FOXO4

FOXO4-DRI is a synthetic peptide based on part of FOXO4, a transcription factor (a protein that switches genes on and off), joined to a short sequence that helps it enter cells. It is made in D-retro-inverso form: mirror-image amino acids placed in reverse order, a design used to make peptides less easily broken down by enzymes. It was described by Peter de Keizer's group in Rotterdam (Baar et al., Cell 2017). In that study, senescent cells (cells that have permanently stopped dividing) relied on FOXO4 binding to the protein p53 to stay alive. The peptide disrupted this binding and, in culture, triggered cell death selectively in senescent cells. In fast-ageing mice and naturally old mice, the authors reported better fitness, fur density and kidney function after treatment. Later work, mostly from other groups, used mice and cultured cells, for example ageing Leydig cells in the testis, lung scarring and human cartilage cells. The findings do not all point one way: in a mouse study of lung blood vessels, removing senescent cells, including with FOXO4-DRI, made pulmonary hypertension worse (Born et al., Circulation 2023). No human trials have been published, and its pharmacokinetics and safety in people are unknown. Supplied for laboratory research use only.