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FOXO4-DRI

Tier 3 · Reported use
Also known as FOXO4 D-Retro-Inverso · FOXO4-DRI peptide · Proxofim

The strongest evidence is Tier 2 — animal (in vivo mouse) and in vitro mechanistic studies, anchored by the 2017 Cell paper (Baar et al.). There are zero completed or registered human clinical trials and no human pharmacokinetic data; all efficacy and safety evidence is animal or in vitro. Many physical-description, dosing, and side-effect specifics come from Tier-3 vendor pages, some of which are mutually contradictory. One human-observational claim concerns fisetin (a FOXO4-axis modulator), not FOXO4-DRI itself.

Half-life
~48 h
Routes
Intraperitoneal (used in animal studies) · Subcutaneous (reported in some preclinical work and unvalidated human protocols) · Intravenous (reported in subsequent preclinical work) · Intramuscular (unvalidated human regimen)
Goals
Longevity / anti-aging · Senolytic / senescent-cell clearance · Tissue repair / regeneration · Anti-fibrotic · Cognitive (reported in review only)
Cost / mg
Not recorded

How it works

Vendor and educational guides describe FOXO4-DRI as a synthetic peptide designed to selectively kill senescent ('zombie') cells — cells that have stopped dividing but remain metabolically active and secrete inflammatory signals. According to these sources, senescent cells survive by using a protein called FOXO4 to hold the tumor-suppressor protein p53 captive in the nucleus, blocking p53's ability to trigger cell death. A vendor guide explains that FOXO4-DRI mimics the part of FOXO4 that binds p53, competitively displacing the real FOXO4 so that p53 is released and can move to the mitochondria to switch on the cell's self-destruct (apoptosis) program, specifically in senescent cells. The peptide is built from D-amino acids in a retro-inverso arrangement, which sources say roughly preserves its shape while making it resistant to the enzymes that would normally break peptides down.

Overview

Overview

FOXO4-DRI (also marketed as FOXO4 D-Retro-Inverso and Proxofim) is described by vendor and educational guides as a synthetic D-retro-inverso peptide designed to selectively kill senescent cells by disrupting the FOXO4-p53 binding interaction inside the cell (src-1, src-3, src-4, src-8, src-10, src-11). An anti-aging peptide guide states that its landmark characterization was published in Cell in 2017 (Baar et al.), developed at Erasmus University Medical Center by de Keizer and colleagues, establishing it as one of the first mechanistically targeted senolytic peptides (src-1, src-5, src-6, src-7, src-8). Vendor sources cite the founding paper's PubMed ID inconsistently as PMID 28340339 (src-1, src-8) and PMID 28340347 (src-5, src-27), creating some ambiguity about the exact reference.

How It Is Described to Work

A vendor guide explains that in senescent cells FOXO4 protein is upregulated and sequesters p53 in the nucleus, preventing p53 from executing its pro-apoptotic function, and that FOXO4-DRI mimics the FOXO4 domain binding the p53 transactivation domain, competitively displacing endogenous FOXO4 from p53 (src-5, src-6, src-7, src-11). Vendor and mechanistic sources state that this releases p53 to translocate to mitochondria and activate the intrinsic apoptosis pathway specifically in senescent cells (src-5, src-6, src-11, src-20). An educational guide notes that FOXO4 is a member of the FOXO transcription factor family with roles in stress response, metabolism, cellular longevity and homeostasis, and that senescent cells remain metabolically active and secrete pro-inflammatory cytokines, proteases, growth factors and ECM-modifying signals (src-11).

An in vitro study reported that FOXO4 expression was markedly increased in senescent fibroblasts compared with other FOXOs, that FOXO4-DRI dose-dependently competed with FOXO4 for p53 binding with higher affinity, reduced viability only in senescent (not normal) fibroblasts, and that its apoptotic activity is caspase-dependent (src-13). A structural in vitro study reported that FOXO4-DRI binds p53 forming a transiently folded complex, with both the FOXO4-derived region and the cationic cell-permeability peptide contributing to the interaction, and that p53 phosphorylation enhances affinity for both FOXO4 and FOXO4-DRI (src-18). An animal study characterized the mechanism as activating the p53/BCL-2/Caspase-3 pathway, facilitating phosphorylated p53 nuclear exclusion and triggering BAX and cleaved caspase-3 to promote selective apoptosis of senescent endothelial cells (src-20). An educational guide notes that the widely repeated 10:1 selectivity figure — that FOXO4-DRI kills senescent cells ten times more readily than healthy cells — traces to Dr. de Keizer's public commentary rather than a peer-reviewed measurement (src-1).

Physical Identity (Contested)

Sources give wildly inconsistent basic physical descriptions. Vendor sources list the CAS number as 2460055-10-9 and molecular formula as C228H388N86O64 (src-1, src-3, src-6). Molecular weight is reported variously as ~5,358 Da / ~5.4 kDa (src-1, src-6), ~5,382 Da (src-7), and ~1,738 Da (src-9); amino-acid length is given as 34 (src-4), 29 (src-5), 46 (src-6), 48 (src-7), or 16 (src-9) residues (src-1, src-4, src-5, src-6, src-7, src-9). One vendor guide describes it as a 34-amino-acid stapled peptide built entirely from D-amino acids in a retro-inverso configuration (src-4). These figures are mutually incompatible and mostly from tier-3 vendor pages, so the true identity/size of the marketed compound cannot be established from these sources.

Animal & In Vitro Evidence

The landmark 2017 Cell paper (Baar et al.) reported that FOXO4-DRI treatment of naturally aged mice restored fur density, improved renal function, and increased physical fitness including grip strength and treadmill performance, and, per one vendor source, extended median lifespan by 24.8% (src-5) — but this specific lifespan figure is uncorroborated by higher-tier sources and closely matches the ~25% median-lifespan extension reported by Baker et al. for genetic clearance of p16-positive senescent cells in INK-ATTAC transgenic mice (src-6), a different intervention entirely, so the figure has likely been misattributed to the FOXO4-DRI peptide (whose landmark paper primarily reported healthspan rather than a defined lifespan-extension percentage). A vendor guide reports Baar et al. found reduced p21-positive senescent cell burden, restored running distance, improved fur density and renal function versus vehicle controls, with senescent cell clearance confirmed by p21 and p16 immunostaining in liver and kidney (src-4), and that running-wheel distance improved roughly 2-fold with hair regrowth in chemotherapy-induced alopecia models within two weeks (src-4). A summary of the Baar work reported that doxorubicin increased FOXO4 expression in senescent fibroblasts and hepatocytes, and that FOXO4-DRI reversed doxorubicin-induced effects including hepatic IL-6 increase and plasma AST elevation, and increased apoptosis of senescent renal tubular cells restoring kidney function, with similar effects in naturally aging and fast-aging mice (src-13). A tier-2 review of the original work reported that the cell-penetrating peptide induced forced apoptosis, reducing age-associated damage across multiple organs (particularly the kidney) and increasing performance and lifespan (src-26, src-27).

