FOXO4-DRI
FOXO4-D-Retro-Inverso · senolytic peptide · ES2 / FOXO4 peptide
Senolytic that cleared senescent cells in aged mice (Baar 2017); no human data
Overview
FOXO4-DRI is a designed D-retro-inverso peptide — built from D-amino acids in reverse sequence to resist enzymatic breakdown — that disrupts the binding between the transcription factor FOXO4 and the tumor-suppressor p53. In senescent cells, FOXO4 sequesters p53 in the nucleus and keeps those cells alive; breaking that interaction frees p53 to relocate to the mitochondria and trigger apoptosis specifically in the senescent population. This is the textbook example of a targeted 'senolytic.'
Its fame rests almost entirely on a single landmark study. In 2017, Baar and colleagues reported in Cell that FOXO4-DRI (5 mg/kg, given intraperitoneally on alternating days over about three weeks) selectively cleared senescent cells in mice and produced visible rejuvenation: fast-aging mice regrew lost fur within roughly ten days, and naturally aged mice showed improved running endurance, restored coat density, and recovery of kidney function, alongside an approximately 30% drop in p16-positive senescent cells in aged kidneys. A 2025 follow-up further mapped the binding to the disordered transactivation domain of p53.
This entry deliberately leads with caution rather than dosing. The entire evidence base is preclinical — mouse models and cell cultures — and the compound has never been tested in a human clinical trial. There is no validated human dose; the escalating community ladders sometimes quoted (for example 250 mcg daily building to 500 mcg over several weeks) have no human validation whatsoever, and the mechanism itself raises real theoretical hazards. The figures here are documented for reference, not offered as a usable protocol.
Key parameters
- Dose range
- No established human dose; community ladders cite 250–500 mcg
- Frequency
- Experimental (community ladders run in cycles)
- Half-life
- Not well characterized; reportedly short and oxidation-sensitive
- Route
- Subcutaneous (animal studies used intraperitoneal/IV)
- Vial sizes
- 5 mg · 10 mg
- Regulatory status
- Experimental senolytic peptide; preclinical only. Never tested in a registered human clinical trial and not approved by any regulator.
Mechanism of action
FOXO4–p53 interaction disruption
The peptide competitively interferes with FOXO4 binding to p53 inside senescent cells, releasing p53 so it can translocate to the mitochondria and initiate the intrinsic apoptosis pathway.
Selective senolysis
Because senescent cells are unusually dependent on the FOXO4–p53 interaction for survival, disrupting it preferentially kills them while sparing most healthy cells — the defining property of a senolytic (demonstrated in animal models).
D-retro-inverso protease resistance
Constructing the peptide from D-amino acids in reversed order makes it resistant to proteolytic degradation, which is what allows a peptide of this kind to persist long enough to act.
Dosing protocol & phases
| Phase | Weeks | Dose | Notes |
|---|---|---|---|
| Preclinical / experimental | N/A | No validated human protocol exists | There is no established human dose. The compound is preclinical; do not extrapolate animal dosing to humans. |
| Reference animal protocol | ~3 weeks | 5 mg/kg intraperitoneally, alternating days (mice) | The Baar 2017 schedule, included for context only — not a human regimen. |
Reconstitution guide
For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.
5 mg vial + 2 mL bacteriostatic water
Concentration2,500 mcg/mL · 2.5 mg/mL
| Target dose | Draw volume | U-100 units |
|---|---|---|
| 250 mcg | 0.1 mL | 10 |
| 375 mcg | 0.15 mL | 15 |
| 500 mcg | 0.2 mL | 20 |
Illustrative mix only — there is no validated human dose. Rows mirror the microgram ladders sometimes cited in community use, shown for reference rather than recommendation.
Reconstitution calculator
Pre-filled with FOXO4-DRI's vial sizes. Adjust the water volume and target dose to see the exact draw, with warnings for doses that are hard to measure or won't fit a syringe.
At 2,500 micrograms per millilitre, a 250 microgram dose is 0.1 millilitres, or 10 units on a U-100 syringe, giving 20 doses per vial.
