COPPER TRIPEPTIDE-GHK — AGE-REGRESSION.COM

GHK-Cu

Human Plasma Tri-Peptide: GHK

(glycyl-L-histidyl-L-lysine)

GHK 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, 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]. This decline in the GHK-level coincides with a dramatic decrease in the regenerative capacity of all mammals.[1] It is possible that the sharp reduction in GHK-Cu during normal aging reduces the expression of protective anti-cancer genes and increases risk of cancer. [4]

GHK-Cu acts as a potent chemoattractant for mast cells, macrophages, amongst others which promote the release of proteins that stimulate the growth and repair of tissue. [13]

◉ In a 2014 a review article titled; “GHK and DNA: Resetting the Human Genome to Health,” reference [2], the authors detail the genetic targets that GHK-Cu has the ability to reverse. These include:

⫸ (1) The Suppression of Fibrinogen Synthesis. Fibrinogen is an excellent predictor of mortality especially in patients with cardiovascular complications [11, 12]. GHK was isolated as a plasma factor that suppressed fibrinogen synthesis in liver tissue and in mice.

(2) Activation of the Ubiquitin/Proteasome System (UPS). The UPS removes damaged proteins. Higher activities of the UPS appear to retard aging effects [13, 14].

(3) Activation of DNA Repair Genes. DNA damage is promptly repaired in young and healthy cells, however, as we age, DNA damage starts accumulating. Resetting activity of DNA repair genes can diminish deleterious effects of aging.

(4) Antioxidant Genes. Free radicals and toxic end products of lipid peroxidation are linked to atherosclerosis, cancer, cataracts, diabetes, nephropathy, Alzheimer’s disease and other severe pathological conditions of aging.

(5) Suppression of Insulin and Insulin-Like Genes. The insulin family has been proposed as a negative controller of longevity; higher levels of insulin and insulin-like proteins reduce the lifespan [15].

(6) Tissue Repair by TGF Superfamily. General tissue repair by the TGF superfamily as exemplified by COPD (chronic obstructive pulmonary disease).

(7) Cancer Controlling Genes. Caspase, growth regulatory, and DNA repair genes are important in cancer suppression. ⫷ [2]

◉ The number of human genes stimulated or suppressed by GHK with a change greater than or equal to 50% is 31.2%. GHK increases gene expression in 59% of the genes, while suppressing it in 41%. For our studies, we used the gene expression results from 50% . This gave the best correlation with our biological data. Table 1 (see epigenetic section below) presents an estimate of the number of genes affected by GHK at various cutoff points. [1]

◉ GHK-Cu established itself as a powerful protective and regenerative ingredient, which is currently widely used in skin and hair products [1].

◉ In normal human fibroblasts, GHK reduces the secretion of TGF-β and inflammatory cytokines, such as TNF-α and IL-6, to relieve skin inflammation and prevent the formation of hypertrophic scars (Gruchlik et al., 2012) [8]

◉ The treatment of rats, mice, and pigs with GHK effectively activate systemic healing throughout the animal. [2]

◉ 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

• Down Regulation of the TGF-β pathway which was one of two correlates of aging identified by the Conboys.

▶︎ GHK, a naturally occurring copper peptide, which declines with age, upregulates a number of cancer suppressors and downregulates a number of genes associated with cancer progression. As Hong et al. study indicates, GHK reverses expression of genes associated with early stages of aggressive metastatic colon cancer. It modulates gene expression in tissues derived from COPD lungs, switching gene expression to more regeneration, more restructuring and less inflammation. GHK improves wound healing, balances breakdown and synthesis of collagen, and accelerates repair of skin, bones and stomach lining. It possesses anti-oxidant and anti-inflammatory properties and protects the liver from toxins. As a regulatory molecule which appeared very early in evolution, GHK may hold the key to health and wellness through multiple mechanisms, which include regulating copper, activating pathways linked to repair and regeneration as well as acting directly on DNA, modulating gene expression.

It is possible that the sharp reduction in GHK-Cu during normal aging reduces the expression of protective anti-cancer genes and increases risk of cancer. The uniqueness of GHK is that it may allow simultaneous resetting of multiple genes to target an array of various biochemical pathways to increase resistance to cancer and reverse pathological epigenetic changes in cancerous cells. Unlike many other potential therapeutic agents discovered through gene profiling, GHK has a wealth of laboratory data, supporting its ability to protect and repair tissues.

