Preloaded Autoinjector | FOXO4-DRI | 3ml Pen | 10mg

The FOXO4-DRI pen is a preloaded 3ml autoinjector holding the 46-residue all-D senolytic peptide in solution at 10/3 mg/ml, 10 mg in total, with each 0.01 ml graduation carrying (10 × 3.333) µg. An Asn-Gly motif at position 22 deamidates faster than any other sequence in peptide chemistry, and the mirror-image backbone that makes this molecule protease-resistant does nothing at all to slow it.

Specification Table

What Changes When FOXO4-DRI Ships in Solution?

The single most consequential fact about this peptide in water is that its protease resistance protects it from nothing that a sealed cartridge does. D-amino acids stop enzymes. Deamidation is a backbone reaction, and the backbone still deamidates.

Position 22 carries an Asn-Gly motif, the fastest-deamidating sequence in peptide chemistry. It proceeds through a cyclic succinimide intermediate with a half-life of days to weeks at pH 7.4 and 37°C in model peptides, then hydrolyses to a mixture of aspartate and isoaspartate. The isoaspartate product inserts an extra methylene into the backbone, which shifts the local conformation without changing the residue count. Asn26 provides a slower second site. Refrigeration slows both, and stops neither. That is the reason any aqueous formulation of this molecule has a chemically limited life independent of how well it is stored.

This routinely goes unnoticed because the peptide is marketed on its resistance to proteolysis, which is genuine and irrelevant to the question. The mirror-image design that survives serum proteases has no bearing on succinimide chemistry, and no published forced-degradation study has measured how fast the reaction runs in this particular sequence.

The neighbourhood makes it worse. Trp24 sits two residues after the Asn-Gly, so the same short stretch carries the fastest chemical liability and the only strongly photolabile side chain in the molecule. Indole absorbs near 280 nm and photo-oxidises through singlet oxygen and radicals to kynurenine species (Kerwin and Remmele 2007). Tyr19 is secondary. Whatever else is happening across 46 residues, one nine-residue window is doing most of the chemistry.

Charge decides where the material goes. Ten arginines and four lysines give a calculated net charge of +10.9 at pH 7.0 and an isoelectric point near 12.5, so the peptide is strongly cationic across every usable pH. Borosilicate silanols ionise above roughly pH 3, which makes this close to a worst-case adsorber to glass, and it is the same chemistry that lets arginine-rich cell-penetrating sequences bind membranes. Expect meaningful loss at low concentration after dilution.

Self-association runs the other way. That much positive charge produces electrostatic self-repulsion, which disfavours aggregation, and no fibril or aggregation data have been published either way. The real precipitation risk is complexation with polyanions. Arginine-rich cell-penetrating peptides bind heparin, nucleic acids, silica and phosphate- or citrate-containing buffers, and can come out of solution on contact with them. A downstream buffer chosen without that in mind will look like an inactive compound rather than a formulation incompatibility.

There is no manufacturer decision to learn from here, which is unusual even for this catalogue. No sponsor has taken the compound into development, so no company has ever had to answer the formulation question. Baar et al. reported no vehicle or solvent for the injected peptide in mice and no plasma half-life in any species.

FOXO4-DRI Solution Stability: What Sets the Limit?

FOXO4-DRI solution stability is limited by deamidation at Asn22-Gly23 rather than by storage conditions, and no forced-degradation, photostability, pH-dependence or freeze-thaw study of the compound has ever been published.

The only stability-adjacent observation in the literature is cellular rather than chemical: Baar et al. reported uptake into cells within 2 to 4 hours and detectable peptide for at least 72 hours. That is a residence-time measurement inside a cell, not a shelf-life measurement in a cartridge, and the two are unrelated.

Refrigerated dark storage at 2-8°C, never frozen, follows from the indole photochemistry and from what freezing does to a solution: solutes concentrate into a shrinking liquid phase whose pH moves as buffer salts crystallise out at different points, and succinimide formation is strongly pH-dependent. FOXO4-DRI pen stability over a device shelf life is therefore an open question with a known mechanism attached, which is a different situation from the usual absence of data. The storage and stability article covers the general handling case.

