The Human Life Course and the Biodemography of Aging

描述（由申请人提供）：本申请的目标是测试一般假设：(1)早期和频繁暴露于病原体加速免疫系统发育并使免疫系统“启动”到更高水平的基线免疫活性；(2)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。提斯曼人是玻利维亚的采摘园艺师，他们生活在没有电、自来水或废物处理的环境中，获得现代医学的机会极其有限。为了实现我们的目标，对现有的R01“人类生命历程和老龄化的生物人口统计”进行竞争性修订有五个具体目标。目的1是测量提斯曼血清中细胞因子、炎症生物标志物和免疫球蛋白的水平。目的2是在体外用细菌、病毒和蠕虫抗原刺激新鲜全血时测试细胞因子的反应。目的3是用流式细胞术定量体内淋巴细胞和t细胞群，按年龄和性别表征免疫的细胞成分。目的4是检验从上述两个假设中得出的一系列预测。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。这个项目的增加将使我们能够建立一个大型成人样本的横截面和纵向剖面，以模拟感染，免疫系统发育和免疫衰老之间的相互作用，这些人群在前现代，高度传染性的环境中达到成熟。我们将四种方法结合起来调查对感染的免疫反应：1)医师检查与实验室分析相结合，按类型诊断感染；2)血清细胞因子、炎症标志物和免疫球蛋白的测定；3)用常见和新颖的蠕虫、病毒和细菌抗原进行体外全血攻击；4)流式细胞术鉴定记忆型和衰老型T细胞和B细胞表型的数量和比例。由于提斯曼人正在经历快速变化，我们还将能够通过检查文化适应对社区和个人层面免疫力的影响来评估种群内差异。我们还将把我们的结果与美国和其他国家获得的结果进行比较，以评估疾病传染负担对生命过程中免疫的影响。

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.