Kalios
← Compounds

Longevity

FOXO4-DRI

Gray market

Checked · 21 sources · 10 corrections on this page · No vendors · No affiliates · No one buys a word of it

0 human trials published

Limited Evidence · mouse-stage compound

Gray market · No FDA ruling — not on any list

Sold as a research chemical.

Bottom line

A mouse-stage compound with a precise mechanism and no human data.

Also called
  • FOXO4 D-Retro-Inverso
  • FOXO4-D-Retro-Inverso peptide
  • ProxoFIM (early designation)
  • FOXO4-p53 disrupting peptide
Category
Peptide — Senolytic / p53-FOXO4 Interface Disruptor
Class
Senolytic peptide
(D-retro-inverso)
Target
p53-FOXO4 PPI
Source
Synthetic only
First Published
Cell 2017
(Baar et al.)
Route (studied)
IP (mice) · no human study
Route (sold)
SubQ vials (research chemical)
Mouse Dose
~5 mg/kg every 2nd day × 3
FDA Status
Not approved (research only)
Human Data
None published
Cost & Access
Research-only

Also for longevity

The other four questions

What does it do? It targets cells that have stopped dividing but do not die, by breaking the FOXO4–p53 interaction that keeps them alive; p53 then leaves the nucleus and the cell kills itself (Baar et al., 2017). In human cells expanded in the laboratory, it removed more than half of the senescent ones and left younger cells’ numbers unchanged (Huang et al., 2021).
Who uses it? Aging-biology laboratories, as a research probe; it is sold only as a research chemical (see Legal Status).
Does the evidence hold up? One 2017 mouse paper (Baar et al., 2017), with cell and rodent studies after it (Zhang et al., 2020; Huang et al., 2021). No human trial is registered. A later group designed a different peptide, ES2, against the same interaction (Le et al., 2021).
Bottom line? A mouse-stage compound with a precise mechanism and no human data.

Dosing from the Literature

Published for longevity: mouse doses, about 5 mg/kg every other day, three times. Not published: any human dose; no human study exists.

Every published dose of FOXO4-DRI is from a cell or rodent study. No human dose has been published.

ContextDoseFrequencyNotes
In-vitro IMR90 senescent fibroblasts (Baar 2017)25 μMSingle exposure × 24–48 hoursDefining in-vitro concentration; reduces senescent cell viability ~10× more than non-senescent.
In-vivo aged mice (Baar 2017)5 mg/kgIP every other day × 3 dosesTrial: fast-aging XpdTTD/TTD mice and naturally aged mice; fitness, fur density and kidney function were restored (Baar et al., 2017).
Aged Leydig cell mouse model (Zhang 2020)5 mg/kgIP every 2 days × 3Trial: naturally aged mice; the testicular microenvironment improved and age-related testosterone insufficiency was alleviated (Zhang et al., 2020).
In-vitro chondrocyte (PMC8116695, 2021)25 μMSingle exposureHuman chondrocytes expanded in the laboratory: more than half of the PDL9 cells were removed, with no significant change in PDL3 cell number (Huang et al., 2021).
Dosing Disclaimer

No published study has given FOXO4-DRI to a person, and no human dose exists. These rows record what the cell and animal studies gave. Always work with a licensed healthcare provider.

→ Calculator — vial-to-syringe math

What It Is

FOXO4-DRI ("FOXO4 D-Retro-Inverso") is a synthetic peptide engineered to disrupt the protein–protein interaction between forkhead box O transcription factor 4 (FOXO4) and tumor suppressor p53 (TP53) inside senescent cells. It was first described in a March 2017 paper in Cell by Marjolein Baar, Peter de Keizer, and colleagues at Erasmus University Medical Center, Netherlands (Baar MP et al., Cell. 2017;169(1):132-147.e16; PMID 28340339).