Subsequent tissue-specific studies have been reported: an in vitro study found FOXO4-DRI removed more than half of highly-expanded PDL9 chondrocytes but did not significantly affect minimally-expanded PDL3 chondrocytes, though it did not enhance chondrogenic potential (src-2, src-12, src-21, src-36). Studies reported reduction of bleomycin-induced pulmonary fibrosis with downregulated SASP and reset p53 distribution (src-17, src-25), keloid fibroblast apoptosis via p53-serine15 phosphorylation (src-3, src-22), suppression of aortic aging and improved vascular function (src-20, src-44), apoptosis of senescent Leydig cells with improved spermatogenesis and testosterone secretion in aged mice (src-23, src-24), and in a bronchopulmonary dysplasia rat pup model decreased senescence and improved alveolar complexity (src-29). A review reported that in aged mammalian models FOXO4-DRI restored cerebral blood flow and blood-brain barrier integrity, reversed hippocampal atrophy, and improved cognition, including in Alzheimer's and tauopathy models (src-19). Importantly, a peer-reviewed study reported a potential harm signal — that eliminating senescent pulmonary endothelial cells with FOXO4-DRI in SM22-5-HTT mice may worsen pulmonary hemodynamics (src-16).

Human Status

Multiple sources state there are zero published or registered human clinical trials of FOXO4-DRI, with none in ClinicalTrials.gov as of January 2025 and the compound remaining entirely preclinical as of 2026 (src-1, src-3, src-4, src-5, src-6, src-7, src-8, src-10). An educational guide notes the keystone evidence is a single 2017 mouse paper extended by a handful of independent in vitro and in vivo replications (src-1). A longevity source notes Dr. de Keizer has publicly discouraged human self-experimentation and stated mouse data does not translate to humans, and that Cleara Biotech has moved its clinical program to two optimized next-generation candidates rather than the original peptide (src-1, src-57). A 2024 biorxiv preprint (not peer-reviewed) reported a next-generation inhibitor, CPP-CAND, with improved cell permeability, selectivity and cost-effectiveness (src-14). A review noted preliminary human studies of a different FOXO4-axis modulator, high-dose fisetin, showed SASP reductions and cognitive/physical improvements in older adults (src-19) — this concerns fisetin, not FOXO4-DRI.

What the research shows

255 findings extracted from the 30 sources cited below, strongest evidence first within each group. Every one links to the source it came from.

What human studies found

Based on 2 human study findings, 41 animal findings, 19 in vitro findings, 9 expert opinion findings and 2 theoretical findings.

  • human studyPreliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show a reduction in the senescence-associated secretory phenotype (SASP)7

  • human studyPreliminary human studies involving FOXO4-axis modulators, such as high-dose fisetin, show enhancements in cognitive and physical measures among older adults7

  • animalFOXO4-DRI restored tissue function in tissues affected by chemotherapy and aging1

  • animalIn aged mice, FOXO4-DRI treatment restored fur density, improved renal function, and increased physical activity levels5

  • animalGenetic clearance of p16^INK4a-positive senescent cells in INK-ATTAC transgenic mice delayed age-related pathologies and extended median lifespan by approximately 25%6

  • animalIn aged mammalian models, administering FOXO4-DRI decreases the accumulation of senescent cells7

  • animalIn aged mammalian models, administering FOXO4-DRI restores cerebral blood flow and the integrity of the blood-brain barrier (BBB)7

  • animalIn aged mammalian models, administering FOXO4-DRI reverses hippocampal atrophy7

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  • animalIn aged mammalian models, administering FOXO4-DRI enhances cognitive function7

  • animalIn models of Alzheimer's disease (AD) and tauopathy, FOXO4-DRI eliminates amyloid-β and pathological tau7

  • animalIn models of Alzheimer's disease (AD) and tauopathy, FOXO4-DRI leads to improved memory performance7

  • animalFOXO4-DRI significantly improves vascular function and delays vascular aging9

  • animalInjection of FOXO4-DRI in both naturally aged and induced aging mice effectively suppressed aortic aging and improved aortic function9

  • animalFOXO4-DRI alleviates endothelial cell senescence induced by OGD, thereby enhancing endothelial cell function9

  • animalFoxo4 dri administered at P4, P6, P8, and P10 led to outcomes similar to TUDCA and KYC11

  • animalFoxo4 dri administration resulted in decreased cellular senescence, improved alveolar complexity, and partially maintained the numbers of type 2 alveolar cells11

  • animalFOXO4-DRI induced apoptosis in senescent Leydig cells12

  • animalFOXO4-DRI reduced the secretion of certain Senescence-Associated Secretory Phenotype12

  • animalFOXO4-DRI improved the proliferation of cocultured GC-1 SPG cells12

  • animalSM22-5-HTT mice given FOXO4-DRI showed pulmonary hemodynamic alterations and lung pulmonary endothelial cell loss compared with relevant controls13

  • animalIn bleomycin-induced pulmonary fibrosis mouse model, FOXO4-DRI therapeutic administration shows milder pathologic change and less collagen deposition compared with BLM-induced group14

  • animalFOXO4-DRI decreased senescent cells in bleomycin-induced pulmonary fibrosis mouse model15

  • animalFOXO4-DRI attenuated BLM-induced morphological changes and collagen deposition15

  • animalFOXO4-DRI decreased myofibroblasts in bleomycin-induced PF mouse model15

  • animalFOXO4-DRI ameliorates BLM-induced pulmonary fibrosis in mouse15

  • animalFOXO4-DRI improved the testicular microenvironment in naturally aged mice17

  • animalFOXO4-DRI alleviated age-related testosterone secretion insufficiency in naturally aged mice17

  • animalFOXO4-DRI peptide-induced senescent cell depletion reduced age-associated damage and dysfunction in multiple organs, in particular the kidney18

  • animalFOXO4-DRI peptide-induced senescent cell depletion increased performance and lifespan18

  • animalFOXO4-DRI ameliorates the consequences of senescence-associated loss of tissue homeostasis19

  • animalShort treatment blocks produced rapid and visible improvements: better kidney function, restored physical activity, improved fur density, normalized weight after chemotherapy, and reductions in molecular senescence markers such as p16 and SASP cytokines in mice21

  • animalIn aged and fast-aging Xpd-deficient mice, intermittent FOXO4-DRI dosing restored fitness, fur density, and renal function22

  • animalThe keystone evidence is a single 2017 mouse paper in Cell (Baar et al., PMID 28340339), extended by a handful of independent in vitro and in vivo replications in specific tissues25

  • animalBaar et al. (2017, Cell) published mouse data demonstrating that FOXO4-DRI treatment of naturally aged mice restored fur density, improved renal function, increased physical fitness (grip strength, treadmill performance), and extended median lifespan by 24.8% in fast-aging XFE progeroid mice26

  • animalA landmark 2017 Cell paper showed FOXO4-DRI restored fitness, hair density, and kidney function in aged mice27

