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GHK-Cu Peptide for Skin Regeneration and Protective Actions

Updated: Aug 7, 2023

The peptide GHK-Cu (glycyl-l-histidyl-l-lysine) has multiple biological actions, all of which, according to our current knowledge, appear to be health positive. It stimulates blood vessel and nerve outgrowth, increases collagen, elastin, and glycosaminoglycan synthesis, as well as supports the function of dermal fibroblasts. GHK-Cu’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK-Cu has also been found to possess powerful cell protective actions, such as multiple anti-cancer activities and anti-inflammatory actions, lung protection and restoration of chronic obstructive pulmonary disease (COPD) fibroblasts, suppression of molecules thought to accelerate the diseases of aging such as NFκB, anti-anxiety, anti-pain and anti-aggression activities, DNA repair, and activation of cell cleansing via the proteasome system. Recent genetic data may explain such diverse protective and healing actions of one molecule, revealing multiple biochemical pathways regulated by GHK-Cu.


Introduction to GHK-Cu

The copper-binding peptide GHK-Cu (glycyl-l-histidyl-l-lysine) is a small, naturally occurring tri-peptide present in human plasma that also can be released from tissues in case of an injury. Since its discovery in 1973, GHK-Cu established itself as a powerful protective and regenerative ingredient, which is currently widely used in skin and hair products [1].


Up-to-date, it is established that GHK-Cu is able to:

  • Tighten loose skin and reverse thinning of aged skin

  • Repair protective skin barrier proteins

  • Improve skin firmness, elasticity, and clarity

  • Reduce fine lines, depth of wrinkles, and improve structure of aged skin

  • Smooth rough skin

  • Reduce photodamage, mottled hyperpigmentation, skin spots and lesions

  • Improve overall skin appearance

  • Stimulate wound healing

  • Protect skin cells from UV radiation

  • Reduce inflammation and free radical damage

  • Increase hair growth and thickness, enlarge hair follicle size

Skin’s ability to withstand damage and repair itself is highest in children and young individuals because of well-functioning repair and protective mechanisms. However, with age, skin’s ability to repair damage declines. GHK-Cu content is highest in the plasma of young, healthy individuals. At age 20, the plasma level of GHK is about 200 ng/mL (10−7 M), and by the age of 60, it declines to 80 ng/mL. In the experiment that led to discovery of GHK-Cu, plasma from young individuals added to liver tissue obtained from older individuals, caused old liver tissue to produce proteins more characteristic of younger individuals [6].


In the 1980s, Maquart et al. proposed that GHK-Cu may be an early signal for skin repair. The GHK amino acid sequence is present in the alpha 2(I) chain of type I collagen, and when damage activates proteolytic enzymes, GHK-Cu is released into the site of an injury [7]. A number of experiments established that GHK-Cu stimulates synthesis of collagen, selected glycosaminoglycans and small proteoglycan decorin [8,9]. It also modulates activity of key metalloproteinases, which are enzymes that facilitate breakdown of proteins of extracellular matrix, as well as activity of anti-proteases. This suggests a general regulatory effect on protein breakdown in skin, helping to prevent both buildup of damaged proteins and excessive proteolysis [10,11]. Since excessive breakdown of the dermal matrix as well as inadequate removal of damaged proteins can negatively affect skin’s health and appearance, GHK’s ability to regulate both metalloproteinases and their inhibitors can support skin regeneration and improve its appearance.


GHK also demonstrated beneficial effects on skin fibroblasts, which are considered key cells in the skin regeneration process. Fibroblasts not only synthesize structural elements of the dermal matrix but also produce a wide range of growth factors essential for skin repair. GHK, in combination with LED irradiation (light emitting diode irradiation, 625–635 nm), compared with the LED irradiation alone increased: cell viability 12.5-fold, production of the basic fibroblast growth factor (bFGF), 230%, and collagen synthesis, 70% [12].


GHK-Cu has been found to stimulate epidermal basal cells, markedly increasing integrins and p63 expression. The cells’ shape became more cuboidal, which indicates an increase in their stemness [13].


