FOXO4-DRI

proxofim, FOXO4 D-retro-inverso peptide, FOXO4-DRI senolytic

Immune & bioregulators

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Summary

Class: Synthetic 46-amino-acid peptide: a fragment of the human FOXO4 protein built from D-amino acids in reverse order (D-retro-inverso), fused to a cell-penetrating HIV-TAT sequence
Mechanism: Breaks the grip between FOXO4 and p53 inside senescent ("zombie") cells, freeing p53 to trigger their self-destruction while sparing normal cells
Routes studied: Intraperitoneal injection in mice; subcutaneous (community)
Dose range reported: Mouse studies: 5 mg/kg intraperitoneally, three times over roughly a week, repeated as cycles. Community reports: 5–10 mg subcutaneous every other day for 3 doses, repeated once or twice a year; or body-weight-scaled attempts at the mouse dose. No human dose exists
Half-life: Not characterised in humans. D-amino-acid construction resists protease breakdown, so it is expected to persist longer than a natural L-peptide; mouse data suggest hours in plasma
Storage: Lyophilised: refrigerate or freeze, protect from light. Reconstituted: refrigerate, use quickly; community practice is within ~2–4 weeks
Regulatory status: Not approved anywhere; no human trials registered as of review date †

Doses are as reported in studies or by the community — never recommendations.

1What it is

FOXO4-DRI is a designed molecule, not something the body makes. It came out of Peter de Keizer's lab (Erasmus MC, then Utrecht), published in Cell in 2017 (Baar 2017). The idea: senescent cells — old, damaged cells that have stopped dividing but refuse to die and pump out inflammatory signals — rely on the protein FOXO4 holding onto p53 to keep p53 from killing them. A peptide copy of the FOXO4 region that binds p53 can compete for that interaction. Making the peptide from mirror-image (D) amino acids in reverse order keeps its shape but makes it hard for enzymes to break down; a short sequence borrowed from the HIV TAT protein lets it cross cell membranes.

In mice it cleared senescent cells and reversed several signs of ageing. It is one of the most talked-about "longevity" peptides because the concept is elegant and the mouse photos are striking, and it has zero human data. A company (Cleara Biotech) was set up to develop next-generation versions; those are proprietary and distinct from what circulates as "FOXO4-DRI".

2How it's thought to work

Senescent cells raise FOXO4 levels and park it in nuclear bodies together with p53.

FOXO4-DRI binds p53 at the same site FOXO4 uses, displacing FOXO4.

Released p53 leaves the nucleus and triggers mitochondria-driven apoptosis (cell death).

Normal, non-senescent cells have little FOXO4–p53 interaction to disrupt, which is the basis for the claimed selectivity.

Proposed: in senescent cells it frees p53 from FOXO4 in the nucleus, and the cell dies; healthy cells (right) are largely spared (mouse data).Schematic — not to scale

This mechanism was shown in cultured human fibroblasts made senescent by irradiation or chemotherapy, and in mice. Senolytic peptides of this kind are a genuine research field; whether the grey-market peptide is the same sequence, correctly folded and pure, is unknowable from the outside.

3What the research shows

Clearance of senescent cells and ageing signs in mice

In fast-ageing (XpdTTD/TTD) mice and in naturally aged mice, FOXO4-DRI reduced senescent-cell markers, restored fur density, improved running-wheel activity and responsiveness, and improved kidney function markers. In mice given the chemotherapy doxorubicin, it reduced liver toxicity (Baar 2017, Cell). Single lab, since partially replicated by others in different models. [1]

Graded C/D

Chemotherapy-induced senescence

Cell and mouse work shows the peptide kills cells made senescent by doxorubicin and reduces downstream tissue damage. Preclinical.

Age-related testosterone decline and other mouse models

FOXO4-DRI cleared senescent Leydig cells and partly restored testosterone in aged mice (Zhang 2020, Aging). Other groups have reported effects in models of osteoarthritis and intervertebral disc degeneration. Early-stage, rodent. [3]

Graded B (not FOXO4-DRI)

Senolytics as a class in humans

The only human senolytic data come from other agents: a 14-patient open-label pilot of dasatinib plus quercetin in idiopathic pulmonary fibrosis reported improved physical function (Justice 2019, EBioMedicine), and a small study in diabetic kidney disease reported reduced senescent-cell burden in fat tissue (Hickson 2019, EBioMedicine). These show the concept can be tested in people; they say nothing about this peptide. [6][7]

Human ageing, skin, joints, hair

No published human data of any kind. Community reports of "feeling younger" or improved hair after cycles are anecdotal and uncontrolled.

