FOXO4-DRI

FOXO4-DRI is a lab-designed peptide studied as a senolytic — something designed to selectively kill off aging ('senescent') cells while sparing healthy ones, by disrupting an interaction between two proteins (FOXO4 and p53) so the senescent cell self-destructs. In a landmark 2017 mouse study, this approach was linked to improvements in kidney function, fur, fitness, and memory in aged and chemo-damaged mice. It is not FDA-approved, has essentially no published human trial results, and is investigational only; outside research it's available only through unregulated supply chains and is complex and costly to manufacture.

FOXO4-DRI has been studied as a senolytic — a compound meant to clear aged ("senescent") cells. In a foundational 2017 mouse study it selectively killed senescent cells and was associated with improvements in kidney function, fur density, fitness, and cognitive markers in aged and chemotherapy-damaged mice. There are essentially no published human Phase II or III results, so the evidence in people is very limited and largely extrapolated from animal work.

Not FDA-approved for any indication. FOXO4-DRI is investigational only — Cleara Biotech (spun out of the de Keizer Erasmus University laboratory) has reportedly conducted small Phase I exploratory work, but no published Phase II or III clinical-trial results exist for the original FOXO4-DRI construct in published literature. The foundational evidence base is the Baar 2017 Cell mouse work plus follow-on preclinical and limited clinical-investigation publications.[¹] Available exclusively as a research compound through unregulated research-supply chains; the original FOXO4-DRI peptide is complex (40+ residues, D-amino-acid retro-inverso) and substantially more expensive to manufacture than the typical research-peptide library entries. Not DEA-scheduled. WADA status: not explicitly named on the 2026 Prohibited List as of last review. Research-community use is more constrained than for the peptide-axis library entries given the manufacturing cost and the investigational-only status — research-community use is concentrated among the longevity-research community rather than the broader body-composition / research-community use cases.

FOXO4-DRI is not FDA-approved, is investigational, and its human safety is not established; the senolytic drug class carries theoretical concerns such as low platelet or white-cell counts, making blood monitoring important. VialWise is a research and educational reference, not medical advice — consult a licensed professional.

⚠️ For research and educational purposes only. FOXO4-DRI is not FDA-approved for any indication and has not been the subject of a published Phase II or III clinical trial. The foundational evidence base is mouse data (Baar 2017 Cell) plus limited follow-on preclinical and clinical-investigation work. FOXO4-DRI is available exclusively as a research compound through unregulated research-supply chains. Information in this entry is informational, not medical advice. Always confirm dose calculations with the in-app calculator and consult appropriate professional guidance before any protocol decisions.

⚠️ FOXO4-DRI is a senolytic peptide — it selectively kills senescent cells. Unlike the metabolic modulators, GHS-axis peptides, GLP-1 ra family, and other Vialwise library entries that produce reversible pharmacological effects, FOXO4-DRI's mechanism is cytotoxic apoptosis of senescent cells. The biological basis: in senescent cells, the transcription factor FOXO4 sequesters tumor suppressor p53 in the nucleus and prevents p53's mitochondrial apoptosis function. FOXO4-DRI competitively binds FOXO4 and releases p53, which then translocates to mitochondria and induces cell-intrinsic apoptosis of the senescent cell. Healthy non-senescent cells are not affected because they do not have the same FOXO4-p53 sequestration arrangement.[¹] This makes FOXO4-DRI mechanistically a "senolytic" — alongside the broader senolytic drug class (dasatinib + quercetin, navitoclax/ABT-263, fisetin, and others). FOXO4-DRI is the only published senolytic peptide; the others are small molecules.

⚠️ The published evidence base is concentrated in the Baar 2017 Cell foundational mouse study plus limited follow-on preclinical work — published human clinical-trial data are essentially absent. The Baar 2017 publication demonstrated FOXO4-DRI's senolytic effects in naturally-aged mice (improvements in renal function, fur density, fitness markers, and cognitive markers over 10 months of treatment) and in chemotherapy-damaged mice (preservation of renal function and reduction of chemotherapy-induced senescence markers).[¹] Cleara Biotech (the spin-out from the de Keizer Erasmus University laboratory) has reportedly conducted small Phase I exploratory work in cancer-chemotherapy populations, but published Phase II or III clinical-trial results for the original FOXO4-DRI construct have not been disclosed in the published literature. Research-community use of FOXO4-DRI in humans operates on the substantial preclinical-to-clinical translation gap — similar to AICAR, 5-amino-1MQ, and Adipotide entries but with a more sophisticated mechanism and a more developed clinical-translation pipeline at Cleara Biotech.

