Fat Cells Genetically Altered To Extend Lifespan and Improve Health

Fat cells genetically altered to overproduce a hormone called FGF21 resulted in improved metabolic health and an extended lifespan in mice that were fed a high-fat diet, UT Southwestern Medical Center researchers report. The findings, published in Cell Metabolism, could lead to new interventions that have the same positive effects in humans.

“This is the first long-term aging study to demonstrate the powerful protective effects that FGF21 exerts through fat tissue,” said Philipp Scherer, Ph.D., Professor of Internal Medicine and Cell Biology and Director of the Touchstone Center for Diabetes Research at UT Southwestern. “We found that FGF21 lowers harmful lipids called ceramides, particularly in visceral fat, which are closely linked to heart disease and diabetes. These findings support FGF21 as a promising target for treating or preventing diseases such as Type 2 diabetes, cardiovascular disease, fatty liver disease, and kidney disease. Elevating FGF21 levels may also offer benefits for healthy aging.”

The study was directed by Dr. Scherer in collaboration with first author Christy M. Gliniak, Ph.D., now Assistant Professor of Nutritional Sciences at Rutgers University, who conducted the research during her time as a postdoctoral fellow and Instructor in the Scherer Lab.

More than a decade ago, a team led by UTSW researchers David Mangelsdorf, Ph.D., Chair and Professor of Pharmacology and Professor of Biochemistry, and Steven Kliewer, Ph.D., Professor of Molecular Biology and Pharmacology, discovered that boosting FGF21 could dramatically extend the lifespan of lab mice while also improving their insulin sensitivity and other markers of metabolic health. They have since discovered that FGF21 also appears to speed recovery from alcohol overuse.

Because the liver is the main site of FGF21 production in the body, the researchers achieved these effects by genetically altering liver cells. However, this model involved lifelong overexpression of FGF21 starting at birth, which resulted in growth suppression, making it difficult to isolate how FGF21 affects aging in adults.

To address this, Dr. Scherer, Dr. Gliniak, and their colleagues genetically altered mice to produce extra FGF21 starting in adulthood in their fat cells – another site of natural FGF21 production, and the area in the body where the hormone appears to exert many of its metabolic effects. To mimic real-world factors experienced by human patients, the mice were fed a high-fat diet.

They lived up to 3.3 years – equivalent to very old age in humans – compared to an average of 1.8 years for unaltered littermates.

In addition, the mice with extra FGF21 never became obese or developed fatty liver disease, unlike most of the control group. The FGF21 overproducers also had better blood sugar control, insulin sensitivity, and cholesterol levels, and they didn’t accumulate inflammatory immune cells in their body fat.

“By discovering how a naturally occurring hormone protects against chronic disease, we are laying the foundation for future treatments that extend not just lifespan, but also quality of life,” Dr. Scherer said.

Reference: Gliniak CM, Gordillo R, Youm YH, et al. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression. Cell Metab. 2025;37(7):1547-1567.e6. doi: 10.1016/j.cmet.2025.05.011

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