FOXO4-DRI

Research-Grade

FOXO4-DRI is a modified peptide designed to selectively eliminate senescent cells — dysfunctional cells that accumulate with age, secrete pro-inflammatory factors (the senescence-associated secretory phenotype, SASP), and drive tissue dysfunction and age-related disease. The peptide was developed by Peter de Keizer's group at Erasmus University Medical Center and published in Cell in 2017. Its mechanism targets a specific survival strategy of senescent cells: the interaction between FOXO4 and p53 in PML nuclear bodies. In senescent cells, FOXO4 sequesters p53 away from the mitochondria, preventing p53-mediated apoptosis. FOXO4-DRI disrupts this interaction, releasing p53 to trigger intrinsic apoptosis selectively in senescent cells. The 'D-retro-inverso' modification reverses both the amino acid sequence and the chirality (L→D), producing a peptide that is resistant to proteolysis while maintaining the binding surface geometry needed to interact with p53. This dramatically improves in vivo stability compared to the native L-peptide. In naturally aged mice (24+ months), FOXO4-DRI treatment restored fitness, fur density, and renal function. In fast-aging XpdTTD/TTD mice, it improved healthspan markers. These are among the most visually striking senolytic results published. However, significant challenges remain for translation: the peptide is large (difficult to manufacture at scale), requires IV or IP administration, and no human trial has been conducted. The senolytic field has since moved toward small-molecule approaches (dasatinib + quercetin, fisetin) that are easier to develop clinically.