Concentration and Increment Arithmetic for the FOXO4-DRI Pen

The FOXO4-DRI pen holds 10 mg in 3 ml, which is 10/3 mg/ml and (10 × 0.06221) mM at an average molecular weight of 5358.06 g/mol, with each 0.01 ml graduation carrying (10 × 3.333) µg.

The strength is not stated on the product record, so the arithmetic is given as formulas. Concentration is 10 divided by 3 in mg/ml. Molarity is that figure divided by 5358.06 and multiplied by 1,000, which reduces to 10 multiplied by 0.06221 in millimolar. One 0.01 ml graduation on a U-100 scale holds (10 × 3.333) µg and 0.1 ml holds (10 × 33.33) µg. The peptide calculator completes these once the fill is confirmed.

Worked at the commonest vial size, and only as an illustration until the fill is confirmed: 10 mg in 3 ml is 3.3333 mg/ml, 0.622 mM, 33.3 µg or 6.22 nmol per 0.01 ml, and 333 µg per 0.1 ml. At 5 mg the same volume is 1.6667 mg/ml, 0.311 mM, and 16.7 µg per 0.01 ml.

The comparison with published work is where this compound differs from almost everything else in the catalogue. Its active concentration is micromolar, not nanomolar. Baar et al. worked at 25 µM in IMR90 fibroblasts across a range of 12.5 to 50 µM, which is a 25-fold dilution from a 622 µM stock and 12.4-fold from 311 µM. Receptor-binding peptides in this format need dilutions of a hundred thousand-fold or more to reach their working range. This one needs roughly one order of magnitude, which changes the arithmetic and the error budget completely. The only published in-vivo quantity is 5 mg/kg in mice, and no validated human-equivalent conversion exists.

FOXO4-DRI Pen vs Vial: What Does the Format Suit?

The FOXO4-DRI pen vs vial question is decided by the Asn-Gly motif rather than by convenience. A pen keeps a fast-deamidating sequence in water for the whole shelf life; a lyophilized cake does not.

The format suits work needing many equivalent draws from one lot inside a short window, where reconstitution error would otherwise be a per-session variable, and it suits an arginine-rich peptide better than repeated manual transfers do, because every transfer is another glass or plastic surface for a molecule at +10.9. The preloaded autoinjector category page sets out the general case for the format.

It suits long-running work badly, and more so than for most compounds here. The foxo4-dri solution vs lyophilized comparison favours the dry form whenever the interval between first and last draw is measured in months, because succinimide formation is running the whole time at a rate nobody has measured. A lyophilized 10mg vial dissolved on the day of use starts that clock at zero, and it also allows the buffer to be chosen so that no phosphate or citrate meets a peptide with ten arginines.

The foxo4-dri pen or vial decision otherwise follows the general trade-offs set out in the pen versus vial article. What is particular here is that the deciding variable is time in water, and the format fixes that variable at its maximum.

What the Product Record Does Not State

The product record does not state the fill strength, the salt form, the excipient system, the solution pH or the fill date, and for this compound the first two carry more weight than they would for a small peptide.

Strength comes first because everything else on this page is a formula until it is known. Salt form comes second for an unusual reason: with roughly 15 basic sites, a fully protonated trifluoroacetate salt can add 20 to 25 percent to gross mass, so a nominal 10 mg might be 7.5 to 8 mg of peptide. That is not a rounding error, and at the micromolar working concentrations this compound uses it moves a stock calculation by a visible margin. Ask for net peptide content by amino acid analysis or nitrogen determination, not for chromatographic purity alone.

Then the routine gaps, with one addition. Excipients enter every assay the solution is added to, and here the question is specifically whether any phosphate or citrate is present, since either can complex a polycationic peptide. Solution pH sets the succinimide rate directly. The fill date says how much of the deamidation clock has already run before the device arrives, and for this molecule that is the single most useful number on a certificate of analysis. No CAS number has been confirmed against a primary registry, so any CAS on a vendor sheet should be treated as unsupported rather than as an identifier.

