Humanin – A Novel Mitochondrial Derived Peptide
Mitochondria, the powerhouse of the cell, is formed due to the engulfment of individual prokaryotes. The eukaryotes, at some point, engulf the prokaryotic (single celled) organism where the prokaryotes form an endosymbiotic relation with the host cell and gradually develop into mitochondria (1).
Mitochondria is known to be responsible for several vital cellular activities including production of energy, regulation of apoptosis, hemostasis, and formation of heme proteins, among several other functions. All these functions are regulated by mitochondria via its communications to the cell through several retrograde signals. These signals are encoded by the nuclear genome present in the mitochondria due to its prokaryotic origin (2).
A small peptide is derived from this genome called Humanin. Since this genome plays such an important role, this peptide has been explored for its role in several ailments including cancer, diabetes, and neurodegeneration.
What is Humanin?
Humanin is a short natural peptide with proven effects on cell metabolism, survival, and inflammation responses (3).
A mitochondrial genome called ‘16S ribosomal RNA gene’ is known to encode the Humanin peptide (4).
The length of the peptide is dependent on the location of its synthesis. The peptide contains 21 amino acids if synthesized inside the mitochondria; whereas it contains 24 amino acids if synthesized outside mitochondria but inside the cytosol (5). Both of these peptides have proven biological activity.
Discovery of the Peptide
Humanin was recently discovered in the early 2000s (6) by three different laboratories while all were studying different aspects.
During the research for cytoprotective proteins that could help prevent Alzheimer’s disease, The Nishimoto lab discovered Humanin (4).
While searching for proteins that could interact with immunoglobulin, the second lab – Pinchas Cohen lab – discovered the peptide (7).
Lastly, the Reed lab found the peptide when searching for proteins that would interact with chemicals involved in apoptosis (8).
How Does Humanin Act in the Body?
The peptide exerts its different functions via binding with intracellular molecules and cell membrane receptors, and thereby induce cytoprotective and neuroprotective functions (9).
Humanin binds with the Bcl-2 associated X protein (also called Bax protein). Bax protein plays a vital role in cellular death (apoptosis) process. Upon binding with the inactive form of the Bax protein, Humanin inhibits the changes in the Bax protein and thereby prevents cellular apoptosis(9).
Besides Bax, Humanin also binds with other intracellular molecules such as actinin-4 and phosphoprotein 8, which are both involved in cellular apoptosis. Upon binding with these proteins, Humanin induces cytoprotective actions.
Humanin binds with two G protein coupled peptide receptors namely FPRL-1 and FPRL-2 receptors. Both these receptors are functionally involved in the pathophysiology of Alzheimer’s disease (9).
By binding with this receptor, Humanin prevents amyloid β to bind with the FPRL-1 and FPRL-2 receptors, which thereby prevents the occurrence of Alzheimer’s. This exhibits the neuroprotective properties of the peptide.
What Are the Health Benefits of Humanin?
The main health benefits of the peptide include:
- Enhances the functioning of mitochondria
- Cytoprotective ability – protects the cell from dying
- Increased longevity
- Improved short term memory
- Treatment of Alzheimer’s disease
- Combats neurotoxicity
- Prevents insulin resistance
- Prevents obesity
- Protection against hypoxia and ischemia
- Protects cardiovascular system
- Colon protection
- Anxiety relief
- Prevents damages induced by chemotherapy
Research and Clinical Studies
Enhancement of Mitochondrial Functions
Mitochondria is very susceptible towards reactive oxygen species (ROS) which reduces its functioning. Humanin causes inhibition of these reactive oxygen species and thereby prevents the mitochondria from dying (10).
This was confirmed through a study(10) where the retinal pigment epithelial cells were isolated and treated with 150 microM tert-butyl hydroperoxide to exert oxidative stress in the cells. Some of these cells were treated with 0.5 to 10 microg/mL of Humanin for 24 hours.
When examined, the Humanin treated cells demonstrated inhibited formation of tert-butyl hydroperoxide induced reactive oxygen species. This restored the bioenergetics in the retinal pigment epithelial cells and increased the functioning of mitochondria.
Increased Cellular Longevity
Studies (11) were conducted on several mice models to determine the relation between Humanin with growth hormone (GH) and immunoglobulin (IGF-1).
In the GH-transgenic mice, the levels of growth hormones and IGF-1 are extremely high, which leads to an increased size of the body, accelerated aging, and reduced life span. The levels of Humanin were extremely low by 70% in this model.
In the other model of Ames mice, they consisted of mutated prop-1 gene, which had undetectable levels of GH and IGF-1, along with 40% increase in the Humanin levels. These mice showed an increased life span compared to normal mice.
This determines that Humanin is negatively correlated to GH and IGF-1 levels and directly correlates to cellular longevity.
Treatment of Alzheimer’s Disease
A study (12) was conducted where a 9-month-old mice model was employed, which already possessed high levels of amyloid proteins. These amyloid chemicals are indicative of Alzheimer’s disease.
While some of these mice were treated with Humanin and the others were treated with placebo.
