Humanin (10mg)

Humanin Peptide

Humanin is an endogenously occurring unique peptide encoded by mitochondrial DNA. The peptide may exist in two different forms found in the cell: a 21 amino acid sequence found inside the cell’s mitochondria, and a 24 amino acid sequence found outside the cell’s cytosol. Both forms appear to act as cytoprotective proteins and may protect cells from the process of apoptosis (programmed cell death) by interfering with the operation of the Bcl2-related X protein (Bax).^[1]

Bax is considered a pro-apoptotic protein that promotes apoptosis by disrupting the mitochondrial outer membrane. It is believed to facilitate the release of cytochrome c from mitochondria into the cytosol, which then triggers a cascade of events leading to cell death. By interfering with Bax’s function, Humanin may help support the initiation of this apoptotic pathway. Researchers posit that Humanin may “[support] the translocation of Bax from the cytosol to mitochondria. Conversely, reducing Humanin expression by small interfering RNAs sensitizes cells to Bax and increases Bax translocation to membranes.”

Apart from research into its possible interaction with Bax, Humanin studies suggest the peptide may also bind with other intracellular molecules, such as actinin-4 and phosphoprotein 8, which are both involved in cellular apoptosis. Binding with these proteins is also thought to contribute to Humanin’s cytoprotective potential.^[2] Thus, studies suggest that Humanin may be important for protecting a variety of cells, most notably neurons. In addition, studies also suggest it may have a protective potential for cells in heart tissue, muscle cells, the retina of the eye, and the lining of blood vessels.

Specifications

Molecular Weight: 2687.3 g/mol

Molecular Formula: C₁₁₉H₂₀₄N₃₄O₃₂S₂

Sequence: Met-Ala-Pro-Arg-Gly-Phe-Ser-Cys-Leu-Leu-Leu-Leu-Thr-Ser-Glu-Ile-Asp-Leu-Pro-Val-Lys-Arg-Arg-Ala

Other Known Titles: formyl humanin, HNGF6A protein

Humanin Research

Humanin and Neurodegeneration Models

Murine experiments have suggested that Humanin (HN) may exert protective effects on nerve cells in Alzheimer’s models and potentially influence the formation of beta-amyloid plaques.[3] Scientists noted that “HN exhibits multiple intracellular and extracellular anti-cell death actions and antagonizes various AD-associated pathomechanisms including amyloid plaque accumulation.” Amyloid plaques are considered significant in Alzheimer’s models due to their composition of amyloid beta (Abeta).

This peptide is thought to contribute to nerve cell protection through interaction with two specific G protein-coupled peptide receptors: Formyl Peptide Receptor-Like 1 (FPRL-1) and Formyl Peptide Receptor-Like 2 (FPRL-2) — receptors believed to be expressed on neuronal cell surfaces and proposed to participate in neurological signaling pathways. By binding to FPRL-1 and FPRL-2, Humanin may reduce amyloid beta interaction with these receptors, potentially attenuating certain forms of neurological degradation observed in Alzheimer’s disease models.[2]

Research further suggests that Humanin may support the preservation of excitotoxic neurons in experiments involving NMDA pulses, with this potential implication possibly contributing to the delay or arrest of neurodegeneration in experimental models of Alzheimer’s disease and other forms of dementia. Under normal conditions, Bcl2 family proteins may signal the release of proteins from mitochondrial membranes, activating caspases and coordinating the orderly destruction and recycling of cells. While this process serves important functions — such as limiting the spread of tissue damage during viral invasion — it may become dysregulated under certain conditions, leading to widespread unsuppressed cell death. Humanin appears to bind to the Bcl2-stimulating proteins Bid and tBid, blocking their function and potentially shutting down the apoptotic pathway at its point of origin.

Humanin and Neurotoxicity Models

Recent laboratory investigations suggest that Humanin may attenuate neurotoxicity induced by Calyculin A in cortical neurons.[4] Calyculin A is recognized as an inhibitor of protein phosphatases PP2A and PP1 — enzymes critical for dephosphorylation — with inhibition of these phosphatases potentially leading to hyperphosphorylation of tau protein, increased oxidative stress, and neuronal damage. In experiments using cultured cortical neurons, preincubation with Humanin appeared to preserve cell viability and protect neurons from the harmful effects induced by Calyculin A.

Humanin may alleviate oxidative stress by reducing levels of malondialdehyde (MDA) — a byproduct of lipid peroxidation serving as a marker for oxidative membrane damage — suggesting a potential protective effect on neuronal membrane integrity. The peptide may also enhance the activity of superoxide dismutase (SOD), an essential antioxidant enzyme that catalyzes the conversion of superoxide radicals into less harmful compounds such as hydrogen peroxide and oxygen. Observations further indicate that Humanin may help restore PP2A activity, facilitating tau protein dephosphorylation. By potentially reducing tau overphosphorylation at specific amino acid residues, Humanin may help preserve the structural components essential for neuronal shape, function, and intercellular communication. The interplay between Humanin and cellular pathways involved in oxidative stress and tau phosphorylation underscores the peptide’s proposed capacity to modulate neuronal responses to neurotoxic insults — potentially influencing multiple dimensions of neuronal survival and function under stress conditions.

