Humanin: Research in Neuroprotection, Cardioprotection, and Retinal Health

Humanin, a naturally occurring micro-peptide, appears to possess unique characteristics as research indicates the peptide may be encoded in the mitochondrial DNA, which is considered to be exclusively present in mitochondria. This peptide appears to exert its biological functions as a cytoprotective protein, as researchers have suggested its potential to shield cells from the intricate process of apoptosis, also known as programmed cell death. This protective mechanism may possibly be accomplished through the disruption of the normal functionality of the Bcl2-associated X protein (Bax).⁽¹⁾ Extensive research has posited the vital role of Humanin in safeguarding neurons, cardiac tissue, muscle cells, the retinal structures of the eye, and the endothelial lining of blood vessels.

What is the mechanism by which Humanin exerts its potential?

Research has suggested that both Humanin and Aβ42 may be likely to activate the G protein-coupled formylpeptide-like-1 receptor (FPRL1), potentially serving as chemoattractants for monocytes and activating microglia. However, Humanin appears to prevent the intracellular accumulation of Aβ42. Furthermore, Humanin has been suggested by research teams to directly interact with FPRL1 and FPRL2 receptors, as well as STAT signaling, indicated its potential multifaceted engagement in cellular processes. Different cell types may employ distinct receptors to respond to Humanin, with phagocytic cells appearing to express FPRL1 and FPRL2 receptors while neurons may utilize other receptors.

In addition to receptor-mediated pathways, Humanin may possibly interact with Aβ directly and potentially alter the structure of Aβ aggregates. Notably, Humanin may exhibit divergent action on insulin/IGF signaling depending on the tissue type, possibly enhancing signaling in primary mouse neurons but potentially showing differential action in the mouse heart. 

The Reed laboratory has hypothesized the peptide’s possible interaction with key pro-apoptotic proteins, such as BAX, tBID, and BimEL, possibly inhibiting downstream signaling and preventing apoptosis. While discrepancies exist in the literature, likely due to variations in cell types and experimental conditions, these findings collectively suggest the diverse and intricate mechanisms by which Humanin demonstrates a degree of protective potential.⁽²⁾

 

Research Studies on Humanin Peptide

Humanin Peptide and Neuroprotection

Data from rat studies suggests that Humanin may exhibit protective effects against programmed cell death, extending beyond apoptosis. Researchers also posit that Humanin may also safeguard neurons in the context of neurodegenerative disorders, counteracting cell death induced by the accumulation of beta-amyloid plaques.⁽³⁾ Furthermore, research has indicated that Humanin may protect against excitotoxic neuronal death induced by NMDA pulses.⁽⁴⁾

Similar findings were observed when investigating neuronal death associated with prion disease.⁽⁵⁾ These discoveries indicate that Humanin may slow down or even halt the progression of neurodegenerative disorders. These studies observe that “amyloidogenic peptides can induce prolonged activation of proapoptotic marker expression in cultured neurons even at sublethal concentrations. These effects could contribute to chronic neuronal dysfunction and increase susceptibility to additional metabolic insults in neurodegenerative disorders. If so, targeting of therapeutic strategies against neuronal caspase activation early in the disease course could be beneficial in AD and prion diseases.”⁽⁶⁾

Studies report that Humanin appears to potentially safeguard neurons through two distinct mechanisms, both aimed at preventing the activation of the apoptosis pathway within mitochondria. Normally, the Bcl-2 family of proteins signals the release of proteins from the mitochondrial membrane, initiating a cascade involving caspases that orchestrate the regulated destruction and recycling of cells. Although this process is considered to be essential in various contexts, such as during viral invasions, dysregulation may occur in certain disease conditions, leading to uncontrolled and widespread cell death. Humanin appears to bind to Bcl-2 stimulating proteins Bid and tBid, potentially impeding their function and blocking the initiation of the apoptosis pathway.⁽⁷⁾

Studies also suggest that astrocytes may release Humanin to probably protect synapses in hippocampal neurons.⁽⁸⁾ It is speculated that, similar to many natural regulatory processes, the function of Humanin may decline with age, potentially contributing to age-related memory loss and increased susceptibility to neurodegenerative diseases in certain laboratory test models.