After the studies, it was found that the vehicle-treated mice still showed impaired memory and poor learning skills, whereas the mice treated with Humanin for 3 months showed significantly improved learning ability and enhanced memory.
This was indicative that Humanin can be used as a therapeutic agent to prevent Alzheimer’s disease.
In another study (13), experimentally induced mice with impaired memory were treated with Humanin and a similar peptide called PAGA, at the dose of 0.2 micromol/kg via intraperitoneal route. Both the peptides revered the impairment of the memory.
Prevention of Insulin Resistance and Weight Gain
In order to determine whether Humanin can help postpone or treat diabetes, a study (14) was conducted on nonobese diabetic mice. In these mice, on treatment with Humanin, it restored the levels of glucose tolerance within 6 weeks of treatment. Furthermore, Humanin treatment also delayed the onset of diabetes in the mice treated for 20 weeks. This suggests that Humanin may be fruitful in the future to treat or possibly prevent diabetes in humans.
In another study (15), 12-week-old mice were subjected to a 60% high fat diet and were administered with 2mg/kg Humanin dose via intraperitoneal route for 4 weeks. After the treatment, there was no difference in the food intake, however, the body weight gain had reduced by about 20%. Furthermore, there was a high expenditure of energy and decreased levels of fasting glucose, in addition to increased insulin levels. This event suggested that the peptide helps prevent the accumulation of high fats (due to increased energy expenditure) and prevents body weight gain.
Role in Hypoxia and Ischemia
A study (16) was conducted where the isolated retinal cells were treated with cobalt chloride, which induces hypoxia leading towards cell apoptosis. When the hypoxia induced cells were treated with Humanin, the peptide would reverse the effects of cobalt chloride and protect the cell from reduced oxygen levels.
Also, studies (17) have shown that Humanin is capable of increasing the metabolic activity and thereby the cell survival rates, in the event of death of lymphocytes. This suggests that Humanin can potentially be used in the treatment of poor metabolism and brain ischemia.
Potential Treatment for Stroke
This study (18) was conducted to further examine the neuroprotective effects of Humanin in the presence of cerebral ischemia.
As a part of this study, mice were experimentally induced with cerebral artery occlusion. Mice were pretreated with 0.1 microg Humanin for 30 minutes via intracerebroventricular route and then also post-treated with 1 microg Humanin at 0, 2, 4 and 6 hours after ischemia via intraperitoneal route. Other mice were solely treated with 1 microg Humanin 1 hour prior to ischemia.
It was noted that pretreatment with 0.1-1 microg of peptide reduced the ischemia volume by almost 30%. Posttreatment with the peptide further reduced the ischemic effects. This study shows that Humanin can protect against cerebral ischemia and thereby can potentially be used to treat stroke.
Potential Treatment for Anxiety
Studies(19) have shown that Humanin binds with the FPR2 receptor in the brain which leads to producing anxiolytic effects. Consequently, Humanin has shown to relieve anxiety and prevent a benzodiazepine induced memory impairment and anxiety.
Potential Treatment for Cancer
In this study (20), carcinogenic mice were induced with 2 injections per week for Bortezomib (0.8 to 1 mg/kg) and for Humanin (1 microg). Bortezomib is a relatively new medication currently being studied for childhood factors.
While Bortezomib induced cell apoptosis, Humanin and Bortezomib co treatment was fully effective, and it reversed the apoptosis of the healthy cells. This study shows that Humanin is able to protect the cells from the harmful effects of chemotherapeutic agent and prevent carcinogenesis.
What Regulates the Levels of Humanin?
Below listed are the factors that either increase or decrease the concentrations of Humanin the human body.
Which Factors Increase the Humanin Concentration?
- Exercise and fasting: Owing to suppressed levels of immunoglobulin
- Supplements such as vitamins
- Medications such as Humanin G (same as Humanin, only one change in one of the terminals)
Which Factors Decrease the Humanin Concentration?
- Increased age
- Increased levels of hydrogen peroxide
- Increased levels of immunoglobulin and growth hormone
What are the Limitations of Humanin?
Humanin is an endogenous peptide and is tolerated in the subject. Until now, no major side effects of the peptide are known. As research is still ongoing, the limitations in humans are yet to be determined.
Some of the commonly known side effects of the peptides include, but not limited to:
- Pain at the site of administration
Humanin is an endogenous one-of-a-kind peptide that is derived from the mitochondrial genome. Humanin consists of 21 to 24 amino acids, depending on its location of synthesis.
It primarily acts by either binding with the intracellular or extracellular receptors of the body and thereby exerting its neuroprotective and cytoprotective effects. Humanin has shown to play a vital role in the inhibition of diseases such as ischemia and Alzheimer’s, in addition to various other health benefits including prevention of cellular apoptosis, increased longevity, and reduced insulin resistance.
While research so far has shown extremely promising results upon Humanin administration, clinical trials on Humanin are still pending, given that the peptide was recently discovered about 15 to 20 years ago. Clinical trials are in process to fully explore the profile of this peptide and thereby potentially establish its use as a therapeutic agent in treating frequently occurring neuro disorders.
