# FOXO4-DRI Human Trials: Status, Evidence Gaps, and What to Watch (2026)

> As of July 2026, zero FOXO4-DRI human trials are registered. What the animal evidence shows, why translation has stalled, and what to watch for.

Source: https://peptpedia.org/research/foxo4-dri-human-trials | Published: 2026-07-22 | Last updated: 2026-07-22

## Direct Answer

As of July 2026, no human trial of FOXO4-DRI has ever been registered or published. ClinicalTrials.gov, the registry where any legitimate trial must appear before enrollment, returns zero studies for the compound, and no trial report exists in the PubMed literature. Everything currently claimed about FOXO4-DRI rests on roughly a dozen animal and cell-culture studies. This article walks through what that evidence actually is, why no trial has started, and what would count as real progress.

## Key Data

| Parameter | Value | Note |
| --- | --- | --- |
| Registered Human Trials | 0 | ClinicalTrials.gov, checked July 22, 2026 |
| Human In Vivo Data | None | Never administered in a registered study |
| Animal (in vivo) Studies | 7 published | 2017–2024, mice/rats |
| Human Cell (ex vivo) Studies | 3 published | Chondrocytes, keloid fibroblasts, endothelial cells |
| Most Advanced Senolytic | Dasatinib + Quercetin | Phase 2 RCT published 2024 |

## The Registry Check: Zero Trials, Verified

On July 22, 2026, we searched ClinicalTrials.gov, the registry where any legitimate human trial in the US (and most trials worldwide) must be registered before enrollment, for "FOXO4-DRI." The result: [zero studies](https://clinicaltrials.gov/search?term=FOXO4-DRI). A broader search for "FOXO4" returns a single oncology trial that mentions the gene in passing and has nothing to do with the peptide.

The published literature tells the same story. PubMed indexes 18 records mentioning FOXO4-DRI (checked the same day): the original 2017 mouse study, a handful of follow-up animal and cell studies, mechanistic work, and reviews. None is a clinical trial. No registered trial, no published trial, no human dosing data of any kind. For any vendor claim to the contrary, the burden of proof is one registry entry away, and it does not exist.

This matters because FOXO4-DRI is widely sold by research-chemical vendors and discussed in longevity forums as if it were a proven therapy. The gap between that marketing reality and the regulatory reality is the entire point of this page.

## What Evidence Actually Exists (2017–2026)

The preclinical record is genuinely interesting, and it is also entirely preclinical. Here is all of it, by category.

**In living animals (7 studies):** the founding **Baar et al. 2017** paper in *Cell* ([PMID 28340339](https://pubmed.ncbi.nlm.nih.gov/28340339/)), which introduced FOXO4-DRI and showed restored fitness, fur density, and renal function in aged and chemotherapy-damaged mice; **Zhang et al. 2020** ([PMID 31959736](https://pubmed.ncbi.nlm.nih.gov/31959736/)), testosterone restoration in aged mice; **Meng et al. 2021** ([PMID 34877934](https://pubmed.ncbi.nlm.nih.gov/34877934/)), radiosensitization of lung tumors and reduced radiation fibrosis in mice; **Han et al. 2022** ([PMID 35510614](https://pubmed.ncbi.nlm.nih.gov/35510614/)) and **Liu et al. 2023** ([PMID 37074394](https://pubmed.ncbi.nlm.nih.gov/37074394/)), two independent bleomycin pulmonary-fibrosis studies; **Li et al. 2024** ([PMID 39025385](https://pubmed.ncbi.nlm.nih.gov/39025385/)), improved spermatogenesis in aged mice; and, importantly, **Born et al. 2023** in *Circulation* ([PMID 36515093](https://pubmed.ncbi.nlm.nih.gov/36515093/)), which found that clearing senescent cells, including with FOXO4-DRI, *promoted* pulmonary hypertension in rodent models. The evidence base cuts in both directions, and any honest account has to say so.

**In human cells grown outside the body (3 studies):** osteoarthritic chondrocytes ([Huang 2021, PMID 33996787](https://pubmed.ncbi.nlm.nih.gov/33996787/)), keloid scar fibroblasts ([Kong 2025, PMID 39994346](https://pubmed.ncbi.nlm.nih.gov/39994346/)), and endothelial cells ([Hu 2025, PMID 41625068](https://pubmed.ncbi.nlm.nih.gov/41625068/)). These show the peptide acts on human tissue in a dish, which is a necessary step but says nothing about what happens in a person.

**Mechanism:** Bourgeois et al. 2025 (*Nature Communications*, [PMID 40593617](https://pubmed.ncbi.nlm.nih.gov/40593617/)) mapped the interaction at atomic detail, showing that FOXO4-DRI targets the disordered transactivation domain of p53 and confirming the target the original paper proposed. A 2026 review covers the FOXO4-p53 axis as a pharmacological strategy ([Alameen et al., PMID 42024235](https://pubmed.ncbi.nlm.nih.gov/42024235/)).