  • animalSenolytic activity confirmed in senescent Leydig cells in aged mice27

  • animalSong et al. 2022 in bleomycin-induced lung fibrosis mouse model showed pulmonary fibrosis reduction27

  • animalBaar et al. reported reduced p21-positive senescent cell burden, restored fitness measured by running distance, and improved fur density and renal function in treated mice compared with vehicle controls28

  • animalSenescent cell clearance was confirmed by p21 and p16 immunostaining in liver and kidney tissue28

  • animalRunning wheel distance improved roughly 2-fold in aged treated mice versus vehicle28

  • animalHair regrowth occurred in chemotherapy-induced alopecia models within two weeks of dosing28

  • animalAnti-senescence compounds have shown ability to restore tissue homeostasis in old mice29

  • animalAnti-senescence compounds improve kidney function and general health- and lifespan in mice29

  • in vitroCPP-CAND showed high selectivity and potency in inducing apoptosis in senescent cells by disrupting FOXO4-p53 foci and activating caspase pathways2

  • in vitroCPP-CAND has improved selectivity, efficacy, and cost-effectiveness as a therapeutic candidate2

  • in vitroFOXO4-DRI treatment removed more than half of the cells in PDL9 chondrocytes3

  • in vitroFOXO4-DRI did not significantly affect the cell number of PDL3 chondrocytes3

  • in vitroSenescence level in FOXO4-DRI treated PDL9 chondrocytes was significantly reduced compared to untreated control3

  • in vitroFOXO4-DRI pre-treatment did not enhance the chondrogenic potential of PDL9 chondrocytes based on standard pellet culture3

  • in vitroCartilage tissue generated from FOXO4-DRI pretreated PDL9 cells displayed lower expression of senescence-relevant secretory factors than untreated control3

  • in vitroFOXO4-DRI treatment removed more than half of the cells in PDL9 (highly expanded chondrocytes) but did not significantly affect the cell number of PDL3 (minimally expanded) chondrocytes4

  • in vitroCompared to untreated control, senescence level in FOXO4-DRI treated PDL9 chondrocytes was significantly reduced4

  • in vitroCartilage tissue generated from FOXO4-DRI pretreated PDL9 cells displayed lower expression of senescence-relevant secretory factors than untreated control group4

  • in vitroFOXO4-DRI promotes apoptosis in pro-senescence models of keloid organ cultures and fibroblasts8

  • in vitroFOXO4-DRI treatment removed more than half of the cells in PDL9 chondrocytes16

  • in vitroFOXO4-DRI did not significantly affect the cell number of PDL3 chondrocytes16

  • in vitroSenescence level in FOXO4-DRI treated PDL9 chondrocytes was significantly reduced compared to untreated control16

  • in vitroFOXO4-DRI pre-treatment did not enhance the chondrogenic potential of PDL9 chondrocytes based on standard pellet culture16

  • in vitroCartilage tissue generated from FOXO4-DRI pretreated PDL9 cells displayed lower expression of senescence-relevant secretory factors than untreated control group16

  • in vitroSubsequent studies confirmed senolytic activity in human chondrocytes27

  • in vitroSenolytic activity confirmed in senescent endothelial cells27

  • in vitroGao et al. 2025 showed in vitro keloid fibroblast apoptosis via p53-serine 15 phosphorylation27

  • expert opinionNo human clinical trials have been published as of 20265

  • expert opinionThe evidence scope for FOXO4-DRI's efficacy for longevity is 6.5 / 10 mechanistic and animal data strongly support senolytic and functional benefits, but there are no human trials21

  • expert opinionFOXO4-DRI is experimental with no human evidence21

  • expert opinionNo registered human clinical trials have read out, and all efficacy data come from rodent senolytic experiments22

  • expert opinionThere are zero published human clinical trials of FOXO4-DRI as of June 202625

  • expert opinionCleara Biotech has since moved its clinical program to two optimized next-generation candidates rather than the original FOXO4-DRI peptide25

  • expert opinionThe landmark characterization was published in Cell in 2017 (Baar et al., PMID: 28340347) and established FOXO4-DRI as one of the first mechanistically targeted senolytic peptides26

  • expert opinionFOXO4-DRI data is predominantly from in vitro and mouse models; no published Phase 1 or Phase 2 human clinical trial as of April 202626

  • expert opinionZero completed or registered human clinical trials for FOXO4-DRI appear in ClinicalTrials.gov as of January 202528

  • theoreticalFOXO4-DRI was first described in a landmark 2017 publication in the journal Cell6

  • theoreticalAs of 2026, FOXO4-DRI remains entirely in the preclinical research stage, with no completed human clinical trials6

How it works

Based on 3 human study findings, 25 animal findings, 33 in vitro findings, 20 expert opinion findings and 13 theoretical findings.

  • human studyp53 signaling pathway is activated in fibroblasts isolated from IPF fibrotic lung tissues14

  • human studyFOXO4 transcription factor is specially expressed in human Leydig cells17

  • human studyFOXO4 translocation to the nucleus in the elderly is related to decreased testosterone synthesis17

  • animalFOXO4-DRI is a cell-penetrating peptide that selectively targets senescent cells for apoptosis1

  • animalDoxorubicin increased FOXO4 expression in senescent fibroblasts and hepatocytes1

  • animalFOXO4-DRI specifically disrupts the interaction between FOXO4 and P53, thereby inducing apoptosis in senescent cells9

  • animalFOXO4-DRI functions by activating the p53/BCL-2/Caspase-3 signaling pathway to promote selective apoptosis of senescent endothelial cells9

  • animalFOXO4-DRI prevents the binding of FOXO4 to P53, facilitating the phosphorylated P53 nuclear exclusion, which subsequently trigger BAX and cleaved caspase-3, leading to the apoptosis of senescent cells9

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  • animalFOXO4-DRI promotes the nuclear export of phosphorylated P53 by inhibiting the binding of FOXO4 to P53 in endothelial cells, thereby facilitating the apoptosis of senescent endothelial cells and alleviating aging9

  • animalCellular senescence increases in rat and human BPD lungs, as evidenced by increased oxidative DNA damage, tumor suppressors, GL-13 stain, and inflammatory cytokines with decreased cell proliferation and lamin B expression11

  • animalCellular senescence-related transcripts in BPD rat lungs were enriched at P10 and P2111

  • animalSingle-cell RNA sequencing showed increased cellular senescence in several cell types, including type 2 alveolar cells11

  • animalFoxo4-p53 binding increased in BPD rat lungs11

  • animalFOXO4 is highly expressed in senescent cells12

  • animalFOXO4 binds p53 in the nucleus, preventing senescent cell apoptosis and maintaining senescent cells in situ12

  • animalLeydig cell senescence leads to deterioration of the microenvironment of the testes and impairs spermatogenesis12

  • animalFOXO4-DRI is a specific FOXO4-p53 binding blocker12

  • animalFOXO4-DRI is a cell-permeable FOXO4-p53 interfering peptide used for senescent cell clearance13

