Project 1 - Dixit

PROJECT SUMMARY: Aging of thymus precedes the aging of other organs. Notably, the new T cell specificities can only be generated in a functional thymus and peripheral proliferation of pre-existing T cell clones provides limited immune-vigilance in the elderly. Therefore, loss of thymic function contributes to restriction of T cell repertoire. Consistent with this, age-related thymic involution is a cardinal feature of immune-senescence that leads to increased risk and severity of emerging infections (including COVID-19), certain cancers, vaccination failures, and delayed T cell reconstitution in patients undergoing hematopoietic stem cell transplantations. The mechanism driving of thymic aging and endogenous targets that can delay or reverse thymic involution remain unknown. Fibroblast growth factors (FGFs) constitute a family of growth factors that regulate diverse biological processes such as cell growth, development, differentiation. FGF21 is a unique metabolic hormone as it is produced in response to caloric restriction to stimulate fatty acid oxidation, ketone body production and to maintain homeostasis. Recent studies from our PPG team have demonstrated that overexpression of FGF21 protects against immune-senescence by increasing thymic function in aged mice. Notably, a major phenotype of age-related thymic degeneration is loss of thymic epithelial cells, emergence of fibroblasts and the accumulation of ectopic lipid within thymus. This project is based on our recent findings that FGF21 overexpression within thymus delays protects against loss of naïve T cells in aged mice and enhances their healthspan. The central hypothesis of this proposal is that FGF21 activates sympathetic nervous system (SNS) to induce fatty acid oxidation and ketogenesis that consumes the ectopic lipid substrates in immunological organs to protect against immune-senescence and inflammaging. This hypothesis will be tested in collaboration with project 2 (metabolism), project 3 (SNS) and studies will be supported by Core A and B. The, the long term goal of this project is to develop FGF21 agonists as clinical intervention to lower inflammation and improve T cell dependent immune-surveillance in elderly.