Uncategorized
FOXO4-DRI: Senolytic Research and Senescent Cell Clearance
May
- FOXO4-DRI is a D-retro-inverso peptide (~4900 Da) engineered to interfere with the FOXO4-p53 protein-protein interaction in senescent cells.
- D-amino acid configuration with reversed sequence confers extreme protease resistance — a research-tool design pattern for peptide-based protein-protein-interaction inhibitors.
- Research investigates restoration of p53-mediated apoptotic clearance selectively in senescent cell populations.
What is FOXO4-DRI?
FOXO4-DRI (D-retro-inverso FOXO4) is a synthetic peptide engineered to disrupt the protein-protein interaction between FOXO4 (a forkhead box O transcription factor) and p53 (the tumour suppressor protein) in senescent cells. With an approximate molecular weight of 4900 Da and a D-retro-inverso configuration (all amino acids in D-stereochemistry, sequence reversed relative to native FOXO4 peptide), the compound is a research-tool example of peptide-based protein-protein-interaction inhibition. Researchers can access FOXO4-DRI research peptide at Advanced Peptide Science within the Longevity & Immune Support category.
Research Background: Baar et al. 2017 and Senolytic Pharmacology
FOXO4-DRI was reported by Baar et al. (Cell, 2017) as a proof-of-concept senolytic — a compound that selectively eliminates senescent cells while sparing non-senescent cells. The discovery represented a significant methodological extension of the cellular senescence research field, demonstrating that selective senescent-cell clearance could be achieved pharmacologically rather than only through genetic approaches. The compound has subsequently become a foundational research tool in senolytic compound investigation.
Mechanism of Action
Mechanism research investigates FOXO4-DRI sequestration of p53 from FOXO4 specifically in senescent cells. The mechanism rests on a key feature of cellular senescence: senescent cells exhibit elevated FOXO4 expression, and the elevated FOXO4 sequesters p53, preventing the normal p53-mediated apoptotic clearance pathway from operating. The result is the characteristic apoptosis resistance of senescent cells. FOXO4-DRI displaces p53 from the FOXO4 sequestration complex, allowing p53 to engage its normal apoptotic signalling pathway and trigger apoptosis selectively in senescent cells.
Key Research Findings
FOXO4-p53 Protein-Protein Interaction
Senescent cells overexpress FOXO4 relative to non-senescent cells. The elevated FOXO4 binds p53 directly, sequestering p53 from its normal nuclear apoptotic-signalling role. FOXO4-DRI competitively disrupts this binding — restoring free p53 availability for apoptotic pathway engagement.
Selective Senescent-Cell Apoptosis
The selectivity of FOXO4-DRI for senescent cells arises from the elevated FOXO4 expression specifically in senescent cell populations. Non-senescent cells lack the FOXO4-p53 sequestration that FOXO4-DRI disrupts — so non-senescent cells are not affected. The mechanism is cell-state-selective rather than cell-type-selective.
D-Retro-Inverso Design Strategy
The D-retro-inverso configuration is a research-tool peptide design pattern: all amino acids in D-stereochemistry with the sequence reversed relative to the native L-peptide. The combined modifications produce a peptide that maintains the same side-chain spatial arrangement as the native L-peptide (enabling target binding) while being resistant to virtually all proteases (which recognise L-amino acid sequences). FOXO4-DRI demonstrates the design pattern’s utility for protein-protein-interaction inhibitor research.
Research Applications
FOXO4-DRI research applications include senescent-cell clearance pharmacology, FOXO4-p53 protein-protein interaction biology, apoptosis pathway restoration research in senescent fibroblast models, and D-retro-inverso peptide design methodology research. Within the Longevity & Immune Support category, FOXO4-DRI complements Epitalon (telomerase activation), SS-31 (mitochondrial-targeted), and MOTS-c (AMPK-pathway) for multi-mechanism longevity research frameworks.
Research Specifications
| Molecular Weight | ~4900 Da |
| Configuration | D-retro-inverso (all D-amino acids, reversed sequence) |
| Target | FOXO4-p53 protein-protein interaction |
| Selectivity | Senescent cells (elevated FOXO4 expression) |
| Reference | Baar et al., Cell 2017 (proof-of-concept senolytic) |
| Format | Lyophilized powder in sterile vial |
| Purity | ≥ 99% (HPLC verified) |
| Storage | -20 °C, protect from light |
Frequently Asked Questions
What does D-retro-inverso mean?
D-retro-inverso refers to a peptide design pattern with two combined modifications: all amino acids in D-stereochemistry (mirror image of natural L-amino acids) and the sequence reversed relative to the native L-peptide. The combined modifications maintain side-chain spatial arrangement while conferring protease resistance.
How does FOXO4-DRI selectively target senescent cells?
Senescent cells overexpress FOXO4, which sequesters p53 and prevents normal apoptotic clearance. FOXO4-DRI disrupts the FOXO4-p53 binding, restoring p53-mediated apoptosis selectively in senescent cells. Non-senescent cells lack the elevated FOXO4 and are not affected.
Where can researchers source FOXO4-DRI?
FOXO4-DRI research peptide is available at Advanced Peptide Science at 99%+ HPLC-verified purity in 1mg and 5mg vials plus kit configurations.
Is FOXO4-DRI approved for human use?
Advanced Peptide Science supplies FOXO4-DRI exclusively for in vitro and in vivo scientific research. Not for human consumption. Research use only.
For Research Use Only. Not for human consumption. Not intended to diagnose, treat, cure, or prevent any disease.