Verifying the Device and Confirming the Contents Are Intact

Hold the cartridge against a white background and look at the solution before every draw. It should be clear and colourless, and cloudiness that appears when a sample meets a downstream buffer points at polyanion complexation rather than at anything wrong with the cartridge.

Deamidation is the measurement that matters, and it is not mass-silent. Conversion of asparagine to aspartate or isoaspartate adds 0.98 daltons, which is resolvable on a high-resolution instrument at this mass but easy to miss in a 5358 dalton envelope without deliberate looking. The aspartate and isoaspartate products are isobaric with one another and separate chromatographically rather than by mass, so reversed-phase or ion-exchange chromatography is the method that reports the ratio. A specific isoaspartate methyltransferase assay quantifies the isomer directly where the distinction matters.

Ultraviolet absorbance at 280 nm works because Trp24 and Tyr19 are both present, and a falling reading with a rising shoulder between 320 and 360 nm indicates indole photo-oxidation. Tryptophan fluorescence near 350 nm falls earlier. The changes that stay mass-silent are adsorptive loss, which shows only as a shortfall in peak area against a freshly dissolved standard, and any epimerisation at the D-centres, which nobody has measured for this sequence.

Warm the device to ambient temperature before actuating: a spring mechanism pushes less through a cold, more viscous solution. Verify delivered volume gravimetrically once per device across five or more actuations, and record the date of first actuation, because for this peptide the interval since the fill is an experimental variable rather than a housekeeping detail.

What Do the Reported FOXO4-DRI Benefits Actually Rest On?

The reported foxo4-dri benefits rest on a single 2017 paper from a single laboratory, plus cell-culture work in one fibroblast line, and no independent in-vivo replication has been published.

Baar et al., Cell 2017;169(1):132-147.e16, is the founding and still the principal study. In IMR90 human fibroblasts the peptide selectively reduced senescent-cell viability across roughly 12.5 to 50 µM, with 25 µM as the working concentration, and the pan-caspase inhibitor Q-VD-OPh blocked the apoptosis, which is the control that makes the mechanism argument. FOXO4-L, the same sequence built from L-amino acids, and FOXM1-DRI were the comparison peptides. In mice the regimen was 5 mg/kg on days 1, 3 and 5, given intravenously in a doxorubicin-toxicity model and intraperitoneally in aged-mouse renal work, with reported outcomes of restored fitness, fur density and renal function in aged animals and reduced chemotoxicity in the treated model. Those are mouse outcomes, and stating them without the species is the standard misrepresentation.

The mechanism, as published, involves no receptor at all. In senescent cells the transcription factor FOXO4 holds p53 at DNA-damage foci, keeping the cell viable rather than apoptotic; the peptide occupies that interaction surface, p53 relocates to the mitochondria, and apoptosis follows. Non-senescent cells do not depend on the interaction, which is where the selectivity argument comes from (Bourgeois and Madl 2018). Roughly a quarter of the molecule does none of this: the C-terminal RRRQRRKKRG is a reversed HIV-1 TAT sequence whose job is membrane crossing.

The counterweight is rarely stated alongside the claims. Senescent cells contribute to wound repair and to tumour suppression, so removing them systemically is not a consequence-free operation, and no study has characterised what that costs.

Has There Been a FOXO4-DRI Human Clinical Trial?

No FOXO4-DRI human clinical trial appears in the indexed literature. There is no published trial, case series, pharmacokinetic study or safety dataset in humans, and no investigational sponsor is on record for the compound.

Registry status carries one qualification worth stating plainly: ClinicalTrials.gov could not be reached during the research for this page, so “no registered trial” is unverified as a registry search. What is verifiable is the absence of human data from the published record, which is a stronger and simpler claim.

The gaps extend well past the absence of a foxo4-dri human clinical trial. No pharmacokinetic study has been published in any species, so there is no half-life, clearance, volume of distribution or bioavailability figure to quote. No subcutaneous administration has been published in any species; the mouse work used intravenous and intraperitoneal routes. There is no repeat-dose toxicology, no genotoxicity work, no immunogenicity assessment and no dose-ranging beyond three administrations of 5 mg/kg in mice. Extrapolating a human quantity from that single mouse regimen is a fabrication rather than a calculation.