1. The origin of mitochondria and chloroplasts. https://www.nature.com/scitable/content/the-origin-of-mitochondria-and-chloroplasts-14747702/
2. Lee, Changhan et al. “Humanin: a harbinger of mitochondrial-derived peptides?.” Trends in endocrinology and metabolism: TEM vol. 24,5 (2013). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3641182/
3. Gong, Zhenwei et al. “Humanin and age-related diseases: a new link?.” Frontiers in endocrinology vol. 5 210. 4 Dec. 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255622/
4. Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci U S A. 2001 May 22;98(11):6336-41. https://pubmed.ncbi.nlm.nih.gov/11371646/
5. Yen K, Lee C, Mehta H, Cohen P. The emerging role of the mitochondrial-derived peptide humanin in stress resistance. J Mol Endocrinol. 2013 Jan 11;50(1):R11-9. https://pubmed.ncbi.nlm.nih.gov/23239898/
6. Gong, Zhenwei et al. “Humanin and age-related diseases: a new link?.” Frontiers in endocrinology vol. 5 210. 4 Dec. 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255622/
7. Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC. Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature. 2003 May 22;423(6938):456-61. https://pubmed.ncbi.nlm.nih.gov/12732850/
8. Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P. Interaction between the Alzheimer’s survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13042-7. https://pubmed.ncbi.nlm.nih.gov/14561895/
9. Gong, Zhenwei et al. “Humanin and age-related diseases: a new link?.” Frontiers in endocrinology vol. 5 210. 4 Dec. 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255622/
10. Sreekumar PG, Ishikawa K, Spee C, Mehta HH, Wan J, Yen K, Cohen P, Kannan R, Hinton DR. The Mitochondrial-Derived Peptide Humanin Protects RPE Cells From Oxidative Stress, Senescence, and Mitochondrial Dysfunction. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1238-53. https://pubmed.ncbi.nlm.nih.gov/26990160/
11. Changhan Lee et al, IGF-I regulates the age-dependent signaling peptide humanin. Published 18 July 2014, Vol 13 Issue 5. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12243
12. Zhang W, Zhang W, Li Z, Hao J, Zhang Z, Liu L, Mao N, Miao J, Zhang L. S14G-humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice. Pharmacol Biochem Behav. 2012 Jan;100(3):361-9. https://pubmed.ncbi.nlm.nih.gov/21993310/
13. Krejcova G, Patocka J, Slaninova J. Effect of humanin analogues on experimentally induced impairment of spatial memory in rats. J Pept Sci. 2004 Oct;10(10):636-9. https://pubmed.ncbi.nlm.nih.gov/15526713/
14. Hoang PT, Park P, Cobb LJ, Paharkova-Vatchkova V, Hakimi M, Cohen P, Lee KW. The neurosurvival factor Humanin inhibits beta-cell apoptosis via signal transducer and activator of transcription 3 activation and delays and ameliorates diabetes in nonobese diabetic mice. Metabolism. 2010 Mar;59(3):343-9. https://pubmed.ncbi.nlm.nih.gov/19800083/
15. Zhenwei Gong et al, Central effects of humanin on hepatic triglyceride secretion, Endocrinology and Metabolism. https://journals.physiology.org/doi/full/10.1152/ajpendo.00043.2015
16. Men J, Zhang X, Yang Y, Gao D. An AD-related neuroprotector rescues transformed rat retinal ganglion cells from CoCl₂-induced apoptosis. J Mol Neurosci. 2012 May;47(1):144-9. doi: 10.1007/s12031-011-9701-5. Epub 2012 Jan 5. https://pubmed.ncbi.nlm.nih.gov/22222604/
17. Kariya S, Takahashi N, Hirano M, Ueno S. Humanin improves impaired metabolic activity and prolongs survival of serum-deprived human lymphocytes. Mol Cell Biochem. 2003 Dec;254(1-2):83-9. https://pubmed.ncbi.nlm.nih.gov/14674685/
18. Xu X, Chua CC, Gao J, Hamdy RC, Chua BH. Humanin is a novel neuroprotective agent against stroke. Stroke. 2006 Oct;37(10):2613-9. Epub 2006 Sep 7. https://pubmed.ncbi.nlm.nih.gov/16960089/
19. Zhao H, Sonada S, Yoshikawa A, Ohinata K, Yoshikawa M. Rubimetide, humanin, and MMK1 exert anxiolytic-like activities via the formyl peptide receptor 2 in mice followed by the successive activation of DP1, A2A, and GABAA receptors. Peptides. 2016 Sep;83:16-20. https://pubmed.ncbi.nlm.nih.gov/27475912/
20. Emma Eriksson, Malin Wickström, Lova Segerström Perup, John I. Johnsen, Staffan Eksborg, Per Kogner, Lars Sävendahl, Protective Role of Humanin on Bortezomib-Induced Bone Growth Impairment in Anticancer Treatment, JNCI: Journal of the National Cancer Institute, Volume 106, Issue 3, March 2014, djt459, https://doi.org/10.1093/jnci/djt459
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