  • animalFOXO4-DRI resets the distribution of intranuclear p5314

  • animalFOXO4-DRI decreases total ECM proteins content14

  • animalFOXO4-DRI selectively kills senescent cells in aged mice15

  • animalFOXO4-DRI downregulated the expression of senescence-associated secretory phenotype (SASP)15

  • animalFOXO4-DRI increased the percentage of type 2 alveolar epithelial cells (AEC2) and fibroblasts15

  • animalFOXO4-DRI inhibition of myofibroblast leads to downregulation of extracellular matrix (ECM) receptor interaction pathway15

  • animalCell-penetrating FOXO4-DRI peptide induced forced apoptosis18

  • animalFOXO4 protects senescent cell viability by keeping p53 sequestered in nuclear bodies, preventing it from inducing apoptosis19

  • animalDisrupting the interaction between FOXO4 and p53 with an all-D amino acid peptide (FOXO4-DRI) restores p53's apoptotic role19

  • animalThe 2017 FOXO4-DRI mouse study (Baar et al., Cell) tested whether a designer peptide could selectively induce apoptosis in senescent cells and thereby improve health in aged, progeroid, and chemotherapy-damaged mice21

  • in vitroFOXO4 expression was markedly increased in senescent fibroblasts compared with other FOXOs1

  • in vitroInhibiting FOXO4 expression promoted apoptotic events and reduced senescent fibroblasts' viability and colony density1

  • in vitroFOXO4-DRI targets the interaction between FOXO4 and p531

  • in vitroFOXO4-DRI's apoptotic activity is caspase-dependent1

  • in vitroThe interaction between FOXO4 and p53 sustains cell survival2

  • in vitroThe peptide inhibitor was designed by identifying key regions in the p53 transactivation domain (TAD) involved in FOXO4 binding2

  • in vitroFOXO4-DRI selectively kills senescent cells3

  • in vitroFOXO4-DRI is a senolytic peptide that selectively kills senescent fibroblasts4

  • in vitroFOXO4-DRI is a D-retro-inverso peptide with reversed amino acid sequence and mirror-image D-amino acids, making it resistant to enzymatic degradation while maintaining binding activity5

  • in vitroFOXO4-DRI selectively induces apoptosis in senescent cells by disrupting the FOXO4-p53 interaction5

  • in vitroFOXO4-DRI disrupts the FOXO4-p53 interaction, freeing p53 to initiate targeted apoptosis specifically in senescent cells5

  • in vitroThe D-Retro-Inverso modification provides protease resistance5

  • in vitroFOXO4-DRI is a 46-amino-acid synthetic peptide engineered using the D-retro-inverso (DRI) strategy to selectively eliminate senescent cells6

  • in vitroThe peptide sequence is reversed compared to the parent FOXO4 fragment and synthesized entirely from D-amino acids6

  • in vitroFOXO4-DRI targets a specific protein-protein interaction between the forkhead box O4 (FOXO4) transcription factor and the tumor suppressor p53 that is uniquely upregulated in senescent cells6

  • in vitroFOXO4-DRI competitively disrupts the FOXO4-p53 interaction, releasing p53 from nuclear sequestration and allowing it to translocate to mitochondria and trigger intrinsic apoptosis exclusively in senescent cells6

  • in vitroKeloids show enhanced expression of senescence-associated secretory phenotype genes8

  • in vitroKeloids have elevated p16 protein and more β-galactosidase-positive cells8

  • in vitroKeloids show up-regulated p53-serine15 phosphorylation (p53-pS15)8

  • in vitroFOXO4-DRI decreases G0/G1 phase cells in pro-senescence models of keloid organ cultures and fibroblasts8

  • in vitroFOXO4-DRI treatment is accompanied with p53-pS15 nuclear exclusion8

  • in vitroThe FOXO4-p53 axis is pivotal in maintaining the viability of senescent cells10

  • in vitroFOXO4-DRI binds to p53 and forms a transiently folded complex10

  • in vitroBoth the FOXO4-derived region and the cationic cell permeability peptide contribute to the interaction with p5310

  • in vitrop53 phosphorylation enhances the affinity for both FOXO4 and FOXO4-DRI10

  • in vitroFOXO4-DRI is a synthesis peptide that acts as a specific FOXO4 blocker14

  • in vitroFOXO4-DRI selectively induces dissociation of the FOXO4-p53 complex and nuclear exclusion of p5314

  • in vitroFOXO4-DRI kills TGF-β-induced myofibroblast in vitro15

  • in vitroFOXO4-DRI is a senolytic peptide that selectively kills senescent fibroblasts16

  • in vitroFOXO4-DRI is able to remove senescent cells in PDL9 chondrocytes16

  • in vitroFOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis17

  • in vitroFOXO4-DRI disrupts the FOXO4-p53 interaction17

  • in vitroFOXO4-DRI selectively induces p53 nuclear exclusion and apoptosis in senescent Leydig cells17

  • expert opinionFOXO4-DRI was previously reported to selectively kill senescent fibroblasts3

  • expert opinionFOX04-DRI (FOXO4-D-Retro-Inverso) is a synthetic research peptide consisting of 16 amino acids designed to selectively disrupt the interaction between FOXO4 and p53 proteins20

  • expert opinionD-retro-inverso peptide chemistry involves reversing the amino acid sequence and using D-amino acids instead of L-amino acids to enhance proteolytic stability20

  • expert opinionFOXO4-DRI is a synthetic D-retro-inverso peptide designed to disrupt the FOXO4–p53 interaction and trigger apoptosis in senescent cells21

  • expert opinionFOXO4‑DRI is a D‑retro‑inverso peptide engineered to mimic the FOXO4 region that binds p53, but with reversed and D‑amino‑acid structure for stability21

  • expert opinionFOXO4-DRI is a D-retro-inverso senolytic peptide designed by Baar, Brandt, Putavet and colleagues in the Peter de Keizer laboratory at Erasmus University, published in Cell in 201722

  • expert opinionThe sequence is derived from the FOXO4 transcription factor's interaction interface with p53 but synthesized entirely from D-amino acids in reverse order, producing a protease-resistant compound22

  • expert opinionFOXO4-DRI disrupts the FOXO4-p53 complex inside senescent cells and frees nuclear p53 to trigger apoptosis selectively in cells with senescence-associated secretory phenotype while sparing healthy proliferating cells22

  • expert opinionFOXO4-DRI is an experimental senolytic peptide designed to eliminate senescent "zombie" cells by disrupting the FOXO4–p53 interaction23

  • expert opinionFOXO4 is a member of the FOXO (Forkhead box O) transcription factor family, which plays major roles in stress response, metabolism, cellular longevity and homeostasis23

  • expert opinionIn senescent cells, FOXO4 expression goes up and helps bind p53 in the nucleus, preventing p53 from driving those cells into apoptosis23

  • expert opinionBy mimicking the part of FOXO4 that binds p53, FOXO4-DRI competes for that interaction, frees p53, causes its nuclear exclusion and triggers apoptosis in the senescent cell23

