Mitochondrial determinants of monocyte dysfunction in aging

老龄化是几乎所有慢性病的主要风险因素，此外，老龄化还与 一些急性传染病的严重程度。这些现象与先天的失调有关。 免疫系统，导致免疫功能障碍(免疫衰老)和慢性低级别 炎症(发炎)。单核细胞是循环和释放促炎因子的关键先天免疫细胞 细胞因子有助于炎症，但也有抑制炎症反应的感染性或 老年人的炎症性挑战。衰老的单核细胞也有异常的线粒体功能，但这 观察结果与炎症功能障碍没有联系，尽管众所周知， 细胞代谢和免疫功能。 在这一应用中，我们在目标1中建议研究与线粒体功能障碍有关的代谢机制 复合体I对老年人单核细胞炎症反应的损害。此外，我们在AIM中提出 2.利用一种新的线粒体移植程序来挽救衰老中的代谢功能，从而逆转 老年单核细胞的细胞功能障碍。我们将利用人类和老鼠的实验来研究这些 假设。 这项研究的结果将建立一个髓系细胞代谢途径，介导免疫功能障碍 单核细胞在老化过程中。这一通路的描绘可能为治疗疾病提供新的治疗靶点。 与炎症和/或免疫衰老有关。由于老龄化是许多慢性和慢性疾病的主要风险因素 传染病，这可能会有广泛的影响。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，它是针对细胞类型的，并已知在调节方面有效 其他系统中髓系细胞的炎症功能。这项研究的结果将加深我们对 衰老过程中的先天免疫功能障碍，导致相关疾病的新疗法。

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.