Humanin and Heart Cells

A Mayo Clinic study proposed that Humanin may be expressed on vascular walls and may interfere with the production of reactive oxygen species in response to LDL oxidation.[5] The peptide appears to hold potential to reduce active oxygen species in the vascular system by up to 50% and may similarly reduce apoptosis by up to 50%. In addition to its primary mechanism involving interaction with Bax, researchers suggested that an additional underlying mechanism may involve activation of the Akt/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. Western blot analysis indicated that Humanin may upregulate this pathway, potentially supporting cell survival and reducing apoptotic activity in cardiac cells.

The peptide also appeared to increase the ratio of cardiomyocytes to fibroblasts in cardiac tissue, potentially reflecting a reduction in fibrotic activity — given that fibroblasts are key contributors to fibrosis through collagen production. Immunofluorescence staining revealed alterations in cell type proportions, with a possible decrease in fibroblast proliferation. A reduction in collagen deposition within the myocardium following Humanin exposure was also noted — as collagen constitutes a major component of fibrotic extracellular matrix, its decreased presence may reflect attenuated fibrotic processes. The study additionally observed potential downregulation of profibrotic cytokines including transforming growth factor-beta1 (TGF-beta1), fibroblast growth factor-2 (FGF-2), and matrix metalloproteinase-2 (MMP-2), all of which are involved in extracellular matrix remodeling and fibrosis progression.

Humanin and Retinal Disease

The retinal pigment epithelium (RPE) is a retinal layer that covers and nourishes vision-supporting cells, playing a role in light absorption and scattering, filtration of blood components reaching the inner retina, and the establishment of ocular immune properties. RPE damage has been associated with age-related macular degeneration, diabetic retinopathy, and other ocular conditions.

Current studies suggest that Humanin may represent an important component of RPE and may reduce oxidative stress within this tissue.[6] Humanin exposure in cell culture appears to support RPE function and enhance tissue resistance to apoptosis, potentially contributing to research into retinal disorders such as macular degeneration.

Humanin and Bone Function

Bone loss represents a serious clinical concern, with glucocorticoids commonly employed to manage severe inflammation — including autoimmune inflammation — though high concentrations or prolonged exposure may induce significant bone loss. Researchers in Sweden and South Korea have proposed that Humanin may influence bone health through two potential mechanisms.[7] First, Humanin has been suggested to support chondrocyte survival — chondrocytes being the cells responsible for producing the collagen matrix within which bone is formed — potentially without interfering with glucocorticoid activity. This may help promote bone and cartilage growth or offset some of the accelerated bone loss associated with glucocorticoid use.

Second, Humanin has been proposed to reduce osteoclast formation. Osteoclasts are the cells responsible for bone resorption and remodeling, and their overactivation may result in significant bone loss. By modulating osteoclast formation, Humanin may potentially reduce excessive bone remodeling. This effect may be mediated through activation of AMP-activated protein kinase (AMPK) — an enzyme with a recognized role in cellular energy regulation — with earlier studies indicating that Humanin may induce AMPK phosphorylation, which may in turn negatively regulate receptor activator of nuclear factor-kB ligand (RANKL), a protein considered crucial for the differentiation and activation of osteoclasts.

Humanin also appears to reduce the expression of several genes involved in osteoclastogenesis, including nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) — a master transcription factor considered critical for osteoclast differentiation; osteoclast-associated receptor (OSCAR), proposed to be involved in osteoclast maturation and function; cathepsin K (CTSK), an enzyme involved in bone matrix protein degradation; and tartrate-resistant acid phosphatase (TRAP), an osteoclast marker enzyme involved in bone resorption.

Humanin and Insulin Signaling

Researchers have proposed that Humanin may “represent a novel link between T2DM and neurodegeneration.” Studies in murine models indicate that Humanin might support insulin sensitivity in liver cells,[8] potentially through activation of Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathways in the hypothalamus — a central nervous system region responsible for hormonal regulation. This activation appears significant, as simultaneous inhibition of hypothalamic STAT-3 appeared to diminish the insulin-sensitizing potential of Humanin, suggesting the effect may be centrally mediated. Research also indicates that a single Humanin exposure may significantly reduce blood glucose levels in diabetic murine models, though further studies are needed to confirm this potential. Additionally, a decline in detectable Humanin levels within the hypothalamus may potentially contribute to the worsening of insulin resistance observed in type 2 diabetes models.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. 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.
2. Gong Z, Tas E, Muzumdar R. Humanin and age-related diseases: a new link? Front Endocrinol (Lausanne). 2014 Dec 4;5:210. doi: 10.3389/fendo.2014.00210. PMID: 25538685; PMCID: PMC4255622.
3. 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.
4. Zhao, J., Zeng, Y., Wang, Y., Shi, J., Zhao, W., Wu, B., & Du, H. (2021). Humanin protects cortical neurons from calyculin A-induced neurotoxicities by increasing PP2A activity and SOD. The International journal of neuroscience, 131(6), 527–535. https://doi.org/10.1080/00207454.2020.1769617
5. 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.
6. 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.
7. 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.
8. Muzumdar, R. H., Huffman, D. M., Atzmon, G., Buettner, C., Cobb, L. J., Fishman, S., Budagov, T., Cui, L., Einstein, F. H., Poduval, A., Hwang, D., Barzilai, N., & Cohen, P. (2009). Humanin: a novel central regulator of peripheral insulin action. PloS one, 4(7), e6334. https://doi.org/10.1371/journal.pone.0006334