  • expert opinionSenescent cells remain metabolically active and secrete a variety of pro-inflammatory cytokines, proteases, growth-factors and extracellular-matrix modifying signals23

  • expert opinionFOXO4-DRI is a synthetic D-retro-inverso peptide designed to selectively kill senescent cells by disrupting the FOXO4-p53 binding interaction inside the cell25

  • expert opinionThe selectivity claim that FOXO4-DRI kills senescent cells 10 times more readily than healthy cells comes from de Keizer's public commentary25

  • expert opinionFOXO4-DRI is a 29-amino acid D-retro-inverso synthetic peptide designed to selectively induce apoptosis in senescent cells by disrupting the FOXO4–p53 protein-protein interaction26

  • expert opinionIn senescent cells, FOXO4 protein is upregulated and sequesters p53 in the nucleus, preventing p53 from executing its pro-apoptotic function26

  • expert opinionFOXO4-DRI mimics the FOXO4 domain that binds the p53 transactivation domain (p53TAD), competitively displacing endogenous FOXO4 from p5326

  • expert opinionThis disruption releases p53 from FOXO4 sequestration, allowing p53 to translocate to mitochondria where it activates the intrinsic apoptosis pathway26

  • expert opinionFOXO4 is elevated in senescent cells but not in normal proliferating cells, so the FOXO4–p53 axis is predominantly active in senescent cells26

  • theoreticalCellular senescence is marked by irreversible cell cycle arrest and the secretion of proinflammatory factors, contributing to aging and cancer recurrence2

  • theoreticalSenescent cells overexpress FOXO4, which sequesters p53 to prevent apoptosis in zombie cells5

  • theoreticalFOXO4-DRI selectively disrupts the FOXO4-p53 complex, inducing apoptosis in senescent cells while preserving healthy tissue7

  • theoreticalFOXO4-dependent senescence significantly contributes to neuroinflammation, synaptic dysfunction, and impaired neurogenesis in the aging brain7

  • theoreticalThe peptide operates through competitive inhibition of the FOXO4-p53 protein complex, theoretically promoting apoptosis in senescent cells while sparing healthy cells20

  • theoreticalD-retro-inverso operations approximately preserve the side-chain topology of the original L-peptide while making the backbone largely invisible to mammalian proteases25

  • theoreticalFOXO4-DRI is a synthetic D-amino acid retro-inverso peptide designed to selectively eliminate senescent cells27

  • theoreticalFOXO4-DRI disrupts the FOXO4-p53 protein interaction that keeps senescent cells alive27

  • theoreticalFOXO4-DRI triggers apoptosis specifically in senescent cells without affecting healthy surrounding tissue27

  • theoreticalThe retro-inverso D-amino acid structure confers protease resistance, enhancing in vivo stability compared to L-peptide equivalents27

  • theoreticalFOXO4-DRI disrupts FOXO4-p53 interaction to induce senescent-cell apoptosis28

  • theoreticalFOXO4-DRI is a 34-amino-acid stapled peptide built entirely from D-amino acids arranged in a retro-inverso configuration28

  • theoreticalIschemia-reperfusion injury during transplantation can induce senescence and accelerate aging29

Dosing

Based on 5 animal findings, 1 expert opinion finding and 1 theoretical finding.

  • animalThe Baar et al. 2017 Cell study used 5 mg/kg intraperitoneal injection three times per week in aged mice5

  • animalAll published studies used intraperitoneal injection in mice5

  • animalIntraperitoneal injection in the original mouse studies; subcutaneous and intravenous routes appear in subsequent preclinical work22

  • animalPreclinical mouse protocol dosing: 5 mg/kg subcutaneous every other day for 3 doses27

  • animalFOXO4-DRI treated fast-aging XpdTTD/TTD mice, irradiation-damaged mice, and naturally aged mice at approximately 5 mg/kg intraperitoneally three times per week for 10 days28

  • expert opinionTypical dose 250–500 mcg once daily SC with no validated human dose22

  • theoreticalThe molecular weight matters for dosing arithmetic, because a 1 mg dose of FOXO4-DRI corresponds to only ~0.187 µmol of compound25

How the body handles it

Based on 3 animal findings, 2 in vitro findings, 6 expert opinion findings and 5 theoretical findings.

  • animalThree-times-weekly dosing suggests the peptide maintains sufficient functional concentrations for at least 48-72 hours per dose5

  • animalD-amino-acid retro-inverso peptides can maintain structural integrity long enough to reach intracellular targets, at least in rodent pharmacokinetic models28

  • animalD-amino-acid retro-inverso peptides extend in-vivo half-life significantly compared with their L-amino-acid counterparts28

  • in vitroFOXO4-DRI dose-dependently competed with FOXO4 for p53 binding and had higher affinity for p531

  • in vitroD-retro-inverso modification confers marked resistance to proteolytic degradation by endogenous proteases while preserving the three-dimensional spatial arrangement of amino acid side chains necessary for biological activity6

  • expert opinionNo formal pharmacokinetic study measuring plasma half-life, volume of distribution, or clearance has been published for FOXO4-DRI in any species5

  • expert opinionThis modification typically increases peptide half-life from minutes to several hours in biological systems20

  • expert opinionThe all-D retro-inverso architecture confers resistance to most proteases, extending plasma exposure substantially beyond an L-amino acid peptide of the same sequence; precise human PK data are not published22

Show the remaining 8

  • expert opinionFOXO4-DRI is built using a D-retro-inverso peptide topology (using D‐amino acids, reversed sequence) which makes it highly stable and resistant to proteolysis23

  • expert opinionThe D-retro-inverso (DRI) structural modification produces a peptide that is resistant to all natural proteases, extending plasma half-life to 48+ hours vs. minutes for unmodified L-peptides of equivalent length26

  • expert opinionPharmacokinetic data in humans — plasma half-life, tissue distribution, clearance — is entirely unknown27

  • theoreticalConventional L-amino acid peptides of this size are degraded within minutes by serum proteases5

  • theoreticalThe DRI modification extends functional persistence from minutes to an estimated hours-to-days range5

  • theoreticalFOXO4-DRI is above the typical renal filtration threshold, suggesting renal clearance may contribute to elimination5

  • theoreticalOral bioavailability is expected to be negligible given the peptide's large size5

  • theoreticalTheoretical bioavailability through subcutaneous injection ranges from 15-30% based on similar peptide structures20

Safety and side effects

Based on 10 animal findings, 6 in vitro findings, 12 expert opinion findings and 4 theoretical findings.

