FOXO4-DRI
Senolytic Peptide | FOXO4-p53 Disruption for Cellular Aging Research
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What is FOXO4-DRI?
FOXO4-DRI is a lab-made peptide built from D-form amino acids arranged in reverse order, a chemistry trick that makes it more resistant to breaking down in the body. Researchers study it in animal models for its ability to selectively target aged, damaged ("senescent") cells while leaving healthy cells alone. No human clinical trials have been conducted, all available evidence comes from mouse and cell studies, and it's sold here strictly as a research chemical for laboratory study.
Key terms:
FOXO4-DRI is a synthetic d-retro-inverso peptide with cell-penetrating domain.
FOXO4-DRI is a lab-made peptide of 46 amino acids, built to clear senescent cells, worn-out cells that build up with age and leak harmful inflammatory signals (called SASP). It uses D-form amino acids in reverse order, so enzymes struggle to break it down while it still binds its target. It pries apart the FOXO4-p53 pairing that keeps senescent cells alive. Freed p53 leaves the nucleus, moves to the mitochondria, and triggers the cell's self-destruct program. In mouse studies, aged animals regained fur density, kidney function, and physical fitness, and the peptide protected against chemotherapy toxicity. Reports describe 11.73-fold selectivity for senescent cells over healthy ones. No human clinical trials have been run; all effect data comes from preclinical animal and cell studies. Dr. Peter de Keizer and colleagues at Erasmus University Medical Center first described it in 2017.
Key research areas
- Selective senescent cell elimination
- Tissue homeostasis restoration
- Potential longevity effects
Researched dosing
This table shows the dosing schedules used in published mouse studies with FOXO4-DRI, presented as research methodology reference, no human dosing schedule has been established.
| Phase | Dose | Frequency | Route |
|---|---|---|---|
| Mouse study protocol (IV) | 5 mg/kg | Every other day × 3 doses | IV |
| Mouse study protocol (IP) | 5 mg/kg | Every other day × 3 doses | IP |
| Unverified community protocol (SubQ) | ~25 mg per injection | Every other day × 3 doses (75-100 mg total per cycle) | SubQ |
Commonly cycled 1 weeks on, 3+ weeks off.
How it works
At the cell level, FOXO4-DRI research looks at how the peptide disrupts a specific protein interaction inside aged cells, which appears to selectively trigger their breakdown, the terms below just name that pathway.
Disrupts FOXO4-p53 interaction in senescent cells, causing p53 nuclear exclusion. Free p53 translocates to mitochondria, triggering caspase-dependent apoptosis specifically in senescent cells while sparing healthy cells (11.73-fold selectivity demonstrated).
Molecular data
These figures, molecular weight, chain length, sequence, are the chemistry fingerprint researchers use to confirm a FOXO4-DRI sample's identity; its D-amino-acid, reversed-sequence design makes it more complex to manufacture and verify than most peptides here.
- Weight
- 5358.2 Da
- Length
- 46 amino acids
- Type
- D-Retro-Inverso peptide with cell-penetrating domain
H-ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg-OH (all D-amino acids, lowercase denotes D-form)
Pharmacokinetics
This chart shows how a research dose of FOXO4-DRI is absorbed and cleared over time in animal studies, read it like a timer: the peak is when levels are highest, then the curve trails off as the compound clears.
- Peak
- 4 hr
- Half-life
- 48 hrs
- Cleared
- ~240 hrs
Baar et al. 2017 Cell
What the studies report
This section lists the body systems and research areas scientists have studied for FOXO4-DRI, entirely from mouse and cell-culture studies so far, summarizing what's been studied in the literature, not medical claims about people.
Longevity
Selectively eliminates 'zombie' senescent cells that accumulate with age and secrete harmful inflammatory factors (SASP). Mouse studies show restoration of tissue function including fur regrowth, renal function, and physical fitness.
Cellular
Demonstrates 11.73-fold selectivity for senescent vs healthy cells, with caspase-dependent apoptosis specifically targeting damaged cells.
Inflammation
Reducing senescent cell burden decreases SASP (senescence-associated secretory phenotype) inflammatory factor secretion.
Hormonal
Mouse studies showed significant increase in serum testosterone levels in aged mice. Enhanced expression of testosterone synthesis enzymes (3β-HSD, CYP11A1). Decreased testicular senescence markers and reduced inflammatory cytokines.
Dosage reference
- Doses used in research
- No established research dose. Mouse studies used 5 mg/kg; unverified community reports mention ~25 mg.
- Frequency in studies
- Every other day × 3 doses per cycle
- Handling
- Reconstituted solution, research use only; not for administration
- Timeline reported in studies
- Mouse studies showed improvements in 1-4 weeks. Human timelines unknown.
- Storage
- Lyophilized: -20°C. Reconstituted: 2-8°C, use within 7-10 days
- Cycle length
- 5 days per cycle (3 injections on days 1, 3, 5)
- Break between cycles
- Anecdotal protocols suggest monthly cycles
Interactions
This list shows which other longevity-research compounds are studied alongside FOXO4-DRI, including some that may need a washout period before or after use in a study.
