Side-by-side · Research reference
FOXO4-DRIvsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AAnimal-StrongHUMAN-REVIEWED12/45 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
FOXO4-DRI
Senolytic Peptide · D-Retro-Inverso
SQ · Animal models only
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
FOXO4-DRI
PE 22-28
Primary target
FOXO4-p53 protein complex in senescent cellsBourgeois 2025Tripathi 2021
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
FOXO4-DRI binds disordered p53 transactivation domain → displaces FOXO4 → nuclear p53 exclusion → p53-mediated apoptosis in senescent cells
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Selective apoptosis of senescent cells; clearance restores tissue homeostasisTripathi 2021Alameen 2026
Antidepressant-like activity in forced swim test and tail suspension test; reduced A1-like reactive astrocyte activation; neuroprotection via NF-κB pathway modulationDjillani 2017Cong 2023Wu 2021
Feedback intact?
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N/A — direct ion channel blockade; not receptor-mediated endocrine axis
Origin
D-retro-inverso modification — inverted amino acid sequence, D-amino acids for protease resistance
Synthetic truncation of spadin (PE 12-28), itself derived from the sortilin propeptide C-terminus. Residues 22-28: Val-Val-Arg-Gly-Trp-Leu-Arg.Djillani 2017Mazella 2018
Antibody development
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Not reported in animal studies
02Dosage Protocols
Parameter
FOXO4-DRI
PE 22-28
Animal dose (mouse)
5 mg/kg
SQ injection, aged mouse model (testosterone restoration).
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Frequency (animal)
Variable — single or intermittent dosing
Protocol-dependent; no standardised regimen.
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Human equivalent (theoretical)
~0.4 mg/kg (28 mg / 70 kg adult)
Extrapolated using allometric scaling; no clinical validation.
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Evidence basis
Animal / mechanistic
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Route
SQ (animal)
No human route established.
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Duration
Weeks to months (animal studies)
Senescent cell clearance observed within weeks.
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Clinical status
No human trials completed
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Animal dose (antidepressant)
—
0.3–3 µg/kg IP
Effective in forced swim test, tail suspension test, CUMS models.
Animal dose (neuroprotection)
—
0.03 µg/kg IPPietri 2019
Low-dose TREK-1 activation post-stroke for 7 days, then high-dose blockade.
Frequency
—
Once daily
Sustained antidepressant effect over 7+ days.
Onset (animal)
—
Within hours (acute); full effect 4–7 days
Comparison to fluoxetine
—
PE 22-28 outperforms fluoxetine in CUMS-sensitive rats by day 7
Chronic administration shows superior long-term efficacy.
Human equivalent (extrapolated)
—
Not established — no clinical trials
Allometric scaling from rodent data unavailable.
04Side Effects & Safety
Parameter
FOXO4-DRI
PE 22-28
Pulmonary hypertension risk
Senescent cell elimination promoted PH development/progression in rodent modelsBorn 2023
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Context-dependent toxicity
Beneficial effects may be tissue/context-specific; elimination not universally protectiveBorn 2023
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Off-target apoptosis
Theoretical risk of non-senescent cell apoptosis (selectivity not absolute)
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Immune perturbation
Senescent cells contribute to immune surveillance; clearance effects unknown
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Human safety unknown
No clinical trials — toxicity profile in humans not established
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Toxicity (animal)
—
No adverse effects reported at therapeutic doses
Cardiovascular (theoretical)
—
TREK-1 expressed in cardiac tissue; arrhythmia risk unclear
Weight change
—
Not reported in animal studies
Neurological
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No seizures or behavioral abnormalities noted
Long-term safety
—
Unknown — longest animal study 28 days
Absolute Contraindications
FOXO4-DRI
- ·Pulmonary hypertension or vascular disease (preclinical evidence of harm)Born 2023
- ·Pregnancy / lactation (no safety data)
PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
FOXO4-DRI
- ·Active malignancy (senescence as tumour suppressor mechanism)
- ·Wound healing / tissue repair (senescent cells involved in fibrosis resolution)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
FOXO4-DRI
PE 22-28
1. Pre-clinical route
Subcutaneous injection used in rodent models. No human administration protocol exists.
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Reconstitution (animal)
Typically reconstituted in sterile saline or PBS for animal experiments. Stability data limited.
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. Dosing schedule
Variable — single bolus or intermittent dosing over weeks. No standardised human protocol.
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
4. Clinical development status
No registered human trials. Commercialisation by Cleara Biotech (Netherlands) in development phase.
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.
5. Safety monitoring (proposed)
Would require cardiovascular assessment, pulmonary function, immune panel, tumour surveillance if human trials proceed.
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