  • animalElimination of senescent pulmonary endothelial cells by FOXO4-DRI senolytic intervention may worsen pulmonary hemodynamics13

  • animalPreclinical animal studies in aged mice receiving 5 mg/kg doses showed no immediate adverse reactions within 24-48 hours post-administration20

  • animalLonger observation periods revealed transient elevation of liver enzymes (ALT increased 1.5-2.0x baseline) in approximately 30% of treated animals after 7 days20

  • animalInjection site reactions occurred in roughly 15-20% of animals, presenting as mild erythema and swelling lasting 2-3 days20

  • animalTransient fatigue observed in 10-15% of animals with onset 12-24 hours and typical duration 1-2 days20

  • animalGastrointestinal upset occurred in 5-10% of animals with onset 4-8 hours and duration 6-12 hours20

  • animalNo serious adverse events have been documented in the limited animal research conducted with FOX04-DRI20

  • animalAcross all reported cohorts, there were zero adverse reactions recorded and 100% of treated mice showed positive responses21

Show the remaining 24

  • animalSelective clearance of p21-positive (senescent) cells was confirmed; no significant damage to normal cells was documented26

  • animalNo gross toxicity was noted at the doses used in Baar study, though the observation window was short28

  • in vitroFOXO4-DRI reduced cellular viability only in senescent fibroblasts, not normal fibroblasts1

  • in vitroFOXO4-DRI selectivity leaves healthy proliferating and quiescent cells unaffected6

  • in vitroCell culture experiments demonstrate dose-dependent cytotoxicity beginning at concentrations above 10 μM20

  • in vitro50% cell viability reduction (IC50) occurring at approximately 25-30 μM in non-senescent cell lines20

  • in vitroIn vitro studies demonstrate clear dose-dependent cytotoxicity, with minimal effects below 5 μM concentration and progressive cell death above 10 μM20

  • in vitroSenescent cell selectivity diminishing significantly at concentrations exceeding 15 μM20

  • expert opinionDue to FOX04-DRI's research-only status, documented side effects in humans remain unavailable from controlled clinical trials20

  • expert opinionAnimal studies lasting beyond 30 days are currently unavailable20

  • expert opinionThe evidence scope for FOXO4-DRI's long term human safety is −1.9 / 10 because there are no human safety trials and there are strong mechanistic reasons to worry about disrupting FOXO4–p53 signaling21

  • expert opinionThere have been no human trials, no chronic toxicity studies, and only very limited animal testing, all with short follow-up windows measured in weeks21

  • expert opinionInvestigational research peptide only; not FDA, EMA, or MHRA approved22

  • expert opinionNo validated human delivery route has been published22

  • expert opinionNo FDA, EMA, or PMDA approval25

  • expert opinionNo active publicly disclosed IND25

  • expert opinionDr. Peter de Keizer has publicly discouraged human self-experimentation and has stated that mouse data does not translate to humans25

  • expert opinionSASP heterogeneity across cell types means FOXO4-DRI may not be universally effective in all senescent cell populations26

  • expert opinionNo human clinical trials have been completed27

  • expert opinionFOXO4-DRI is not FDA approved; compounding access curtailed by 2024 FDA guidance28

  • theoreticalTheoretical projections based on mechanism of action suggest potential for DNA damage response alterations in healthy cells20

  • theoreticalDisruption of FOXO4-p53 interactions could theoretically interfere with normal cellular stress responses, potentially increasing cancer risk over extended periods20

  • theoreticalTheoretical modeling suggests that chronic administration could lead to cumulative cellular damage in organs with high turnover rates, including the gastrointestinal tract, bone marrow, and skin20

  • theoreticalOff-target apoptosis in stem cell compartments is a theoretical risk that requires systematic evaluation before human use28

What people use it for

Based on 10 animal findings, 7 in vitro findings, 7 expert opinion findings and 5 theoretical findings.

  • animalFOXO4-DRI treatment reversed doxorubicin-induced effects including hepatic IL-6 expression increase and plasma AST level elevation1

  • animalFOXO4-DRI treatment improved accelerated hair loss and exploratory behavior in fast-aging mice1

  • animalFOXO4-DRI treatment increased apoptosis of senescent renal tubular cells and restored kidney function in aging mice1

  • animalFOXO4-DRI treatment effects were similar in naturally aging mice as in fast-aging mice1

  • animalFoxo4 dri was administered intraperitoneally to mitigate cellular senescence11

  • animalAttenuating cellular senescence via Foxo4 dri is a potential therapeutic strategy for halting BPD progression11

  • animalIn naturally aged mice, FOXO4-DRI-treated aged mice exhibited increased sperm quality12

  • animalFOXO4-DRI improved spermatogenesis in naturally aged mice12

Show the remaining 21

  • animalFOXO4-DRI may be a promising therapeutic approach to treating pulmonary fibrosis14

  • animalFOXO4-DRI has therapeutic potential for the treatment of male late-onset hypogonadism17

  • in vitroCPP-CAND is a peptide inhibitor targeting FOXO4-p53 interaction designed with improved cell permeability2

  • in vitroCPP-CAND is effective against senescent cancer cells induced by doxorubicin and cisplatin2

  • in vitroFOXO4-DRI is able to remove senescent cells in PDL9 chondrocytes3

  • in vitroFOXO4-DRI pre-treatment did not enhance the chondrogenic potential of PDL9 chondrocytes based on standard pellet culture results4

  • in vitroFOXO4-DRI is able to remove senescent cells in PDL9 chondrocytes but its utility in promoting cartilage formation from in vitro expanded chondrocytes needs further investigation4

  • in vitroKeloids exhibit increased proportion of pro-inflammatory and mesenchymal fibroblast subpopulations and senescent fibroblasts8

  • in vitroFOXO4-DRI is a senolytic peptide that can target senescent cells selectively10

  • expert opinionFOXO4-DRI is a senolytic peptide developed at Erasmus University Medical Center by de Keizer et al. and published in Cell (2017)5

  • expert opinionPeter de Keizer's group has expressed intent to pursue clinical safety studies, with glioblastoma multiforme proposed as an initial indication6

  • expert opinionSenescent cell depletion through cell-penetrating FOXO4-DRI peptide is a therapeutic strategy for senescence depletion in the context of renal aging and disease18

  • expert opinionFOX04-DRI currently holds research-only status with no FDA approval for human therapeutic use20

  • expert opinionFOXO4-DRI was never intended for human clinical use, it was explicitly designed as a research probe21

  • expert opinionBy clearing dysfunctional cells that drive chronic inflammation and tissue aging, FOXO4-DRI represents a promising frontier in longevity and regenerative medicine research23

  • expert opinionFOXO4-DRI is sold in the United States exclusively as a research chemical for in vitro use, not for human consumption25

  • theoreticalFOXO4-DRI shows potential as a treatment targeting senescence and apoptosis resistance in keloids8

  • theoreticalFOXO4-DRI may serve as a basis for development of p53 inhibitors to treat diseases linked to cellular senescence such as cancers10

  • theoreticalSenescent cell removal may increase the donor pool and improve long-term transplantation outcome29

  • theoreticalAnti-senescence compounds hold promise to improve quality of marginal donor kidneys29

  • theoreticalFOXO4-DRI is a peptide of anti-aging30

Other findings

Based on 1 expert opinion finding, 1 anecdotal finding and 2 theoretical findings.

