A novel approach of human geroprotector discovery by targeting the converging subnetworks of aging and age-related diseases

Abstract

A key goal of geroscience research is to discover effective interventions to extend human healthspan, the years of healthy life. Currently, majority of the geroprotectors are found by testing compounds in model organisms; whether these compounds will be effective in humans is largely unknown. Here we present a novel strategy called ANDRU (aging network based drug discovery) to help the discovery of human geroprotectors. Instead of relying on model organisms, this approach is driven by human genomic and pharmacogenomic data. It first identifies human aging subnetworks that putatively function at the interface between aging and age-related diseases; it then screens for pharmacological or genetic interventions that may \"reverse\" the age-associated transcriptional changes seen in these subnetworks. We applied ANDRU to human adipose and artery tissues. In adipose tissue, PTPN1, a target for diabetes treatment and APOE, a known genetic factor for human longevity and diseases like Alzheimers disease, were ranked at the top. For small molecules, conjugated linoleic acid and metformin, a drug commonly used to treat type 2 diabetes, were ranked among the top compounds. In artery tissue, N-methyl-D-aspartate antagonists and curcumin were ranked at the top. In summary, ANDRU represents a promising human data-driven strategy that may speed up the discovery of interventions to extend human healthspan.