Single-dose gene therapy extends healthy lifespan in older mice

A research team from the Universitat Autònoma de Barcelona (UAB) has shown that a one-time administration of a gene therapy expressing the metabolic factor FGF21 can prolong health span in old mice. The 27-month pharmacology study, published in Molecular Therapy, shows sustained beneficial effects across multiple endpoints associated with aging and health span.

A study developed at the Center for Animal Biotechnology and Gene Therapy (CBATEG) of the Universitat Autònoma de Barcelona (UAB) has shown that a one-time administration of a gene therapy that induces the production by the skeletal muscle of the metabolic factor FGF21 - fibroblast growth factor 21 - can prolong health span in old and geriatric mice. The study, led by Professor Fatima Bosch and published in the journal Molecular Therapy, the leading scientific journal in the field of gene therapy, shows sustained beneficial effects throughout the organism.

The research evaluated an adeno-associated viral vector (AAV) gene therapy that induces the expression and secretion of native FGF21 via administration to skeletal muscle, enabling systemic effects in aged mice. The treatment was carried out in elderly male and female mice by means of a single intramuscular injection. The results show that this intervention prolongs both life expectancy and disease-free life. In particular, the treated animals showed a 20.54% increase in life expectancy thanks to the administration of the gene therapy.

Overall improvement of metabolism and organ function

The treatment produced sustained improvements in multiple physiological functions, with a reduction in the deterioration associated with aging in different organs. The AAV-FGF21 gene therapy normalized body weight and fat accumulation, improved insulin sensitivity and glucose homeostasis, and increased energy expenditure and functional capacity of various tissues.

The treatment showed beneficial effects in multiple organs and tissues of the treated animals. In adipose tissue, a reduction in adiposity and inflammation was observed, along with an increase in mitochondrial function. In the liver, the therapy allowed the preservation of detoxification capacity and prevented alterations associated with aging, such as amyloidosis. In the kidney, a reversal of markers of renal damage and the absence of signs of age-related kidney disease were evidenced. In the heart, fibrosis and amyloidosis were avoided, maintaining both its structure and function. In addition, physical performance was preserved, with improvements in coordination, strength and muscular endurance, while at the brain level a marked improvement in memory and learning comparable to that of young animals was detected.

Cellular adaptations that counteract aging

Transcriptomic and histological analyses demonstrated the benefits of the treatment through specific adaptations of each tissue that improve energy homeostasis and cellular function. These adaptations are based on coordinated molecular changes in different tissues. Specifically, an improvement in mitochondrial function was observed, with an increase in the pathways involved in energy production. In parallel, the therapy restored proteostasis by activating protein synthesis. Finally, an increase in the capacity of hepatic detoxification was also detected, attributed to the regulation of key enzymes involved in these processes.

According to Fatima Bosch, director of the research, "these results position gene therapy based on FGF21 as a potentially translational strategy to promote healthy aging."

The work demonstrates for the first time that a gene therapy driving the expression of native FGF21 administered to old and geriatric animals not only improves metabolic parameters but also extends health span and delays age-associated multiorgan deterioration.

It should be noted that the same research group had previously demonstrated that this gene therapy based on AAV-FGF21 vectors can reverse metabolic dysfunction-associated steatohepatitis (MASH) in mouse models, a liver disease associated with obesity and diabetes (Jimenez, V et al. Mol. Ther. 2024; 32:4285-4302). Recently, FDA has allowed the clinical trial to proceed for the treatment of patients with MASH, which will be carried out by the biopharmaceutical company Kriya Therapeutics (https://kriyatherapeutics.com/) and is scheduled to begin in 2026.