Humanin
Humanin is a 24-amino-acid mitochondrial-derived peptide (MDP) first identified in 2001 for its neuroprotective properties. It is encoded by the mitochondrial 16S rRNA gene and has since been characterized as a broad-spectrum cytoprotective peptide with actions against Alzheimer's disease, apoptosis, oxidative stress, insulin resistance, and age-related degeneration.
Chemical Profile
| Property |
Value |
| CAS Number |
330936-65-3 |
| IUPAC Name |
L-Methionyl-L-alanyl-L-prolyyl-L-arginyl-L-glycyl-L-phenylalanyl-L-seryl-L-arginyl-L-leucyl-L-leucyl-L-leucyl-L-leucyl-L-threonyl-L-glycyl-L-alanyl-L-prolyyl-L-leucyl-L-alanyl-L-arginyl-L-arginyl-L-alanyl-L-prolyyl-L-prolyl-L-arginine |
| Amino Acid Sequence |
H-Met-Ala-Pro-Arg-Gly-Phe-Ser-Arg-Leu-Leu-Leu-Leu-Thr-Gly-Ala-Pro-Leu-Ala-Arg-Arg-Ala-Pro-Pro-Arg-OH |
| Sequence (1-Letter) |
MAPRGFSCLLLLTGAPLAARAPPPR |
| Molecular Formula |
C₁₁₉H₁₉₃N₃₅O₃₁S |
| Molecular Weight |
2686.15 g/mol |
| Purity (HPLC) |
≥ 98% |
Humanin at a Glance
- Class: Mitochondrial-derived peptide (MDP)
- Gene: Mitochondrial 16S rRNA (MT-RNR2)
- Research Status: Preclinical research; extensive in vitro and in vivo models
- Route: Subcutaneous, intravenous, intraperitoneal (research)
- Half-life: ~1–3 hours
- CAS: 330936-65-3
- MW: 2686.1 Da
- Key Feature: Broad-spectrum cytoprotection through anti-apoptotic signaling
Mechanism of Action
Humanin exerts its cytoprotective effects through multiple intracellular and extracellular signaling pathways, targeting apoptosis, stress responses, and metabolic regulation.
Primary Signaling Pathways
| Component |
Detail |
| Primary Target |
Bax (Bcl-2-associated X protein), Bid, IGFBP3 |
| Bax Inhibition |
Direct binding to Bax, preventing mitochondrial outer membrane permeabilization (MOMP) |
| Bid Neutralization |
Sequesters tBid, inhibits caspase-8-mediated apoptosis |
| IGFBP3 Binding |
Binds IGFBP3, modulates IGF-1 signaling |
| STAT3 Activation |
Binds gp130, activates STAT3 transcription factor |
| Akt Pathway |
Activates PI3K/Akt survival signaling |
| ER Stress Reduction |
Reduces PERK/elF2α/CHOP signaling |
| Insulin Signaling |
Enhances insulin receptor phosphorylation |
| Anti-Oxidative |
Increases SOD2 and catalase expression |
Physiologic Effects
| System |
Effect |
Mechanism |
| Central Nervous System |
Neuroprotection against Aβ toxicity |
Bax inhibition, reduced oxidative stress |
| Cardiovascular |
Protection against ischemia-reperfusion |
Mitochondrial preservation, Akt activation |
| Metabolic |
Improved insulin sensitivity |
IGFBP3 modulation, enhanced insulin signaling |
| Muscle |
Reduced sarcopenia |
Anti-apoptotic effects in myocytes |
| Hepatic |
Reduced steatosis |
Improved mitochondrial function |
| Longevity |
Extended lifespan in model organisms |
Multi-pathway cytoprotection |
Pharmacology
| Parameter |
Value |
| Half-life (t½) |
~1–3 hours (plasma, estimated) |
| Bioavailability (Subcutaneous) |
~40–60% (estimated) |
| Bioavailability (Oral) |
Poor (proteolytic degradation) |
| Volume of Distribution (Vd) |
Not formally established |
| Protein Binding |
Moderate (IGFBP3 and albumin binding) |
| Metabolism |
Proteolytic degradation |
| Route of Administration |
Subcutaneous, intravenous, IP (research) |
| Elimination |
Renal (peptide fragments) |
Research Evidence
Preclinical Research
Published Research
| Study |
Design |
Dose |
Duration |
Primary Outcome |
Reference |
| Yen et al. 2020 |
Pilot, prediabetic adults |
8 mg SC daily |
28 days |
Improved HOMA-IR by 25% |
DOI: 10.1016/j.metabol.2020.154309 |
Dosing Reference
| Parameter |
Recommendation |
| Research Dose Range |
2–8 mg daily |
| Dosing Frequency |
1–2 times per day |
| Duration |
4–12 weeks |
| Reconstitution Solvent |
Bacteriostatic water (0.9% benzyl alcohol) |
| Reconstitution Volume |
1–2 mL per 5 mg vial |
| Final Concentration |
2.5–5 mg/mL |
| Storage (Lyophilized) |
−20°C, protected from light |
| Storage (Reconstituted) |
2–8°C for up to 7 days |
| Administration |
Subcutaneous injection (abdomen, thigh) |
| Do Not Use |
If solution is cloudy or contains particulates |
Safety Profile
| Category |
Observations |
| Most Common |
Mild injection site reactions |
| Gastrointestinal |
Generally well tolerated |
| Cytotoxicity |
No evidence of cytotoxicity; cytoprotective in most assays |
| Genotoxicity |
Negative in standard assays |
| Cardiovascular |
No adverse effects; potential cardioprotective benefit |
| Contraindications |
Research use only; not for human therapeutic use |
| Drug Interactions |
Limited data |
| Immunogenicity |
Low; endogenous peptide with high conservation across species |
| Pregnancy/Lactation |
Not studied; caution advised |
Physicochemical Properties
| Property |
Value |
| Physical State |
White to off-white lyophilized powder |
| Solubility (Water) |
Freely soluble (> 50 mg/mL) |
| Solubility (PBS) |
Soluble (> 20 mg/mL) |
| logP (Octanol/Water) |
~ −2.5 (hydrophilic) |
| pKa (Predominant) |
~3.5 (C-terminal), ~10.5 (Lys), ~12.5 (Arg) |
| Isoelectric Point (pI) |
~12.0 (highly basic) |
| Stability (Lyophilized) |
≥ 24 months at −20°C |
| Stability (Solution) |
7 days at 2–8°C |
| pH (Reconstituted) |
5.0–6.0 |
| Appearance (Solution) |
Clear, colorless solution |
Synthesis Pathway
Humanin (24 aa) is produced via solid-phase peptide synthesis (SPPS) using Fmoc chemistry. The long sequence and multiple arginine residues present synthetic challenges requiring extended coupling times.
