Drug repurposing for ageing research using model organisms

Abstract

Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against ageing, despite many genes and pathways shown to be important in the ageing process and numerous studies demonstrating that genetic interventions can lead to a healthier ageing phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate ageing in the invertebrates C. elegans and Drosophila. Our approach combines information on genetic effects on ageing, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate ageing. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating ageing, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human ageing.