AAV-mediated FGF21 gene therapy promotes healthspan extension by whole-body tissue-specific adaptations.

Veronica Jimenez, Victor Sacristan, Miquel Garcia, Claudia Jambrina, Estefania Casana, Sergio Muñoz, Laia Vilà, Ignasi Grass, Maria Luisa Jaén, Carles Roca, Xavier León, Sara Marcó, Maria Molas, Albert Ribera, Ivet Elias, Jordi Rodó, Tura Ferré, Fatima Bosch

Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain.Center of Animal Biotechnology and Gene Therapy (CBATEG), Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Department of Biochemistry and Molecular Biology, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, 28029 Madrid, Spain. · pubmed

Paper

Abstract

The decline of organ function during aging limits healthspan. Despite the potential of lifestyle interventions to improve health, sustained maintenance of healthspan is challenging, and no gerotherapeutic drugs have been approved. Here, we demonstrated that aged and geriatric male and female mice treated with muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy extended healthspan and lifespan with sustained organ benefits. This treatment normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis, preserved hepatic detoxification capacity, counteracted age-related kidney disease, promoted cardiac health, and muscular function, and enhanced cognition. Transcriptomic and histopathological analyses indicated improved whole-body energy homeostasis and cellular fitness, which were mediated by tissue-specific adaptations, including enhanced mitochondrial function, restored proteostasis, and reversion of inflammation, fibrosis and amyloidosis. AAV-FGF21 treatment also activated AMPK signaling. These results highlight FGF21 gene therapy as a potential strategy to promote healthspan and delay age-related deterioration.

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Research summary

AAV-mediated FGF21 gene therapy extends healthspan and lifespan in aged mice through tissue-specific adaptations. This paper addresses the root causes of aging by demonstrating a gene therapy approach that promotes healthspan and mitigates age-related decline, making it relevant to longevity research.

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