Evidence Grade D — Primarily preclinical. 17 published studies, mostly animal models. 0 registered clinical trials.
Medically reviewed by a licensed medical professional
FOXO4-DRI is a 46-amino-acid peptide designed to selectively kill senescent cells — damaged cells that accumulate with age and release inflammatory signals that harm surrounding tissue. It uses a mirror-image design that resists the body's enzymes. A single high-profile publication (in Cell, 2017) demonstrated effects in three mouse models. No human clinical trials have been conducted.
FOXO4-DRI is also known by these brand and alternate names:
17 published studies: 7 human, 5 animal, 5 in-vitro, 4 reviews
FOXO4-DRI has no marketing authorisation. No human clinical trials have been conducted. The evidence comes from a single high-profile publication (Cell, 2017) demonstrating effects in three mouse models.
The senolytic field is an active area of pharmaceutical research, but FOXO4-DRI faces significant challenges for clinical translation, including its large size (46 amino acids), manufacturing complexity, and the absence of human pharmacokinetic or safety data. Products available through unregulated channels — which would need to reliably synthesise a 46-amino-acid all-D-amino-acid peptide — face exceptional quality assurance challenges.
Research suggests FOXO4-DRI works by disrupting an interaction between two proteins (FOXO4 and p53) that keeps senescent cells alive. In normal cells, this interaction is absent, so the peptide has no effect. In senescent cells, blocking this interaction is proposed to release p53 to trigger cell self-destruction. This selective senolytic mechanism has been demonstrated in cell culture and mouse models in a single landmark publication.
Research suggests the original Cell publication includes rigorous controls, and independent groups have subsequently validated the mechanism in different disease contexts including osteoarthritis and radiation-induced fibrosis. A 2025 structural study provided molecular confirmation of how the peptide works. Active commercial development by a biotech company (Cleara Biotech) indicates industry interest. However, no human data of any kind exist. Manufacturing a 46-amino-acid all-D-amino-acid peptide to pharmaceutical standards is exceptionally complex and expensive, raising serious doubts about the quality of products from unregulated sources. Theoretical concerns about eliminating senescent cells that serve beneficial roles (wound healing, tumour suppression) remain unresolved.
PeptideTrace tracks 0 registered clinical trials for FOXO4-DRI sourced from ClinicalTrials.gov.
No trials registered on ClinicalTrials.gov for this compound.
FOXO4-DRI is a 46-amino-acid D-retro-inverso peptide designed to selectively eliminate senescent cells by disrupting the FOXO4-p53 interaction that maintains their viability. The sequence consists of all D-amino acids (lowercase convention: ltlrkepaseiaqsileaysqngwanrrsggkrppprrrqrrkkrg), comprising a 34-residue FOXO4 domain plus a 12-residue cell-penetrating peptide tag. Molecular formula is C228H388N86O64, molecular weight 5,358.05 Da (CAS: 2460055-10-9). Also known as Proxofim. The D-amino acid composition confers protease resistance, giving an extended half-life of hours versus minutes for equivalent L-peptides. Developed by Peter de Keizer at Utrecht University. Research administration is via intraperitoneal injection in animal studies. Not approved by any regulatory agency.
In senescent cells, FOXO4 is upregulated and binds p53 in the nucleus, sequestering phosphorylated p53 (Ser46) and preventing it from translocating to mitochondria to trigger apoptosis. This keeps senescent cells alive while they secrete inflammatory SASP factors (IL-6, IL-1beta, IL-8, TNF-alpha). FOXO4-DRI enters cells via its cell-penetrating peptide domain and competitively displaces endogenous FOXO4 from p53. Released p53 translocates to mitochondria and induces transcription-independent intrinsic apoptosis. Selectivity arises because FOXO4 is elevated specifically in senescent cells and minimally expressed in healthy adult tissues. Research confirms FOXO4-DRI removed over 50% of senescent chondrocytes while not significantly affecting healthy cells. A 2025 Nature Communications study (Bourgeois et al.) solved the NMR structure of the p53TAD2/FOXO4-DRI complex, showing that both the FOXO4 domain and CPP tag contribute to binding, and p53 phosphorylation enhances affinity.
The landmark paper by Baar et al. (Cell, 2017, 169(1):132-147.e16) demonstrated across three mouse models that FOXO4-DRI (5 mg/kg IP, 3 doses on alternate days) restored tissue homeostasis: neutralized doxorubicin-induced liver damage, restored fitness and fur density in fast-aging XpdTTD/TTD mice, and restored fitness, fur density, and renal function in naturally aged mice (normalized renal tubular IL-6, LMNB1 loss, and plasma blood urea levels). Zhang et al. (2020, Aging) showed selective apoptosis of senescent Leydig cells with improved testicular microenvironment and testosterone secretion in aged mice. Huang et al. (2021) removed over 50% senescent chondrocytes versus no effect on healthy cells (p < 0.01 to p < 0.0001). Meng et al. (2021, JCI Insight) demonstrated radiosensitization of NSCLC and reduced radiation-induced pulmonary fibrosis. Cleara Biotech BV (Netherlands), founded by de Keizer, raised 2.5 million euros seed funding (September 2022) for optimized 4th-generation FOXO4-based D-peptides. No human clinical trials have been registered.
The information on this page is provided for educational and research reference purposes only. This is not medical advice. Always consult a qualified healthcare professional before making any health-related decisions.
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GHK has no pharmaceutical authorisation. Small cosmetic studies of the copper-complexed form (GHK-Cu) have reported improvements in skin appearance measures. No pharmaceutical clinical trials for injectable use have been completed. As with GHK-Cu (#85), the cosmetic evidence base for topical use should be distinguished from claims about injectable use. Gene expression profiling studies have reported broad effects, but observational genomic changes do not constitute evidence of therapeutic efficacy. This entry overlaps substantially with GHK-Cu (#85).
Argireline has no pharmaceutical authorisation. It is widely available as a cosmetic ingredient in over-the-counter skincare products. Small industry-sponsored studies have reported wrinkle depth reductions of 17–30% with topical application. The key scientific question is whether sufficient peptide penetrates intact skin to reach neuromuscular junctions and produce a meaningful effect. The molecule's size exceeds the conventional limit for transdermal absorption. Argireline's cosmetic use in formulated skincare products represents a fundamentally different risk profile from injectable use.
GHK-Cu has no pharmaceutical authorisation from any regulatory agency. It is widely available as a cosmetic ingredient in over-the-counter skincare products, where it is marketed for skin conditioning. A small study comparing GHK-Cu cream to vitamin C and retinoic acid creams reported improvements in skin appearance measures. No pharmaceutical clinical trials for injectable GHK-Cu have been completed. The compound's cosmetic use (topical, in formulated skincare products) should be clearly distinguished from its unregulated availability as an injectable research compound. These represent fundamentally different risk profiles.
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
