Mitochondrial function, immune aging, and frailty among people with and without HIV

这是约翰霍普金斯老年美国人独立中心的行政副刊 (OAIC)旨在利用该中心在交叉生物路径方面的专业知识， 通过对艾滋病病毒携带者的研究，在一部分艾滋病毒携带者中早期出现身体虚弱 线粒体功能衰退，如本提案所述。在艾滋病毒携带者(PWH)中，脆弱 预测死亡率、合并症和住院，是生活质量的重要指标。 脆弱发展的潜在机制可能是多方面的，部分原因是特征 生物老化，如线粒体衰退和慢性炎症。经济增长的主要驱动力之一 PWH的衰老过程是线粒体损伤，由慢性HIV感染引起 炎症，以及一些抗逆转录病毒疗法的效果。然而，变化在以下方面的作用 线粒体功能在PWH虚弱的病因中的作用尚不清楚。此外，每个 免疫细胞类型可能会对应激反应产生不同的代谢适应。相互影响 虚弱病因中线粒体功能与免疫激活和衰老的关系 事态发展仍不明朗。我们建议评估免疫细胞类型之间的关联- 特定的线粒体功能测量，包括线粒体含量、细胞膜 潜在的，和超氧化物，通过利用纵向数据，与艾滋病毒感染和脆弱， 样本和基础设施来自两个已建立的艾滋病毒队列：1)艾滋病与 静脉注射经验队列；以及2)多中心艾滋病队列研究。这些队列 独特的包括威斯康星医院和类似的未感染艾滋病毒的成年人。我们提出以下目标： 实现这些目标：(1)表征免疫细胞的激活和衰老以及细胞类型- 根据HIV感染状态分层的特定线粒体功能；以及(2)评估两者之间的联系 在纵向随访中，细胞类型特异性线粒体功能与脆性之间的关系 艾滋病病毒携带者和非艾滋病患者。我们将应用一种新的机器学习方法来表征 免疫衰老和线粒体功能的复杂和高维生物标志物数据 实现这些目标。借助OAIC的专业知识和资源，我们将提供有关 脆性前后细胞类型特异性线粒体功能谱的纵向变化 发展，这将使我们能够观察人与人之间线粒体功能的变化 不管有没有感染艾滋病毒。这些目标将提供对艾滋病毒之间相互作用的新理解 感染、免疫老化和线粒体功能在虚弱的病因中的作用。

This administrative supplement to the the Johns Hopkins Older Americans Independence Center (OAIC) is designed to capitalize on the Center's expertise on intersecting biological pathways that drive early onset of physical frailty in a subset of individuals living with HIV through the study of mitochondrial decline as articulated in this proposal. Among people with HIV (PWH), frailty predicts mortality, comorbidities, and hospitalization, and is an important indicator of quality of life. The underlying mechanisms for frailty development are likely multifaceted, due in part to features of biological aging such as mitochondrial decline and chronic inflammation. A major driver of the aging process in PWH is mitochondrial damage, resulting from chronic HIV infection, chronic inflammation, and the effects of some antiretroviral therapies. However, the role of changes in mitochondrial function in the etiology of frailty among PWH remains unclear. Furthermore, each immune cell type may develop different metabolic adaptations in response to stress. The interplay between mitochondrial function and immune activation and senescence in the etiology of frailty development remains unclear. We propose to evaluate the association of immune cell type- specific mitochondrial function measurements, including mitochondrial content, membrane potential, and superoxide, with HIV infection and frailty by leveraging longitudinal data, specimens, and infrastructure from two established HIV cohorts: 1) the AIDS Linked to the IntraVenous Experience cohort; and 2) the Multicenter AIDS Cohort Study. These cohorts uniquely include PWH and comparable HIV uninfected adults. We propose the following aims to accomplish these goals: (1) to characterize immune cell activation and senescence and cell type- specific mitochondrial function, stratified by HIV infection status; and (2) to assess the association between cell type-specific mitochondrial function and frailty during longitudinal follow-up among people with and without HIV. We will apply a novel machine learning approach to characterize the complex and high-dimensional biomarker data in immune aging and mitochondrial function to achieve these aims. With expertise and resources from the OAIC, we will provide data on the longitudinal change of cell type-specific mitochondrial function profiles before and after frailty development, which will allow us to observe variations in mitochondrial function among people with and without HIV. These aims will provide new understanding of the interplay between HIV infection, immune aging, and mitochondrial function in the etiology of frailty.