Fibroblast growth factor 21 (FGF21) has been developed as a potential therapeutic agent for metabolic syndromes. Moreover, FGF21 is considered a pro-longevity hormone because transgenic mice overexpressing FGF21 display extended lifespan, raising the possibility of using FGF21 to promote healthy aging. We recently showed that visceral fat directed FGF21 gene therapy improves metabolic and immune health in insulin resistant BTBR mice. Here, we used a fat directed rAAV-FGF21 vector in 17-month-old female mice to investigate whether long-term FGF21 gene transfer could mitigate aging-related functional decline. Animals with FGF21 treatment displayed a steady, significant lower body weight over 7-month of the study compared to age-matched control mice. FGF21 treatment reduced adiposity and increased relative lean mass and energy expenditure associated with almost 100 folds higher serum level of FGF21. However, those changes were not translated into benefits on muscle function and did not affect metabolic function of liver. Overall, we have demonstrated that a single dose of fat-directed AAV-FGF21 treatment can provide a sustainable, high serum level of FGF21 over long period of time, and mostly influences adipose tissue homeostasis and energy expenditure. High levels of FGF21 alone in aged mice is not sufficient to improve liver or muscle functions.
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We thank the Comparative Pathology & Mouse Phenotyping Shared Resource at the Ohio State University’s College of Veterinary Medicine and the Small Animal Imaging Core of The Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University for their technical assistance. This work was supported by NIH grants AG041250, CA166590, and CA163640, as well as internal funding from The Ohio State University Comprehensive Cancer Center.
LC and WH are inventors of a patent application related to the liver-restricting AAV vector. LC is co-founder of Zvelt Therapeutics. All other authors declare no conflicts of interest.
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Anderson, J.M., Arnold, W.D., Huang, W. et al. Long-term effects of a fat-directed FGF21 gene therapy in aged female mice. Gene Ther (2023). https://doi.org/10.1038/s41434-023-00422-0