FOXO4-DRI
Also known as: FOXO4-D-Retro-Inverso, Proxofim
Senolytic Peptide | p53-FOXO4 Disruptor
Overview
FOXO4-DRI is a senolytic peptide designed to selectively eliminate senescent 'zombie' cells that accumulate with age and contribute to tissue dysfunction. It works by disrupting the FOXO4-p53 interaction that keeps senescent cells alive. The 'DRI' modification (D-retro-inverso) uses reversed D-amino acids to increase potency and stability. Preclinical research shows restoration of fur density, fitness, and organ function in aged mice.
Key benefits
- Selective elimination of senescent cells
- Restoration of tissue homeostasis
- Improved fitness and physical function in aged models
- Restored fur density in aged mice
- Improved kidney function
- Alleviates chemotherapy-induced senescence
- Restores testosterone in aged males
- Reduces senescent chondrocytes in cartilage
- High selectivity spares healthy cells
Mechanism of action
FOXO4-DRI competes with FOXO4 for binding to p53, disrupting their protective interaction in senescent cells. This causes p53 to be excluded from the nucleus and triggers cell-intrinsic apoptosis (programmed cell death). Critically, this mechanism is highly selective: the FOXO4-p53 interaction is a specific vulnerability of senescent cells, while FOXO4 is minimally expressed in healthy tissues, leaving functional cells largely unharmed.
Molecular data
- Type
- D-retro-inverso peptide
- Half-life
- Not established
Indications
What the research community uses this compound for, with self-reported effectiveness.
Anti-Aging
Senescent Cell Clearance
EffectiveSelectively induces apoptosis in senescent cells while sparing healthy tissue.
Tissue Rejuvenation
EffectiveRestores tissue homeostasis and function in naturally aged animal models.
Physical Function
EffectiveImproved fitness, mobility, and physical appearance in aged mice.
Organ Function
Kidney Function
EffectiveRestored renal function in aged and fast-aging mouse models.
Testicular Function
EffectiveImproved testicular microenvironment and testosterone secretion in aged mice.
Cartilage Health
ModerateRemoves senescent chondrocytes, potentially benefiting joint health.
Chemoprotection
Chemotherapy Recovery
EffectiveNeutralizes doxorubicin-induced chemotoxicity by clearing treatment-induced senescent cells.
Dosing protocols
Common protocols by delivery method. Adjust the curve below to model accumulation in your own cycle.
Injectable
Currently in experimental stages. The original 2017 mouse study used 5 mg/kg intraperitoneally, three times on alternate days. For a 60kg human, this translates to approximately 25 mg per dose. Self-experimenters have reported using subcutaneous injection. Storage at -20°C required due to peptide stability concerns.
| Protocol | Dose | Frequency | Route / duration |
|---|---|---|---|
| Standard senolytic protocol | 25-33 mg | 3 doses, every other day (6 days total) | SubQ or IV |
| Mouse study equivalent | 5 mg/kg (translates to ~25 mg for 60kg human) | 3 doses on alternate days | IP (original study) |
Preparation
You will need
- Sterile water or appropriate buffer
- Syringes
- Alcohol swabs
- Cold storage capability
Steps
- Store peptide at -20°C until use
- Reconstitute according to research protocol
- Use immediately or store at 4°C short-term
- Avoid repeated freeze-thaw cycles
Work out the water volume and syringe units in the reconstitution calculator →
Interactions
Pairwise interactions with other compounds you might be cycling — the same data behind the cycle builder's safety check.
Fisetin
SynergisticOther senolytics may have additive effects on senescent cell clearance.
Dasatinib + Quercetin
CompatibleDifferent senolytic mechanisms; sequential use may be considered.
Humanin
CompatibleDifferent mechanisms; Humanin protects healthy cells while FOXO4-DRI clears senescent ones.
Timeline
Typical week-by-week effects reported in clinical and observational data.
- Hours-Days
Senescent cell apoptosis initiated
- Days-Weeks
Clearance of senescent cells
- Weeks-Months
Tissue regeneration and functional improvements
- Long-term
Sustained benefits with periodic treatment
Safety
Reported adverse effects, contraindications, and what to monitor on cycle.
Common side effects
- Limited human data available
- Generally well-tolerated in animal studies
Rare side effects
- Unknown - ongoing research
Stop signs — stop and seek advice
- Allergic reactions
- Unexpected adverse effects
Contraindications
- Not yet approved for human use
- Pregnancy or breastfeeding
- Unknown safety in immunocompromised individuals
- Active cancer (theoretical - consult oncologist)
Monitoring
- Experimental peptide - medical supervision essential
- Monitor organ function during treatment
Quality checks
What a legitimate product looks like, what should give pause, and what should make you stop.
Good signs
- Stored at -20°C or below
- White lyophilized powder
- High purity (>95%)
- Clear solution after reconstitution
Warning signs
- Temperature excursions may affect potency
Stop signs — don't use
- Exposed to room temperature for extended periods
- Discoloration
- Repeated freeze-thaw cycles
References
Primary literature and clinical-trial data informing this entry.
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis
Cell · 2017
FOXO4-DRI restored fitness, fur density, and renal function in aged mice using 5 mg/kg IP, 3 doses on alternate days. Well-tolerated under therapeutic conditions.
An Example of Senolytic Self-Experimentation with FOXO4-DRI
Fight Aging! · 2017
Self-experimenters have translated the mouse protocol to ~25 mg per injection subcutaneously, 3 doses every other day, for 75-100 mg total per treatment cycle.
FOXO4-DRI Alleviates Age-Related Testosterone Secretion Insufficiency
Theranostics · 2020
FOXO4-DRI improved testicular microenvironment and testosterone secretion by clearing senescent Leydig cells.
FOXO4-DRI Removes Senescent Cells from Human Chondrocytes
Frontiers in Bioengineering and Biotechnology · 2021
Removed >50% of senescent chondrocytes without affecting healthy early-passage cells.
The Disordered p53 Transactivation Domain is the Target of FOXO4-DRI
Nature Communications · 2025
Structural analysis revealed FOXO4-DRI binds disordered p53TAD2, forming transiently folded complex.
Last updated . How this page was sourced is described in the methodology.