  • expert opinionMolecular weight is approximately 1,738 Da20

  • anecdotalGrey-market cost range is USD 80 to 300 per vial, highly variable purity28

  • theoreticalFOXO4-DRI is approximately 5382 Da and 48 amino acids5

  • theoreticalFOXO4-DRI is a senolytic FOXO4-D-retro-inverso-isoform peptide8

Points of contention

Where the evidence is unsettled, thin, or says less than the popular claim — worth knowing before you draw conclusions.

Contested

The founding 2017 Cell paper is cited with two different PubMed IDs

Some sources cite Baar et al. 2017 as PMID 28340339 (FOXO4-DRI Peptide Guide 2026: Senolytic Evidence Review, FOXO4-DRI Dosage Chart, Schedule & Reconstitution Protocol) while others cite PMID 28340347 (FOXO4-DRI Research Guide — Senolytic Peptide, FOXO4–p53 Protein-Protein Interaction Disruption & Senescent Cell Clearance (2026) - Your Peptide Brand, Rejuvenation by Therapeutic Elimination of Senescent Cells.), creating ambiguity about the exact reference.

Contested

Safety picture differs between sources: some report zero adverse events, others report measurable toxicity and a potential harm signal

FOXO4-DRI Available for Research Use Only 25 mg on ... states zero adverse reactions across all mouse cohorts with 100% positive response; FOX04-DRI Peptide Side Effects: Overview (tier-3 vendor) reports transient ALT elevation in ~30% of animals, injection site reactions in 15-20%, fatigue in 10-15%, and GI upset in 5-10%; and Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression. (peer-reviewed) reports that FOXO4-DRI eliminating senescent pulmonary endothelial cells may WORSEN pulmonary hemodynamics. The unsourced quantitative side-effect percentages in FOX04-DRI Peptide Side Effects: Overview are not corroborated by higher-tier sources.

Limited evidence

No human data of any kind exists; all efficacy and safety evidence is animal or in vitro

Every source agrees there are zero completed or registered human clinical trials and no human pharmacokinetic data. The developer (de Keizer) has reportedly discouraged human self-experimentation and stated mouse data does not translate to humans, and has moved the clinical program to next-generation candidates rather than FOXO4-DRI itself.

Single source

The 10:1 senescent-vs-healthy selectivity figure traces to informal commentary, not a published measurement

FOXO4-DRI Peptide Guide 2026: Senolytic Evidence Review explicitly notes the claim that FOXO4-DRI kills senescent cells 10 times more readily than healthy cells comes from de Keizer's public commentary rather than a peer-reviewed quantification.

Preprint

Next-generation successor data comes from an unreviewed preprint

The CPP-CAND peptide (an improved FOXO4-p53 inhibitor) claims of high selectivity, potency and cost-effectiveness are from a 2024 biorxiv preprint (Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis | bioRxiv) that has not been peer-reviewed.

Limited evidence

A key half-life claim (48+ hours) is a vendor assertion, not a measured value

FOXO4-DRI Research Guide — Senolytic Peptide, FOXO4–p53 Protein-Protein Interaction Disruption & Senescent Cell Clearance (2026) - Your Peptide Brand asserts plasma half-life extends to 48+ hours, and FOXO4-DRI - Research Peptide infers 48-72 hours functional persistence from dosing frequency, but FOXO4-DRI - Research Peptide and FOXO4-DRI Dosage Chart, Schedule & Reconstitution Protocol also state no formal PK study measuring half-life, distribution or clearance has ever been published in any species.

Safety and side effects

Safety & Side Effects

No human safety data of any kind exists. Multiple sources state FOXO4-DRI has no FDA, EMA, PMDA or MHRA approval, no active publicly disclosed IND, and is sold in the United States exclusively as a research chemical for in vitro use, not for human consumption (src-1, src-3, src-4, src-8, src-9). A longevity source states the peptide was never intended for human clinical use and was explicitly designed as a research probe, rating its evidence scope for long-term human safety at −1.9/10 (no human safety trials, strong mechanistic reasons to worry) while rating its efficacy scope for longevity at 6.5/10 (mechanistic and animal data supportive but no human trials) (src-10).

Reported Animal Safety (Conflicting)

The safety picture differs sharply between sources. A longevity source states that across all reported mouse cohorts there were zero adverse reactions recorded and 100% of treated mice showed positive responses, while noting there have been no human trials, no chronic toxicity studies, and only very limited animal testing with short follow-up measured in weeks (src-10). A vendor guide reports no gross toxicity at the doses used in the Baar study, though the observation window was short, and that selective clearance of p21-positive senescent cells was confirmed with no significant damage to normal cells documented (src-4, src-5, src-6).

In contrast, a tier-3 side-effects vendor page reports specific (uncorroborated) figures: preclinical aged mice receiving 5 mg/kg showed no immediate adverse reactions within 24-48 hours, but longer observation revealed transient liver enzyme elevation (ALT increased 1.5-2.0x baseline) in about 30% of treated animals after 7 days, injection site reactions in roughly 15-20% (mild erythema and swelling lasting 2-3 days), transient fatigue in 10-15%, and gastrointestinal upset in 5-10% (src-9). The same page reports cell-culture dose-dependent cytotoxicity beginning above 10 μM, with an IC50 around 25-30 μM in non-senescent lines, minimal effects below 5 μM, and senescent-cell selectivity diminishing significantly above 15 μM (src-9). These quantitative percentages are not corroborated by higher-tier sources.

Potential Harm Signals & Theoretical Risks

A peer-reviewed study reported that in SM22-5-HTT mice, FOXO4-DRI caused pulmonary hemodynamic alterations and lung endothelial cell loss versus controls, noting about 30% of lung senescent cells are pulmonary endothelial cells in normoxia, and concluded that eliminating senescent pulmonary endothelial cells may worsen pulmonary hemodynamics (src-16). A vendor guide cautions that off-target apoptosis in stem cell compartments is a theoretical risk requiring systematic evaluation before human use, and that SASP heterogeneity across cell types means FOXO4-DRI may not be universally effective in all senescent cell populations (src-4, src-5, src-6). A side-effects vendor page states that no serious adverse events have been documented in the limited animal research, that documented human side effects and animal studies beyond 30 days are unavailable, and that theoretical modeling suggests chronic administration could cause DNA damage response alterations, interfere with normal cellular stress responses potentially increasing cancer risk, and lead to cumulative damage in high-turnover organs including the gastrointestinal tract, bone marrow, and skin (src-9).

Market & Access Notes

A vendor guide reports that FOXO4-DRI compounding access was curtailed by 2024 FDA guidance (src-4), and that grey-market cost ranges from USD 80 to 300 per vial with highly variable purity (src-4).

Reconstitution and handling

Dosing

No dose has been established for this compound. No regulatory label exists for FOXO4-DRI, and multiple sources confirm there are zero completed or registered human clinical trials, no validated human dose, and no validated human delivery route (src-1, src-3, src-4, src-5, src-6, src-7, src-8, src-10, src-31). The figures below are what sources report — not guidance.

