The Human Life Course and the Biodemography of Aging

描述（由申请人提供）：本申请的目的是测试以下一般假设：（1）早期和频繁暴露于病原体加速免疫系统发育，并将免疫系统“激发”至更高水平的基线免疫活性，以及2）这种终生慢性免疫系统激活导致更快的免疫衰老和防御新病原体的能力下降。Tsimane是玻利维亚的觅食园艺家，他们生活在没有电，自来水或废物处理的环境中，并且获得现代医学的机会非常有限。 为了实现我们的目标，有五个具体的目标，这个竞争性的修订现有的R 01“人类生命历程和老龄化的生物人口学”。目的1是测量Tsimane血清中细胞因子、炎性生物标志物和免疫球蛋白的水平。目的2是测试细胞因子的反应，在体外刺激新鲜全血与细菌，病毒和蠕虫抗原。目的3是用流式细胞术定量体内淋巴细胞和T细胞群，以按年龄和性别表征免疫的细胞组分。目的4是检验由上述两个假设得出的一系列预测。目的5探讨疾病状态、功能状态、死亡率与免疫系统功能的关系. 该项目的增加将使我们能够建立一个大样本成人的横截面和纵向概况，以模拟在前现代，高传染性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。我们结合了联合收割机四种方法来研究对感染的免疫应答：1）医生检查结合实验室分析，以按类型诊断感染; 2）测量血清细胞因子、炎症标志物和免疫球蛋白; 3）用常见和新型蠕虫、病毒和细菌抗原进行体外全血激发; 4）流式细胞术以鉴定记忆和衰老T和B细胞表型的数量和比例。由于Tsimane正在经历快速的变化，我们也将能够通过检查文化适应对社区和个人免疫力的影响来评估人口内的差异。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，以评估疾病的传染负担对整个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感染性疾病和免疫反应的详细信息，在生命过程中的前现代人口的觅食园艺南美洲经历了高病原体负担。对大样本老年人免疫系统发育和衰老的研究可以揭示免疫系统如何对病原体暴露强度做出反应以及整个生命过程中免疫系统激活的增加如何影响免疫衰老的速率。由于世界上大部分人仍然生活在发展中国家，寄生虫，病毒和细菌的共同感染，这项研究的结果，结合美国和印度尼西亚等其他人口的老龄化和疾病的措施，将有助于规避环境和社会背景下疾病流行病学的趋势。

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.