FOXO4-DRI
Also known as: FOXO4-D-retro-inverso · Proxofim
Contents
MW
3730 Da
Amino Acids
31 AA
Half-Life
6-12 hours
Route
SubQ, IV
Mechanism of Action
FOXO4-DRI is a D-retro-inverso (DRI) peptide designed to selectively eliminate senescent cells (senolytics). The "D-retro-inverso" structure means it uses D-amino acids in reverse sequence, creating a mirror-image peptide that resists protease degradation while maintaining the same spatial side-chain presentation as the L-peptide.
PRIMARY MECHANISM — FOXO4-p53 DISRUPTION: In senescent cells, the transcription factor FOXO4 sequesters p53 in PML (promyelocytic leukemia) nuclear bodies. This prevents p53 from reaching the mitochondria and triggering apoptosis — keeping senescent "zombie cells" alive despite their damaged state. FOXO4-DRI competes with endogenous FOXO4 for p53 binding, releasing p53 to trigger apoptosis specifically in senescent cells.
SELECTIVITY: Non-senescent cells do not have the FOXO4-p53 sequestration complex, so FOXO4-DRI has no target to disrupt — leaving healthy cells unaffected.
In the landmark Baar et al. 2017 paper (Cell), aged mice treated with FOXO4-DRI showed restored fitness, improved fur density, and improved renal function — reversing multiple hallmarks of aging.
Dosing Protocol
Low Dose
███ – ███ mcg/day
Standard Dose
███ mcg/day
High Dose
███ – ███ mcg/day
Dosing protocols are for paid members
Get exact dosing ranges, injection frequency, timing rationale, and reconstitution math.
Get Clinical Access — $79/moFrequency
Animal protocol: 3x/week for 3 weeks (intraperitoneal).
Half-Life
6-12 hours
Reconstitution Guide
Full reconstitution protocol with BAC water volumes, concentration math, and units-to-draw per dose is available on the Clinical plan.
Unlock reconstitution guide →Clinical Warnings
NO HUMAN DATA whatsoever.
Extremely expensive to synthesize (D-amino acids).
Unknown off-target effects in humans.
Unknown dose conversion from animal models.
Potential cardiac risk if cardiac senescent cells are disrupted.
Completely uncharacterized human pharmacology.
Contraindications
Absolute
Pregnancy
Active cancer
Bone marrow disorders
Relative Cautions
Autoimmune disease
Immunosuppression
Advanced age with frailty
Side Effect Profile
Mild
- ●Injection site reaction
- ●Mild fatigue
- ●Muscle soreness
Moderate
- ●Flu-like symptoms
- ●Transient weakness
- ●Joint pain
Severe (Rare)
- ●Excessive senescent cell clearance
- ●Immune disruption
- ●Tissue damage
Synergistic Peptides
Common Stacks
NAD+
Epithalon
Research Status
PRECLINICAL. PMID 28575665 (Baar 2017 Cell): Original paper — aged mice restored fitness, fur, renal function after senescent cell clearance. PMID 32014102 (Zhang 2020): Leydig cell senescence reversal + testosterone restoration in aged mice. Zero human trials. Extremely early stage.
Frequently Asked Questions
How does FOXO4-DRI work?
FOXO4-DRI is a D-retro-inverso (DRI) peptide designed to selectively eliminate senescent cells (senolytics). The "D-retro-inverso" structure means it uses D-amino acids in reverse sequence, creating a mirror-image peptide that resists protease degradation while maintaining the same spatial side-chain presentation as the L-peptide. PRIMARY MECHANISM — FOXO4-p53 DISRUPTION: In senescent cells, the transcription factor FOXO4 sequesters p53 in PML (promyelocytic leukemia) nuclear bodies. This preve
What is the standard dose of FOXO4-DRI?
FOXO4-DRI dosing protocols are available with a ClinPep Clinical subscription. Dosing varies by indication and patient factors — consult a licensed healthcare provider. General frequency: Animal protocol: 3x/week for 3 weeks (intraperitoneal).
What is the half-life of FOXO4-DRI?
The half-life of FOXO4-DRI is 6-12 hours. This determines optimal dosing frequency and timing.
Who should not use FOXO4-DRI?
FOXO4-DRI is absolutely contraindicated in: Pregnancy; Active cancer; Bone marrow disorders. Use with caution in: Autoimmune disease; Immunosuppression; Advanced age with frailty.
What are the side effects of FOXO4-DRI?
Common mild side effects include: Injection site reaction, Mild fatigue, Muscle soreness. Moderate effects: Flu-like symptoms, Transient weakness, Joint pain.
What peptides stack well with FOXO4-DRI?
FOXO4-DRI is commonly stacked with: NAD+, Epithalon, SS-31.
How do you reconstitute FOXO4-DRI?
FOXO4-DRI is reconstituted with bacteriostatic water. Exact volumes, concentrations, and units-to-draw calculations are available in the ClinPep Clinical plan. Always follow your compounding pharmacy's instructions.
How long should you cycle FOXO4-DRI?
FOXO4-DRI cycle protocols vary by indication. Detailed cycle length, on/off schedules, and monitoring guidelines are available with ClinPep Clinical access. Consult your healthcare provider for personalized cycling guidance.
References & Citations
4 PubMed studies · 1 clinical trials
The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.
Bourgeois Benjamin, Spreitzer Emil, Platero-Rochart Daniel, Paar Margret et al.. Nature communications. 2025
A central process contributing to the phenotype of aging is cellular senescence. We recently identified the FOXO4 - p53 axis as pivotal in maintaining the viability of senescent cells, and that senesc
FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation.
Kong Yu-Xiang, Li Zhi-Shuai, Liu Yuan-Bo, Pan Bo et al.. Communications biology. 2025
Keloids are pathological scars exhibiting tumour-like aggressiveness and high recurrence rate. Here we find increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senes
Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.
Born Emmanuelle, Lipskaia Larissa, Breau Marielle, Houssaini Amal et al.. Circulation. 2023
Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the
FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.
Zhang Chi, Xie Yun, Chen Haicheng, Lv Linyan et al.. Aging. 2020
Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore
Registered Clinical Trials
Celecoxib Plus R-CHOP vs R-CHOP in Newly Diagnosed Advanced CD5+ DLBCL
Symptom Indications
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Complete FOXO4-DRI Protocol
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This information is for educational and research reference purposes only. ClinPep does not provide medical advice, diagnosis, or treatment recommendations. All protocols should be reviewed by a licensed healthcare provider.