Humanin is a special micropeptide since DNA encodes it only in mitochondria (mitochondria have a very limited quantity of DNA for encoding proteins). The Bcl2-related X protein (Bax) seems inhibited by this protein, which may prevent cells from undergoing apoptosis (programmed cell death). Researchers speculate that Humanin "inhibits the translocation of Bax from the cytosol to mitochondria" [i]. Instead, cells may possibly become more Bax-sensitive when Humanin expression is downregulated using short interfering RNAs. Neurons, cardiac tissue, muscle cells, the retina, and the lining of blood vessels are all vulnerable to damage, and research suggests that Humanin may have a role in defending against this.

What are Micro-Peptides?

Micro-peptides are not altered in any way after they have been created since they are encoded via a short open reading frame (sORF). Most sORFs are between 100 and 150 amino acids in length.[ii] Interacting with other proteins, they facilitate mRNA processing, repair DNA damage, and assemble complex macro-proteins. One of the shortest micropeptides discovered to date is Humanin, which clocks in at only 24 amino acids. Research suggests that it seems to control apoptosis by interacting with the Bcl2-related X protein (Bax) and, if required, possibly blocking Bax activity to protect cells.

Humanin Peptide and the Brain

Animal research on Alzheimer's disease suggests that micro-peptides may shield neurons from the toxicity of beta-amyloid plaques and possibly save cells from dying.[iii] Researchers have hypothesized that "HN exhibits multiple intracellular and extracellular anti-cell death actions and antagonizes various AD-associated pathomechanisms, including amyloid plaque accumulation." 

Further research suggests that peptides may protect neurons from excitotoxic NMDA spikes. Findings imply that Alzheimer's disease and other kinds of dementia may be slowed or stopped if Humanin can perform this role. Typically, Bcl2 family proteins activate caspases and coordinate the orderly death and recycling of cells by signaling the release of proteins from mitochondrial membranes. This technique has several real-world applications, including limiting the spread of an infection by destroying just a fraction of the invading virus's host cells. Unfortunately, in some circumstances, dysregulation of the process may cause widespread unsuppressed cell death. Investigations purport that Humanin may possibly bind to Bid and tBid, two proteins that stimulate Bcl2 and inhibit their activity. By doing this, it may stop the apoptotic process where it begins.

Humanin Peptide and IGF-1 Peptide

Humanin and insulin-like growth factor 1 (IGF1) have been linked in new research from the University of Southern California to altering natural Humanin levels and decreasing circulating levels of IGF1 and IGF1.[iv] Peptides have been suggested to synergistically affect apoptosis, insulin sensitivity, inflammation, and cardiovascular disease protection.

Humanin Peptide and the Heart

Research conducted at the Mayo Clinic suggests that Humanin may be expressed on the lining of blood vessels, which might block the formation of free radicals caused by LDL oxidation.[v] Data suggests that it could cut apoptosis in half and lower active oxygen species in the cardiovascular system by 50%. Researchers in the field of cardiology have been looking for blood markers to measure mitochondrial activity in cardiovascular illness for quite some time. Humanin levels may be useful as a measure of cardiovascular disease severity, as research suggested.

Humanin Peptide and Retinal Conditions

The retina layer responsible for vision is the retinal pigment epithelium (RPE). Researchers speculate that it may help filter blood components before they reach the retina, where they may absorb and scatter light. Most importantly, it lays the groundwork for understanding the nature of immunological privilege inside the eye. Many significant eye disorders, such as age-related macular degeneration and diabetic retinopathy, cause damage to the retinal pigment epithelium (RPE). Recent research suggests that Humanin could be a significant component of RPE and may lower oxidative stress in this tissue.[vi] Findings imply that adding Humanin to cell culture might enhance RPE function and decrease apoptosis in cultured RPE cells. 

Humanin Peptide and Bone Nutrition

Bone loss is considered to result from a variety of conditions. The most notorious culprits which may possibly onset such bone loss are glucocorticoids, which are typically to mitigate severe inflammation (including autoimmune inflammation). When exposed to such compounds for extended durations, they might cause bone loss. Humanin has been theorized to possibly help bones in two distinct ways by researchers in Sweden and South Korea.[vii] 

Initially, it was proposed that micropeptides may stop the death of chondrocytes (cells that generate the collagen matrix from which bones are constructed) without interfering with the anti-inflammatory actions of glucocorticoids like dexamethasone. As a result, bone and cartilage formation would be stimulated, mitigating some of the rapid bone loss brought on by glucocorticoids. Investigations purport that Humanin seems to have the capacity to inhibit osteoclast formation simultaneously as it stimulates the growth of chondrocytes. Bone resorption and remodeling are processes triggered by osteoclasts. The significant bone loss seen in pathological circumstances is caused by the overactivation of these cells, which are otherwise helpful and needed for normal physiologic function. Scientists hypothesize that Humanin may potentially mitigate abnormally high rates of bone remodeling and loss by inhibiting the development of osteoclasts.

Visit Core Peptides' website for more educational information, like the one in this article.

References

[i] 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. doi: 10.1038/nature01627. Epub 2003 May 4. PMID: 12732850.

[ii] Sousa ME, Farkas MH. Micropeptide. PLoS Genet. 2018 Dec 13;14(12):e1007764. doi: 10.1371/journal.pgen.1007764. PMID: 30543625; PMCID: PMC6292567.

[iii] Niikura T. Humanin and Alzheimer’s disease: The beginning of a new field. Biochim Biophys Acta Gen Subj. 2022 Jan;1866(1):130024. doi: 10.1016/j.bbagen.2021.130024. Epub 2021 Oct 7. PMID: 34626746.

[iv] 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.

[v] Qin Q, Mehta H, Yen K, Navarrete G, Brandhorst S, Wan J, Delrio S, Zhang X, Lerman LO, Cohen P, Lerman A. Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1127-H1136. doi: 10.1152/ajpheart.00685.2017. Epub 2018 Jul 13. PMID: 30004252; PMCID: PMC6415743.

[vi] Li Z, Sreekumar PG, Peddi S, Hinton DR, Kannan R, MacKay JA. The humanin peptide mediates ELP nanoassembly and protects human retinal pigment epithelial cells from oxidative stress. Nanomedicine. 2020 Feb;24:102111. doi: 10.1016/j.nano.2019.102111. Epub 2019 Oct 23. PMID: 31655204; PMCID: PMC7263384.

[vii] Kang N, Kim KW, Shin DM. Humanin suppresses receptor activator of nuclear factor-κB ligand-induced osteoclast differentiation via AMP-activated protein kinase activation. Korean J Physiol Pharmacol. 2019 Sep;23(5):411-417. doi: 10.4196/kjpp.2019.23.5.411. Epub 2019 Aug 26. PMID: 31496878; PMCID: PMC6717796.