Studies suggest that Humanin is a micropeptide encoded by DNA supposedly only in mitochondria (mitochondria have a very limited quantity of DNA for encoding proteins). Research suggests it may function as a cytoprotective protein, potentially preventing apoptosis (programmed cell death) through inhibiting Bcl2-related X protein (Bax) activity. The study's authors speculate Humanin "blocks the movement of Bax from the cytoplasm to the mitochondria." In contrast, findings imply that downregulating Humanin expression using siRNAs may make cells more Bax-sensitive and boost Bax membrane localization. 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.
Humanin Peptide Research and Studies
Micropeptides do not appear to be altered in any way after creation as they are encoded via a short open reading frame (sORF). Numerous sORFs between 100 and 150 amino acids in length have been found in organisms [i]. Investigations purport that they may help with mRNA processing, DNA damage repair, and the assembly of large macro-proteins via interactions with other proteins, among many other tasks. Humanin, one of the shortest known micropeptides, consists of only 24 amino acids. Researchers speculate that apoptosis regulation seems to occur via its interaction with the Bcl2-related X protein (Bax), which may be inhibited to spare cells that would otherwise be killed.
Humanin Peptide and Neuroprotection Studies
Micropeptides have shown potential in protecting neurons against Alzheimer's disease and halting cell death brought on by beta-amyloid deposits in rat models [ii]. Their study suggested that "HN exhibits multiple intracellular and extracellular anti-cell death actions and antagonizes various AD-associated pathomechanisms, including amyloid plaque accumulation."
Experiments using NMDA pulses have also suggested that peptides may protect neurons from death. Scientists hypothesize that Alzheimer's disease and other kinds of dementia may be slowed through such a process. Normal cell death and recycling are coordinated by Bcl2 family proteins signaling the release of proteins from mitochondrial membranes, activating caspases. This technique has several real-world applications, including limiting the spread of infection by destroying just a fraction of the invading virus's host cells.
Unfortunately, the process may become dysregulated under some circumstances, leading to widespread unsuppressed cell death. Studies suggest that the Bcl2-stimulating proteins Bid and tBid seem to be bound by Humanin, inhibiting their activity. This might prevent the apoptotic process from commencing.
Humanin Peptide and IGF-1
New research from the University of Southern California suggests that Humanin and insulin-like growth factor 1 (IGF1) may impact natural Humanin levels [iii]. 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 [iv]. Data suggests that it may 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. Important for estimating tissue ischemia and disease development and knowing when to treat, it is a key indicator of cardiac overall health. A drop in Humanin levels may be an effective predictor of cardiovascular disease severity, as Russian research suggested.
Humanin Peptide and the Retina
The layer of the retina responsible for vision is called the retinal pigment epithelium (RPE). It helps 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. Age-related macular degeneration, diabetic retinopathy, and other prevalent, severe eye disorders all cause damage to the RPE.
New research suggests that Humanin may play a key role in RPE by decreasing oxidative stress [v]. Findings imply that Humanin may enhance RPE function and boost tissue resilience to apoptosis when cultured in vitro.
Humanin Peptide and Bones
Loss of bone density is a common age-related health problem. It is considered to be an end result of several phsyiological issues. The most notorious gamblers within the latter group are glucocorticoids employed with severe inflammation (including autoimmune inflammation). When exposed for extended durations, they might cause severe bone loss.
Investigations purport that Humanin may help bones in two separate ways, as suggested by theories put forward by researchers in Sweden and South Korea [vi]. Dexamethasone and other glucocorticoids are often employed with inflammation, but they may also kill chondrocytes (the cells that create the collagen matrix from which bones are constructed). This would have the opposite effect of the increased bone loss produced by glucocorticoids and, instead, promote the formation of bone and cartilage. Humanin seems to be able to inhibit osteoclast formation while simultaneously fostering chondrocyte growth. Bone resorption and remodeling are processes triggered by osteoclasts. In pathological situations, when they serve a crucial physiological purpose, their overactivation leads to devastating bone loss. Researchers speculate that Humanin may potentially inhibit the development of osteoclasts, hence decreasing the bone remodeling and loss rate.
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References
[i] Sousa ME, Farkas MH. Micropeptide. PLoS Genet. 2018 Dec 13;14(12):e1007764. doi: 10.1371/journal.pgen.1007764. PMID: 30543625; PMCID: PMC6292567.
[ii] 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.
[iii] 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.
[iv] 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.
[v] 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.
[vi] 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.