What Is the Safety and Regulatory Position?

FOXO4-DRI holds no marketing authorisation anywhere, has no approved or pending application at FDA, EMA, PMDA Japan, TGA or Health Canada, and has no investigational sponsor on record. It is a laboratory reagent.

Its compounding position is unusual for a peptide of this profile. It appears neither on FDA’s Category 2 list of bulk drug substances that may present significant safety risks nor on the nominated-but-withdrawn list, because it has never been nominated for compounding at all. Compounds such as BPC-157, CJC-1295, epitalon and AOD-9604 all sit on the withdrawn list; this one is simply absent from the process. There is no 503A or 503B pathway, no nomination and no monograph. The wider legal position for research compounds is covered in the article on peptide legality.

It is also not named on the WADA Prohibited List in any section reviewed for this page. Whether it falls under the S0 catch-all for non-approved substances is a reasonable reading of that provision, but it has not been verified against the current List text and is stated here as unverified rather than as fact.

On safety the position is that the absence of toxicology is itself the finding. Baar et al. described the peptide as well tolerated in mice at the quantities used, across three administrations. Beyond that single observation there is no repeat-dose, reproductive or safety-pharmacology study in any species and no human exposure of any kind. Supply is for laboratory research alone, and the device is not offered for administration to humans or animals.

How Does the FOXO4-p53 Interaction Actually Work?

Senescent cells accumulate damage that would normally trigger apoptosis, and they survive anyway. The mechanism Baar and colleagues proposed in 2017 is that FOXO4 protein binds p53 in the nucleus of a senescent cell and holds it there, keeping it away from the mitochondria where it would otherwise drive cell death. Break that interaction and p53 relocates, BAX and the rest of the intrinsic apoptosis machinery engage, and the cell dies.

The peptide is built to break it. FOXO4-DRI is a retro-inverso sequence taken from the p53-binding region of the FOXO4 protein: the residue order is reversed and every residue is the D enantiomer, which reproduces the side-chain arrangement while making the molecule invisible to ordinary peptidases. It competes with the endogenous copy for p53 and displaces it. The reported selectivity comes from the fact that healthy cells do not depend on the FOXO4-p53 interaction for survival, so displacing it does nothing to them.

The published readouts follow from that. Apoptosis in treated senescent cultures was measured by TUNEL staining and by caspase and BAX activity, with senescent cells dying and proliferating controls largely spared. Whole-animal work in fast-ageing and naturally aged mice reported restored fur density, recovered renal function and improved fitness. Later reports extended the approach to senescent Leydig cells and to fibrosis models, again with the FOXO4-p53 interaction as the stated target.

What Is a Senolytic, and What Does SASP Have to Do With It?

A senolytic is a compound that kills senescent cells selectively rather than suppressing what they do. The distinction matters because such cells are not inert: they secrete a mixture of cytokines, proteases and growth factors known as the senescence-associated secretory phenotype, and SASP is what makes a small number of these cells disruptive to the tissue around them. TNF-α and TGF-β are among the SASP components most often measured, and TGF-β signalling in particular links the phenotype to fibrosis, which is why pulmonary fibrosis models recur in this literature.

Two senolytic strategies exist and they are often confused. The dasatinib plus quercetin combination, usually written D+Q, works by inhibiting survival kinase pathways and has been through early human trials in idiopathic pulmonary fibrosis and diabetic kidney disease. The flavonoid half of that pair has weak activity alone and wide availability, and its presence in the literature is what lets supplement marketing borrow the senolytic label. This peptide works by a different mechanism entirely and has been through no human trial.

The wider framing is worth stating carefully. Cellular senescence is a real and well-characterised process, telomere shortening is one of several triggers for it, and clearing them improves tissue function and tissue homeostasis in mouse models by a substantial margin. That is a strong preclinical story about healthy aging. It is not evidence that any particular senolytic works in humans, and obesity, which drives senescent cell burden in adipose tissue, is one of several conditions where the hypothesis has been proposed and not yet tested with this compound.

