FOXO4-DRI — Research, Dosing & Price Guide

FOXO4-DRI is a D-retro-inverso peptide that selectively induces apoptosis in senescent cells — making it a true senolytic agent. Developed by Peter de Keizer at Erasmus University Medical Center, it works by disrupting the interaction between FOXO4 and p53 that keeps senescent cells alive. In aged mice, it restored fitness, fur density, and renal function.

Senescent cells resist apoptosis through a specific survival mechanism: the transcription factor FOXO4 binds to p53 and sequesters it within promyelocytic leukemia (PML) nuclear bodies. This prevents p53 from translocating to the mitochondria, where it would normally trigger the intrinsic apoptotic cascade via Bax/Bak activation and cytochrome c release. FOXO4-DRI is an all-D-amino acid retro-inverso peptide that mimics a portion of FOXO4 and competitively disrupts the FOXO4-p53 interaction. Once liberated, p53 exits the nucleus, localizes to the mitochondrial outer membrane, and initiates apoptosis specifically in senescent cells. Healthy cells are spared because they do not rely on FOXO4-p53 sequestration for survival — their p53 activity is regulated through normal MDM2-mediated degradation pathways. The D-retro-inverso design confers protease resistance, extending the peptide's half-life in vivo substantially compared to L-amino acid versions.

• De Keizer et al. published the landmark study in Cell (2017) demonstrating FOXO4-DRI selectively eliminated senescent cells and restored health markers in fast-aging XpdTTD/TTD mice and naturally aged mice
• Treated mice showed restored fur density, improved renal function (reduced plasma creatinine), and increased voluntary running activity
• In vitro studies confirmed FOXO4-DRI induces apoptosis exclusively in senescent cells while leaving healthy proliferating cells unaffected
• The senolytic effect was confirmed across multiple senescence-inducing stimuli: irradiation, oncogene activation, and replicative senescence
• Self-experimenter reports from the longevity community have described improved skin quality, reduced inflammation markers, and faster exercise recovery
• The D-retro-inverso design showed 10-fold increased serum stability compared to L-peptide analogs

• Research dose (mouse studies): 5 mg/kg IV, administered 3 times per week for 3 weeks
• Self-experimenters have reported using 1–5 mg/kg subcutaneous injection, 2–3 times per week for 2–3 weeks
• Some protocols use a once-monthly high-dose approach (5 mg/kg) for 3 consecutive months
• No established human clinical dosing protocol exists — all doses are extrapolated from preclinical data
• Cost is a significant barrier: typical human-equivalent doses require 200–500 mg per course at current pricing
• Cycle: 2–3 weeks of active dosing, then reassess. Can repeat every 3–6 months
• Subcutaneous injection preferred over IV for practical self-administration

Known Side Effects

• Transient flu-like symptoms as senescent cells are cleared and release inflammatory contents (expected senolytic response)
• Injection site reactions: redness, swelling, and mild pain due to relatively large injection volumes
• Potential for temporary increase in inflammatory markers (IL-6, TNF-α) during the clearance phase
• Theoretical risk of excessive cell death in tissues with high senescent cell burden — start with lower doses
• Gastrointestinal discomfort reported by some self-experimenters
• Fatigue and malaise during the first 3–5 days of treatment

Safety Profile

FOXO4-DRI safety data is limited to preclinical mouse studies and anecdotal self-experimenter reports. In the original de Keizer study, no significant toxicity was observed in treated mice — liver enzymes, blood counts, and body weight remained normal. The selectivity for senescent cells is a key safety feature, as healthy cells are not affected. However, important unknowns remain: the long-term consequences of periodic senescent cell clearance in humans are not established, and the potential for clearing beneficial senescent cells (e.g., those involved in wound healing or tumor suppression) has not been fully characterized. The cost barrier (thousands of dollars per course) has limited widespread experimentation. Contraindications include active wound healing, recent surgery, pregnancy, and immunosuppression. Those with cancer should exercise extreme caution — while senolytic therapy may theoretically benefit cancer outcomes, the interaction between FOXO4-DRI and tumor-associated senescence is complex.

Week 1: Possible flu-like symptoms (fatigue, mild joint aches, low-grade temperature) as senescent cells begin undergoing apoptosis. This is considered an expected response indicating senolytic activity. Inflammatory markers may temporarily spike. Weeks 2–3: Flu-like symptoms resolve. Early reports of improved energy and reduced joint stiffness. Skin may appear clearer as senescent dermal fibroblasts are cleared. Weeks 4–8 post-treatment: Progressive improvements in tissue quality, exercise recovery, and inflammatory markers. Self-experimenters have reported improved blood biomarkers (reduced CRP, improved lipid panels) at the 6–8 week mark. Effects are expected to build over 2–3 months as tissues remodel following senescent cell removal. Subsequent courses (3–6 months later) continue to clear newly accumulated senescent cells.

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