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AAV-mediated FGF21 gene therapy promotes health span extension by whole-body tissue-specific adaptations

Veronica Jimenez1, Victor Sacristan1, Miquel Garcia1

  • 1Center 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.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|June 3, 2026
PubMed

Insights

Muscle-directed fibroblast growth factor 21 (FGF21) gene therapy in aged mice improved healthspan and lifespan. This intervention normalized body weight, enhanced organ function, and boosted cognition, offering a potential gerotherapeutic strategy.

Area of Science:

  • Aging research
  • Gene therapy
  • Metabolic diseases

Background:

  • Organ function decline limits healthspan in aging.
  • Lifestyle interventions show potential but sustained healthspan maintenance is difficult.
  • No gerotherapeutic drugs are currently approved.

Purpose of the Study:

  • To investigate the efficacy of muscle-directed adeno-associated viral (AAV) vector-mediated fibroblast growth factor 21 (FGF21) gene therapy in aged mice.
  • To assess the impact of AAV-FGF21 on healthspan, lifespan, and organ function.
  • To explore the underlying molecular mechanisms of AAV-FGF21 treatment.

Main Methods:

  • Administration of muscle-directed AAV-FGF21 gene therapy to aged and geriatric male and female mice.
  • Assessment of various physiological parameters including body weight, adiposity, insulin sensitivity, glucose homeostasis, hepatic detoxification, kidney function, cardiac health, muscle function, and cognition.
  • Transcriptomic and histopathological analyses to evaluate whole-body energy homeostasis, cellular fitness, mitochondrial function, proteostasis, inflammation, fibrosis, and amyloidosis.
  • Investigation of AMPK signaling pathway activation.

Main Results:

  • AAV-FGF21 treatment extended healthspan and lifespan in aged mice.
  • The therapy normalized body weight and adiposity, improved insulin sensitivity and glucose homeostasis.
  • Significant improvements were observed in hepatic detoxification, kidney health, cardiac function, muscle strength, and cognitive performance.
  • Transcriptomic and histopathological analyses revealed enhanced energy homeostasis and cellular fitness, with restored mitochondrial function, proteostasis, and reduced inflammation, fibrosis, and amyloidosis.
  • AMPK signaling was activated by AAV-FGF21 treatment.

Conclusions:

  • Muscle-directed FGF21 gene therapy is a promising strategy to extend healthspan and lifespan.
  • This approach effectively counteracts age-related physiological decline and improves multiple organ functions.
  • FGF21 gene therapy demonstrates potential as a gerotherapeutic intervention by improving whole-body energy homeostasis and cellular resilience.
Keywords:
Fibroblast growth factor 21 FGF21adeno-associated viral, AAV vectorsaginggene therapyhealth spanlifespan

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