A designed 46-amino-acid peptide that kills senescent cells in mice by freeing p53 from FOXO4; it has never been given to humans in a trial.
Also called FOXO4 D-retro-inverso peptide, FOXO4-p53 interfering peptide
FOXO4-DRI is a lab-designed peptide from Peter de Keizer's group at Erasmus University Medical Center in Rotterdam, published in Cell in 2017. It targets senescent cells: damaged cells that stop dividing but do not die, and that release inflammatory signals as they accumulate with age. Drugs that kill these cells are called senolytics.
Senescent cells stay alive partly because a protein called FOXO4 holds the tumor-suppressor protein p53 in the nucleus, where p53 cannot trigger cell death. FOXO4-DRI is a mirror-image copy of the part of FOXO4 that grabs p53, joined to a carrier sequence from the HIV TAT protein that gets it into cells. It competes for p53, p53 leaves the nucleus, and the senescent cell self-destructs. In culture it was about 12 times more toxic to senescent human fibroblasts than to normal ones.
In mice, a short course of injections improved fur density and kidney function in fast-aging and naturally old animals, raised running-wheel activity in the fast-aging strain, and reduced liver damage from the chemotherapy drug doxorubicin. Later mouse work found improved testosterone output in old males and healthier aortas. No human trial has been registered. A 2023 mouse study also showed that clearing senescent cells, including with FOXO4-DRI, can make pulmonary hypertension worse, so killing these cells is not harmless in every tissue.
What it binds to, and what happens inside the body after that, step by step.
In senescent cells FOXO4 rises and binds p53 inside the nucleus, keeping these damaged cells alive. FOXO4-DRI binds the disordered transactivation domain of p53, in a 2025 NMR study at the same site FOXO4 uses, and blocks that interaction. p53 is then pushed out of the nucleus and triggers the mitochondrial route to apoptosis, so the senescent cell dies while most normal cells, which rely less on FOXO4, survive. Because it is built from D-amino acids in reverse order, protein-cutting enzymes break it down slowly.
Human results and animal results are kept apart below. A result in rats tells you a mechanism is plausible. It does not tell you what happens in a person.
Every result is from cell culture or mice. Human tissue appears only in the dish: expanded cartilage cells and keloid scar tissue, where the peptide removed senescent cells. There is no human dose, no human safety data, and one mouse study showing that clearing senescent cells can worsen lung blood pressure.
No human studies are among the key studies for FOXO4-DRI. Everything known comes from animals or cells.
Senescent human IMR90 fibroblasts; fast-aging XpdTTD/TTD mice; naturally aged mice; doxorubicin-treated mice
11.73-fold selectivity for senescent over normal cells in culture; in mice, 5 mg/kg doses (three doses every other day in the chemotherapy and naturally aged groups) improved fur density and kidney function and reduced doxorubicin toxicity.
Read the studyPurified proteins, NMR structural study
FOXO4-DRI binds the same disordered p53 region as FOXO4 and binds more tightly to phosphorylated p53.
Read the studyMouse and rat pulmonary hypertension models, plus lung tissue from patients
Removing senescent cells by gene switch, ABT263, or FOXO4-DRI worsened lung pressures and caused loss of lung endothelial cells in several models.
Read the studyNaturally aged mice and senescent mouse Leydig cells
Cleared senescent testosterone-making cells and improved age-related testosterone output in old mice.
Read the studyHuman cartilage cells from healthy donors, expanded in culture
Removed more than half of heavily expanded cells while sparing early cells, but did not improve cartilage formation.
Read the studyHuman keloid scar tissue and fibroblasts in organ culture
Triggered apoptosis of senescent keloid fibroblasts with p53 moving out of the nucleus.
Read the studyNaturally aged and progeroid mice; senescent endothelial cells
Injections reduced aortic aging markers and improved aortic function via the p53, BAX, caspase-3 pathway.
Read the studyThese are questions the published research has not answered.
No product containing FOXO4-DRI is approved as a medicine by the FDA.
Not approved anywhere and no registered human trial on ClinicalTrials.gov as of October 2026. Cleara Biotech, in which developer Peter de Keizer holds shares, partly funded a 2025 FOXO4-DRI study, and he and coauthors hold published patents on compounds that block FOXO4 from binding p53. Vials sold online as FOXO4-DRI are unregulated research chemicals. Falls under WADA S0 (non-approved substances), banned in and out of competition.
No human half-life has been published for FOXO4-DRI, so we do not draw a clearance curve. Half-lives quoted online for it are usually estimates from animal data.
No human study or approved label has published a dose for FOXO4-DRI, so there is no table to show.
No dose of FOXO4-DRI has been tested in a published human study or approved on a label. Numbers that circulate online come from animal studies scaled up by guesswork or from sellers. We do not reproduce them.
Which symptoms are expected and which mean stop and get help: side effects and red flags.
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It improved fur, activity, and kidney markers in old and fast-aging mice over about a month. It has never been tested in a person.
Selectivity was about 12-fold in culture, not absolute. It triggered cell death in kidney slices, and clearing senescent cells worsened pulmonary hypertension in rodents.
Old mice made more testosterone after senescent Leydig cells were cleared. There are no human hormone data.
No FOXO4-DRI trial is registered on ClinicalTrials.gov as of October 2026. All published work, including company-funded studies, is preclinical.
No independent testing of these products has been published. The published molecule is 46 D-amino acids; identity and purity of online vials are unknown.
These pairings come up often. Almost none have been tested together in a trial, and the evidence note on each says so plainly.
Online longevity stacks pair clearing senescent cells with a mitochondria-targeted peptide.
EvidenceNo study, in any species, has tested this combination.
No published stability study. Labs generally keep freeze-dried peptides frozen at about -20 C, dry and away from light.
In the 2017 mouse study, stock was dissolved at 5 mg/ml in PBS and kept on ice until injection. Longer stability in solution has not been published.
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