Immune and inflammatory system changes in SuperAgers

摘要（项目2） 免疫和炎症系统功能对于响应感染是重要的，然而， 有证据表明，这些系统的改变伴随着正常的衰老和神经退行性疾病 变化（如阿尔茨海默病，AD）。不太深入了解的是这些系统的结构性影响， 器官和细胞在整个生命周期。在拟议的工作中，我们将探讨免疫的潜在影响， 以及这些过程对抵抗和恢复的影响， 与年龄相关的认知变化，导致超级衰老。这种方法的基础是有据可查的 免疫和炎症系统的变化，注意到在正常老化，促炎性小胶质细胞的变化， 与衰老和AD相关，并且出现了经过充分验证的AD遗传风险因素， 证明了免疫和炎症系统基因在疾病风险中的重要性。这些发现 表明免疫和炎症系统可能在对感染的急性反应中起作用， 对大脑健康、与年龄相关的认知变化和/或对大脑相关疾病的恢复力产生长期影响。 疾病 超级老龄化联盟的项目2将通过对独特个体的研究来探索这个问题 在一般人群中，表现出认知超级衰老表型的人--一种被定义为两个-- 十年，或更大的记忆容量的优势时，与年龄匹配的同龄人相比。我们建议 免疫和炎症系统功能与超级衰老个体的认知恢复力有关- 与AD的风险相反。我们假设超级老人（SA）将展示一个 与对照组和AD参与者相比，向神经保护和较低的促炎特征转变， 这些差异将阐明对年龄相关现象的恢复机制。这些假设将是 追求三个目标。在目标1中，我们将分析小胶质细胞和其他细胞的单个转录组， 来自SA、对照和AD参与者的脑组织。在目标2中，我们将研究三种不同的措施， 适应性免疫和炎症系统-细胞因子水平，T和B细胞受体库，抗体 轮廓-在SA、对照和AD参与者的外周样本中。最后，在目标3中，我们将研究 SA和对照组中约500种不同免疫和炎症系统基因的DNA序列变异。这 研究设计将使我们能够解开潜在的免疫和炎症过程之间的联系， 和抵抗与年龄相关的认知能力下降。

ABSTRACT (Project 2) Immune and inflammatory system functions are important to respond to infection, however, emerging evidence suggests that alterations in these systems accompany normative aging and neurodegenerative disease changes (like Alzheimer's disease, AD). Less deeply understood is the constitutive impact of these systems on organs and cells throughout the life span. In the proposed work we will explore the potential impact of immune and inflammatory processes on the brain and the influence of these processes on resistance and resilience to age-related cognitive changes that contribute to SuperAging. The basis for this approach is the well documented immune and inflammatory system changes noted in normative aging, the pro-inflammatory microglial changes associated with aging and AD, and the emergence of well-validated genetic risk factors for AD that have demonstrated the importance of immune and inflammatory system genes in risk for the disease. These findings suggest the immune and inflammatory system may play both a role in acute responses to infection as well as exert a long-term impact on brain health, age-related cognitive changes, and/or resilience to brain-related diseases. Project 2 of the SuperAging Consortium will explore this question through the study of unique individuals within the general population who exhibit the phenotype of cognitive SuperAging – a trait defined as a two- decade, or greater, superiority of memory capacity when compared to age-matched peers. We propose that immune and inflammatory system function is related to the cognitive resilience seen in SuperAging individuals – in the opposing way that it is related to risk for AD. We hypothesize that SuperAgers (SA) will demonstrate a shift toward neuroprotection and lower pro-inflammatory profiles compared to Control and AD participants and that these differences will clarify mechanisms of resilience to age-related phenomena. These hypotheses will be pursued through three aims. In Aim 1 we will profile the individual transcriptomes of microglia and other cells in brain tissue from SAs, Controls, and AD participants. In Aim 2 we will examine three different measures of the adaptive immune and inflammatory systems – cytokine levels, T- and B-cell receptor repertoires, and antibody profiles – in peripheral samples from SAs, Controls, and AD participants. Lastly, in Aim 3, we will investigate the DNA sequence variations in ~500 different immune and inflammatory system genes in SAs and Controls. This study design will allow us to unravel the link between potentially modifiable immune and inflammatory processes and resistance to age-related decline of cognitive capacity.