FOXO4-DRI
Senolytic Peptide | FOXO4-p53 Disruption for Cellular Aging Research
FOXO4-DRI (FOXO4-D-Retro-Inverso) is a synthetic 46-amino acid peptide designed to selectively eliminate senescent cells -damaged cells that accumulate with age and secrete harmful inflammatory factors (SASP). The peptide uses D-amino acids in reversed sequence, making it resistant to proteolytic degradation while maintaining binding function. FOXO4-DRI works by disrupting the FOXO4-p53 interaction that keeps senescent cells alive, causing p53 nuclear exclusion and redirecting it to mitochondria to trigger apoptosis. In mouse studies, it restored fur density, renal function, and physical fitness in aged animals while protecting against chemotherapy-induced toxicity. Notably, it shows 11.73-fold selectivity for senescent over healthy cells. No human clinical trials have been conducted; all efficacy data comes from preclinical animal and cell studies. The peptide was first described by Dr. Peter de Keizer and colleagues at Erasmus University Medical Center in 2017.
Daily dose
~25 mg (anecdotal human translation)
Frequency
Every other day × 3 doses
Cycle length
5 days per cycle
Storage
-20°C (lyophilized)
Key benefits
Selective senescent cell elimination, tissue homeostasis restoration, anti-aging research compound
How it works
Disrupts FOXO4-p53 interaction, causing p53 nuclear exclusion and mitochondrial translocation. Triggers apoptosis specifically in senescent cells with 11.73-fold selectivity over healthy cells.
Dosage protocols
Goal
Mouse Research Protocol
Dose
5 mg/kg · Every other day × 3
Route
IV or IP
Goal
Anecdotal Human Translation
Dose
~25 mg · Every other day × 3
Route
SubQ
Research indications
anti Aging
cellular
inflammation
Administration
Interactions
Safety notes
No human clinical trials conducted
All safety data from mouse studies
Avoid Rapamycin, Quercetin, corticosteroids concurrently
Anecdotal: injection site reactions reported
p53 pathway involvement -theoretical oncogenic concerns
May not benefit healthy young individuals
Research studies
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis (2017)
Mouse | 5 mg/kg IV | 3 doses every other day | Fast-aging & naturally aged mice
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.
View study →FOXO4-DRI Alleviates Age-Related Testosterone Secretion Insufficiency (2020)
Mouse | 5 mg/kg IP | Every other day × 3 | Aged mice (20-24 months)
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.
View study →Senolytic FOXO4-DRI Removes Senescent Human Chondrocytes (2021)
Human cells in vitro | Passaged chondrocytes | Senescence model
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.
View study →FOXO4-DRI Ameliorates Bleomycin-Induced Pulmonary Fibrosis (2022)
Mouse | BLM-induced fibrosis model | Therapeutic administration
Similar efficacy to approved drug Pirfenidone. Decreased senescent cells, downregulated SASP factors, attenuated collagen deposition. Increased type 2 alveolar epithelial cells while selectively killing TGF-β-induced myofibroblasts.
View study →FOXO4-DRI Targets ECM Production in Pulmonary Fibrosis (2023)
Mouse | Bleomycin model | ECM pathway analysis
Confirmed FOXO4-DRI resets p53 nuclear distribution and decreases total ECM protein content. Therapeutic administration showed milder pathologic changes and less collagen deposition than untreated fibrosis group.
View study →