Cosmetic Use of GHK-Cu

A number of clinical studies confirmed GHK-Cu’s ability to improve appearance of aging skin. A facial cream containing GHK-Cu applied for 12 weeks to the facial skin of 71 women with mild to advanced signs of photoaging increased skin density and thickness, reduced laxity, improved clarity, reduced fine lines and the depth of wrinkles [14].


A GHK-Cu eye cream applied for 12 weeks to around-the-eye area of 41 women with mild to advanced photodamage performed better than placebo and vitamin K cream. It reduced lines and wrinkles, improved overall appearance, and increased skin density and thickness [15].


GHK-Cu applied to thigh skin for 12 weeks improved collagen production in 70% of the women treated, in contrast to 50% treated with the vitamin C cream, and 40% treated with retinoic acid [16]. In addition to improving skin laxity, clarity, firmness and appearance, reducing fine lines, coarse wrinkles and mottled pigmentation, and increasing skin density and thickness, GHK-Cu cream applied twice daily for 12 weeks also strongly stimulated dermal keratinocyte proliferation [17].


With their pilot study for topical application of copper tripeptide complexes in aged skin, Krüger et al. confirmed an increase in skin thickness in the range of the epidermis and dermis, improved skin hydration, a significant smoothing of the skin by stimulating collagen synthesis, increased skin elasticity, a significant improvement in skin contrast and an increased production of collagen I [18,19].


GHK-Cu at 0.01, 1 and 100 nM incubated with human adult dermal fibroblasts increased production of elastin and collagen. GHK also increased gene expression of MMP1 and MMP2 at the 0.01 nM. All concentrations increased TIMP1. The effects of GHK-Cu were also investigated in a randomised, double–blind clinical trial. Female volunteers applied GHK-Cu, encapsulated in nano-lipid carrier twice a day in the course of 8 weeks using either carrier alone or the commercially available peptide Matrixyl® 3000 as controls. Compared to Matrixyl® 3000, GHK-Cu produced a 31.6% reduction of wrinkle volume. Compared to control serum, GHK-Cu reduced wrinkle volume 55.8% and wrinkle depth 32.8% [20].


Animal Studies Confirm Wound Healing Activity of GHK-cu

Multiple animal studies have established the wound healing activity of GHK. It appears that GHK-Cu stimulates wound healing through a variety of mechanisms. In rabbit experimental wounds, GHK-Cu alone or in combination with high dose helium–neon laser improved wound contraction and formation of granular tissue, as well as increasing activity of antioxidant enzymes and stimulating blood vessel growth [21,22]. Collagen dressing with incorporated GHK-Cu (PIC-Peptide Incorporated Collagen) accelerated healing of wounds in healthy and diabetic rats. The treated group displayed higher glutathione (GSH) and ascorbic acid levels, better epithelialization, as well as increased synthesis of collagen and activation of fibroblasts and mast cells in wounds. In healthy rats, treatment of wounds with PIC increased collagen 9-fold [23,24]. GHK-Cu improved healing of ischemic open wounds in rats. Wounds displayed faster healing, decreased concentration of metalloproteinases 2 and 9 as well as of TNF-β (a major inflammatory cytokine) compared with vehicle alone or with untreated wounds [25].


Stimulation of Blood Vessel and Nerve Growth

Nerve and blood vessel growth is an important factor in skin healing and regeneration.


Sage et al. observed that GHK-Cu and related peptides are produced in the course of protein breakdown after an injury from a SPARC protein. SPARC (Secreted Protein Acidic and Rich in Cysteine) is a glycoprotein, mostly expressed in embryonic tissues and in tissues undergoing repair and remodeling. At initial stages of tissue repair, GHK and other peptides containing the GHK-Cu sequence (such as KGHK), which are released from SPARC in the course of proteolysis, stimulate new vessels growth. Later in the healing process, GHK-Cu and GHK-related peptides inhibit blood vessel growth [26].


Anti-Oxidant and Anti-Inflammatory Actions

As animal experiments show, treatment of wounds with GHK leads to elevated levels of antioxidant enzymes. GHK also possesses strong antioxidant and anti-inflammatory actions. GHK inactivated damaging free radical by-products of lipid peroxidation, such as 4-hydroxynoneal, acrolein, malondialdehyde, and glyoxal, protecting cultured skin keratinocytes from ultraviolet (UV)-radiation [31]. GHK was shown to completely block Cu(2+)-dependent oxidation of low density lipoproteins (LDL). Another well-known anti-oxidant, which is also widely used in skin care, superoxide dismutase (SOD1), gave only 20% protection [32]. GHK also prevents damaging effects of lipid peroxidation, by binding its by-products such as acrolein and 4-hydroxynonenal [33,34].


