Adeno-Associated Viral Vectors as a Platform for Understanding and Modifying Aging-Related Disease

Abstract

Over the past century, the average human lifespan has increased from approximately 49 to 72 years. This 23-year gain is largely the result of advances in disease prevention, detection, and treatment, driven by technological innovation and a growing understanding of the fundamental biological processes of the body. Despite these gains, the pursuit of further extension of healthy human lifespan remains a major focus of the pharmaceutical and biotechnology industries. Among the technologies that have transformed our ability to combat disease, adeno-associated viral (AAV) vectors have emerged as a powerful platform for both therapeutic intervention and disease modeling. AAV enables the efficient and sustained delivery of genetic material to diverse tissues, allowing precise control over gene expression in vivo. Importantly, AAV-mediated gene delivery can be performed directly in young, adult, and aged organisms, overcoming limitations of traditional germline genetic models and enabling the study of late-onset and age-dependent disease processes. This temporal flexibility, combined with the tissue- and cell-type specificity achieved through diverse capsid tropisms, makes AAV particularly well suited for investigating aging-related pathologies. In addition to its utility as a modeling tool, AAV-mediated gene delivery has demonstrated significant translational potential as a gene therapy vector, with established clinical success across multiple genetic and degenerative diseases. Long-term expression, favorable safety profiles, and scalable manufacturing have positioned AAV at the forefront of gene-based therapeutics. Together, these properties allow AAV to bridge mechanistic studies and therapeutic development. In the context of aging, this dual capacity is particularly powerful. In this work, adeno-associated viral vectors are leveraged as a platform to probe age related germline and somatic genetic lesions. Specifically, this work details methods to extend lifespan in a progeroid mouse model, and to model the induction of age-related clonal hematopoiesis. These works together demonstrate two novel use cases for further utilization of AAV to enhance our understanding and modification of age-related diseases.