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FOXO4-DRI

Emerging

Senolytic Peptide | p53-FOXO4 Disruptor

Dose 25-33 mg per injection (based on mouse study 5 mg/kg)
Frequency 3 doses total, administered every other day (Day 1, 3, 5)
Cycle 6 days (3 doses total = 75-100 mg per treatment cycle)
Storage Lyophilized: -20°C frozen; Reconstituted: 2-8°C refrigerated, use immediately or within short term; avoid freeze-thaw cycles

FOXO4-DRI is a senolytic peptide designed to selectively eliminate senescent 'zombie' cells that accumulate with age and contribute to tissue dysfunction. It works by disrupting the FOXO4-p53 interaction that keeps senescent cells alive. The 'DRI' modification (D-retro-inverso) uses reversed D-amino acids to increase potency and stability. Preclinical research shows restoration of fur density, fitness, and organ function in aged mice.

Mechanism of Action

FOXO4-DRI competes with FOXO4 for binding to p53, disrupting their protective interaction in senescent cells. This causes p53 to be excluded from the nucleus and triggers cell-intrinsic apoptosis (programmed cell death). Critically, this mechanism is highly selective: the FOXO4-p53 interaction is a specific vulnerability of senescent cells, while FOXO4 is minimally expressed in healthy tissues, leaving functional cells largely unharmed.

Key Benefits

  • Selective elimination of senescent cells
  • Restoration of tissue homeostasis
  • Improved fitness and physical function in aged models
  • Restored fur density in aged mice
  • Improved kidney function
  • Alleviates chemotherapy-induced senescence
  • Restores testosterone in aged males
  • Reduces senescent chondrocytes in cartilage
  • High selectivity spares healthy cells
Molecular Weight
~4,800 Da
Chain Length
~45 amino acids
Type
D-retro-inverso peptide

Anti-Aging

  • Senescent Cell Clearance

    Selectively induces apoptosis in senescent cells while sparing healthy tissue.

  • Tissue Rejuvenation

    Restores tissue homeostasis and function in naturally aged animal models.

  • Physical Function

    Improved fitness, mobility, and physical appearance in aged mice.

Organ Function

  • Kidney Function

    Restored renal function in aged and fast-aging mouse models.

  • Testicular Function

    Improved testicular microenvironment and testosterone secretion in aged mice.

  • Cartilage Health

    Removes senescent chondrocytes, potentially benefiting joint health.

Chemoprotection

  • Chemotherapy Recovery

    Neutralizes doxorubicin-induced chemotoxicity by clearing treatment-induced senescent cells.

Currently in experimental stages. The original 2017 mouse study used 5 mg/kg intraperitoneally, three times on alternate days. For a 60kg human, this translates to approximately 25 mg per dose. Self-experimenters have reported using subcutaneous injection. Storage at -20°C required due to peptide stability concerns.

GoalDoseFrequencyRoute
Standard senolytic protocol25-33 mg3 doses, every other day (6 days total)SubQ or IV
Mouse study equivalent5 mg/kg (translates to ~25 mg for 60kg human)3 doses on alternate daysIP (original study)

Reconstitution Instructions

Materials Needed:
  • Sterile water or appropriate buffer
  • Syringes
  • Alcohol swabs
  • Cold storage capability
  1. 1 Store peptide at -20°C until use
  2. 2 Reconstitute according to research protocol
  3. 3 Use immediately or store at 4°C short-term
  4. 4 Avoid repeated freeze-thaw cycles
Fisetin

Other senolytics may have additive effects on senescent cell clearance.

synergistic
Dasatinib + Quercetin

Different senolytic mechanisms; sequential use may be considered.

compatible
Humanin

Different mechanisms; Humanin protects healthy cells while FOXO4-DRI clears senescent ones.

compatible
Hours-Days

Senescent cell apoptosis initiated

Days-Weeks

Clearance of senescent cells

Weeks-Months

Tissue regeneration and functional improvements

Long-term

Sustained benefits with periodic treatment

Common Side Effects

  • Limited human data available
  • Generally well-tolerated in animal studies

Stop Signs - Discontinue if:

  • Allergic reactions
  • Unexpected adverse effects

Contraindications

  • Not yet approved for human use
  • Pregnancy or breastfeeding
  • Unknown safety in immunocompromised individuals
  • Active cancer (theoretical - consult oncologist)

Good Signs

  • Stored at -20°C or below
  • White lyophilized powder
  • High purity (>95%)
  • Clear solution after reconstitution

Warning Signs

  • Temperature excursions may affect potency

Bad Signs

  • Exposed to room temperature for extended periods
  • Discoloration
  • Repeated freeze-thaw cycles
  • Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis
    Cell (2017)

    FOXO4-DRI restored fitness, fur density, and renal function in aged mice using 5 mg/kg IP, 3 doses on alternate days. Well-tolerated under therapeutic conditions.

  • An Example of Senolytic Self-Experimentation with FOXO4-DRI
    Fight Aging! (2017)

    Self-experimenters have translated the mouse protocol to ~25 mg per injection subcutaneously, 3 doses every other day, for 75-100 mg total per treatment cycle.

  • FOXO4-DRI Alleviates Age-Related Testosterone Secretion Insufficiency
    Theranostics (2020)

    FOXO4-DRI improved testicular microenvironment and testosterone secretion by clearing senescent Leydig cells.

  • FOXO4-DRI Removes Senescent Cells from Human Chondrocytes
    Frontiers in Bioengineering and Biotechnology (2021)

    Removed >50% of senescent chondrocytes without affecting healthy early-passage cells.

  • The Disordered p53 Transactivation Domain is the Target of FOXO4-DRI
    Nature Communications (2025)

    Structural analysis revealed FOXO4-DRI binds disordered p53TAD2, forming transiently folded complex.

Disclaimer

This information is for educational and research purposes only. Consult a healthcare professional before use.