FOXO4-DRI is supplied exclusively as a research-grade synthetic peptide. There is no FDA-approved or any-jurisdiction-approved therapeutic version, no investigational therapeutic program with an active IND, and no compounding-pharmacy availability. The only legitimate sources are research-reagent vendors and custom academic synthesis houses selling material strictly for laboratory use.

Mechanism of Action

FOXO4-DRI's mechanism is a precise, single-target intervention on a specific protein–protein interaction. Unlike most "research peptides" with broad pleiotropic (having many effects at once) activity, FOXO4-DRI was rationally designed to do exactly one thing:

  • Senescent cells upregulate FOXO4 — In response to DNA damage, oncogenic stress, or replicative exhaustion, cells can enter a senescent state — proliferation arrest plus a senescence-associated secretory phenotype (SASP) that releases pro-inflammatory cytokines, matrix metalloproteinases, and growth factors into surrounding tissue. Senescent cells upregulate FOXO4 as part of their survival apparatus. FOXO4 is a member of the FOXO transcription factor family alongside FOXO1, FOXO3, and FOXO6, and is normally expressed only at low levels in most adult tissues.
  • FOXO4 sequesters p53 in nuclear bodies — In senescent cells, FOXO4 binds the disordered N-terminal transactivation domain of p53, locking p53 into nuclear PML-body sequestration. This prevents p53 from doing its normal apoptosis-driving job: it cannot transcriptionally activate pro-apoptotic genes (Bax, Puma, Noxa) and cannot translocate to mitochondria where it can directly trigger transcription-independent apoptosis (programmed cell death) via interaction with Bcl-2 family proteins (Mihara et al., 2003 mechanism).
  • FOXO4-DRI competitively displaces p53 from FOXO4 — The peptide binds FOXO4's p53-interaction surface, competitively displacing endogenous p53. Released p53 phosphorylated at Ser15 (active form) is excluded from the nucleus and translocates to mitochondria, where it engages Bax/Bak and triggers cytochrome-c-dependent caspase activation and apoptosis (Bourgeois & Madl, FEBS Lett 2018).
  • Senescent-cell selectivity — Because FOXO4 is upregulated specifically in senescent cells, the peptide preferentially affects senescent cells. In healthy cells with low FOXO4 expression, the same peptide produces minimal effect. In human chondrocytes expanded in the laboratory, it removed more than half of the senescent cells while leaving the younger cells’ number unchanged (Huang et al., 2021); the selectivity is not absolute, and no paper read for this page gives a ratio.
  • Structural insights — 2025 Nature Communications — Recent NMR and structural-biology work (Nat Commun 2025; doi 10.1038/s41467-025-60844-9) confirmed that FOXO4-DRI binds the disordered N-terminal transactivation domain of p53 with a binding mode similar to native FOXO4. The peptide-p53 interaction involves the same hydrophobic pocket that other transcriptional (at the gene-switching level) cofactors use to engage p53's transactivation domain, providing structural rationale for the competitive disruption mechanism.
  • Pathway engagement — Downstream of disrupted FOXO4-p53 binding, the senescent cell undergoes intrinsic apoptosis: mitochondrial outer-membrane permeabilization → cytochrome-c release → caspase-9 activation → executioner caspase (3/7) activation → DNA fragmentation and apoptotic cell death. SA-β-gal-positive cell counts decline within hours of effective dosing in cell culture; in vivo effects on senescent-cell burden are reported 2–7 days post-dosing.
  • Selectivity for FOXO4 over FOXO1/FOXO3 — The peptide sequence corresponds to a region of FOXO4 that differs from FOXO1 and FOXO3 in primary amino-acid composition, giving the DRI peptide preferential affinity for FOXO4 over its FOXO siblings. This isoform selectivity is important because FOXO1 and FOXO3 have substantially broader physiological functions in healthy cells and broad pan-FOXO inhibition would be far less safe.

