Network-driven discovery of repurposable drugs targeting hallmarks of aging.

Abstract

Despite the thousands of genes implicated in age-related phenotypes, effective interventions for aging remain elusive, due to the multifactorial nature of longevity and the interconnectedness of molecular components involved. Here we introduce a network medicine framework to map 2,358 longevity-associated genes onto the human interactome to identify drug-repurposing candidates capable of modulating specific hallmarks of aging. We find that genes associated with each hallmark form a connected subgraph, or hallmark module, allowing us to measure the network proximity of 6,442 compounds to each hallmark. We then introduce a transcription-based metric, pAGE, which evaluates whether drug-induced expression shifts reinforce or counteract known age-related expression changes within each hallmark module. By integrating network proximity and pAGE, we identify drug-repurposing candidates targeting specific hallmarks and provide a falsifiable framework to leverage genomic discoveries for accelerating drug repurposing in longevity. Our findings are interpretable, revealing molecular mechanisms through which drugs modulate hallmarks.