LongevityAnti-AgingEmerging

FOXO4-DRI

FOXO4-D-Retro-Inverso Peptide

Overview

FOXO4-DRI is a synthetic D-amino acid retro-inverso peptide designed to selectively eliminate senescent cells by interfering with the interaction between the FOXO4 transcription factor and p53 that senescent cells depend on for survival. It represents one of the most targeted senolytic approaches developed to date acting specifically on the aberrant survival pathway of senescent cells without affecting normal healthy cells. Research published in Cell in 2017 demonstrated dramatic effects including restoration of fur density fitness and kidney function in aged mice generating significant excitement in the longevity research community.

Compound Data

Molecular Formula

C228H388N86O64

Molecular Weight

5358.00 g/mol

IUPAC Name

(4R)-5-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-5-amino-1-[[(2R)-4-amino-1-[[2-[[(2R)-1-[[(2R)-1-[[(2R)-4-amino-1-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[2-[[2-[[(2R)-6-amino-1-[[(2R)-1-[(2R)-2-[(2R)-2-[(2R)-2-[[(2R)-1-[[(2R)-1-[[(2R)-1-[[(2R)-5-amino-1-[[(2R)-1-[[(2R)-1-[[(2R)-6-amino-1-[[(2R)-6-amino-1-[[(2R)-5-carbamimidamido-1-(carboxymethylamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-1,4-dioxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-[[(2R)-2-[[(2R,3R)-2-[[(2R)-2-[[(2R)-5-amino-2-[[(2R)-2-[[(2R,3R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-2-[[(2R)-1-[(2R)-2-[[(2R)-6-amino-2-[[(2R)-2-[[(2R)-2-[[(2R,3S)-2-[[(2R)-2-amino-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]-4-carboxybutanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylpentanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-oxopentanoic acid

PubChem CID

167312269

Where does FOXO4-DRI sit?

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Mechanism of Action

Senescent cells avoid apoptosis through an abnormal survival pathway in which FOXO4 binds to p53 in the nucleus sequestering it and preventing p53-mediated apoptosis induction. FOXO4-DRI is designed to competitively disrupt this FOXO4-p53 interaction. By blocking FOXO4 from sequestering p53 the peptide liberates p53 to execute its normal apoptotic function in senescent cells restoring their ability to undergo programmed cell death. Normal healthy cells do not depend on the FOXO4-p53 interaction for survival making FOXO4-DRI selectively toxic to senescent cells. The D-amino acid retro-inverso design makes the peptide resistant to protease degradation improving its pharmacokinetic stability compared to L-amino acid versions while retaining the ability to penetrate cells and reach the nuclear FOXO4-p53 complex.

Dosage Information

Typical Dose

5 mg/kg (animal study doses)

Frequency

3 times per week (animal protocols)

Administration

Intraperitoneal injection (animal studies), subcutaneous in human research contexts

Notes

No established human dosing protocol. The 2017 Cell paper used mouse models. Human self-experimentation exists in the research community but safety and efficacy data in humans is essentially absent. Approach with significant caution.

Potential Side Effects

Very limited human safety dataTheoretical risk of eliminating beneficial senescent cells involved in wound healingInjection site reactionsUnknown long-term effects

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Quick Facts

Administration: Intraperitoneal injection (animal studies), subcutaneous in human research contexts
Typical Dose: 5 mg/kg (animal study doses)
Frequency: 3 times per week (animal protocols)
References: 0 curated + 42 from PubMed
Evidence Score: 35.4 / 100