# Competing Renewal P01

> **NIH NIH P01** · YALE UNIVERSITY · 2023 · $2,465,405

## Abstract

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.

## Key facts

- **NIH application ID:** 10694231
- **Project number:** 5P01AG051459-07
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** VISHWA DEEP DIXIT
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,465,405
- **Award type:** 5
- **Project period:** 2016-09-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10694231

## Citation

> US National Institutes of Health, RePORTER application 10694231, Competing Renewal P01 (5P01AG051459-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10694231. Licensed CC0.

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