While cancer causes and treatments are very complex, it is possible that GHK-Cu, which has multiple effects on gene expression and has been shown to exhibit favorable gene effects reversing gene expression back to health in metastasis prone colon cancer gene signature and COPPD gene signature, can help slow or regress selected cancers in humans.

GHK has an excellent safety record and a long history of use in skin care. GHK can be administered intravenously, orally (in liposomal form [48]) or applied to skin. GHK and its copper complexes penetrate the stratum corneum and can be delivered transdermally in creams, gels or skin patches [49,50]. Considering GHK’s potential in having generalized health-positive gene effects which have been confirmed to encourage tissue remodeling and wound healing, its gene effects in breast cancer and prostate cancer cells have to be further investigated for possible practical application in anti-cancer therapy. ◀︎[4]

▶︎ The human peptide GHK (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’s ability to improve tissue repair has been demonstrated for skin, lung connective tissue, boney tissue, liver, and stomach lining. GHK 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 NFkB, 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.

GHK 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 increams, liposomes, dermal patches or delivered through microneedles.

At present, it is not formulated into dietary supplements, so in our opinion, developing and testing GHK-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 also has the potential to be developed into an anti-anxiety and anti-pain supplemental treatment, and it may be an essential component in a future complex approach to COPD therapy.

The number of human genes stimulated or suppressed by GHK, is greater than 4000, with a change greater than or equal to 50% is 31.2%. GHK increases gene expression in 59% of the genes, while suppressing it in 41%.◀︎[1]

▶︎ Copper tripeptide (Cu-GHK, lamin®) complex (Sequence: Copper Gly-l-His-l-Lys) is one of the most well-examined peptides. It plays a role in the extracellular matrix, and is released in wounds or inflammation to support healing. It acts as signal and carrier peptide, promotes regular collagen, elastin, proteoglycan, and glycosaminoglycan synthesis, and provides anti-inflammatory and antioxidant responses. In cosmetic applications, Cu-GHK is used in anti-aging, anti-wrinkle, after-sun, skin renewal, skin moisturizer, hair growth stimulating products [33].

Cu-GHK stimulates cellular regulatory molecules and regenerates, and heals skin and other tissues. Stem cells treated with GHK regenerated and expressed more stem cell markers. GHK and Gly-Gly-His (GGH) reduce TNF-α induced cytokines IL-6 [34], thus ensuring better wound healing. Pickart et al. described that GHK significantly increased the expression of DNA repair genes, while 47 genes are stimulated and five genes are suppressed [35]. GHK is involved with different mechanisms of action and can apparently promote regeneration, healing, and repair. It furthermore achieves good effects against the aging processes.

Cu-GHK can stimulate hair growth. The copper tripeptide complex ensures follicular enlargement and helps covering the follicle with a downy hair; the effect is comparable with that of Minoxidil [36]. The results of a hair transplant showed significant improvement [37] following application with a copper tripeptide product. Topical Cu-GHK products stimulate collagen synthesis on the scalp, strengthen existing hair, and encourage hair growth [38].

Several studies confirming Cu-GHK efficacy in various areas have been performed. These include: increasing keratinocyte proliferation, improving appearance, firmness, elasticity, skin thickness, wrinkles, spotty hyperpigmentation and light damage, skin collagen, strengthening proteins of skin protection barrier, and improvement of skin appearance.

Experiments have shown that in vitro Cu-GHK increases and stimulates the synthesis of collagen, glycosaminoglycans and other extracellular matrix molecules. Several placebo-controlled clinical trials have confirmed the observed effects [37]. A topically applied cream with Cu-GHK was shown to stimulate dermal skin procollagen synthesis. Synthesis induced by the copper tripeptide was significantly superior to vitamin C, tretinoin, or melatonin in comparison.

Similarly, a study of 20 women compared the skin’s production of collagen after applying creams containing Cu-GHK, vitamin C, or retinoic acid to thighs daily for one month. New collagen production was determined by skin biopsy samples using immunohistological techniques. After one month, Cu-GHK increased collagen in 70% of those treated, versus 50% treated with vitamin C, and 40% treated with retinoic acid [39].

Leyden et al. confirmed in two different studies (12 weeks of application by 71 or 41 women) the clinically beneficial effects of Cu-GHK formulations on both aged and sun damaged skin. The Cu-GHK face cream and an eye cream reduced the visible signs of skin aging and caused an increase in skin density and thickness. The researchers observed improved skin elasticity and skin humidity, significant smoothing of the skin by stimulating the synthesis of collagen, a significant improvement of the skin contrast, and diminished wrinkles [36].

