D tier · weak
The entire clinical case rests on one 2017 Cell paper plus a scattering of rodent and in vitro follow-ups, with zero registered human trials on ClinicalTrials.gov.
foxo4-dri
FOXO4-DRI is an all-D retro-inverso peptide designed to disrupt the FOXO4-p53 interaction that keeps senescent cells alive, triggering apoptosis selectively in those cells. It has produced striking results in aged and progeroid mice but has never been tested in a registered human trial, so all claims about human effects are extrapolation.
// we supply this one
available as a research reagent
≥ 99% HPLC · lyophilised powder · batch certificate published. Grade D above is our own and is not adjusted because we stock it.
the explanation
As cells age some of them stop dividing but refuse to die, and they leak inflammatory signals into surrounding tissue. This peptide was engineered to break a protein interaction that keeps those stuck cells alive, and in old mice it restored fur, kidney markers and running endurance - but no one has run a proper human study.
regulatory status
Unapproved research chemical
FOXO4-DRI has no approval, no investigational new drug programme that has produced a registered trial, and no pharmacopoeial monograph. A query of ClinicalTrials.gov returns zero studies. Material sold online is manufactured and sold outside any pharmaceutical regulatory framework.
how it works · proposed mechanism
The peptide is a competitive interaction inhibitor aimed at a protein-protein interface rather than an enzyme active site.
FOXO4-p53 interface disruption
In senescent cells FOXO4 sequesters p53 in nuclear foci, blocking its ability to drive apoptosis. FOXO4-DRI outcompetes native FOXO4 for the p53 transactivation domain, releasing p53.
Retro-inverso protease resistance
Building the peptide from D-amino acids in reversed sequence order approximates the parent topology while resisting proteolysis. This was the design strategy intended to make an otherwise fragile peptide usable in vivo.
TAT-mediated cell entry
The fused HIV-TAT basic sequence carries the peptide across membranes. Later structural work found the TAT portion itself contributes to p53 binding, complicating the clean modular picture.
what’s reported
evidence shape
5 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
This is one of the clearest cases in the whole index of a compound whose reputation vastly outruns its evidence: a single high-profile 2017 Cell paper generated a market, and nine years later there is still not one registered human trial. Selectively killing cells by unleashing p53 is a mechanism with obvious dose-limiting hazards that have never been characterised in a human safety study.
key published findings
- Rodent (Baar et al., Cell 2017): in fast-ageing XpdTTD progeroid mice, patches of missing fur began recovering approximately 10 days after treatment began; the study ran over roughly 10 months with infusions three times weekly.
- Rodent (Baar et al., Cell 2017): treated aged mice ran roughly double the distance of untreated controls after about three weeks, and showed improved kidney function markers about a month after treatment.
- Rodent (Zhang et al., Aging 2020): in naturally aged C57BL/6 mice (20-24 months), FOXO4-DRI at 5 mg/kg intraperitoneally, three doses every other day, increased serum testosterone and levels of the steroidogenic enzymes 3beta-HSD and CYP11A1, with effects persisting 30 days after treatment.
- In vitro (Frontiers in Bioengineering and Biotechnology 2021): the peptide selectively depleted senescent cells from in vitro expanded human chondrocyte cultures.
- In vitro / structural (Nature Communications 2025): FOXO4-DRI binds p53 transactivation domain 2 with higher affinity than native FOXO4, with both partners folding synergistically on binding, and affinity increased by p53 phosphorylation at Ser46 and Thr55.
limitations of the evidence
- Zero human trials of any phase; there is no human pharmacokinetic, dosing, or safety dataset whatsoever.
- The foundational 2017 result has not been reproduced by an independent group at the same scale, and mouse senescence models translate poorly to human ageing.
- The published rodent work used intraperitoneal infusion schedules under laboratory conditions that bear no relationship to how consumer material is handled.
documented safety signals
- No human safety data exist at any dose or duration.
- The mechanism deliberately releases p53-driven apoptosis; the consequences of off-target p53 activation in healthy proliferating tissue in humans are uncharacterised.
- Senolytic clearance of large senescent cell burdens raises theoretical concerns about impaired wound healing and tissue repair, since senescent cells have documented roles in both.
- Grey-market material has no verified identity, purity, sterility or endotoxin testing; a 46-residue peptide with 10 arginines is also synthetically demanding, making truncation and deletion impurities plausible.
identity
| full name | FOXO4 D-Retro-Inverso peptide |
| category | Longevity |
| modality | peptide |
| formula | C228H388N86O64 |
| molar mass | 5358.1 g/mol |
| sequence | ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg (46 residues, all-D retro-inverso; FOXO4 forkhead-domain fragment fused to an HIV-TAT cell-penetrating sequence) |
laboratory handling
| storage | Reference material is handled as a lyophilised powder stored frozen (typically -20C or colder), protected from light and moisture; highly basic arginine-rich peptides are hygroscopic and degrade in solution, so reconstituted stability is short. |
| solubility | The arginine-rich TAT segment makes the peptide readily water-soluble; supplier data generally report solubility in water or aqueous buffer, though no independently verified solubility figure was located. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
5 citedUS National Library of Medicine, ClinicalTrials.gov · 2026 · official
Cell · 2017 · preclinical
Nature Communications · 2025 · preclinical
Aging (Albany NY) · 2020 · preclinical
Frontiers in Bioengineering and Biotechnology · 2021 · preclinical
others in Longevity