⚠️ FOXO4-DRI is structurally complex (40+ residues, D-amino-acid retro-inverso) — research-supply quality varies substantially. Unlike the simpler GHS-axis or GLP-1 ra family peptides where research-supply manufacturing is well-established, FOXO4-DRI's D-retro-inverso architecture (all 40+ residues are D-stereoisomers in reverse sequence) requires substantially more rigorous synthesis and purification. Research-supply FOXO4-DRI quality varies considerably, with reports of: (a) products that are L-amino-acid sequences (not the retro-inverso architecture) sold as "FOXO4-DRI" — these would have substantially shorter plasma half-life and likely no senolytic activity; (b) products with incorrect sequence or incomplete D-amino-acid substitution; (c) products with poor purity from challenging synthesis. Source verification via mass spectrometry or HPLC purity testing is more important for FOXO4-DRI than for any other library entry — the manufacturing complexity is qualitatively higher.

⚠️ Theoretical safety considerations include transient thrombocytopenia and senolytic-class adverse-event signals. The broader senolytic class (especially navitoclax / ABT-263) has documented thrombocytopenia and neutropenia signals in human clinical trials; whether FOXO4-DRI specifically produces the same hematological signals in human use is theoretical but mechanistically plausible (senescent platelets and immune cells may be eliminated by senolytic activity). The Baar 2017 mouse study did not characterize hematological toxicity in detail. Research-community use of FOXO4-DRI without baseline + cycle CBC monitoring is high-risk.

Based on PubMed-indexed research, FOXO4-DRI is a senolytic D-retro-inverso peptide designed by the Peter de Keizer laboratory at Erasmus University (later spun out as Cleara Biotech for clinical development) as a selective therapeutic targeting senescent cells.[¹] The peptide is approximately 40 amino acids in length and uses the D-retro-inverso (DRI) architecture — all residues are D-stereoisomers and the sequence runs in the reverse direction relative to the parent L-peptide. This architecture confers substantial protease resistance vs an all-L-amino-acid equivalent while maintaining the side-chain topology required for binding to the target protein (FOXO4).

Mechanism. FOXO4-DRI's mechanism is mechanistically novel compared to the rest of the Vialwise library:[¹] (a) In normal cells: the FOXO4 transcription factor and p53 tumor suppressor have minimal interaction; p53 functions normally and senescence/apoptosis are regulated by other pathways; (b) In senescent cells: FOXO4 expression is upregulated and FOXO4 sequesters p53 in the nucleus, preventing p53's mitochondrial apoptosis function; this is part of how senescent cells "resist" apoptosis and accumulate over time; (c) FOXO4-DRI mechanism: competitively binds FOXO4 at the FOXO4-p53 interaction interface; releases p53 from FOXO4 sequestration; releases p53 then translocates to mitochondria and induces cell-intrinsic apoptosis; the senescent cell is selectively eliminated; (d) Selectivity for senescent cells: because the FOXO4-p53 sequestration arrangement is specific to senescent cells, FOXO4-DRI's effect is largely restricted to senescent cells; healthy non-senescent cells are not affected.

The senolytic concept. Cellular senescence is a state of permanent cell-cycle arrest induced by stress, oncogene activation, telomere attrition, or other triggers. Senescent cells accumulate with age and contribute to aging-associated tissue dysfunction via the senescence-associated secretory phenotype (SASP) — secretion of pro-inflammatory cytokines, growth factors, and proteases that disrupt local tissue homeostasis. Senolytic drugs selectively kill senescent cells while sparing healthy cells, potentially reducing aging-related tissue dysfunction. The senolytic concept emerged from the Campisi laboratory (Buck Institute) and related research groups; major senolytic candidates include dasatinib + quercetin (combination, repurposed cancer drugs), navitoclax / ABT-263 (BCL-2/Bcl-xL inhibitor), fisetin (a natural flavonoid), and FOXO4-DRI (the de Keizer / Erasmus peptide). FOXO4-DRI is the only senolytic peptide in clinical development — the others are small molecules.

