Computational identification of natural senotherapeutic compounds that mimic dasatinib based on gene expression data

Abstract

The highest risk factor for chronic diseases is chronological age, and age-related chronic diseases account for the majority of deaths worldwide. Targeting senescent cells that accumulate in disease-related tissues presents a strategy to reduce disease burden and to increase healthspan. Our goal was the computational identification of senotherapeutic repurposing candidates that potentially eliminate senescent cells, based on their similarity in gene expression effects to dasatinib, a tyrosine-kinase inhibitor that induces apoptosis in certain senescent cell types, and that is frequently used as a senolytic together with quercetin. The natural senolytic piperlongumine (a compound found in long pepper), and the natural senomorphics parthenolide, phloretin and curcumin (found in various edible plants) were identified as potential substitutes of dasatinib. The gene expression changes underlying the repositioning highlight apoptosis-related genes and pathways. The four compounds, and in particular the top-runner piperlongumine, may be combined with quercetin to obtain natural formulas emulating the dasatinib + quercetin (D+Q) formula that is frequently used in clinical trials targeting senescent cells.