Overview
FOXO4-DRI (FOXO4 D-Retro-Inverso) is a synthetic peptide designed by the de Keizer lab at the Hubrecht Institute, published in Cell in 2017 (Baar et al.). It is built from D-amino acids in reverse order (a 'retro-inverso' design that resists protease degradation) to mimic the FOXO4 binding interface to p53, and is intended to displace p53 from FOXO4 in senescent cells, freeing p53 to drive apoptosis selectively in those cells. The 2017 mouse data was striking: aged mice showed reduced markers of frailty, restored fur density, improved renal function, and improved running endurance after IV dosing. The paper kicked off enormous community interest in 'senolytic' peptides. Crucially, there are no published human trials of FOXO4-DRI as of this entry. Vendor / longevity-clinic use is extrapolation from a single mouse study.
Mechanism
Disrupts FOXO4-p53 binding in senescent cells, releasing p53 to trigger apoptosis selectively in cells that have entered senescence (senescent cells over-express FOXO4 and are 'addicted' to FOXO4-p53 interaction for survival). Healthy cells should be unaffected because the FOXO4-p53 binding is not critical for their survival. The retro-inverso D-amino-acid design is intended to extend half-life and resist proteolytic degradation, allowing the peptide to reach intracellular targets after IV administration.
Evidence by indication
We classify each indication separately. The same peptide can be Tier 1 for one use and Tier 4 for another. Tiers reflect the published literature, not the strength of community framing.
Senescent-cell clearance / 'cellular reprogramming' in aged mice
Single landmark study (Baar 2017, Cell) demonstrating preferential senescent-cell killing and frailty-marker improvement in aged mice. Effect size was striking. There is no replication in independent human or non-human primate work, and no completed published human trial.
Anti-aging / longevity in humans
No human RCT. No published Phase 1 safety data. Community framing as a 'reset for cellular age' has zero translational evidence. Mechanism-as-evidence reasoning, with the additional caveat that systemic apoptotic-induction peptides have very real safety questions in untrialed populations.
No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.
Studied dose ranges
The ranges below come from published trial protocols where available, and from documented self-experimenter consensus where the literature does not include human dose-finding work. The notes flag which is which.
The original Baar 2017 mouse protocol used ~5 mg/kg IV, three doses over a week, repeated every several weeks. Direct human extrapolation from mouse mg/kg is fraught — vendor 'protocols' for 5–50 mg/kg ranges have no human PK or dose-finding to anchor them. The dose range listed here is descriptive of community/clinic claims, not endorsed.
Contraindications
- Any active malignancy (selectively triggering apoptosis is not benign in patients with mixed-population tumors and pre-malignant lesions)
- Pregnancy and breastfeeding (no safety data)
- Pediatric and adolescent use (inappropriate for any preclinical-only compound outside trials)
- Active or recent chemotherapy / radiation (combined apoptotic stress is uncharacterized)
- Known hypersensitivity
- Use without informed-consent acknowledgment that this is preclinical-only
Reported side effects
- Unknown in humans — no published Phase 1 safety data
- Anecdotal community / clinic reports: flu-like symptoms during the first 24–48 hours after dosing (consistent with a cytokine-release-like response that would be expected from large-scale senescent-cell apoptosis); these reports are uncontrolled
- Theoretical: off-target apoptotic induction in non-senescent cells with high FOXO4 dependency
- Theoretical: any senolytic carries hypothetical risk if the senescent state is performing useful biology (e.g., wound-healing senescence, tumor surveillance)
Reconstitution & storage
Vendor preparations are typically lyophilized powder reconstituted with sterile saline or BAC water for IV / SubQ use. Injection volumes for 'senolytic-protocol' doses can be substantial. There is no validated commercial-grade formulation.
Storage. Vendor-dependent. Lyophilized powder typically refrigerated; reconstituted within 7–14 days due to limited stability data.
Open the peptide calculator → to compute exact draw volumes for your specific vial and BAC water choice.
Editorial note
DRAFT — pending Wayne's review. FOXO4-DRI is the canonical example of a longevity-community peptide that has gone wide on the basis of one striking mouse paper. Editorial position: respect the science, name the singular-source nature of the evidence, refuse to soften the lack of human trials. The 'reset cellular age' marketing is the kind of claim the harm-reduction frame exists for. Tier 4 across the board, no human-applicable indication.
Citations
- [1]Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and AgingBaar MP, Brandt RMC, Putavet DA, et al. (de Keizer PLJ, group) · Cell · 2017 · PMID 28340339The single landmark mouse study underlying all FOXO4-DRI claims. Only published preclinical anchor.View source