High-throughput Screening Platform for Longevity Gene and Anti-aging Drug Discovery

Aging is a complex biological process that remains one of the greatest risk factors for numerous chronic diseases, including cancer, cardiovascular disorders, and neurodegenerative conditions. As global demographics shift towards an aging population, there is an urgent need to develop interventions that can delay the onset of age-related declines and promote healthy longevity. This thesis presents a groundbreaking high-throughput screening platform for identifying genetic and pharmacological interventions that extend lifespan in the model organism Saccharomyces cerevisiae (budding yeast).The foundation of this platform is the development of a novel genetic construct, the Daughter Arrest Program (DAP), which selectively arrests daughter cell division while allowing mother cells to continue dividing. By combining the DAP with innovative microfluidic devices and fluorescence-based assays, we have established a robust system for rapid and efficient measurement of yeast replicative lifespan. This high-throughput approach enables the screening of thousands of compounds and genetic modifications, vastly expanding the potential for discovery in the field of gerontology. Leveraging this platform, we conducted comprehensive screenings of FDA-approved drug libraries and bioactive compound libraries, leading to the identification of several promising anti-aging compounds, including mTOR inhibitors, GSK-3 inhibitors, and topoisomerase inhibitors. Additionally, we performed genetic screenings using non-essential gene deletion mutants and the Decreased Abundance by mRNA Perturbation (DAmP) library, revealing the diverse roles of various genes in regulating aging processes, such as nutrient sensing, stress response, and cellular repair mechanisms. The findings from this research provide valuable insights into the genetic and molecular pathways underlying aging and longevity, paving the way for the development of targeted interventions to promote healthy aging.