What Does the D-Amino Acid Design Change for Verification?

Everything about how the material should be checked. A DRI peptide has the same mass as its L-form counterpart and the same amino acid composition, so mass spectrometry cannot distinguish an all-D synthesis from an all-L one, and neither can standard amino acid analysis after hydrolysis. A supplier could ship the wrong stereochemistry and a routine CoA would not catch it.

Circular dichroism is the method that does catch it: the all-D peptide gives a spectrum that is the mirror image of the L-form, so the sign of the signal settles the question in one measurement. Chiral amino acid analysis after hydrolysis is the other route. Ask for one of them explicitly. A synthetic peptide sold on the strength of its D configuration should come with evidence of that configuration, and purity by HPLC alone does not provide it.

The rest of the certificate is ordinary: purity by HPLC with the gradient described, an accurate mass, water content, counter-ion percentage and, for a 46-residue sequence, an assessment of deletion sequences, which become more likely as chain length grows. NAD precursors, quercetin and the other compounds sold alongside this one in longevity catalogues have entirely different verification requirements, and a single CoA format does not serve all of them.

What Else Do FOXO Proteins Do Besides Bind p53?

A good deal, and it is the reason a peptide aimed at one interaction deserves careful reading. The FOXO family in humans comprises FOXO1, FOXO3, FOXO4 and FOXO6, all forkhead box O transcription factors, all regulated by insulin and growth factor signalling through AKT. When AKT is active the FOXOs are phosphorylated and held in the cytoplasm. When it is not, they enter the nucleus and switch on programmes for stress resistance, DNA damage repair, cell cycle arrest, apoptosis and autophagy.

Autophagy is the part most relevant to ageing. FOXO3 in particular drives transcription of the core autophagy genes, and autophagy is the clearance system that removes damaged mitochondria and aggregated protein. Autophagic capacity falls with age, and the resulting accumulation of damage is one of the routes into cellular senescence, which is why autophagy induction is pursued as a longevity strategy alongside senolytics rather than in competition with them. The relationship runs both ways: autophagy also supports the secretory phenotype in cells that have already become senescent, so more of it is not always better.

DNA damage is the other shared thread. Persistent DNA damage response signalling is the commonest trigger for senescence, telomere attrition being one source of it, and the FOXOs sit downstream of that signalling as part of the decision between repair, arrest and apoptosis. Apoptosis is one of several outcomes they govern, which is worth holding in mind: this peptide targets a single protein-protein interaction in one FOXO member, and the family it belongs to has functions well beyond the one being disrupted. No published work has examined what displacing that interaction does to the rest of what FOXO4 does.

On measurement, TUNEL is the assay that recurs in this literature and it is worth knowing what it reports. TUNEL labels the free 3-prime ends produced when DNA is fragmented, so a TUNEL-positive nucleus indicates late-stage apoptosis rather than the decision to enter it. Caspase activity and BAX translocation report earlier steps. A study using TUNEL alone has counted dead cells without establishing the route they took, and apoptosis assays disagree with one another often enough that the distinction is worth checking in any paper cited for this compound.

Published Literature

Each entry below was located in a primary database or at the publisher. All concern the compound, its mechanism or the formulation chemistry; nothing has been published on this delivery format.

1. Baar MP, Brandt RMC, Putavet DA, et al. Cell. 2017;169(1):132-147.e16. DOI: 10.1016/j.cell.2017.02.031 PMID: 28340339
2. Bourgeois B, Madl T. FEBS Lett. 2018;592(12):2083-2097. DOI: 10.1002/1873-3468.13057
3. Alameen AAM, Al-Kuraishy HM, Fawzy MN, et al. Naunyn Schmiedebergs Arch Pharmacol. 2026;399(10):14659-14676. DOI: 10.1007/s00210-026-05309-6
4. Kerwin BA, Remmele RL. J Pharm Sci. 2007;96(6):1468-1479. DOI: 10.1002/jps.20815
5. US Food and Drug Administration. Certain bulk drug substances for use in compounding that may present significant safety risks.

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