What the Research Shows

FOXO4-DRI's published evidence base is unusually concentrated. The vast majority of citations trace back to one landmark 2017 Cell paper plus a small set of follow-up studies. The published evidence falls into four buckets:

  • The Baar 2017 landmark paper — Baar MP, Brandt RMC, Putavet DA, Klein JDD, et al. Cell. 2017 Mar 23;169(1):132-147.e16. PMID 28340339. The defining publication. Demonstrated: (a) FOXO4-DRI selectively kills senescent IMR90 fibroblasts in vitro with ~10-fold selectivity; (b) p53 nuclear exclusion and mitochondrial translocation as the apoptotic mechanism; (c) in-vivo administration to fast-aged XpdTTD/TTD mice (DNA-repair-deficient progeroid model) and naturally aged 24-month-old mice restored fitness, fur density, and renal function; (d) FOXO4-DRI neutralized doxorubicin chemotherapy-induced premature senescence in mouse cancer models. The paper was accompanied by a commentary in the same Cell issue (PMID 28340347) framing it as a proof-of-concept for "rejuvenation by therapeutic elimination of senescent cells."
  • Mechanistic and structural follow-up — Bourgeois & Madl, FEBS Letters 2018 (DOI 10.1002/1873-3468.13057). The first dedicated mechanistic review establishing the FOXO4-p53 axis as a regulated cellular senescence checkpoint and characterizing FOXO4-DRI's specificity vs FOXO1 and FOXO3. Nature Communications 2025 structural work confirmed the disordered p53 transactivation domain as the binding target.
  • In-vitro confirmatory studies — He L et al. PMC8116695 (2021) — chondrocyte senescence model showing FOXO4-DRI removes >50% of PDL9 senescent chondrocytes with reduction in SA-β-gal staining and altered SOX9, MMP12, MMP13 expression. Yu Y et al. Communications Biology 2025 (s42003-025-07738-0) — keloid fibroblast (a cell that builds collagen) model showing FOXO4-DRI selectively eliminates senescent keloid fibroblasts via p53-pS15 nuclear exclusion. These independent confirmatory studies replicate the senolytic (clearing worn-out cells) mechanism in disease-relevant cell systems.
  • Aged Leydig cell mouse study — Zhang C, Xie Y, Chen H, Lv L, et al. Aging (Albany NY). 2020;12(2):1272-1284. PMID 31959736. FOXO4-DRI administered to aged mice reduced p53, p21, and p16 in testes and partially restored testosterone secretion via senescent-Leydig-cell elimination. One of the few published in-vivo aging-tissue studies replicating the original Baar findings in a different organ system.
  • Computational / next-generation peptide design — Le HH, Cinaroglu SS, Manalo EC, et al. EBioMedicine. 2021;73:103646. PMC8601985. Computational modeling of the FOXO4-TP53 interface led to design of "ES2" peptides reportedly 3–7× more potent than FOXO4-DRI in vitro and in vivo. This work positions FOXO4-DRI as a first-generation tool already improved upon in the academic pipeline.
  • No completed human clinical trials — As of April 2026, no FOXO4-DRI clinical trial is registered on ClinicalTrials.gov, no IND application is publicly disclosed, and no Phase 1 safety study has been published. The only "human-relevant" data is in-vitro work on human cell lines.
Critical Context — Single-Study Compound

FOXO4-DRI is the prototypical "single-published-study" peptide. The 2017 Baar paper is rigorous, mechanistically detailed, and published in a top-tier journal — but it is one paper. Independent replication exists in chondrocyte, keloid, and Leydig cell systems, but comprehensive whole-animal long-term safety, dose-response in healthy adults, and human data are absent. The 10:1 in-vitro selectivity is real but not absolute, and the long-term consequences of repeated p53-pathway perturbation in healthy older adults are unknown. Anyone framing FOXO4-DRI as a validated longevity intervention is overstating the evidence base by several orders of magnitude.

