FOXO4-DRI
Senolytic PeptideresearchAlso known as: FOXO4-D-Retro-Inverso, Proxofim, Senolytic Peptide
A D-retro-inverso peptide that selectively induces apoptosis in senescent cells by disrupting the FOXO4-p53 interaction, representing a targeted senolytic approach to aging.
Overview
FOXO4-DRI is a modified peptide designed to selectively eliminate senescent (zombie) cells — damaged cells that refuse to die and accumulate with age, secreting inflammatory factors that damage surrounding tissue. Developed by Peter de Keizer's lab at Erasmus University Medical Center, FOXO4-DRI works by disrupting the interaction between FOXO4 and p53 proteins. In senescent cells, FOXO4 binds to p53 and prevents it from triggering apoptosis (programmed cell death). FOXO4-DRI competes with endogenous FOXO4, freeing p53 to activate cell death pathways specifically in senescent cells. The D-retro-inverso (DRI) modification uses D-amino acids in reversed sequence, making the peptide resistant to protease degradation while maintaining biological activity. In aged mice, FOXO4-DRI restored fur density, kidney function, and physical fitness, generating enormous excitement in the longevity field.
Mechanism of Action
FOXO4-DRI works through a highly specific mechanism: (1) In senescent cells, FOXO4 forms a complex with p53, sequestering p53 in the nucleus and preventing apoptosis; (2) FOXO4-DRI is a peptide that mimics the FOXO4 domain responsible for p53 binding; (3) It competitively displaces endogenous FOXO4 from p53 in senescent cells; (4) Freed p53 then activates mitochondrial apoptosis pathways (BAX/BAK), triggering programmed cell death; (5) Non-senescent cells are unaffected because they don't rely on the FOXO4-p53 interaction for survival; (6) The DRI modification (D-amino acids, reversed sequence) provides protease resistance for improved bioavailability.
Molecular Formula
Not publicly disclosed (proprietary sequence)
Molecular Weight
~4800 g/mol (estimated, 48 amino acids)
Sequence
D-retro-inverso modified peptide corresponding to FOXO4 p53-binding domain (proprietary)
Dosage Protocols
Dose Range
5mg/kg – 10mg/kg
Frequency
Every other day or 3 times per week
Route
intravenous or intraperitoneal
Cycle Length
Short courses (1-3 weeks)
Dosing based on mouse studies (5mg/kg IP, 3x/week). Human dosing has NOT been established. Self-experimentation communities have attempted various protocols but no validated human data exists. Extremely expensive due to peptide length and DRI modification.
Source: de Keizer et al., Cell 2017 (mouse study)
Side Effects
| Effect | Severity |
|---|---|
| Unknown human side effects | unknown |
| Potential off-target cell death | moderate |
| Injection site reaction | mild |
| Transient inflammation | mild |
Pros & Cons
First-in-class targeted senolytic peptide with a clear, elegant mechanism for eliminating senescent cells
Demonstrated remarkable rejuvenation effects in aged mice: restored fur, kidney function, and fitness
Selective for senescent cells — does not harm healthy cells in preclinical studies
DRI modification provides protease resistance, extending biological half-life
No human clinical trials — entirely preclinical at this stage
Extremely expensive to synthesize due to length (48 amino acids) and D-amino acid modification
Human dosing, safety, and pharmacokinetics are completely unknown
Long-term effects of senescent cell clearance in humans are not understood
Quality and purity concerns with research-grade suppliers; verification is difficult
Research Studies
Legal Status
Experimental research compound only. Not approved by any regulatory agency. Not commercially available through standard pharmaceutical channels. Available from select research peptide suppliers. No clinical trials in humans yet.
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