Single-Dose AAV-FGF21 Gene Therapy Extends Health Span by 20.54% in Aged Mice
核心洞察
A single intramuscular injection of AAV-FGF21 (搜索) gene therapy increased life expectancy by 20.54% in elderly male and female mice in a 27-month pharmacology study.
The therapy normalized body weight, improved insulin sensitivity and glucose homeostasis, and preserved organ function across adipose tissue, liver, kidney, heart, and brain.
Transcriptomic analyses revealed coordinated tissue-specific adaptations including improved mitochondrial function, restored proteostasis, and enhanced hepatic detoxification capacity.
A research team from the Center for Animal Biotechnology and Gene Therapy (CBATEG) at the Universitat Autònoma de Barcelona (UAB) has demonstrated that a single-dose gene therapy expressing the metabolic factor FGF21 (搜索) can significantly prolong health span in aged and geriatric mice. The 27-month pharmacology study, led by Professor Fatima Bosch and published in Molecular Therapy, provides the first evidence that AAV-mediated delivery of native FGF21 not only improves metabolic parameters but also extends disease-free life and delays age-associated multiorgan deterioration.
The treatment was administered to elderly male and female mice via a single intramuscular injection of an adeno-associated viral vector (AAV) gene therapy designed to induce expression and secretion of native FGF21 (搜索) from skeletal muscle, enabling systemic effects throughout the organism. Treated animals showed a 20.54% increase in life expectancy compared to untreated controls.
Multiorgan Benefits Across Key Physiological Systems
The AAV-FGF21 (搜索) gene therapy produced sustained improvements across multiple physiological functions, normalizing body weight and fat accumulation, improving insulin sensitivity and glucose homeostasis, and increasing energy expenditure and functional capacity of various tissues.
In adipose tissue, researchers observed a reduction in adiposity and inflammation alongside increased mitochondrial function. The liver showed preserved detoxification capacity and prevention of aging-associated alterations such as amyloidosis. In the kidney, the therapy reversed markers of renal damage, with no signs of age-related kidney disease evident. Cardiac tissue was protected from fibrosis and amyloidosis, maintaining both structure and function.
Physical performance was preserved, with improvements documented in coordination, strength, and muscular endurance. At the brain level, the treated animals exhibited a marked improvement in memory and learning comparable to that of young animals.
Cellular Mechanisms Underlying Healthy Aging
Transcriptomic and histological analyses revealed that the therapeutic benefits stem from coordinated molecular changes across tissues. The therapy improved mitochondrial function by upregulating pathways involved in energy production. It also restored proteostasis through activation of protein synthesis and increased hepatic detoxification capacity via regulation of key enzymes.
"These results position gene therapy based on FGF21 (搜索) as a potentially translational strategy to promote healthy aging," said Professor Fatima Bosch, director of the research.
Translational Path Toward Clinical Development
The same UAB research group had previously demonstrated that AAV-FGF21 (搜索) vectors can reverse metabolic dysfunction-associated steatohepatitis (MASH) (搜索) in mouse models, a liver disease associated with obesity and diabetes (Jimenez, V et al. Mol. Ther. 2024; 32:4285-4302). Building on these findings, the U.S. Food and Drug Administration has allowed a clinical trial to proceed for the treatment of patients with MASH. The trial will be conducted by the biopharmaceutical company Kriya Therapeutics (搜索) and is scheduled to begin in 2026.
The current study, published as Jimenez, V. et al. "AAV-mediated FGF21 (搜索) gene therapy promotes health span extension by whole-body tissue-specific adaptations" in Molecular Therapy (2026), represents the first demonstration that gene therapy driving native FGF21 expression in old and geriatric animals can simultaneously extend health span and delay multiorgan deterioration associated with aging.