Human Data

There is no published human clinical trial data on FOXO4-DRI for any indication. As of April 2026:

  • No registered clinical trial — A search of ClinicalTrials.gov and EudraCT returns no FOXO4-DRI protocols, completed or in progress.
  • No Phase 1 safety data — No first-in-human safety/PK study has been published.
  • No IND filing publicly disclosed — Although Cleara Biotech (the Erasmus-University spinout founded by de Keizer to commercialize FOXO4-DRI and successor compounds) has stated intent to advance senolytic peptides to human studies, no public IND filing or Phase 1 launch has occurred.
  • No human pharmacokinetic data — All published PK is from rodent IP / SubQ administration. Plasma half-life, distribution to senescent-cell-rich tissues, and metabolic clearance pathways in humans are unknown.
  • Anecdotal community use — A small number of self-experimenters in the longevity community have reported FOXO4-DRI use (typically ~5 mg/kg SubQ for 3 doses) on podcasts and forums. These reports are not clinical data — they are uncontrolled, unblinded, often single-individual, and rarely include before/after biomarker characterization. They do not constitute evidence of safety or efficacy.
  • In-vitro human cell data — Multiple papers have shown FOXO4-DRI senolytic activity in human cell lines (IMR90 fibroblasts, A375 melanoma, in-vitro-expanded chondrocytes, keloid fibroblasts). This is the closest available "human" data — it confirms the mechanism operates on human cells in culture but cannot establish in-vivo safety, pharmacokinetics, dose, or efficacy.

Reconstitution & Storage

No label or guideline gives a strength, storage condition or shelf life for FOXO4-DRI; it is sold only as a research reagent. The published studies dissolved it for injection into mice (Baar et al., 2017; Zhang et al., 2020) or added it to cultured cells (Huang et al., 2021).

→ Calculator — vial-to-syringe math

Side Effects & Risks

Important

No published study has given FOXO4-DRI to a person, so its effects in people are unknown. In mice it was “well tolerated in vivo” at the doses used (Baar et al., 2017). Consult a licensed healthcare provider.

FOXO4-DRI's safety profile is essentially uncharacterized in humans. Known and theoretical risks:

  • p53 and cancer — The peptide works by releasing p53, the tumour-suppressor protein most often mutated in human cancer. What that does in a person with an undiagnosed tumour has not been studied. A later group found that peptides designed against the same interaction killed senescent human cancer cells in culture and in mouse models (Le et al., 2021).
  • Senescent cells that help — No study read for this page measured what removing senescent cells does to wound healing or tissue repair in a person.
  • p53 pathway perturbation — Long-term consequences of repeated FOXO4-p53 disruption in healthy adults are unknown. Single-cycle administration in mouse studies appears tolerated; chronic repeated dosing has not been characterized in long-term whole-animal studies in healthy older mammals.
  • Animal tolerance — The 2017 paper reports the peptide was well tolerated in mice at the doses used (Baar et al., 2017); a related peptide given repeatedly to older mice showed “minimal toxicity” (Le et al., 2021). No toxicology study in another species appears in the documents read for this page.
  • Pregnancy and children — No study in either appears in the documents read for this page.
  • Drug interactions — None has been studied. In mice, the 2017 paper reports that the peptide neutralized doxorubicin-induced chemotoxicity (Baar et al., 2017).
  • What is in a vial — FOXO4-DRI is sold as a research chemical; no analysis of such products appears in the documents read for this page.

Bloodwork & Monitoring

No trial, label or guideline sets monitoring for FOXO4-DRI, and no human has been studied. The published studies measured senescence markers and cell numbers in culture (Huang et al., 2021), and in mice fitness, fur density and kidney function (Baar et al., 2017) and testosterone and testicular tissue (Zhang et al., 2020).

Commonly Stacked With

No study has tested FOXO4-DRI with anything. In the 2017 paper, mice given it alongside doxorubicin were protected from that drug’s chemotoxicity (Baar et al., 2017).

Stacking this? Read the receipt →

→ Calculator — vial-to-syringe math

Legal Status

Current Status — April 2026

FOXO4-DRI is not approved by the FDA, EMA, or any other regulator for any indication. No Investigational New Drug (IND) application has been publicly disclosed, no Phase 1 trial has been registered on ClinicalTrials.gov, and no IND-enabling toxicology package has been published.

