Educational reference only. Not medical advice. Consult a healthcare provider before starting any protocol.
FOXO4-DRI
FOXO4 D-Retro-Inverso Peptide (Proxofim)
What it is
A synthetic 46-amino-acid D-retro-inverso cell-penetrating peptide designed to disrupt the FOXO4-p53 interaction in senescent cells. FOXO4-DRI competitively binds p53's disordered transactivation domain 2, releasing p53 from FOXO4 sequestration in PML nuclear bodies and triggering caspase-3/7-dependent intrinsic apoptosis selectively in senescent cells. The DRI modification (reversed sequence, all D-amino acids) confers protease resistance while preserving binding topology. The C-terminal HIV-TAT-derived sequence enables cellular uptake. Studied in mouse models of accelerated aging, chemotoxicity, and natural aging (Baar et al., Cell 2017), where it was observed to restore fur density, renal function, and exploratory behavior. No human clinical trials have been conducted.
Community-reported ranges
Ranges sourced from community forums, biohacking protocol databases, and published preclinical literature. Mouse-to-human dose translations are allometric extrapolations. Not dosing guidance.
Reported dose range
1000–5000 mcg
Estimated half-life
~1-3 days (theoretical)
Source: DRI-class peptide pharmacology extrapolation; no formal PK study published
Reported cycle length
1–2 weeks on
4-12 weeks off
Route
subcutaneous
Common vial sizes
2mg, 5mg, 10mg
Reported timing
AM (pulse protocol)
Reported frequency
every other day x3 doses (pulse protocol)
Frequently discussed alongside
Based on community forum discussions. Not a recommendation to combine compounds.
Epithalon
Discussed together in longevity contexts as complementary anti-aging mechanisms (telomerase activation vs. senescent cell clearance)
SS-31 (Elamipretide)
Both studied as peptide interventions targeting hallmarks of aging — mitochondrial dysfunction and cellular senescence respectively
Humanin
Opposing but complementary strategies in aging biology — Humanin protects cells from apoptosis while FOXO4-DRI induces apoptosis in senescent cells
Published research
The landmark Baar et al. 2017 Cell study demonstrated that FOXO4-DRI (5 mg/kg IP, 3 doses on alternating days) selectively cleared senescent cells and restored tissue homeostasis in fast-aging XpdTTD/TTD mice, doxorubicin-treated mice, and naturally aged mice. A 2020 follow-up (Zhang et al., Aging) showed the peptide alleviated age-related testosterone insufficiency by targeting senescent Leydig cells. A 2025 structural study (Bourgeois et al., Nature Communications) characterized the binding mechanism between FOXO4-DRI and the disordered p53 transactivation domain. In vitro studies show 11.7-fold selectivity for senescent over non-senescent fibroblasts. No peer-reviewed human clinical trials have been conducted as of March 2026. Community dosing protocols are allometrically scaled from mouse data and are not clinically validated.
Reported side effects
From community self-reports. Not from controlled studies.
Community users have reported injection site burning and itching, fatigue, muscle soreness, nausea, and mild flu-like symptoms during pulse protocols. Theoretical concerns from researchers include potential cardio/muscle toxicity (FOXO4 is expressed in muscle tissue) and unknown long-term effects of p53 modulation. Systematic safety data in humans does not exist.
Regulatory status
FDA (United States)
Not approved. Not specifically named on the FDA Category 2 bulk drug substances list. Exists in a regulatory gray area as a research-use-only compound.
Health Canada
Not authorized as a therapeutic product. No DIN assigned.
WADA (Competitive Athletes)
Not specifically named on the 2025/2026 Prohibited List. Likely prohibited under S0 (Non-approved substances) for competitive athletes.
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