📚 Wiki Longevity & Anti-Aging FOXO4-DRI

FOXO4-DRI

● Preclinical
FOXO4-D-Retro-Inverso Peptide (Senolytic)
Also known as: FOXO4-p53 peptide, Senolytic peptide, FOXO4-DRI peptide
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Quick Summary

FOXO4-DRI is a D-retro-inverso peptide that selectively disrupts the interaction between FOXO4 and p53 in senescent cells. In normal cycling cells, p53 is free to trigger apoptosis when needed.

Longevity & Anti-Aging Preclinical
FOXO4-DRI is a D-retro-inverso peptide that selectively disrupts the interaction between FOXO4 and p53 in senescent cells. In normal cycling cells, p53 is free to trigger apoptosis when needed. In senescent cells, FOXO4 sequesters p53 in the nucleus, preventing apoptosis and allowing senescent cells to persist and secrete pro-inflammatory cytokines (the SASP, senescence-associated secretory phenotype). FOXO4-DRI releases p53, restoring the apoptotic pathway specifically in senescent cells, causing them to die while leaving healthy cells unharmed.
Storage Stability
Lyophilized
1–2 years (-20°C)
Reconstituted
~30 days (2–8°C)
Room temp
Avoid

Mechanism of Action

FOXO4-p53 Disruption

In senescent cells, FOXO4 translocates to the nucleus and binds p53, forming a complex that prevents p53 from activating pro-apoptotic genes. Senescent cells survive despite their dysfunction by exploiting this survival mechanism.

D-Retro-Inverso Design

FOXO4-DRI is constructed from D-amino acids (not L-amino acids) in a reversed sequence, a DRI (D-Retro-Inverso) peptide. This structure mimics the natural FOXO4 alpha-helix that contacts p53, but is resistant to proteolytic degradation, extending its half-life dramatically.

Selective Apoptosis in Senescent Cells

By displacing FOXO4 from p53, the peptide frees p53 to activate apoptosis. In healthy proliferating cells, FOXO4 does not sequester p53 in the same manner, so they are not affected.

Research Summary

Landmark 2017 Mouse Study

de Keizer et al. (Nature Medicine, 2017) showed FOXO4-DRI treatment in fast-aging mice (XPD mutant) restored fur density, kidney function, and exercise capacity. In naturally aged mice, it improved fitness and liver function.

Fitness & Health span

Treated mice showed significantly better exercise performance, improved renal function, and denser fur compared to vehicle controls, suggesting restoration of multiple age-associated phenotypes.

Selectivity

Histological analysis confirmed selective clearance of p21+ senescent cells without damage to surrounding healthy tissue, a critical safety validation for the senolytic mechanism.

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Research Protocols

Note: FOXO4-DRI has only been studied in animal models. No human dosing data exists. The following reflects preclinical research protocols only.

Animal Protocol

5 mg/kg intraperitoneally or subcutaneously, 3 times per week for 10–14 days. De Keizer's protocol used IP injection.

No Human Protocol

Human dose extrapolation from mouse data is unreliable for senolytics. Proceed with extreme caution in any research context.

Storage & Handling

Store lyophilized" class="wiki-gloss-link">lyophilized at -20°C. D-peptides are highly stable to proteolysis but can still degrade thermally. Reconstitute in sterile water or DMSO (per source protocol). Store reconstituted solution at -80°C if long-term. Use within 48 hours at 4°C after thawing.


References

  • [1]de Keizer PL, et al. "Elimination of senescent cells by FOXO4-DRI peptide restores fitness and extends healthspan." Nature Medicine, 2017.
  • [2]Kirkland JL, Tchkonia T. "Senolytic drugs: from discovery to translation." J Intern Med, 2020.
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Data Sources & External References
Source: peer-reviewed literature  ·  Domain: ascendpeptide.org
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