Cleara Biotech, the Erasmus-University spinout founded by Peter de Keizer to commercialize the FOXO4-DRI platform and successor senolytic peptides, has stated intent to advance toward clinical trials but has not publicly disclosed an active human-trial program as of April 2026. Computational follow-on work (Le et al., EBioMedicine 2021) suggests the academic pipeline has moved beyond first-generation FOXO4-DRI to "ES2" and related more potent peptides, which may further delay any FOXO4-DRI specific clinical-development pathway.

FOXO4-DRI is not on the FDA Category 2 Bulk Drug Substances list, and it was not among the 12 peptides FDA removed from that list in April 2026 (FDA 503A categories list, April 22, 2026). As a synthetic D-retro-inverso peptide with no approved reference product, it falls outside the standard 503A compounding pathway. U.S. compounding pharmacies cannot legally compound FOXO4-DRI under current FDA rules.

FOXO4-DRI is not named on the WADA Prohibited List, but S0 prohibits it at all times: no government has approved it for human therapeutic use (WADA Prohibited List 2026).

Internationally, FOXO4-DRI has no approved status in any jurisdiction. It exists exclusively as a research reagent in the United States, EU, China, Australia, and elsewhere.

Cost & Access

FOXO4-DRI is not approved for human use. It is available through research suppliers for laboratory research purposes only.

U.S. compounding pharmacies cannot legally compound FOXO4-DRI under current FDA rules — there is no FDA-approved reference product, no investigational therapeutic program with an active IND, and FOXO4-DRI is not a recognized 503A bulk ingredient. Synthetic peptide for laboratory research is supplied by specialty vendors and custom academic synthesis houses at variable purity and pricing depending on synthesis quality and quantity.

FOXO4-DRI was not among the 12 peptides FDA removed from Category 2 in April 2026 (FDA 503A categories list, April 22, 2026). As a synthetic D-retro-inverso peptide with no approved reference product and no investigational program, it is unlikely to enter the standard FDA pathway absent a sponsor advancing it through formal IND-enabling toxicology and Phase 1 safety studies. Cleara Biotech's apparent pivot toward more potent successor peptides (ES2 and related) suggests FOXO4-DRI specifically may remain a research-only molecule even as the underlying senolytic-peptide approach matures.

Estimated pricing as of April 2026. Actual costs vary by provider, location, and prescription status. Kalios does not sell compounds.

