Fibroblast growth factors (FGFs) constitute a family of 22 proteins that regulate diverse biological processes such as growth, development, differentiation, and wound repair. FGF21 is a unique metabolic hormone as it is secreted in blood from liver in response to starvation and nutrient deprivation to stimulate fatty acid oxidation and to maintain energy balance. Recent studies from our PPG team (Drs Kliewer and Mangelsdorf) have demonstrated that overexpression of FGF21 in mice extends lifespan. Interestingly, FGF21 is also expressed in thymus, however, the impact of FGF21 on ability of thymus to produce T cells and immune system decline during aging is unknown. 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 delays aging of thymus and reduces the generation of ectopic lipid and inflammation in thymus. Based on our novel findings that FGF21 improves thymic function, the central hypothesis of this proposal is that approaches to enhance FGF21 signaling in thymic epithelial cells (TECs) will rejuvenate thymic lymphopoiesis and expand T cell repertoire diversity during aging.
Aim1 will be using loss and gain of function models where FGF21 signaling is specifically targeted to thymic epithelial cell.
This aim will test the hypothesis that FGF21 supports thymic function during aging through autocrine and paracrine action on thymic stromal cells.
Aim2 will test the impact of FGF21 on thymic rejuvenation in aged mice and will test the hypothesis that FGF21 mimics a molecular state that signals energy deficit which reprograms thymic stromal cell metabolism towards utilization of lipid as energy substrate.
Aim3 will evaluate thymus-independent effects of FGF21on systemic age-related inflammation. Thus, 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.

Public Health Relevance

STATEMENT Thymus produces immune cells called as T-lymphocytes that are critical for protection against infections and cancers. However, with progressive aging, thymus is replaced with fat cells and its ability to produce T- lymphocytes is dramatically diminished. This research project is designed to understand the effect of pro- longevity hormone FGF21 on thymus and immune system. The aim of this project is to unravel underlying process of immune dysfunction in aging with a long-term goal of developing novel therapeutic approaches to strengthen immunity and enhance healthspan of elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-6 (M2))
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Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
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Zhu, Yi; Zhao, Shangang; Deng, Yingfeng et al. (2017) Hepatic GALE Regulates Whole-Body Glucose Homeostasis by Modulating Tff3 Expression. Diabetes 66:2789-2799
Rutkowski, Joseph M; Pastor, Johanne; Sun, Kai et al. (2017) Adiponectin alters renal calcium and phosphate excretion through regulation of klotho expression. Kidney Int 91:324-337
Ghaben, Alexandra L; Scherer, Philipp E (2017) Pas de Deux: Glucagon and Thyroid Hormone Moving in Perfect Synchrony. Circ Res 120:762-764
Camell, Christina D; Sander, Jil; Spadaro, Olga et al. (2017) Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature 550:119-123
Spadaro, Olga; Camell, Christina D; Bosurgi, Lidia et al. (2017) IGF1 Shapes Macrophage Activation in Response to Immunometabolic Challenge. Cell Rep 19:225-234
Goldberg, Emily L; Dixit, Vishwa Deep (2017) Carnitine acetyltransferase (CRAT) expression in macrophages is dispensable for nutrient stress sensing and inflammation. Mol Metab 6:219-225
Suyama, Shigetomo; Ralevski, Alexandra; Liu, Zhong-Wu et al. (2017) Plasticity of calcium-permeable AMPA glutamate receptors in Pro-opiomelanocortin neurons. Elife 6:
Crewe, Clair; An, Yu Aaron; Scherer, Philipp E (2017) The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest 127:74-82
Goldberg, Emily L; Asher, Jennifer L; Molony, Ryan D et al. (2017) ?-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares. Cell Rep 18:2077-2087
Ferrandino, Giuseppe; Kaspari, Rachel R; Spadaro, Olga et al. (2017) Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proc Natl Acad Sci U S A 114:E9172-E9180