Humanin Peptide and Cardioprotection

Studies have shed light on the expression and protective potential of Humanin in vasculature, suggesting it may be present in the walls of blood vessels, possibly playing a crucial role in safeguarding these vessels from the detrimental impact of oxidized low-density lipoprotein (LDL) cholesterol. Specifically, studies suggest that Humanin may intervene in the process of LDL oxidation and may inhibit the production of reactive oxygen species (free radicals) in response to this oxidative stress. By doing so, Humanin is suggested to reduce reactive oxygen species levels in the vasculature by 50% and concomitantly decreases apoptosis by 50% as well.⁽⁹⁾

Moreover, it has been indicated that Humanin levels may decline with age, and emerging research suggests that certain disease states may also impact the levels of this micro-peptide. Cardiology researchers have long sought to identify blood markers that can quantitatively assess mitochondrial function in the context of cardiovascular dysfunction. Such markers are critical in evaluating the health status of test models with heart disease, providing insight into tissue ischemia severity, disease progression, and aiding in determining the need for intervention. Research conducted in Russia indicates that Humanin levels may serve as a promising marker in this regard, as they appear to decline proportionally with the severity of cardiovascular disease.⁽¹⁰⁾

Humanin Peptide and Retinal Health

The retinal pigment epithelium (RPE) is a specialized layer of cells in the retina that serves various crucial functions, including light absorption, scattering, and blood component filtration, as well as maintaining the immune-privileged status of the inner eye. Recent research has proposed the probable significance of Humanin in the RPE, highlighting its possible role in reducing oxidative stress within this ocular tissue. In cell culture experiments, supplementation with Humanin appears to enhance RPE functionality and enhance its resilience against apoptosis, the programmed cell death.⁽¹¹⁾

Humanin Peptide and IGF-1 Interaction

A recent study has uncovered a possible interaction between Humanin and insulin-like growth factor 1 (IGF-1). It has been suggested that these two peptides may influence each other, with Humanin possibly exerting a down-regulatory effect on the circulating levels of IGF-1, while IGF-1 possibly influences the levels of Humanin. The precise mechanism underlying this interaction remains to be fully elucidated, but the existing data suggests that Humanin plays a novel and potentially significant role in the signaling of IGF-1. Notably, these peptides may exhibit synergistic effects, working in conjunction to inhibit apoptosis, possibly enhance insulin sensitivity, probable mitigation of inflammation, and potential protection against specific forms of heart disease. Conversely, in certain scenarios, the peptides may act antagonistically. Scientists state that “although the exact mechanism for how Humanin and IGF-I regulate each other still needs to be elucidated, it is clear that Humanin is a new player in IGF-I signaling.”⁽¹²⁾

Humanin Peptide and Bone Health

Research suggests Humanin may exhibit the ability to prevent chondrocyte death, chondrocyte cells being considered responsible for producing the collagen matrix crucial for bone formation. Humanin is believed to exhibit potential to achieve this effect, possibly without compromising the anti-inflammatory properties of glucocorticoids, such as dexamethasone.⁽¹³⁾ This action appears to promote the growth of bone and cartilage, counteracting the accelerated bone loss triggered by glucocorticoids. Concurrently, Humanin appears to suppress the formation of osteoclasts, the cells responsible for bone resorption and remodeling. Although osteoclasts are considered to play a vital role in regulatory physiological processes, their excessive activation in pathological conditions is believed to cause severe bone loss. By inhibiting osteoclast formation, researchers indicate Humanin may help to mitigate excessive bone remodeling and subsequent bone loss.⁽¹⁴⁾

Synopsis

Researchers consider Humanin to be a naturally occurring micro-peptide encoded in mitochondrial DNA, that appears to play a possible role in cell protection through apoptosis prevention and preserving the viability of neurons, cardiac tissue, muscle cells, retinal tissue, and blood vessels. Studies suggest the peptide may exhibit diverse mechanisms, including interactions with apoptosis-related proteins and modulation of insulin/IGF signaling, making it a compelling subject for further investigations and studies. 