References

  1. Baar MP, Brandt RMC, Putavet DA, Klein JDD, Derks KWJ, Bourgeois BRM, Stryeck S, Rijksen Y, van Willigenburg H, Feijtel DA, van der Pluijm I, Essers J, van Cappellen WA, van IJcken WF, Houtsmuller AB, Pothof J, de Bruin RWF, Madl T, Hoeijmakers JHJ, Campisi J, de Keizer PLJ. Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell. 2017;169(1):132-147.e16. PMID: 28340339. (The defining FOXO4-DRI paper.)
  2. Krimpenfort P, Berns A. Rejuvenation by Therapeutic Elimination of Senescent Cells. Cell. 2017;169(1):3-5. PMID: 28340347. (Editorial commentary in same Cell issue framing the Baar 2017 paper as a senolytic field milestone.)
  3. Bourgeois B, Madl T. Regulation of cellular senescence via the FOXO4-p53 axis. FEBS Lett. 2018;592(12):2083-2097. DOI: 10.1002/1873-3468.13057. (The first dedicated mechanistic review establishing the FOXO4-p53 axis as a senescent cell survival checkpoint.)
  4. Zhang C, Xie Y, Chen H, Lv L, Yao J, Zhang M, Xia K, Feng X, Li Y, Liang X, Sun X, Deng C, Liu G. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging (Albany NY). 2020;12(2):1272-1284. PMID: 31959736.
  5. Le HH, Cinaroglu SS, Manalo EC, Ors A, Gomes MM, Duan Sahbaz B, et al. Molecular modelling of the FOXO4-TP53 interaction to design senolytic peptides for the elimination of senescent cancer cells. EBioMedicine. 2021;73:103646. PMC: PMC8546421. (Computational design of "ES2" peptides 3–7× more potent than FOXO4-DRI.)
  6. Huang Y, He Y, Makarcyzk MJ, Lin H. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes. Front Bioeng Biotechnol. 2021;9:677576. PMC: PMC8116695.
  7. Kong YX, Li ZS, Liu YB, et al. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation. Commun Biol. 2025. DOI: 10.1038/s42003-025-07738-0. (Independent confirmation of senolytic mechanism in keloid fibroblast model.)
  8. Bourgeois B, Spreitzer E, Platero-Rochart D, et al. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI. Nat Commun. 2025;16. DOI: 10.1038/s41467-025-60844-9. (NMR / structural-biology characterization of the FOXO4-DRI binding mode on p53.)
  9. Zhao Y, Tyshkovskiy A, Muñoz-Espín D, et al. Naked mole rats can undergo developmental, oncogene-induced and DNA damage-induced cellular senescence. Proc Natl Acad Sci U S A. 2018;115(8):1801-1806. PMID: 29432174. (Comparative senescence-biology context.)
  10. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256. PMID: 29988130. (The Mayo Clinic D+Q senolytics paper — comparator framework.)
  11. Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020;288(5):518-536. PMID: 32686219. (Senolytics field overview placing FOXO4-DRI in context.)
  12. Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine. 2019;47:446-456. PMID: 31542391. (The first published human senolytic clinical trial — comparator context for the absence of any FOXO4-DRI human trial.)
  13. Justice JN, Nambiar AM, Tchkonia T, LeBrasseur NK, Pascual R, Hashmi SK, Prata L, Masternak MM, Kritchevsky SB, Musi N, Kirkland JL. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554-563. PMID: 30616998. (D+Q pilot in IPF — comparator framework.)
  14. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM. p53 has a direct apoptogenic role at the mitochondria. Mol Cell. 2003;11(3):577-590. PMID: 12667443. (Mechanistic foundation for the mitochondrial p53 apoptotic pathway that FOXO4-DRI engages.)
  15. de Keizer PL, Burgering BM, Dansen TB. Forkhead box o as a sensor, mediator, and regulator of redox signaling. Antioxid Redox Signal. 2011;14(6):1093-1105. PMID: 20626320. (Pre-FOXO4-DRI mechanistic background on FOXO4 as a stress sensor.)
  16. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013;14(2):83-97. PMID: 23325358. (Comprehensive FOXO transcription factor family review.)
  17. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21(12):1424-1435. PMID: 26646499. (Cellular senescence field background.)
  18. Freund A, Patil CK, Campisi J. p53 and the senescence-associated secretory phenotype. Aging Cell. 2011;10(4):636-647. (Foundational p53-SASP relationship paper.)
  19. Cleara Biotech corporate disclosures. Erasmus University Medical Center spinout pursuing senolytic peptide development. (Public-domain corporate context for the FOXO4-DRI commercial pipeline.)
  20. ClinicalTrials.gov / EudraCT. Search results for "FOXO4-DRI" — no registered trials as of April 2026. (Documentation of the absence of any registered human clinical trial.)
  21. FDA. Bulk Drug Substances Nominated for Use in Compounding Under Section 503A of the FD&C Act (503A categories list), versions updated April 15, April 22 and May 14, 2026. fda.gov/media/94155/download. Read October 3, 2026. (Notice that 12 peptides would leave Category 2 because their nominations were withdrawn; their removal; GHK-Cu, except injectable, back in Category 1.)

Also for longevity

Tested together in people

None published · Read the receipt →

See every change to this page → · Status now →

Checked 18 Oct 2026