Mitochondrial determinants of monocyte dysfunction in aging

衰老过程中单核细胞功能障碍的线粒体决定因素

• 批准号: 10514864
• 负责人: Brandt D. Pence
• 金额: $ 41.41万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10514864
• 关键词: Acute; Acute Disease; Aging; Antigens; Area; Blood Cells; Cells; Chronic; Chronic Disease; Citric Acid Cycle; Communicable Diseases; Complex; Disease; Elderly; Electron Transport; Etiology; Functional disorder; Future; Gene Expression; Histones; Human; Immune; Immune System Diseases; Immune response; Immunity; Immunologic Tests; Immunosuppression; Impairment; In Vitro; Individual; Inflammaging; Inflammation; Inflammatory; Inflammatory Response; Innate Immune System; Knowledge; Link; Lysine; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Mitochondria; Modification; Mus; Myeloid Cells; Natural Immunity; Nature; Older Population; Outcome; Pathway interactions; Permeability; Phagocytes; Phagocytosis; Preclinical Testing; Predisposition; Procedures; Process; Proteins; Pyruvate; Research; Risk Factors; Role; Severities; Signal Transduction; System; Therapeutic; Transplantation; Work; acute infection; age related; aged; cell type; cytokine; experimental study; immune function; immunoregulation; immunosenescence; macrophage; mitochondrial dysfunction; monocyte; new therapeutic target; novel; preclinical study; therapeutic target; young adult

Aging is the primary risk factor for nearly all chronic diseases, and additionally is associated with increased severity of a number of acute infectious diseases. These phenomena are linked by dysregulation of the innate immune system, which contributes both to immune dysfunction (immunosenescence) and chronic low-grade inflammation (inflammaging). Monocytes are key innate immune cells that circulate and release pro-inflammatory cytokines to contribute to inflammaging, but also have suppressed inflammatory responses upon infectious or inflammatory challenge in older individuals. Aged monocytes also have aberrant mitochondrial function, but this observation has not been linked to inflammatory dysfunction, despite the well-known association between cellular metabolism and immune function. In this application, we propose in Aim 1 to investigate a metabolic mechanism linking dysfunction of mitochondrial complex I to impaired inflammatory responses in monocytes from older adults. Additionally, we propose in Aim 2 to utilize a novel mitochondrial transplant procedure to rescue metabolic function in aging, thereby reversing cellular dysfunction in aged monocytes. We will utilize human and mouse experiments to investigate these hypotheses. Results from this study will establish a myeloid cell metabolic pathway which mediates immune dysfunction in monocytes during aging. Delineation of this pathway could provide new therapeutic targets for treating conditions associated with inflammaging and/or immunosenescence. As aging is a primary risk factor for many chronic and infectious diseases, this could have wide-ranging implications. Additionally, we will conduct preclinical testing of a simple and relatively inexpensive therapy which is cell-type specific and known to be efficacious in regularizing inflammatory function in myeloid cells in other systems. Results from this study will enhance our understanding of innate immune dysfunction during aging, leading to new treatments for associated diseases.

衰老是几乎所有慢性疾病的主要危险因素，并且还与 一些急性传染病的严重程度。这些现象与先天失调有关 免疫系统，导致免疫功能障碍（免疫衰老）和慢性低度恶性 炎症（发炎）。单核细胞是循环和释放促炎物质的关键先天免疫细胞 细胞因子促进炎症，但也抑制感染或感染时的炎症反应 老年人的炎症挑战。衰老的单核细胞也有异常的线粒体功能，但这 观察结果尚未与炎症功能障碍相关，尽管众所周知 细胞代谢和免疫功能。 在此应用中，我们在目标 1 中建议研究与线粒体功能障碍相关的代谢机制。 复合物 I 对老年人单核细胞炎症反应受损的影响。此外，我们在 Aim 中提出 2 利用新型线粒体移植手术来挽救衰老过程中的代谢功能，从而逆转 老化单核细胞的细胞功能障碍。我们将利用人类和小鼠实验来研究这些 假设。 这项研究的结果将建立一个介导免疫功能障碍的骨髓细胞代谢途径 衰老过程中的单核细胞。这条途径的描述可以为治疗疾病提供新的治疗靶点 与炎症和/或免疫衰老有关。由于衰老是许多慢性病和慢性病的主要危险因素 传染病，这可能会产生广泛的影响。此外，我们还将进行临床前测试 一种简单且相对便宜的疗法，具有细胞类型特异性，并且已知可有效调节细胞类型 其他系统中骨髓细胞的炎症功能。这项研究的结果将增强我们的理解 衰老过程中先天免疫功能障碍的研究，导致相关疾病的新治疗方法。