Human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases.

A key goal of geroscience research is to identify effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by screening compounds in model organisms; whether they will be effective in humans is largely unknown. Here we present a new strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological interventions that may "reverse" the age-associated transcriptional changes occurred in these subnetworks. We applied ANDRU to human adipose gene expression data from the Genotype Tissue Expression (GTEx) project. For the top 31 identified compounds, 19 of them showed at least some evidence supporting their function in improving metabolic traits or lifespan, which include type 2 diabetes drugs such as pioglitazone. As the query aging genes were refined to the ones with more intimate links to diseases, ANDRU identified more meaningful drug hits than the general approach without considering the underlying network structures. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.