Humanin is a 24-amino acid, cytoprotective peptide encoded by the mitochondrial genome. It was first discovered in 2001 by Nishimoto and colleagues during a search for factors that could rescue neuronal cells from death induced by mutant amyloid precursor protein (APP) and presenilin-1, proteins associated with familial Alzheimer’s disease. Its discovery was significant as it represented the first identified bioactive peptide translated from the mitochondrial DNA, challenging the traditional view of mitochondrial DNA as solely encoding respiratory chain components. Humanin has since emerged as a critical endogenous cytoprotective factor with broad significance in aging research, neuroprotection, and metabolic regulation, demonstrating protective effects against a wide array of cellular stressors and disease-associated insults in various model systems.
Quick Facts
| Also Known As | HN, HNG, HN-S14G, Humanin G, Humanin derivative |
|---|---|
| Sequence | MAPRGFSCLLLLTSEIDLPVKRRA |
| Molecular Formula | C119H204N34O32S2 |
| Molecular Weight | 2687.2 Da |
| PubChem CID | 16131438 |
Research Parameters
| Half-Life | Unknown in humans. Estimated to be short (minutes to a few hours) based on peptide characteristics, but specific pharmacokinetic data is lacking. |
|---|---|
| Stability | Lyophilized powder is stable for at least 24 months when stored at -20°C, protected from light and moisture. After reconstitution in sterile buffer (e.g., PBS) or bacteriostatic water, it is recommended to aliquot and store at -20°C or -80°C to minimize degradation. Stability after reconstitution is typically several weeks when frozen, but repeated freeze-thaw cycles should be avoided. |
| Solubility | Recommended reconstitution in sterile phosphate-buffered saline (PBS, pH 7.4) or bacteriostatic water (0.9% benzyl alcohol). It is also soluble in cell culture media for in vitro applications. |
| Vial Size | 1 mg |
| Storage (Lyophilized) | -20°C or below, protected from light and moisture. Desiccated storage is recommended. |
| Storage (Reconstituted) | Aliquoted and stored at -20°C or -80°C. Avoid repeated freeze-thaw cycles. For short-term use, may be stored at 2-8°C for up to 7 days. |
| Typical Research Dose | Not established for humans. In rodent research, equivalent doses range from approximately 50-5000 mcg/kg. |
| Cycle Parameters | Not established for humans. Preclinical research protocols vary widely, including single acute doses, daily injections for 1-4 weeks, or chronic administration via osmotic minipumps over several weeks. |
| Amino Acid Count | 24 |
Mechanism of Action
Humanin exerts its cytoprotective effects through a complex, multi-pathway mechanism that involves both extracellular receptor-mediated signaling and intracellular actions. Its primary mode of action is believed to be through binding to specific cell-surface receptors, which then activate pro-survival signaling cascades. These pathways converge to inhibit apoptosis, reduce oxidative stress, and improve cellular metabolism.
Formyl Peptide Receptor 2 (FPR2) Interaction: Humanin binds to and signals through FPR2 (also known as FPRL1), a G-protein coupled receptor. This interaction activates downstream effectors including STAT3, Akt, and ERK1/2, leading to enhanced cell survival and suppression of inflammatory responses.
Cytokine Receptor Complex (CNTFR/WSX-1/gp130): Humanin can also signal through a tripartite receptor complex comprising ciliary neurotrophic factor receptor (CNTFR), WSX-1, and gp130. This JAK/STAT pathway activation is crucial for its neuroprotective and metabolic effects, particularly in neuronal and pancreatic beta-cells.
Inhibition of Apoptotic Signaling: Humanin directly interacts with and inhibits pro-apoptotic proteins. It binds to BAX, preventing its translocation to mitochondria and subsequent cytochrome c release. It also inhibits the activity of pro-apoptotic IGFBP-3 and BIM, further blocking the intrinsic apoptotic pathway.
Enhancement of Cellular Metabolism and Reduction of Oxidative Stress: Humanin upregulates cellular defense mechanisms against oxidative damage. It increases the expression of antioxidant enzymes and improves mitochondrial function, including ATP production. It also appears to modulate insulin-like signaling pathways, contributing to improved metabolic homeostasis.
Research Applications
Neuroprotection and Cognitive Decline: Research indicates Humanin and its analogs protect neurons from toxicity associated with Alzheimer's disease (AD) pathologies, including amyloid-beta and mutant APP. Studies in transgenic AD mouse models show improved cognitive performance and reduced neuronal loss. It also demonstrates protective effects in models of Parkinson's disease and Huntington's disease, suggesting a broad role in neurodegenerative conditions.
Metabolic Regulation and Diabetes: Humanin improves insulin sensitivity and protects pancreatic beta-cells from apoptosis. In rodent models of type 2 diabetes, Humanin treatment reduces blood glucose levels, improves glucose tolerance, and enhances beta-cell survival. It is considered a novel link between mitochondrial function and systemic metabolism.
Cardiovascular Protection: Preclinical studies show Humanin protects cardiomyocytes from ischemia/reperfusion injury and apoptosis. It reduces infarct size in models of myocardial infarction and improves cardiac function, potentially through its anti-apoptotic and anti-inflammatory actions.
Aging and Age-Related Diseases: Circulating levels of Humanin correlate inversely with age and age-related diseases. Research explores its role as a longevity factor, with studies showing it extends lifespan in model organisms and protects against various age-associated cellular dysfunctions, including sarcopenia and vascular aging.
Safety & Side Effects
The safety profile of Humanin in humans is unknown as it has not been evaluated in clinical trials. In animal studies (primarily rodents), no significant adverse effects or toxicity have been reported at the research doses used. Anecdotal reports from the research chemical community are extremely limited and not scientifically validated. Theoretical concerns based on its mechanism include the potential for interfering with normal apoptotic processes necessary for tissue homeostasis or immune cell function. Its interaction with inflammatory pathways via FPR2 also warrants careful investigation for potential immunomodulatory side effects.
Dosage Information
This information is derived solely from preclinical animal research and in vitro studies. There is no established human dosing protocol. In rodent research, typical doses range from 0.05 to 5 mg/kg of body weight. Common routes of administration in studies include intraperitoneal (IP) injection, subcutaneous (SC) injection, and intracerebroventricular (ICV) infusion for central nervous system studies. Dosing frequency in chronic models often involves daily or every-other-day administration. Treatment duration in published studies varies from single acute doses to chronic administration over several weeks, depending on the disease model being investigated.
References
Hashimoto, Y., et al. (2001). A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proceedings of the National Academy of Sciences, 98(11), 6336-6341.nMuzumdar, R. H., et al. (2009). Humanin: a novel central regulator of peripheral insulin action. PLoS One, 4(7), e6334.nYen, K., et al. (2013). The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging, 5(8), 592-598.nZhai, D., et al. (2005). Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. Journal of Biological Chemistry, 280(16), 15815-15824.nIkonen, M., et al. (2003). Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proceedings of the National Academy of Sciences, 100(22), 13042-13047.nLee, C., et al. (2013). The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metabolism, 21(3), 443-454.nTajima, H., et al. (2002). Evidence for in vivo production of Humanin peptide, a neuroprotective factor against Alzheimer's disease-related insults. Neuroscience Letters, 324(3), 227-231.