Baar 2017 Cell foundational study.[¹] The Baar 2017 publication in *Cell* is the foundational FOXO4-DRI publication. The study demonstrated: (a) FOXO4-DRI selectively induces apoptosis in senescent fibroblasts in cell culture without affecting healthy non-senescent fibroblasts; (b) In a fast-aging Xpd^TTD (trichothiodystrophy) progeroid mouse model and in naturally-aged mice receiving FOXO4-DRI treatment for ~10 months, the mice showed improvements in renal function (improved kidney filtration and reduced senescent kidney cells), fur density (reduced age-related hair loss), fitness markers (improved running endurance), and cognitive markers; (c) In chemotherapy-damaged mice receiving FOXO4-DRI after chemotherapy, the mice showed preservation of renal function and reduction of chemotherapy-induced senescence markers; (d) No major adverse events were observed in the mouse treatment courses, though hematological monitoring was not the study's primary focus.[¹] The Baar 2017 paper is widely-cited in the senolytic literature and anchored substantial follow-on academic and biotech research into senolytic therapeutics.

Cleara Biotech clinical translation. Peter de Keizer (the senior author of Baar 2017) co-founded Cleara Biotech to advance FOXO4-DRI and related senolytic peptides through clinical development. Cleara has reportedly conducted small Phase I exploratory work in cancer chemotherapy populations (the chemotherapy-damage thread from the Baar 2017 paper), though published Phase II or III clinical-trial results for the original FOXO4-DRI construct have not been widely disclosed in the published literature. Cleara has also developed next-generation senolytic peptides beyond the original FOXO4-DRI construct.

Regulatory status (US — current). FOXO4-DRI is not FDA-approved for any indication. No published Phase III rct exists. The compound is available exclusively as a research compound through unregulated research-supply chains; not legally compoundable through US 503A pharmacies. Not DEA-scheduled.

Regulatory status (sport — WADA). FOXO4-DRI is not explicitly named on the 2026 WADA Prohibited List as of last review. The broader senolytic class is not currently a WADA-targeted category. Users in regulated sport should verify the current WADA status directly via the WADA Prohibited List and their National Anti-Doping Organization before any use.

Common research interests. Despite the absent published Phase II/III human clinical-trial evidence base, FOXO4-DRI is used in research-community contexts for: - Putative anti-aging / longevity research — the dominant research-community use case, extrapolating from the Baar 2017 mouse data demonstrating improvements in renal function, fur density, fitness, and cognitive markers in naturally-aged mice.[¹] Research-community use is concentrated among the longevity-research community. - Post-chemotherapy recovery support — extrapolating from the Baar 2017 chemotherapy-damage mouse data and the Cleara Biotech Phase I exploratory work. Research-community use is sparse in this context outside academic research. - Putative skin / cosmetic anti-aging effects — extrapolating broadly from the senolytic / SASP-reduction mechanism. Published evidence does not support specific cosmetic indications. - Combined with other senolytic compounds (dasatinib + quercetin, fisetin) — research-community use is reported but is not supported by published evidence and may compound the safety considerations.

Commonly reported

• Mild fatigue during treatment cycle — reported in research-community use; consistent with the senolytic-class clinical experience
• Injection-site reactions — typical of SC injection; less common with IV
• Mild transient flushing during IV administration — uncommon but reported
• Subjective improvements in subjective markers (energy, skin appearance, cognitive function) — reported in research-community use; not characterized in published human evidence
• The published evidence base for FOXO4-DRI in humans is essentially absent. Baar 2017 mouse data + small Cleara Biotech exploratory work are the only documented evidence base; published human Phase II or III data are not available.
• The senolytic-class hematological safety signal (especially thrombocytopenia from navitoclax / ABT-263) is theoretical for FOXO4-DRI — whether FOXO4-DRI specifically produces the same hematological signals in human use is not established. Research-community use without CBC monitoring is high-risk.
• The cancer-biology interaction is complex. Senescence can be tumor-suppressive (preventing cancer cells from proliferating) or tumor-promoting (creating a pro-inflammatory tumor microenvironment via SASP); senolytic effects may have unpredictable consequences in active malignancy populations.

