FOXO4-DRI
Dosage Protocol
FOXO4-DRI is a D-retro-inverso peptide based on the FOXO4 protein domain that interacts with p53 in senescent cells. In senescent 'zombie' cells, FOXO4 sequesters p53 and prevents its pro-apoptotic function. FOXO4-DRI competitively disrupts this interaction, freeing p53 to trigger apoptosis specifically in senescent cells — a novel senolytic mechanism with minimal effects on healthy cells.
What is FOXO4-DRI?
FOXO4-DRI was developed by the de Keizer group at Utrecht University and published in Cell in 2017. The D-retro-inverso (DRI) peptide design — using all D-amino acids in reversed sequence — confers resistance to proteolytic degradation while maintaining the target binding interaction. The peptide was designed to specifically mimic the FOXO4 interacting domain for p53.
Landmark mouse studies showed that three doses of FOXO4-DRI in naturally aged mice produced significant improvements in exercise capacity, fur density restoration, and renal function — with histological evidence of selective senescent cell clearance. The compound represents one of the first peptide-based senolytics, distinct from small-molecule senolytics like navitoclax or dasatinib/quercetin.
Dosing Schedule
Parameters documented in published preclinical and clinical research.
| Phase | Dose | Frequency | Duration | Notes |
|---|---|---|---|---|
| Published mouse dose | 5 mg/kg IP | 3 doses, 3 days apart | Per cycle | Original Cell 2017 protocol used intraperitoneal route — not applicable to SubQ self-administration. |
| SubQ exploratory | 1–3 mg | 3× per cycle (days 1, 3, 5) | Monthly cycles | Practical SubQ protocol. Use within 1–2 weeks of reconstitution — degrades rapidly. Start at 1 mg. |
| Advanced SubQ | 5 mg | 3× per cycle | Monthly cycles | Full vial per dose. Extremely limited human data — use with caution. |
| Off cycle | — | — | 2–4 weeks | Extended rest between senolytic cycles to assess clearance effects. |
Safety & Side Effects
Academic References
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[1]
Baar MP, et al. (2017). Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 169(1):132–47. PubMed ↗
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[2]
Childs BG, et al. (2017). Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 16(10):718–35. PubMed ↗
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[3]
van Deursen JM. (2014). The role of senescent cells in ageing. Nature. 509(7501):439–46. PubMed ↗
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[4]
de Keizer PL. (2017). The fountain of youth by targeting senescent cells. Trends Mol Med. 23(1):6–17. PubMed ↗