PROJECT SUMMARY – OVERALL Age-related inflammation and accumulation of ectopic lipid in multiple organs in elderly is associated with emergence of chronic diseases. The integration of neural and immunometabolic inputs that control organismal aging are largely unknown. The current program project grant (PPG) seeks to assemble a diverse group of investigators at UTSW and Yale University with the goal to deploy their unique research models and expertise in a coordinated fashion to develop a novel course of gerontological research. We have demonstrated that Fibroblast growth factor 21 (FGF21) acts through an obligate co-receptor βKlotho (KLB) to control hallmarks of aging process such as inflammation, immune-senescence and impaired energy metabolism. This PPG is based on our new findings that adipose and thymus specific overexpression of FGF21 controls organ aging, and that FGF21 via AGRP-neuron mediated integration of hypothalamic and autonomic circuits, regulates organismal aging. Therefore, we will test the central hypothesis that FGF21 is a central gero-checkpoint that initiates a prolongevity molecular program by integrating neural- metabolic and immune axes. The corollary is that pharmacological means to elevate FGF21 signaling by new agonist FGF21 variants may serve as therapy to extend the healthspan and lifespan. To take next steps towards pre-clinical translation of FGF21 as a pharmacological gero-protector, we will test the impact of ligating KLB with FGF-21superagonist on healthspan and lifespan. The project 1 (Dixit) will test the impact of FGF21 on immune-senescence. Project 2 (Scherer) will define the role of adipose tissue derived FGF21 on aging and metabolic dysfunction. Project 3 (Horvath/Schelssinger) will investigate the FGF21 hypothalamic AGRP neuron-driven signal transduction to organismal aging. The PPG will be managed by and Administrative and mouse-aging analysis core, which will support the healthspan and lifespan studies. We predict that successful implementation of the proposed goals, will lead to generation of new knowledge that will allow development of new strategies to harness gero-protective effects of FGF-21 against aging and chronic diseases.