Serious

• Thrombocytopenia (low platelets) with bleeding symptoms — the senolytic-class hematological safety signal warrants immediate medical evaluation
• Neutropenia with signs of infection (fever, unusual susceptibility to infection) — warrants immediate medical evaluation
• Severe fatigue or systemic symptoms — beyond expected mild treatment-cycle fatigue
• New cardiovascular symptoms — given the cytotoxic mechanism, off-target effects are theoretically possible
• Severe allergic / hypersensitivity reaction — extremely rare but warrants immediate medical evaluation
• Severe transient liver enzyme elevation — monitor LFTs; significant rises warrant evaluation

Active malignancy — caution given complex senescence-cancer-biology interaction

Active hematological disease (thrombocytopenia, neutropenia, severe anemia) — caution given senolytic-class hematological safety signal

Pregnancy and lactation — no human data; default to contraindicated

Pediatric use — no clinical-trial evidence base; default to contraindicated

Active chemotherapy — caution; not concurrent-chemotherapy-use validated in published evidence

Recent or active severe infection — caution; SASP-reduction may transiently alter immune function

History of severe drug allergy or anaphylaxis — caution given the complex peptide architecture

Regulatory note (US): FOXO4-DRI is not FDA-approved for any indication and is not legally compoundable through US 503A pharmacies.

Regulatory note (sport): Not explicitly named on the 2026 WADA Prohibited List as of last review. Verify directly.

Not DEA-scheduled.

Peptide

A short chain of amino acids, the building blocks of proteins. Many compounds in this library are peptides.

Senolytic

A compound designed to selectively eliminate senescent ("aged") cells.

Subcutaneous

An injection into the fatty layer just under the skin, rather than into a muscle or vein.

Half-life

Roughly how long the body takes to clear half of a dose. A long half-life is why some compounds can be taken only once a week.

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. (2017). Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 169(1):132–147.e16 (March 23, 2017).(PMID 28340339)
2. de Keizer PLJ et al. Cleara Biotech founding and FOXO4-DRI clinical-development pipeline, 2017 onward. The de Keizer Erasmus University laboratory's FOXO4-DRI research was advanced into clinical development via the Cleara Biotech spin-out. Reported small Phase I exploratory work in cancer chemotherapy recovery populations; published Phase II or III results not widely disclosed. Cleara has subsequently developed next-generation senolytic peptides beyond the original FOXO4-DRI construct. Source for: the clinical-translation context; Cleara Biotech's role in FOXO4-DRI development; the post-chemotherapy recovery clinical direction. Registry check 2026-07-18: a ClinicalTrials.gov search returned zero registered trials for sponsor "Cleara" / "Cleara Biotech" and zero for intervention "FOXO4" / "FOXO4-DRI." The reported Phase I exploratory work is therefore reported-but-unregistered and unpublished — the hedged wording throughout this entry is deliberate and should not be firmed up. remains open pending a primary Cleara disclosure or a published trial report.
3. Campisi J. Broader senolytic / cellular senescence research program at Buck Institute for Research on Aging, 1990s onward. The cellular senescence and senolytic concepts emerged in substantial part from the Campisi laboratory at the Buck Institute, including foundational work on the senescence-associated secretory phenotype (SASP), the senescent-cell-as-cancer-suppressor-and-aging-driver dual role, and the rationale for senolytic therapeutics. Campisi was senior co-author of Baar 2017.[¹] Source for: broader cellular senescence research context; SASP framework; the senolytic concept history; the multi-class senolytic landscape (dasatinib + quercetin, navitoclax, fisetin, FOXO4-DRI).
4. Ning N, Wang C, Gao T, et al. (2026). Acylglycerol Kinase Sensitizes Glioblastoma to Temozolomide via Limiting Mitochondrial Damage Related Cellular Senescence. Molecular Carcinogenesis (published online July 2, 2026).(PMID 42391447)

• Adipotide — same mechanism class
• Follistatin — same mechanism class
• PNC-27 — same mechanism class
• Tesofensine — same mechanism class
• Cartalax — shared research area
• Cortagen — shared research area