## Why No Trial Has Started

If the mouse data is so striking, why hasn't anyone dosed a volunteer? The barriers are practical, not conspiratorial.

**Manufacturing cost.** FOXO4-DRI is a 46-amino-acid D-retro-inverso peptide. Building it requires D-amino-acid building blocks that cost far more than natural ones, at a scale and purity regulators demand. Rai reviewed the production barriers for retro-inverso peptides ([PMID 30582286](https://pubmed.ncbi.nlm.nih.gov/30582286/)); they are nontrivial even for well-funded programs.

**No pharmacokinetics.** Nobody has published a half-life, a distribution study, or a clearance pathway for FOXO4-DRI in any species. You cannot design a Phase 1 dose-escalation without knowing whether the peptide circulates for minutes or days.

**No formal toxicology.** The mouse studies observed no obvious harm at the working regimen, but regulatory-grade (GLP) toxicology, meaning dose escalation, repeat dosing, and organ histopathology under audited conditions, has never been published.

**Route.** The animal work used intravenous or intraperitoneal injection. Intraperitoneal is not a standard systemic route in humans, and oral delivery of a 46-residue peptide is a long shot.

**The tell from the inventors themselves.** The company spun out of the lab that created FOXO4-DRI, Cleara Biotech, is developing *optimized successor compounds* (CL04177/CL04183) aimed at p53-impaired cancer cells, not FOXO4-DRI itself ([clearabiotech.com](https://www.clearabiotech.com/)). When the originators invest in second-generation molecules instead of the original, that is a signal about where the development-ready product is thought to be.

## How Other Senolytics Reached Human Trials

The senolytic field does have human data, just not for this molecule. Dasatinib plus quercetin (D+Q) reached Phase 2 within a decade of its first preclinical report, and the reasons are instructive:

- **Hickson et al. 2019** ([PMID 31542391](https://pubmed.ncbi.nlm.nih.gov/31542391/)): first-in-human senolytic trial in diabetic kidney disease (N=9), showing safety and reduced senescent-cell markers.

- **Justice et al. 2019** ([PMID 30616998](https://pubmed.ncbi.nlm.nih.gov/30616998/)): pilot in idiopathic pulmonary fibrosis (N=14), showing the regimen was feasible, with functional improvements.

- **Farr et al. 2024** ([PMID 38956196](https://pubmed.ncbi.nlm.nih.gov/38956196/)): Phase 2 randomized controlled trial in 60 postmenopausal women, published in *Nature Medicine*. The primary bone endpoint was negative overall, with exploratory benefit in women with high senescent-cell burden.

- **Gonzales et al. 2023** ([PMID 37679434](https://pubmed.ncbi.nlm.nih.gov/37679434/)): Phase 1 feasibility trial in early Alzheimer's disease, also in *Nature Medicine*.

D+Q moved fast because both components are old, oral, off-patent small molecules with decades of known human safety data. Dasatinib is a cancer drug; quercetin is a supplement. Nobody had to invent the molecules, solve their synthesis, or guess their pharmacokinetics. The trial question was only whether the *combination's senolytic effect* works in people. FOXO4-DRI is the opposite situation: a novel peptide with no human data of any kind, so every unknown has to be retired before a trial can even be designed. Chaib et al. 2026 reviewed what genuine clinical translation of senescence-targeting therapies requires ([PMID 41053277](https://pubmed.ncbi.nlm.nih.gov/41053277/)); FOXO4-DRI currently checks almost none of those boxes.

## What Would Count as Real Progress

Rather than predictions, here are the concrete events that would change this page's verdict, along with how to check them yourself:

- **A registry entry.** Any legitimate human trial will appear on ClinicalTrials.gov before it enrolls. [This search link](https://clinicaltrials.gov/search?term=FOXO4-DRI) is the ground truth: if it ever shows a study, the status changes from "none" to "recruiting."

- **Pharmacokinetic or GLP toxicology publications.** The first PK or formal tox paper would signal that someone is investing in the expensive groundwork a trial requires.

- **Industry movement.** A licensing deal, an IND announcement, or progress on Cleara's successor candidates would indicate the mechanism is moving toward the clinic, even if FOXO4-DRI itself is not the molecule that gets there.

Until one of those happens, the accurate one-line answer to "is FOXO4-DRI in human trials?" stays what it is today: **no, and nothing registered suggests one is imminent.**

*This page is a status report on the published and registered evidence as of July 22, 2026. It is informational only and not medical advice.*

## Frequently Asked Questions

### Are there any human trials of FOXO4-DRI?

No. As of July 22, 2026, ClinicalTrials.gov lists zero registered studies for FOXO4-DRI, and no completed or ongoing trial has been published in the peer-reviewed literature. We re-verify the registry when this page is updated.