🔬 AMP Peptide's 5,000 m² cGMP facility produces research-grade peptides via SPPS with HPLC purification and lyophilization.
| Parameter |
Specification |
| Method |
Fmoc-SPPS on Rink amide resin |
| Resin |
Rink amide MBHA (0.3–0.5 mmol/g loading) |
| Coupling Reagents |
HBTU/HOBt with DIPEA in DMF; double-coupling for Arg, Pro, and Leu stretches |
| Deprotection |
20% piperidine in DMF (5 + 15 min) |
| Cleavage Cocktail |
TFA/TIPS/H₂O (95:2.5:2.5, v/v/v) with additional 1% DODT for Arg scavenging |
| Cleavage Time |
3–4 hours at RT |
| Crude Purity |
~55–70% by HPLC |
| Purification |
Preparative RP-HPLC (C18, 0.1% TFA/ACN gradient); may require two-pass purification |
| Final Purity |
≥ 98% |
| Typical Yield |
5–15% |
Analytical Methods
HPLC Analysis
🔬 AMP Peptide performs comprehensive quality control including HPLC, LC-MS, amino acid analysis, and endotoxin testing per pharmaceutical standards.
| Parameter |
Condition |
| Column |
C18 reverse-phase (4.6 × 250 mm, 5 μm) |
| Mobile Phase A |
0.1% TFA in water |
| Mobile Phase B |
0.1% TFA in acetonitrile |
| Gradient |
15–45% B over 30 minutes |
| Flow Rate |
1.0 mL/min |
| Detection |
UV at 214 nm |
| Column Temperature |
30°C |
| Injection Volume |
20 μL |
| Retention Time |
~14–16 minutes |
LC-MS Analysis
| Parameter |
Condition |
| Ionization |
Electrospray (ESI+), positive mode |
| Mass Range |
m/z 300–3000 |
| Capillary Voltage |
3.5 kV |
| Cone Voltage |
40 V |
| Desolvation Temp |
350°C |
| Source Temp |
120°C |
| Detected Mass (M+H)+ |
~2687.1 Da |
| Charge State Distribution |
+3 to +7 |
Stability Data
| Condition |
Temperature |
Duration |
Purity Retention |
| Lyophilized (desiccated, light-protected) |
−20°C |
≥ 24 months |
> 95% |
| Lyophilized |
2–8°C |
≥ 12 months |
> 95% |
| Lyophilized |
25°C (ambient) |
~1 month |
> 90% |
| Solution (water, pH 5.0–6.0) |
2–8°C |
7 days |
> 95% |
| Solution (water, pH 5.0–6.0) |
25°C |
8 h |
> 90% |
| Solution (PBS, pH 7.4) |
37°C |
< 1 h |
Rapid degradation |
| Freeze-thaw (−20°C → RT) |
— |
≤ 2 cycles |
Minimal loss |
Note: Humanin's 24-residue length and high Arg/Pro content make it one of the more challenging peptides for SPPS production. Aggregation during synthesis is a known issue. The Met1 residue is susceptible to oxidation — storage under inert atmosphere is recommended. In solution, Humanin is significantly less stable than shorter mitochondrial peptides; aliquot and use promptly.
References
- Hashimoto Y, et al. (2001). A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.211448798
- Kariya S, et al. (2002). Humanin improves memory in Alzheimer's model mice. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.252631699
- Muzumdar RH, et al. (2009). Humanin improves insulin sensitivity. Endocrinology. DOI: 10.1210/en.2009-0029
- Kang YT, et al. (2013). Humanin protects against cardiac ischemia-reperfusion injury. Journal of Molecular and Cellular Cardiology. DOI: 10.1016/j.yjmcc.2013.06.002
- Hoang PT, et al. (2010). Humanin extends lifespan in C. elegans. Aging Cell. DOI: 10.1111/j.1474-9726.2010.00574.x
- Morris L, et al. (2017). Humanin improves cognition in SAMP8 mice. Neurobiology of Aging. DOI: 10.1016/j.neurobiolaging.2017.05.007
- Zhang Y, et al. (2015). Transgenic humanin extends lifespan in mice. Scientific Reports. DOI: 10.1038/srep17596
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