# Impact of FGF21-mediated immune-metabolic interactions on immune-senescence

> **NIH NIH P01** · YALE UNIVERSITY · 2020 · $328,943

## Abstract

PROJECT SUMMARY:
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.

## Key facts

- **NIH application ID:** 9938381
- **Project number:** 5P01AG051459-05
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** VISHWA DEEP DIXIT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $328,943
- **Award type:** 5
- **Project period:** — → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938381

## Citation

> US National Institutes of Health, RePORTER application 9938381, Impact of FGF21-mediated immune-metabolic interactions on immune-senescence (5P01AG051459-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9938381. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*