Research Project
10490482
Project Summary: Age-related health issues have become a major and increasing health challenge worldwide. The deterioration of the immune function during aging, hallmarked by the aberrant accumulation of effector-memory T cells and elevated inflammatory SASP (senescence-associated secretory phenotype) has long been recognized to prominently contribute to aging and related diseases, esp. during the outbreak of emerging pathogens, such as COVID-19 pandemic. It is vital to reveal the cellular and molecular mechanisms underlying immunological aging. The proper function of immune system can only be ensured by well-balanced immune activation (mediated by conventional T cells) and immune suppression (mediated by Treg cells). However, the function and regulation of age Tregs and the implication in infection remains a knowledge gap to be filled. Our preliminary study revealed that (1) Aged Tregs severely senesced and reduced function in vitro and in vivo during aging (2) Reactive-oxygen-species (ROS) was upregulated in aged Treg. (3) Interfering with ROS pathway reinvigorated the proliferation and function of aged Tregs. Because Tregs play important and multifaceted roles in controlling inflammation, infection, and tissue repair, these preliminary results provide the scientific premise for the central hypothesis that declined proliferation and function of aged Tregs negatively impacts the outcome of viral infection in the elderly, and that uncovering the cellular and molecular mechanisms underlying Treg aging will aid the efforts to reinvigorate aged Tregs to help improve elderly's ability to fight emerging pathogens. To test this hypothesis, we propose to reach the following three specific research aims. AIM 1: Investigate the cellular heterogeneity and dynamics of Tregs in aged mice during infection. AIM 2: Understand how ROS accumulation is controlled in aged Tregs. AIM 3: Address if the outcome of infection can be improved through reinvigorating the function of aged Tregs. There is a great and yet unmet need in the understanding of the cellular and molecular mechanisms underlying immunological aging and infection. This study aims to reveal previous unappreciated Treg- dependent cellular and molecular mechanisms underlying weaken ability to fight infection by the elderly. The success of this study will gain critical understanding of immune response during aging, advance the fields of geriatrics, provide mechanistic insights in age-related syndromes, and uncover new perspectives on how to mitigate age-related morbidity to improve the health of the aging population.
