Mitochondrial determinants of monocyte dysfunction in aging

点击翻译按钮获取中文摘要

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.