Published animal dosing

  • A vendor guide reports FOXO4-DRI was tested in fast-aging XpdTTD/TTD mice, irradiation-damaged mice, and naturally aged mice at approximately 5 mg/kg intraperitoneally three times per week for 10 days (src-4).
  • A tier-2 vendor source states the Baar et al. 2017 Cell study used 5 mg/kg intraperitoneal injection three times per week in aged mice, and that all published studies used intraperitoneal injection in mice (src-7).
  • One vendor guide instead describes the preclinical mouse protocol as 5 mg/kg subcutaneous every other day for 3 doses (src-3) — there is disagreement over frequency.
  • A dosing vendor page states the original mouse studies used intraperitoneal injection while subcutaneous and intravenous routes appear in subsequent preclinical work (src-8).
  • A bronchopulmonary dysplasia study dosed rat pups intraperitoneally at postnatal days P4, P6, P8, and P10 (src-29).

Unvalidated human-oriented protocols (from vendor/longevity pages)

  • A dosing vendor page suggests a typical dose of 250-500 mcg once daily subcutaneously with no validated human dose, and outlines an unvalidated escalation protocol of 250 mcg daily (weeks 1-4), 375 mcg daily (weeks 5-8), and 500 mcg daily (weeks 9-16) (src-8).
  • A longevity-focused source lists an unvalidated human-oriented regimen of 25 mg on Days 1, 3, 5, 7, and 9 for a total of 125 mg administered intramuscularly (src-10).

No human trial has tested any of these, and the two circulating protocols differ by roughly two orders of magnitude in total exposure.

Reconstitution Arithmetic

A dosing vendor page describes reconstituting a 10 mg vial in 3 mL bacteriostatic water for a 3.33 mg/mL concentration, giving 0.075 mL (7.5 units on a U-100 syringe) per 250 mcg dose, and estimates the escalation protocol requires 3 vials for 8 weeks, 4 vials for 12 weeks, or 5 vials for 16 weeks (src-8). An educational guide notes that molecular weight matters for dosing arithmetic because a 1 mg dose of FOXO4-DRI corresponds to only ~0.187 µmol of compound (src-1) — though, as noted elsewhere, sources disagree substantially on the peptide's molecular weight.

Pharmacokinetics

Vendor and study sources state the D-retro-inverso modification confers resistance to proteases, extending in vivo stability versus L-amino-acid equivalents while preserving side-chain spatial arrangement (src-3, src-4, src-6, src-7, src-8, src-11, src-13). One vendor guide claims the modification produces a peptide resistant to all natural proteases, extending plasma half-life to 48+ hours versus minutes for unmodified peptides (src-5); a tier-2 vendor source infers functional persistence of at least 48-72 hours per dose from three-times-weekly dosing (src-7), while a side-effects page states the modification typically increases half-life from minutes to 'several hours' (src-9). A tier-2 vendor source notes the peptide is above the typical renal filtration threshold, suggesting renal clearance may contribute to elimination, and that oral bioavailability is expected to be negligible given its size (src-7); another vendor page estimates theoretical subcutaneous bioavailability at 15-30% based on similar peptide structures (src-9). Critically, multiple sources state that no formal pharmacokinetic study measuring plasma half-life, volume of distribution, or clearance has been published for FOXO4-DRI in any species, and human PK data are entirely unknown (src-3, src-7, src-8).

Sources

Ordered by evidence quality — the strongest first.

  1. Cell-Penetrating Peptide Targets Senescent Cells to Restore Tissue Function | dvm360(opens in a new tab)
    Tier 2Web · dvm360.com
  2. Peptide inhibitors targeting FOXO4-p53 interactions and inducing senescent cancer cell-specific apoptosis | bioRxiv(opens in a new tab)
    Tier 2Web · biorxiv.org
  3. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent ...(opens in a new tab)
    Tier 2Web · pmc.ncbi.nlm.nih.gov
  4. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes - PMC(opens in a new tab)
    Tier 2Web · pmc.ncbi.nlm.nih.gov
  5. FOXO4-DRI - Research Peptide(opens in a new tab)
    Tier 2Web · peptpedia.org · 2026
  6. FOXO4-DRI (Proxofim): Research Evidence & Safety Profile | PeptideInsight(opens in a new tab)
    Tier 2Web · peptideinsight.com · 2026
  7. Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain aging and cognitive decline.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2026
  8. FOXO4-DRI induces keloid senescent fibroblast apoptosis by promoting nuclear exclusion of upregulated p53-serine 15 phosphorylation.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  9. FOXO4-DRI regulates endothelial cell senescence via the P53 signaling pathway.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  10. The disordered p53 transactivation domain is the target of FOXO4 and the senolytic compound FOXO4-DRI.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2025
  11. Cellular Senescence Contributes to the Progression of Hyperoxic Bronchopulmonary Dysplasia.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  12. FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2024
  13. Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  14. FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2023
  15. FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2022
  16. Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells FromExpanded Human Chondrocytes.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2021
  17. FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2020
  18. Cellular senescence in the aging and diseased kidney.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  19. Rejuvenation by Therapeutic Elimination of Senescent Cells.(opens in a new tab)
    Tier 2PubMed · pubmed.ncbi.nlm.nih.gov · 2017
  20. FOX04-DRI Peptide Side Effects: Overview(opens in a new tab)
    Tier 3Web · mypeptidematch.com
  21. FOXO4-DRI Available for Research Use Only 25 mg on ...(opens in a new tab)
    Tier 3Web · rapamycin.news
  22. FOXO4-DRI Dosage Chart, Schedule & Reconstitution Protocol(opens in a new tab)
    Tier 3Web · peptidedosage.org
  23. FOXO4-DRI: The Senolytic Peptide That Targets Zombie Cells and Aging – Revolution Health & Wellness(opens in a new tab)
    Tier 3Web · revolutionhealth.org
  24. Instagram(opens in a new tab)
    Tier 3Web · instagram.com
  25. FOXO4-DRI Peptide Guide 2026: Senolytic Evidence Review(opens in a new tab)
    Tier 3Web · thepeptidetoolkit.com · 2026
  26. FOXO4-DRI Research Guide — Senolytic Peptide, FOXO4–p53 Protein-Protein Interaction Disruption & Senescent Cell Clearance (2026) - Your Peptide Brand(opens in a new tab)
    Tier 3Web · yourpeptidebrand.com · 2026
  27. FOXO4-DRI: Senolytic Peptide Research & Dosage | PeptaHub(opens in a new tab)
    Tier 3Web · peptahub.com · 2026
  28. FOXO4-DRI: What the Research Actually Shows About This Senolytic Peptide | HealthRX.com(opens in a new tab)
    Tier 3Web · healthrx.com · 2025
  29. Cellular senescence as a therapeutic target to improve renal transplantation outcome.(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2018
  30. [Molecular regulative mechanisms of aging and interventional effects of Chinese herbal medicine].(opens in a new tab)
    Tier 4PubMed · pubmed.ncbi.nlm.nih.gov · 2017