虫抗原体外刺激新鲜全血时的细胞因子反应。目的3是用流式细胞术定量体内淋巴细胞和T细胞群，以确定免疫的细胞成分的年龄和性别。目标4是检验由上述两个假设得出的一系列预测。目的5研究疾病状态、功能状态、死亡率和免疫系统功能之间的关系。这个项目的加入将使我们能够建立一个大样本成人的横截面和纵向轮廓，以模拟在前现代、高度感染的环境中达到成熟的人群中感染、免疫系统发育和免疫衰老之间的相互作用。我们结合四种方法来研究感染的免疫反应性：1)医生检查结合实验室分析以按类型诊断感染；2)测定血清细胞因子、炎症标志物和免疫球蛋白；3)体外全血挑战常见和新型蠕虫、病毒和细菌抗原；4)流式细胞术确定记忆和衰老T和B细胞表型的数量和比例。由于齐曼人正在经历快速的变化，我们也将能够通过在社区和个人层面上检查适应对免疫的影响来评估种群内的差异。我们还将把我们的结果与美国和其他国家的结果进行比较，以评估疾病的传染性负担对生命过程中免疫力的影响。 公共卫生相关性：这一更新将提供有关南美洲经历高病原体负担的前现代觅食园艺家群体的传染病和生命过程中的免疫反应的详细信息。对大量老年人的免疫系统发育和衰老进行研究，可以揭示免疫系统如何对病原体暴露的强度做出反应，以及一生中免疫系统的激活增加如何影响免疫敏感率的独特见解。由于世界上大部分地区仍然生活在发展中国家，寄生虫、病毒和细菌共同感染，这项研究的结果与美国和印度尼西亚等其他人口的老龄化和疾病测量相结合，将有助于避开环境和社会背景下的疾病流行病学趋势。

DESCRIPTION (provided by applicant): The goal of this application is to test the general hypotheses that: (1) early and frequent exposure to pathogens accelerates immune system development and 'primes' the immune system to higher levels of baseline immune activity and 2) this chronic immune system activation throughout life results in more rapid immunosenescence and a decline in the ability to defend against novel pathogens.. The Tsimane are Bolivian forager-horticulturalists that live with no electricity, running water, or waste disposal, and have extremely limited access to modern medicine. To accomplish our goal, there are five specific aims of this competitive revision to the existing R01 "The Human Life Course and the Biodemography of Aging". Aim 1 is to measure the levels of cytokines, inflammatory biomarkers, and immunoglobulins in Tsimane sera. Aim 2 is to test cytokine responses during in vitro stimulation of fresh whole-blood with bacterial, viral, and helminthic antigens. Aim 3 is to quantify in vivo lymphocyte and T-cell populations with flow cytometry to characterize cellular components of immunity by age and sex. Aim 4 is to test a series of predictions derived from the above two hypotheses. Aim 5 is investigate the relationships between disease states, functional status, mortality and immune system function. The addition of this project will allow us to build a cross-sectional and longitudinal profile of a large sample of adults to model interactions between infection, immune system development and immunosenescence in a population that reached maturity in a pre-modern, highly infectious environment. We combine four methods to investigate immune responsiveness to infection: 1) physician exams combined with laboratory analysis to diagnosis infections by type; 2) measurement of serum cytokines, inflammatory markers and immunoglobulins; 3) In vitro whole blood challenges with common and novel helminthic, viral and bacterial antigens; 4) flow cytometry to identify number and proportions of memory- and senescent- T and B cell phenotypes.). As the Tsimane are undergoing rapid change, we will also be able to assess within-population variance by examining the effects of acculturation on immunity at the community and individual level. We will also compare our results to those obtained in the U.S. and other countries, to assess the impacts of the infectious burden of disease on immunity over the life course. PUBLIC HEALTH RELEVANCE: This renewal will provide detailed information on infectious disease and immune responsiveness over the life course in a pre-modern population of forager-horticulturalists of South America experiencing a high pathogen burden. Investigation of immune system development and senescence in a large sample of older adults can reveal unique insights about how the immune system responds to the intensity of pathogen exposure and how increased activation of the immune system throughout life can affect the rate of immunosenesence. Since much of the world still lives in developing countries, with co-infection of parasites, viruses and bacteria, the results of this research, combined with measures of aging and disease in other populations such as the U.S. and Indonesia, will help eludicate trends in disease epidemiology across environmental and social contexts.