Researchers from Yale University, and the University of Texas Southwestern Medical Center have been awarded a $12.4 million, five-year grant from the National Institute on Aging of the NIH to deploy their unique research models and expertise in a coordinated fashion to develop a novel course of gerontological research.
Vishwa Deep Dixit, DVM, PhD, the Waldemar Von Zedtwitz Professor of Pathology and Professor of Immunobiology and Comparative Medicine and Director of the Yale Center for Research on Aging (Y-Age), is Leader of the Program Project Grant (PPG). Yale Principal Investigators of the PPG include Tamas Horvath, DVM, PhD, the Jean and David W. Wallace Professor of Comparative Medicine and Professor of Neuroscience and of Obstetrics, Gynecology & Reproductive Sciences, and Chair of Comparative Medicine, and Joseph Schlessinger, the William H. Prusoff Professor of Pharmacology and Co-Director of the Yale Cancer Biology Institute.
The team has already demonstrated that Fibroblast growth factor 21 (FGF21), a hormonal protein encoded by the FGF21 gene, acts through an obligate co-receptor βKlotho (KLB) to control hallmarks of the aging process such as inflammation, immune-senescence, and impaired energy metabolism. This project is based on new findings that adipose and thymus specific overexpression of FGF21 controls organismal aging, and that FGF21, via AGRP-neuron mediated integration of hypothalamic and autonomic circuits, regulates aging.
“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,” Dr. Dixit said. “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.”
The PPG involves three projects:
- Dr. Dixit will test the impact of FGF21 on immune-senescence
- Phillip Scherer, PhD, Professor, Department of Internal Medicine, UTSW, will define the role of adipose tissue derived FGF21 on aging and metabolic dysfunction
- Drs. Horvath and Schlessinger will investigate the FGF21 hypothalamic AGRP neuron-driven signal transduction to organismal aging
The PPG will be managed by the Y-Age research team and its core, which will support the healthspan and lifespan studies.
“We predict that successful implementation of the proposed goals will lead to a generation of new knowledge that will allow development of new strategies to harness gero-protective effects of FGF21 against aging and chronic disease,” Dr. Dixit said.