### Has FOXO4-DRI ever been given to a human?

Not in any registered or published study. Reports of people using research-grade FOXO4-DRI outside trials are anecdotes, with no dose validation, no purity guarantee, and no safety monitoring, and they are not evidence of safety or efficacy.

### When will FOXO4-DRI be tested in humans?

There is no public timeline. No registered trial, IND announcement, or industry pipeline lists FOXO4-DRI itself in clinical development as of mid-2026. The inventors' spinout company is working on optimized successor compounds, which suggests FOXO4-DRI proper may never be the molecule that reaches a first-in-human study.

### Which senolytics are being tested in humans?

Dasatinib plus quercetin leads the field: first-in-human in diabetic kidney disease (2019), a pulmonary fibrosis pilot (2019), a Phase 2 randomized trial in postmenopausal women (2024), and an Alzheimer's feasibility trial (2023). Other candidates, including fisetin and BCL-2-family inhibitors, are in earlier clinical stages.

### Do the human-cell studies count as human trials?

No. Studies on human cells grown in a dish, such as chondrocytes (2021), keloid fibroblasts (2025), and endothelial cells (2025), show the peptide acts on human tissue ex vivo. That is a meaningful mechanistic step, but it says nothing about safety or efficacy in a living person.

## References

1. Baar MP, Brandt RMC, Putavet DA, et al.. "Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging." *Cell* (2017). [PMID 28340339](https://pubmed.ncbi.nlm.nih.gov/28340339/) | [doi:10.1016/j.cell.2017.02.031](https://doi.org/10.1016/j.cell.2017.02.031) — The founding FOXO4-DRI study in mice: selective senescent-cell clearance with restored fitness, fur density, and renal function in aged and chemotherapy-damaged animals.
2. Zhang C, Xie Y, Chen H, et al.. "FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice." *Aging (Albany NY)* (2020). [PMID 31959736](https://pubmed.ncbi.nlm.nih.gov/31959736/) | [doi:10.18632/aging.102682](https://doi.org/10.18632/aging.102682) — Independent in vivo replication: senescent Leydig cell clearance with partial restoration of testosterone in aged mice.
3. Meng J, Li Y, Wan C, et al.. "Targeting senescence-like fibroblasts radiosensitizes non-small cell lung cancer and reduces radiation-induced pulmonary fibrosis." *JCI Insight* (2021). [PMID 34877934](https://pubmed.ncbi.nlm.nih.gov/34877934/) | [doi:10.1172/jci.insight.146334](https://doi.org/10.1172/jci.insight.146334) — FOXO4-DRI eliminated senescence-like cancer-associated fibroblasts, radiosensitizing NSCLC tumors and reducing radiation-induced pulmonary fibrosis in mice.
4. Han X, Yuan T, Zhang J, et al.. "FOXO4 peptide targets myofibroblast ameliorates bleomycin-induced pulmonary fibrosis in mice through ECM-receptor interaction pathway." *Journal of Cellular and Molecular Medicine* (2022). [PMID 35510614](https://pubmed.ncbi.nlm.nih.gov/35510614/) | [doi:10.1111/jcmm.17333](https://doi.org/10.1111/jcmm.17333) — Bleomycin fibrosis model: FOXO4-DRI reduced senescent cells, SASP, and collagen deposition comparably to pirfenidone.
5. Liu Y, Hou Q, Wang R, et al.. "FOXO4-D-Retro-Inverso targets extracellular matrix production in fibroblasts and ameliorates bleomycin-induced pulmonary fibrosis in mice." *Naunyn-Schmiedeberg's Archives of Pharmacology* (2023). [PMID 37074394](https://pubmed.ncbi.nlm.nih.gov/37074394/) | [doi:10.1007/s00210-023-02452-2](https://doi.org/10.1007/s00210-023-02452-2) — Second independent bleomycin fibrosis study: FOXO4-DRI reset intranuclear p53 distribution and reduced extracellular matrix deposition.
6. Li Y, Zhang C, Cheng H, et al.. "FOXO4-DRI improves spermatogenesis in aged mice through reducing senescence-associated secretory phenotype secretion from Leydig cells." *Experimental Gerontology* (2024). [PMID 39025385](https://pubmed.ncbi.nlm.nih.gov/39025385/) | [doi:10.1016/j.exger.2024.112522](https://doi.org/10.1016/j.exger.2024.112522) — Follow-up from the Zhang group: FOXO4-DRI reduced Leydig-cell SASP and improved sperm quality in naturally aged mice.
