Also known as: FOXO4-DRI, Proxofim, FOXO4 D-Retro Inverso
Half-life: Extended via DRI backbone (~hours-days)
Last reviewed: · Published:
FOX04-DRI is a synthetic D-retro-inverso (DRI) peptide designed to selectively kill senescent cells by disrupting the FOXO4-p53 interaction inside them. Senescent cells — cells that have permanently exited the cell cycle in response to damage or stress — accumulate with age and contribute to age-related dysfunction through their senescence-associated secretory phenotype (SASP), which drives chronic inflammation in surrounding tissues. Selective elimination of senescent cells (senolysis) has emerged as one of the most promising mechanistic interventions in aging biology.
Mechanistically, FOX04-DRI mimics the portion of the FOXO4 transcription factor that binds p53 in the nucleus of senescent cells. By competitively displacing FOXO4 from p53, the peptide releases p53 to translocate to the mitochondria, where it triggers apoptosis. Crucially, this mechanism is selective for senescent cells because they uniquely depend on the FOXO4-p53 interaction for their continued survival; non-senescent cells are largely unaffected. The "D-retro-inverso" backbone (D-amino acids in reversed sequence) gives the peptide resistance to enzymatic degradation while preserving the binding geometry of the natural L-peptide.
The 2017 publication by Peter de Keizer's group at the Erasmus University Medical Center reported dramatic rejuvenation effects in aged mice: improved fur density, restored renal function, and increased exercise capacity after multiple FOX04-DRI doses. These striking results drove enormous interest in the compound. Subsequent independent work has been more measured — the dramatic mouse phenotype rescue has not been straightforwardly reproduced, and human clinical translation remains early. The compound is widely sold by research-chemical vendors. Human safety and efficacy data are essentially absent.
FOX04-DRI was developed by Peter de Keizer's group at the Erasmus University Medical Center (Rotterdam, Netherlands) and reported in a 2017 Cell paper that received extensive popular-press coverage. The design used the D-retro-inverso peptide chemistry strategy (well-established for producing stable peptide mimetics of intracellular protein-protein interactions). The compound was patented and is being developed clinically under the name Proxofim by Cleara Biotech, the spinoff company founded by de Keizer. As of early 2026, Cleara's program has not advanced to substantial human clinical trial results.
Animal tolerability in published de Keizer-group work has been good, with the mice tolerating multiple doses without major adverse events. Human tolerability is essentially unknown. The theoretical concerns about p53-mediated apoptosis in stressed-but-non-senescent cells (which could include stem and progenitor populations) and about acute inflammatory responses from senescent-cell death are non-trivial and would be the focus of formal clinical safety evaluation.
Dose Range
0.4-5 mg/kg
Frequency
Every other day for 1-2 weeks per cycle
Duration
Cycle-based per protocol
Dosing information is for educational purposes only. Consult a healthcare professional before using any peptide.
Typical Vial Size
10 mg
Water Type
Bacteriostatic water (BAC water)
Mixing Volume
1-2 mL
Half-Life
Extended via DRI backbone (~hours-days)
Molecular Weight
~2,400 Da
Store reconstituted vial refrigerated at 2-8°C. Use within 14-21 days. Subcutaneous administration is the most common research route. The DRI peptide backbone is more stable than typical L-peptides.
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FDA Status
Not FDA approved. In preclinical / early clinical development as Proxofim (Cleara Biotech).
Legal Status
Unregulated research chemical.
USA
Not approvedResearch-only; Cleara Biotech development program
EU
Not approvedNot authorized as medicinal product
UK
Not approvedClassified as research chemical
Netherlands
Not approvedOrigin of research; Cleara Biotech development ongoing
Australia
Not approvedTGA has not evaluated
Canada
Not approvedNot authorized for human use
Baar MP, Brandt RM, Putavet DA, Klein JD, Derks KW, Bourgeois BR, 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 RW, Madl T, Hoeijmakers JH, Campisi J, de Keizer PL
Cell (2017)
Landmark publication describing FOX04-DRI peptide design, in vitro senolytic activity, and dramatic in vivo rejuvenation effects in aged and chemotoxicity-stressed mouse models. The paper that launched the field of peptide senolytics.
View Study →Niedernhofer LJ, Robbins PD
Nature Reviews Drug Discovery (2018)
Authoritative review of the senolytics field including FOX04-DRI and small-molecule alternatives (dasatinib + quercetin, fisetin), framing the therapeutic rationale for senolysis in age-related disease.
View Study →Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM
Nature Reviews Drug Discovery (2017)
Comprehensive review of the biology of cellular senescence and the rationale for senolytic therapeutics, providing the foundational context for understanding FOX04-DRI's mechanism and the therapeutic opportunity.
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