4Reported side effects and interactions

Literature-reported

No human safety data. Mice tolerated the tested regimen without obvious toxicity in the 2017 paper; longer-term safety in animals has not been published in detail.

Community-reported

injection-site pain and lumps (the peptide is large and often injected in sizeable volumes), fatigue and flu-like feelings for a day or two after dosing (sometimes interpreted as a senescent-cell "die-off"; this is an assumption, not a measurement), headache. Reports are few and unverified.

Theoretical. p53 is the central tumour suppressor, and manipulating its binding partners body-wide is not trivially safe. Killing senescent cells wholesale could impair wound healing, which depends on transient senescence, and could affect tissues where senescent cells play a structural role. Off-target effects of a TAT-fused peptide entering every cell type are unstudied in humans. Purity and correct D-amino-acid synthesis of a 46-mer are demanding; degraded or mis-synthesised product is a realistic concern.

Interactions. none established. Combining with other senolytics (dasatinib + quercetin, fisetin) is common in community protocols with no evidence base.

Markers researchers commonly monitor

No FOXO4-DRI-specific markers exist in humans. The rationale for a senolytic suggests:

Marker	Why it's watched
Senescence-associated secretory markers	hs-CRP, IL-6 — as crude proxies for inflammatory burden from senescent cells (research use; these are non-specific).
Kidney function (creatinine, eGFR, urinary protein)	the main organ benefit in mice; also where unexpected toxicity would be most consequential.
Liver enzymes (ALT, AST)	the mouse chemotherapy model focused on liver protection.
CBC	to detect effects on blood-cell production.
General baseline CMP. Research-grade senescence markers (p16INK4a expression in T cells) exist but are not clinically validated

Free for everyone. Safety information is never behind a paywall.

5Reconstitution and handling

Typically supplied as powder in 10 mg vials, sometimes larger. with ; some researchers add a small amount of acetic acid or use sterile water because the peptide can be slow to dissolve — swirl gently and allow time. Protect from light and avoid repeated freeze–thaw. Doses in community use are in the multi-milligram range, so volumes can be large.

Open in calculator, pre-loaded →

6Commonly studied alongside

Dasatinib and quercetin, fisetin (other senolytics — community pairing only), epitalon, NAD⁺ precursors. No combined study exists.

Informational cross-links. Not stack recommendations.

7Regulatory status by region

Region	Status (checked —)
United States	Not FDA-approved. Not known to be on the 2023 Category 2 compounding list †
European Union	Not authorised
United Kingdom	Not licensed
Australia	Not approved
South Africa	Not registered
Sport	Prohibited by WADA under S0 (non-approved substances) †

8Open questions

Does FOXO4-DRI do anything at all in humans? No study has asked.
How selective is it for senescent cells in a whole adult human versus a mouse?
Does the material sold as FOXO4-DRI match the published sequence and chirality?
Is intermittent senolysis safe for wound healing and tissue structure over years?

9References

1Baar MP et al. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. PubMed · DOI
2de Keizer PLJ (2017). The fountain of youth by targeting senescent cells? Trends Mol Med. DOI
3Zhang C et al. (2020). FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice. Aging. PubMed · DOI
4Childs BG et al. (2017). Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. PubMed · DOI
5Kirkland JL, Tchkonia T (2020). Senolytic drugs: from discovery to translation. J Intern Med. PubMed · DOI
6Justice JN et al. (2019). Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. PubMed
7Hickson LJ et al. (2019). Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease. EBioMedicine. PubMed · DOI

References are being resolved to PubMed/DOI identifiers; links search PubMed for the citation until then.

† Being confirmed by our reviewers against current sources.

10Community

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Self-reported side effects Phase 2

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11Page history

25 Oct 2026Profile published — awaiting medical review

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