Reconstitution & storage
This is the standard laboratory method for turning freeze-dried FOXO4-DRI powder into a liquid research solution.
- Allow vial to reach room temperature before reconstitution
- Add sterile water slowly down vial side
- Gently swirl until dissolved - do not shake (protein may denature)
- Solution should be clear; discard if cloudy or precipitated
- Use reconstituted solution within 7-10 days
Lyophilized: -20°C, use within As per manufacturer specification
Reconstituted: 2-8°C, use within 7-10 days
Open the FOXO4-DRI reconstitution calculatorQuality indicators
These are the manufacturing and lab-report checks researchers use to confirm a FOXO4-DRI sample is pure and correctly identified, its complex synthesis makes third-party testing especially important.
No human clinical trials - All data from mouse studies and cell culture. Human pharmacokinetics, safety, and efficacy unknown.
p53 pathway involvement - p53 is a critical tumor suppressor. Long-term effects of repeated FOXO4-p53 modulation unknown.
High synthesis cost - 46 D-amino acids make production expensive. Risk of low-quality or counterfeit products.
Avoid with Rapamycin/Quercetin - May diminish senolytic effects. Require 1-2 week washout period before FOXO4-DRI administration.
High selectivity demonstrated - 11.73-fold selectivity for senescent vs healthy cells in original research.
Third-party testing essential - Due to complex D-amino acid synthesis, verify peptide identity and purity via independent testing.
What to expect
This timeline summarizes what mouse-model research literature has reported at each stage of a study, research context for comparing studies, not a personal-results promise, since no human timeline exists.
No reliable human timeline established
Mouse studies: Improvements seen within 1-4 weeks. Fur density restored in aged mice within 2-3 weeks. Renal function normalized within study period.
Safety notes
This section covers handling and regulatory notes for FOXO4-DRI, research-use-only scope, with an explicit note that no human safety data exists for this compound.
- CRITICAL: No human clinical trials - all safety data from animal studies
- May not be useful for healthy individuals under 40 with low senescent cell burden
- Avoid concurrent use with Rapamycin, Quercetin, corticosteroids
- Theoretical concern: p53 pathway critical for tumor suppression
- Unknown immunogenicity with repeated dosing
- Not FDA-approved for human use
- Not on WADA prohibited list
- All efficacy data from preclinical animal and cell studies only
Regulatory status
- Not approved by the FDA for any indication.
- Supplied and described for laboratory research use only, not for human or veterinary use.
What is not known
The limits of the published work on FOXO4-DRI, stated plainly. Research use only: none of this is guidance for a person.
All of it is mice and cells. No trial in people has been run, so this page does not show what the peptide does in a person.
The peptide is meant to kill worn out cells and spare healthy ones. The selectivity reported is a ratio measured in culture. It says nothing about what happens to healthy cells in a living body.
The mouse papers report changes in fur, in kidney measures and in how much the animals moved. Whether the animals lived longer is a separate question, and these studies do not answer it.
What repeated courses do, and what happens across a full mouse lifetime, is not known.
The peptide is large and built from mirror image amino acids. How much of a dose reaches any particular tissue is not measured in these papers.
The terms, in plain words
Every technical term this page leans on, said again in ordinary words.
- Senescent cell
- A worn out cell that has stopped dividing and does not clear itself away.
- Senolytic
- A compound meant to clear worn out cells and leave the healthy ones.
- SASP
- The mix of inflammatory signals a worn out cell leaks into the tissue around it.
- D-retro-inverso
- A mirror image build, with the amino acids reversed, so enzymes struggle to cut it.
- p53
- A protein inside the cell that can switch on the cell's own self destruct program.
- Leydig cells
- The cells in the testis that make testosterone.
Sources
The published work behind this entry. Each link was opened and each note says what that paper reports, not what it suggests.
- Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging Cell, 2017Mice and cultured cells. The paper that introduced FOXO4-DRI. Reports that it kills worn out cells and that treated old mice recovered fur density, kidney measures and activity.
- FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice Aging, 2020Old mice. Reports higher testosterone and fewer worn out cells in the testis after treatment.
How it is studied
In the published studies listed below. Each one names the species it was run in, the dose, how long it ran, and what it reported.
Landmark study introducing FOXO4-DRI. Demonstrated 11.73-fold selectivity for senescent cells. In aged mice, restored fur density, normalized renal function (plasma urea/creatinine), increased voluntary running activity, and protected against doxorubicin-induced liver damage. No thrombocytopenia or cardiac abnormalities observed.
Treatment significantly increased serum testosterone levels in aged mice. Enhanced expression of testosterone synthesis enzymes (3β-HSD, CYP11A1). Decreased testicular senescence markers (p53, p21, p16) and reduced inflammatory cytokines (IL-1β, IL-6, TGF-β). No toxicity to normal Leydig cells.
Removed over 50% of highly-passaged senescent chondrocytes (PDL9) while not affecting minimally-passaged cells (PDL3). Reduced senescence markers and improved cartilage quality. However, did not enhance chondrogenic potential of treated cells.