898-P: AAV-FGF21 Gene Therapy Extends Healthspan in Old Mice

Introduction & Objective: Aging is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. This deteriorative process is also accompanied by major changes in body composition that lead to an increase in body weight and insulin resistance. As population ages, obesity, diabetes and dementia are three related conditions that are increasing in prevalence and share common pathways. We have previously shown that intramuscular (IM) administration of AAV1 vectors encoding FGF21 (AAV1-FGF21) in young healthy mice prevented the increase in body weight gain, adiposity and insulin resistance associated with aging.

Methods: AAV vectors with high tropism for skeletal muscle carrying a murine FGF21 coding sequence (AAV-FGF21) were administered into the quadriceps, gastrocnemius, and tibialis cranialis muscles of each hind limb of 1-year-old C57Bl6 mice.

Results: IM administration of AAV1-FGF21 in aged mice mediated long-lasting increase in FGF21 circulating levels, which extended health and life span and reverted age-related insulin resistance, body weight gain, and neuromuscular and cognitive decline. Moreover, this treatment also modulated gene expression in major relevant metabolic organs as well as in the brain.

Conclusion: These results underscore the potential of FGF21 gene therapy to promote healthy aging. Moreover, all these results further highlight the safety of the skeletal muscle-directed AAV1-FGF21 gene therapy.