Molecular signatures of longevity identify compounds that extend mouse lifespan and healthspan

Abstract Longevity interventions in mammals are typically discovered on a case-by-case basis, hindering systematic geroprotector development. We developed a platform for the identification of longevity interventions integrating longevity gene expression biomarkers within and across species, in silico chemical screening, analyses of selected compounds in cell culture, short-term dietary interventions coupled with omics profiling, and ultimately lifespan studies in mice. This approach identified compounds (selumetinib, vorinostat, celastrol, AZD-8055, LY-294002) that extended lifespan and/or healthspan in aged C57BL/6JN male mice, with limited effects in females. In addition, selumetinib and vorinostat increased lifespan when administered to young, genetically heterogeneous UM-HET3 mice. Our biomarker-driven platform accelerates geroprotector discovery, offering a scalable approach to target conserved longevity pathways.