Side-by-side · Research reference
HumaninvsPE 22-28
Side-by-side comparison across mechanism, dosage, evidence, side effects, administration, and stack synergies. Citations on every claim where available.
AAnimal-StrongHUMAN-REVIEWED14/52 cited
BAnimal-StrongHUMAN-REVIEWED16/47 cited
Humanin
Mitochondrial-Derived Peptide · Cytoprotective
SQ · Experimental
PE 22-28
TREK-1 Antagonist · Pre-Clinical
IP · SQ · Once Daily (animal models)Djillani 2017Pietri 2019
01Mechanism of Action
Parameter
Humanin
PE 22-28
Primary target
Intracellular: Bax, Bim, tBid (pro-apoptotic Bcl-2 family). Extracellular: FPRL1/2 G-protein-coupled receptorsZhu 2022Lue 2021
TREK-1 two-pore-domain potassium channelDjillani 2017Ma 2020
Pathway
Humanin binds Bax/Bim → inhibits mitochondrial outer membrane permeabilization (MOMP) → blocks cytochrome c release → prevents caspase activation → cell survival
TREK-1 channel blockade → Neuronal membrane depolarisation → Enhanced hippocampal excitability → Increased neuroplasticity
Downstream effect
Suppression of apoptosis, mitochondrial stabilization, reduced oxidative stress, preservation of germ cells and neurons under stressZhu 2022Lue 2021Velentza 2024
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?
Not applicable — peptide acts as anti-apoptotic signal, not hormonal axis
N/A — direct ion channel blockade; not receptor-mediated endocrine axis
Origin
Encoded by short open reading frame in mitochondrial 16S rRNA gene (MTRNR2). 24-28 amino acids. 13 homologous variants (MTRNR2L1-L13) identified.Zhu 2022Shahzaib 2026
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
Not reported in animal models
Not reported in animal studies
02Dosage Protocols
Parameter
Humanin
PE 22-28
Standard experimental dose (HNG)
4 mg/kg IP (rat)
Most common dose in rodent models.
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Ex vivo bone culture
1 µg/mL
Protective against venetoclax-induced bone growth retardation.
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Frequency
Daily (IP)
Once daily
Sustained antidepressant effect over 7+ days.
Duration
8–12 weeks in animal studies
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Evidence basis
Animal models (rat, mouse)Huang 2025El 2022Velentza 2024
Multiple rodent RCTs; behavioral + electrophysiology endpointsDjillani 2017Qi 2018Wu 2021
Human data
None — no clinical trials reported
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Analog (HNG)
Gly[14]-humanin — more potent variant
Substitution at position 14 enhances cytoprotective activity.
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Animal dose (antidepressant)
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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.
Onset (animal)
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Within hours (acute); full effect 4–7 days
Comparison to fluoxetine
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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.
03Metabolic / Fat Loss Evidence
Parameter
Humanin
PE 22-28
Direct fat loss evidence
None
—
Mechanism overlap
Mitochondrial health may indirectly influence metabolic efficiency, but no quantified effect
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04Side Effects & Safety
Parameter
Humanin
PE 22-28
Animal model safety
Well-tolerated in rat and mouse studies at 4 mg/kg for 8–12 weeks
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Human safety data
None — no clinical trials
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Theoretical fibrillation risk
Induces amyloid-like fibrillation of Bax/BID. Long-term sequelae unknown.
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Injection site reaction
Not reported in animal studies (IP route)
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Reproductive safety
Protective in POI model (cyclophosphamide-induced), no adverse effects on fertility notedHuang 2025
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Toxicity (animal)
—
No adverse effects reported at therapeutic doses
Cardiovascular (theoretical)
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TREK-1 expressed in cardiac tissue; arrhythmia risk unclear
Weight change
—
Not reported in animal studies
Neurological
—
No seizures or behavioral abnormalities noted
Long-term safety
—
Unknown — longest animal study 28 days
Absolute Contraindications
Humanin
- ·Unknown — no human data
PE 22-28
- ·Human use — no clinical safety data available
Relative Contraindications
Humanin
- ·Active malignancy (theoretical risk of anti-apoptotic effect on tumour cells)
PE 22-28
- ·Cardiac arrhythmia or channelopathy (theoretical TREK-1 cardiac role)
05Administration Protocol
Parameter
Humanin
PE 22-28
1. Route (experimental)
Intraperitoneal (IP) in animal models. Subcutaneous route untested. No human protocols exist.
Dissolved in sterile saline or vehicle. Intraperitoneal injection, 0.3–3 µg/kg body weight. Once daily administration in rodent behavioral studies.
2. Reconstitution
Synthetic peptide reconstituted in sterile saline or PBS. No commercial formulation available.
Shorter peptide length (7 AA) confers improved plasma stability vs 17-AA spadin. Exact storage conditions not detailed in published protocols.Djillani 2017
3. Timing
Daily administration in animal studies. Optimal timing not characterized.
Enhanced CNS bioavailability vs full spadin, likely due to smaller size. Mechanism (passive diffusion vs active transport) not fully characterized.
4. Storage
Lyophilised powder: -20 °C. Reconstituted: 4 °C, use within 7 days. Avoid freeze-thaw cycles.
Not established — peptide synthesis methods for research use only. No pharmaceutical-grade formulation available.
5. Human use
No FDA approval, no IND, no clinical trials. Experimental research tool only.
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06Stack Synergy
Humanin
+ MOTS-c
Multi-pathwayBoth are mitochondrial-derived peptides. MOTS-c enhances metabolic efficiency and insulin sensitivity via AMPK activation, while humanin prevents mitochondrial apoptosis. Combined, they address mitochondrial function (MOTS-c) and survival signaling (humanin), supporting cellular resilience under metabolic and oxidative stress.
- Humanin
- 4 mg/kg IP · daily (animal model)
- MOTS-c
- 5 mg/kg IP · daily (animal model)
- Frequency
- Once daily
- Primary benefit
- Mitochondrial health, metabolic efficiency, anti-apoptotic signaling
PE 22-28
— no documented stacks