GHK-Cu reduced iron release from ferritin by 87%. Ferritin in blood plasma can store up to 4500 atoms of iron per protein molecule, which is a well-known catalyst of lipid peroxidation—a chain reaction, which produces a slew of free radicals, leading to DNA, protein and cell membrane damage. Disturbances in iron metabolism contribute to many pathological conditions, including brain damage and neuron death under various neurological conditions. When iron is released from ferritin, it can form an Fe(2+)/Fe(3+) complex and start the chain reaction of lipid oxidation [35].


Conclusions

GHK-Cu is a small molecule, which possesses a surprisingly wide range of health-promoting qualities, while new studies are still revealing an even broader scope of GHK-Cus biological effects.


In the past, the wound healing, tissue remodeling, angiogenesis-promoting, cell-growth stimulating, anti-inflammatory and anti-oxidant actions of GHK-Cu were attributed to its unique relationship with copper. Copper is a transitional metal that is vital for all eukaryotic organisms from microbes to humans. Since it can be converted from oxidized Cu(II) to reduced Cu(I) form, it functions as an essential co-factor in a multitude of biochemical reactions involving electron transfer. A dozen enzymes (cuproenzymes) use changes in copper oxidation states to catalyze important biochemical reactions, including cellular respiration (cytochrome c oxidase), antioxidant defense (ceruloplasmin, superoxide dismutase (SOD), detoxification (metallothioneins), blood clotting (blood clotting factors V and VIII), and the connective tissue formation (lysyl peroxidase). Copper is required for iron metabolism, oxygenation, neurotransmission, embryonic development and many other essential biological processes [64].


Even though the copper hypothesis of GHK-Cu’s mode of action is still valid, we feel that it doesn’t explain the gene modulating effects of GHK-Cu. Therefore, in light of the new gene data, a new model of GHK-Cu action is needed, which will require collaboration of researchers from different fields.


As new gene profiling studies reveal, GHK-Cu with and without copper affects a large number of genes related to an organism’s response to stress and injury (tissue remodeling, anti-oxidant, anti-inflammatory, anti-pain, anti-anxiety, blood vessel growth, nerve outgrowth, anti-cancer action). GHK-Cu sequence is included in the collagen molecule, and SPARC protein and GHK-Cu is naturally released after an injury due to protein breakdown.


It is now known that some age-related changes in gene expression are not permanent and can be reversed. Studies show that regular physical exercise of older humans, as little as 30 min daily three times a week, can reset mitochondrial human DNA to a gene expression more like that of a younger person. Other procedures such as healthy diets, wine consumption, and flavonoid supplements are able to modify activity of certain genes, and various types of mediation and anti-stress methods are recommended to improve gene expression [65,66]. However, most biological compounds tested for their effects on gene expression using computer-based tools often lack supporting biological data. GHK has been extensively studied for over four decades and its safety and biological effects has been confirmed in cell, tissue and animal studies.[37].


GHK-Cu is a safe, inexpensive, extensively studied compound that has a wealth of positive and health-promoting effects in many tissues and systems. It has been widely used in anti-aging and cosmetic products in humans for decades without any adverse effects, and can be easily incorporated in creams, liposomes, dermal patches or delivered through microneedles. At present, it is not formulated into dietary supplements, so in our opinion, developing and testing GHK-Cu-based products for internal use to support health of elderly populations and as a complimentary therapy in cancer treatment is one possible direction for future research. Based on both biological and gene data, GHK-Cu also has the potential to be developed into an anti-anxiety and anti-pain supplemental treatment.


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MOTS-C MITOCHONDRIAL DERIVED PEPTIDE

What is MOTS-c? MOTS-c is a relatively new peptide of 16 amino acids that promote metabolic balance. It regulates metabolic functions throughout the body. For instance, it turns glucose into usable en

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