Immune and inflammatory system changes in SuperAgers

摘要（项目 2） 免疫和炎症系统功能对于应对感染很重要，但是，新兴的 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）。人们对这些系统的构成性影响还不太了解。 器官和细胞贯穿整个生命周期。在拟议的工作中，我们将探讨免疫的潜在影响 大脑的炎症过程以及这些过程对抵抗力和恢复力的影响 与年龄相关的认知变化会导致超级老化。这种方法的基础是有据可查的 正常衰老过程中注意到的免疫和炎症系统变化，即促炎性小胶质细胞变化 与衰老和 AD 相关，以及经过充分验证的 AD 遗传风险因素的出现 证明了免疫和炎症系统基因在该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以及 对大脑健康、与年龄相关的认知变化和/或与大脑相关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讨这个问题 在表现出认知超老化表型的普通人群中——这一特征被定义为两种 与同龄人相比，记忆能力具有十年或更长时间的优势。我们建议 免疫和炎症系统功能与超龄个体的认知弹性有关 – 相反，它与 AD 风险相关。我们假设 SuperAgers (SA) 将展示 与对照组和 AD 参与者相比，转向神经保护和较低的促炎特征， 这些差异将阐明与年龄相关的现象的恢复机制。这些假设将 通过三个目标来实现。在目标 1 中，我们将分析小胶质细胞和其他细胞的个体转录组 来自 SA、对照组和 AD 参与者的脑组织。在目标 2 中，我们将研究三种不同的衡量标准 适应性免疫和炎症系统 – 细胞因子水平、T 细胞和 B 细胞受体库以及抗体 配置文件 – 来自 SA、控制和 AD 参与者的外围样本。最后，在目标 3 中，我们将调查 SA 和对照中约 500 个不同免疫和炎症系统基因的 DNA 序列变异。这个 研究设计将使我们能够揭示潜在可改变的免疫和炎症过程之间的联系 以及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.