Longevity
FOXO4-DRI is a research-use product carried by vendors we track, grouped under Longevity. For research use only; an editorial review is pending.
FOXO4-DRI is offered by one or more vendors we track. We have not yet written a detailed editorial summary for this compound. The offerings below reflect what vendors currently carry. For research use only — verify dosing, handling, and safety against primary sources.
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Evidence level
Preclinical only
A D-retro-inverso peptide that disrupts the FOXO4–p53 interaction in senescent cells, triggering selective apoptosis. Promising in mouse models of aging; no published human trials.
Mechanism
Mechanism not yet documented.
Researched benefits
Senolytic activity in mice
Baar et al. (2017) showed that FOXO4-DRI cleared senescent cells in naturally aged and progeroid mice, improving fur density, renal function, fitness, and overall vigor — one of the cleanest senolytic demonstrations in vivo.
Selective mechanism
Targets senescent cells specifically by disrupting the FOXO4–p53 interaction that normally sequesters p53 in the nucleus and prevents apoptosis. Non-senescent cells are largely unaffected at therapeutic concentrations.
Tissue-level rejuvenation markers
Treated aged mice showed improvements in markers like p16Ink4a expression and reduced senescence-associated secretory phenotype (SASP) cytokines in multiple tissues.
Proof of concept for designed senolytics
FOXO4-DRI helped validate the broader hypothesis that targeted senescent-cell clearance can produce systemic benefit in aged organisms, opening the field that now includes navitoclax, dasatinib+quercetin, and other senolytic candidates.
Risks & cautions
No human safety data
Published evidence is mouse and cell-culture only. Tolerability, pharmacokinetics, and adverse-event profile in humans are unknown.
p53 pathway manipulation
p53 is a master tumor suppressor. Even targeted release of p53-driven apoptosis carries theoretical risks in tissues with pre-existing oncogenic mutations. Caution with any history of malignancy.
Possible off-target apoptosis
Selectivity is dose-dependent. At higher concentrations, effects on non-senescent cells (including stem/progenitor populations) have been reported in vitro.
Synthesis quality / identity verification
FOXO4-DRI is a relatively complex retro-inverso peptide. Few suppliers reliably validate identity and purity. Mislabeled product is a real risk in the research-peptide market.
Inflammatory flare from SASP clearance
Rapid senescent-cell apoptosis can transiently release intracellular contents. Mouse studies didn't show major issues at the doses used, but humans haven't been tested.
Dosing
No validated human dose exists. Mouse experiments used intraperitoneal regimens around 5 mg/kg every other day for short cycles.
Vial sizes
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Half-life
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Route
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All published efficacy data is in mice. Direct allometric scaling from murine intraperitoneal dosing is unreliable. Anyone using FOXO4-DRI experimentally should treat it as an uncharacterized investigational compound.
Contraindications
In depth
FOXO4-DRI is a designed peptide developed by Peter de Keizer's group at the Erasmus / Hubrecht institutes and published in a landmark 2017 Cell paper. "DRI" stands for D-retro-inverso: the peptide is built from D-amino acids in reverse sequence, a strategy that mimics the 3D shape of the original L-peptide while resisting protease degradation.
The molecule was designed to disrupt the interaction between FOXO4 and p53 in senescent cells. Senescent cells upregulate FOXO4, which sequesters p53 in the nucleus and prevents it from triggering apoptosis — keeping the senescent cells alive despite their dysfunctional state. Breaking that interaction releases p53 to do its job.
The selectivity comes from the fact that the FOXO4–p53 interaction is upregulated specifically in senescent cells:
The retro-inverso design makes the peptide protease-resistant and cell-permeable enough for systemic dosing in animals.
The 2017 Cell paper remains the foundational dataset:
Follow-up studies in independent labs have been limited; the peptide remains more of a "proof of concept" than a deeply validated drug candidate.
None published. There is no registered clinical trial of FOXO4-DRI for any indication.
In the senolytic literature, FOXO4-DRI is conceptually related to:
There is no published basis for combining FOXO4-DRI with these agents in humans. In animal studies it has been used as a stand-alone intervention.
References