Supplies needed
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Recommended supply
FOXO4-DRI — research vial
From our verified partner Dynotides, with a third-party certificate of analysis per batch.
Injection supplies
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Bacteriostatic water
Diluent for reconstituting lyophilized vials.
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Insulin syringes (U-100)
0.3–0.5 mL, 29–31 G for accurate small draws.
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Alcohol prep pads
Sterile swabs for the vial stopper and site.
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Sharps container
Safe disposal of used needles.
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Storage fridge
Keeps reconstituted vials at 2–8 °C.
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Insulated travel case
Cooled, TSA-friendly case for travel.
Missed-dose guidance
No guidance can be given. FOXO4-DRI is an experimental, preclinical compound with no established human dosing schedule, so there is no meaningful missed-dose rule.
Side effects & safety
| Category | Effect | Trial incidence |
|---|---|---|
| General | Human safety unknownNo human exposure data of any kind; the entire profile is theoretical or extrapolated from animals. | — |
| Theoretical | Off-target apoptosis in non-senescent cellsActivating p53-driven cell death is not perfectly selective; harm to healthy tissue is a plausible, unquantified risk. | — |
| Theoretical | Impaired wound healing / immune clearance burdenA wave of dying cells must be cleared by the immune system, and senescent cells contribute to some repair processes; disrupting them carries theoretical downsides. | — |
| Injection site | Local irritationExpected with subcutaneous injection generally; product quality is an additional major confounder for this compound. | — |
Clinical trials & evidence
Baar et al. — original senolytic study
Preclinical (mouse/cell)~3 weeks (dosing) · Naturally aged and fast-aging mouse models
Selective clearance of senescent cells with fur regrowth, improved running endurance, restored renal function, and ~30% fewer p16-positive cells in aged kidneys.
Trial identifier needs verification
Human clinical trials
NoneN/A · N/A
As of 2026 there are no completed or registered human clinical trials of FOXO4-DRI; it has never been tested in people.
Trial identifier needs verification
Storage & handling
- Lyophilized
- Store lyophilized powder frozen (around −20 °C), kept dry and protected from light.
- Reconstituted
- Refrigerate at 2–8 °C and use promptly; the peptide is reported sensitive to oxidation and freeze–thaw, so prolonged storage in solution is discouraged. Discard cloudy or particle-containing solutions.
Comparisons
| Vs. | Target | Half-life | Dosing | Efficacy | Status |
|---|---|---|---|---|---|
| Epitalon | Senolytic (FOXO4–p53) vs bioregulator (telomerase/pineal) | Not well characterized vs very short | No established human dose vs short courses (community) | Both unproven in controlled human longevity trials; FOXO4-DRI is purely preclinical | Both not approved |
| MOTS-c | Senescent-cell clearance vs mitochondrial metabolic signaling | Not well characterized (both) | No established human dose vs community SC | Different aging strategies (senolysis vs metabolic); both lack human longevity-outcome trials | Both not approved |
Sources & references
Frequently asked questions
What is a 'senolytic'?
A senolytic is an agent meant to selectively eliminate senescent ('aged') cells, which accumulate in tissues and secrete inflammatory signals as we age. FOXO4-DRI is one of the best-known experimental senolytic peptides, but its evidence is confined to animal models.
Is there a known human dose for FOXO4-DRI?
No. The evidence is preclinical only, and no human dose has ever been established or tested. The escalating microgram ladders sometimes circulated in community settings have no clinical validation and should not be treated as a protocol.
Why is the mechanism considered risky?
FOXO4-DRI works by unleashing p53-driven apoptosis. That selectivity is not perfect, so there is a theoretical risk of killing healthy cells, impairing wound healing, or overloading the immune system with cellular debris. None of this has been characterized in humans, which is precisely the problem.
Related protocols
Epitalon
Epithalon
AEDG tetrapeptide; telomerase signal is from cell/animal work, not human RCTs
Looking to match this protocol to a verified research vial? Our partner supplier publishes a certificate of analysis per batch.
For educational and research reference only. Not intended for human consumption, not medical advice. Compounds discussed are sold and used for laboratory research purposes only.