 
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References:

1. Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. FASEB J. 2002 Aug;16(10):1331-3. doi: 10.1096/fj.02-0018fje. Epub 2002 Jun 21. PMID: 12154011. https://pubmed.ncbi.nlm.nih.gov/12154011/ 
2. 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. doi: 10.1530/JME-12-0203. PMID: 23239898; PMCID: PMC3705736. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705736/ 
3. Matsuoka M. Humanin; a defender against Alzheimer’s disease? Recent Pat CNS Drug Discov. 2009 Jan;4(1):37-42. doi: 10.2174/157488909787002609. PMID: 19149712. https://pubmed.ncbi.nlm.nih.gov/19149712/ 
4. Caricasole A, Bruno V, Cappuccio I, Melchiorri D, Copani A, Nicoletti F. A novel rat gene encoding a Humanin-like peptide endowed with broad neuroprotective activity. FASEB J. 2002 Aug;16(10):1331-3. doi: 10.1096/fj.02-0018fje. Epub 2002 Jun 21. PMID: 12154011. https://pubmed.ncbi.nlm.nih.gov/12154011/ 
5. Xu X, Chua CC, Gao J, Chua KW, Wang H, Hamdy RC, Chua BH. Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. Brain Res. 2008 Aug 28;1227:12-8. doi: 10.1016/j.brainres.2008.06.018. Epub 2008 Jun 16. PMID: 18590709; PMCID: PMC2575816. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575816/ 
6. White AR, Guirguis R, Brazier MW, Jobling MF, Hill AF, Beyreuther K, Barrow CJ, Masters CL, Collins SJ, Cappai R. Sublethal concentrations of prion peptide PrP106-126 or the amyloid beta peptide of Alzheimer’s disease activates expression of proapoptotic markers in primary cortical neurons. Neurobiol Dis. 2001 Apr;8(2):299-316. doi: 10.1006/nbdi.2001.0386. PMID: 11300725. https://pubmed.ncbi.nlm.nih.gov/11300725/ 
7. Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC, Reed JC. Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem. 2005 Apr 22;280(16):15815-24. doi: 10.1074/jbc.M411902200. Epub 2005 Jan 20. PMID: 15661737. https://pubmed.ncbi.nlm.nih.gov/15661737/ 
8. Zárate SC, Traetta ME, Codagnone MG, Seilicovich A, Reinés AG. Humanin, a Mitochondrial-Derived Peptide Released by Astrocytes, Prevents Synapse Loss in Hippocampal Neurons. Front Aging Neurosci. 2019 May 31;11:123. doi: 10.3389/fnagi.2019.00123. PMID: 31214013; PMCID: PMC6555273. https://pubmed.ncbi.nlm.nih.gov/31214013/ 
9. Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P, Lerman A. Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res. 2010 Nov 1;88(2):360-6. doi: 10.1093/cvr/cvq191. Epub 2010 Jun 18. PMID: 20562421; PMCID: PMC2952532. https://pubmed.ncbi.nlm.nih.gov/20562421/ 
10. Cai H, Liu Y, Men H, Zheng Y. Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases. Front Endocrinol (Lausanne). 2021 Jun 10;12:683151. doi: 10.3389/fendo.2021.683151. PMID: 34177809; PMCID: PMC8222669. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222669/ 
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12. Xiao J, Kim SJ, Cohen P, Yen K. Humanin: Functional Interfaces with IGF-I. Growth Horm IGF Res. 2016 Aug;29:21-27. doi: 10.1016/j.ghir.2016.03.005. Epub 2016 Apr 7. PMID: 27082450; PMCID: PMC4961574. https://pubmed.ncbi.nlm.nih.gov/27082450/ 
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