7. Born E, Lipskaia L, Breau M, et al.. "Eliminating Senescent Cells Can Promote Pulmonary Hypertension Development and Progression." *Circulation* (2023). [PMID 36515093](https://pubmed.ncbi.nlm.nih.gov/36515093/) | [doi:10.1161/CIRCULATIONAHA.122.058794](https://doi.org/10.1161/CIRCULATIONAHA.122.058794) — Critical counterpoint: senescent-cell clearance — by three approaches including FOXO4-DRI — promoted pulmonary hypertension in rodent models, while PAH patients showed elevated lung senescence markers.
8. Huang Y, He Y, Makarcyzk MJ, Lin H. "Senolytic Peptide FOXO4-DRI Selectively Removes Senescent Cells From in vitro Expanded Human Chondrocytes." *Frontiers in Bioengineering and Biotechnology* (2021). [PMID 33996787](https://pubmed.ncbi.nlm.nih.gov/33996787/) | [doi:10.3389/fbioe.2021.677576](https://doi.org/10.3389/fbioe.2021.677576) — First human-cell evidence: selective removal of senescent osteoarthritic chondrocytes ex vivo.
9. 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." *Communications Biology* (2025). [PMID 39994346](https://pubmed.ncbi.nlm.nih.gov/39994346/) | [doi:10.1038/s42003-025-07738-0](https://doi.org/10.1038/s42003-025-07738-0) — Human keloid fibroblasts and organ cultures: FOXO4-DRI cleared senescent cells via p53 nuclear exclusion.
10. 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." *Nature Communications* (2025). [PMID 40593617](https://pubmed.ncbi.nlm.nih.gov/40593617/) | [doi:10.1038/s41467-025-60844-9](https://doi.org/10.1038/s41467-025-60844-9) — Atomic-level mapping from the original research lineage: FOXO4 and FOXO4-DRI target the disordered transactivation domain of p53.
11. Rai J. "Peptide and Protein Mimetics by Retro and Retroinverso Analogs." *Chemical Biology & Drug Design* (2019). [PMID 30582286](https://pubmed.ncbi.nlm.nih.gov/30582286/) | [doi:10.1111/cbdd.13472](https://doi.org/10.1111/cbdd.13472) — Review of retro-inverso peptide design and the manufacturing barriers relevant to FOXO4-DRI's stalled translation.
12. Hickson LJ, Langhi Prata LG, Boez SA, 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). [PMID 31542391](https://pubmed.ncbi.nlm.nih.gov/31542391/) | [doi:10.1016/j.ebiom.2019.08.069](https://doi.org/10.1016/j.ebiom.2019.08.069) — First-in-human senolytic trial (D+Q, N=9): safety and reduced senescent-cell markers in diabetic kidney disease.
13. Justice JN, Nambiar AM, Tchkonia T, et al.. "Senolytics in Idiopathic Pulmonary Fibrosis: Results from a First-in-Human, Open-Label, Pilot Study." *EBioMedicine* (2019). [PMID 30616998](https://pubmed.ncbi.nlm.nih.gov/30616998/) | [doi:10.1016/j.ebiom.2018.12.052](https://doi.org/10.1016/j.ebiom.2018.12.052) — D+Q pilot in IPF (N=14): feasible administration with functional improvements.
14. Farr JN, Atkinson EJ, Achenbach SJ, et al.. "Effects of Intermittent Senolytic Therapy on Bone Metabolism in Postmenopausal Women: A Phase 2 Randomized Controlled Trial." *Nature Medicine* (2024). [PMID 38956196](https://pubmed.ncbi.nlm.nih.gov/38956196/) | [doi:10.1038/s41591-024-03096-2](https://doi.org/10.1038/s41591-024-03096-2) — The most rigorous senolytic trial to date (N=60): primary bone endpoint negative overall; exploratory benefit in participants with high senescent-cell burden.
15. Gonzales MM, Garbarino VR, Pollet E, et al.. "Senolytic Therapy in Mild Alzheimer's Disease: A Phase 1 Feasibility Trial." *Nature Medicine* (2023). [PMID 37679434](https://pubmed.ncbi.nlm.nih.gov/37679434/) | [doi:10.1038/s41591-023-02543-w](https://doi.org/10.1038/s41591-023-02543-w) — D+Q feasibility trial in early Alzheimer's disease demonstrating CNS penetration and safety.
16. Chaib S, Palmer AK, Wyles SP, et al.. "Translating Cellular Senescence Research into Clinical Practice for Metabolic Disease." *Nature Reviews Endocrinology* (2026). [PMID 41053277](https://pubmed.ncbi.nlm.nih.gov/41053277/) | [doi:10.1038/s41574-025-01187-9](https://doi.org/10.1038/s41574-025-01187-9) — What real clinical translation of senescence therapies requires: biomarkers, patient selection, trial design — the checklist FOXO4-DRI has yet to satisfy.

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