Social Disadvantage and Its Impact on Pathogen Burden and Immune Dysfunction Across the Life Course

项目摘要 衰老的过程往往会导致残疾增加，身体功能丧失，认知能力下降， 和多种慢性病的发展。这一过程的一个关键驱动因素是免疫系统的衰老。 免疫系统，或免疫衰老，已知与慢性炎症有关。然而， 新出现的证据还表明，免疫系统不断受到攻击会导致免疫功能障碍。 由多种持续性感染所致。这些感染和由此导致的免疫功能障碍共同启动了一种 导致免疫衰老加速的一连串事件。因此，加速免疫衰老可能是一种 晚年健康差距的驱动因素。一项新的研究表明，一生中免疫功能障碍的差异 课程可以与社会劣势联系在一起，可以追溯到童年。一个关键的知识差距是如何 早期的社会劣势通过免疫功能障碍加速免疫衰老。 拟议研究的目的是探索病原体负担作为一种关键的介体在 从童年社会劣势到加速衰老的途径，通过炎症和免疫来衡量 功能障碍。为了验证这一假设，我将首先定义儿童社会劣势之间的联系 和整个生命过程中的病原体负担(目标1)。童年社会劣势的定义是两个低 18岁以前的社会经济地位和经历过压力源，如父母死亡或身体虐待 年纪大了。我假设，在童年经历更高水平的社会劣势的人将会有 在整个生命过程中增加病原体负担的水平。然后，我将定义两者之间的关联 病原体负担、免疫系统功能障碍和炎症(目标2)。我将首先通过测试 现有队列研究中病原体负担与炎症之间的关系。我假设更高的 病原体负担的水平将与炎症增加相关。然后我会测试一下这种联系 病原体负担和免疫功能障碍之间的纵向关系。我假设那些经历了更高 处于社会不利地位的儿童在一生中会经历更多的免疫功能障碍。 最后，我将研究儿童社会劣势与社会危害性之间的关联程度 炎症/免疫功能障碍是由病原体负担介导的(目标3)。我假设病原体 负担将部分地调节儿童社会劣势和免疫功能障碍之间的关系 和发炎。 在它的结论，这个项目将产生一个扩展的知识，我们的老化过程在早期 生命历程，特别是童年的社会劣势如何通过 病原体负担的机制和在衰老中的放大差异。最终，这将是可行的，将通知我们的 了解在生命过程中导致疾病、残疾和死亡的可改变的过程。

Project Summary The process of aging often leads to increased disability, loss of physical functioning, cognitive decline, and development of multiple chronic diseases. One critical driver of this process is senescence of the immune system, or immunosenescence, which is known to be associated with chronic inflammation. However, emerging evidence also points to immune dysfunction resulting from continual assault on the immune system by multiple persistent infections. Together, these infections and resulting immune dysfunction set in motion a cascade of events leading to accelerated immunosenescence. Accelerated immunosenescence may then be a driver of health disparities later in life. New research suggests disparities in immune dysfunction across the life course can be linked to social disadvantage extending back to childhood. A critical knowledge gap is how early-life social disadvantage accelerates immunosenescence through immune dysfunction. The objective of the proposed research is to explore pathogen burden as a critical mediator in the pathway from childhood social disadvantage to accelerated aging, as measured by inflammation and immune dysfunction. To test this hypothesis, I will first define the association between childhood social disadvantage and pathogen burden across the life course (Aim 1). Childhood social disadvantage is defined by both low socioeconomic status and experiences of stressors, such as parental death or physical abuse, before 18 years of age. I hypothesize that individuals experiencing higher levels of social disadvantage in childhood will have increased levels of pathogen burden throughout the life course. I will then define the association between pathogen burden and immune system dysfunction and inflammation (Aim 2). I will do this first by testing the association between pathogen burden and inflammation in existing cohort studies. I hypothesize that higher levels of pathogen burden will be associated with increased inflammation. I will then test the association between pathogen burden and immune dysfunction longitudinally. I hypothesize that those experiencing higher levels of childhood social disadvantage will experience increased immune dysfunction over the life course. Lastly, I will examine the degree to which the association between childhood social disadvantage and inflammation/immune dysfunction is mediated by pathogen burden (Aim 3). I hypothesize that pathogen burden will partially mediate the relationship between childhood social disadvantage and immune dysfunction and infllammation. At its conclusion, this project will yield an expansion of our knowledge of the aging process early in the life course, specifically how childhood social disadvantage can induce accelerated aging through the mechanism of pathogen burden and amplify disparities in aging. Ultimately, this will work will inform our understanding of modifiable processes that cause disease, disability, and mortality across the life course.