In another study Cu-GHK cream was applied twice a day for 12 weeks on 67 women. The Cu-GHK cream improved the appearance of photo-damaged, aged skin. By histological analyses of biopsies, it was re-confirmed that the use of topically applied Cu-GHK products intensified skin thickness in the range of the epidermis and dermis, and that keratinocyte proliferation of the skin was greatly stimulated [40]. ◀︎[17]

HSA’s Cu(II) binding "ATCUN" site: [14] Click [√] to Enlarge

Proposed cellular receptor for GHK-cu [3] Click[√] to Enlarge

GHK-Cu Molecular Structure Click[√] to Enlarge

As a dermatological intervention a lot of efficacy and safety data has been developed over the last 40 years since this peptide-copper complex was identified. As a systemic therapeutic there is very little human clinical or practical data available. Multiple animal studies indicate that the peptide has a large safety and therapeutic profile. A transdermal patch is currently under development by Yuvan Life Sciences.

Normal Levels, Safety and Possible Dosages of Copper Peptides

GHK is a human plasma, copper-binding peptide with a stunning array of actions that appear to counter aging-associated diseases and conditions. In studies at the University of California at San Francisco, young (age 20–25), male medical students were found to have about 200 nanograms/mL of GHK in their blood plasma, while the healthy, male medical school faculty (average age of 60) had only 80 nanograms/mL [9]

▶︎ In our studies, the LD50 (median lethal dose in 50% of mice) for GHK-Cu was 8 mgs per 25 g mice for GHK-Cu. Extrapolated to human weight, this would be 320 mg/kg or 22,400 mg in a 70 kg human. The injection of 0.065 milligrams GHK-Cu in a 25 g mouse would correspond to 182 mg in a 70 kg human, suggesting a wide margin of safety.

In the Hong et al. study [2], GHK produced suppression of many cancer metastasis genes at 1 micromolar. If this level was used as in the experiments above, the mice would have been injected with 0.2 ml of liquid containing 0.68 nanograms of GHK. In the Maquart et al. study, GHK-Cu increased fibroblast production of decorin by 302% at 1 nanomolar [34].◀︎[4]

Strong systemic wound healing was induced in pigs at about 1.1 mg GHK-Cu per kilogram body weight which would correspond to about 75 mgs in humans. This is about 300-fold below GHK-Cu’s toxic action (lowering of blood pressure). Much lower dosages may also be effective since GHK-Cu’s actions on cells generally occur at a 1 nanomolar concentration [68]. [10]

▶︎ Russian studies reported that 0.5 micrograms/kg reduced anxiety in rats. Scaled up for a human weight of 70 kg, this would be 35 micrograms in a human [52]. Our studies on activation of systemic healing in mice, rats, and pigs suggest that about 50 milligrams of GHK-Cu would be effective throughout the human body, although dose-ranging to determine the minimum active dosage was never performed. ◀︎[3]

GHK-Cu and Glutathione

The transient GSH-Cu(II)GHK complex was found to be an important reaction intermediate. The kinetic and redox properties of this complex, including tuning of the reduction rate by ternary ligands, suggest that it may provide a missing link in copper trafficking as a precursor of Cu(I) ions, for example, for their acquisition by the CTR1 cellular copper transporter.

[2021] Intermediate Cu(II)-Thiolate Species in the Reduction of Cu(II)GHK by Glutathione: A Handy Chelate for Biological Cu(II) Reduction

Synergistic Effects in Cancer

Linus Pauling’s group once used a copper tripeptide, Gly-Gly-His : Cu(2+) and ascorbic acid as a cancer treatment method. In a recent paper, we used their basic method but with GHK : Cu(2+) and ascorbic acid, which strongly suppressed sarcoma 180 in mice without any evident distress to the animals [7]. GHK altered gene expression in 84 genes (caspases, cytokines, and DNA repair genes) in a manner that would be expected to suppress cell growth. On skin, GHK seems to act most strongly in the late stage of healing, called remodeling, where cellular migration into the wound area is stopped and cellular debris is removed. The anticancer actions of small copper peptides may be a side effect of this system.

The use of GHK : Cu(2+) and ascorbic acid should be investigated in more detail. The mice treated in this manner appeared to remain very healthy and active, in contrast to the toxicities of current cancer chemotherapy.

[2012] Oxidative Stress in Neurodegenerative Diseases and Ageing

[2014] GHK and DNA: Resetting the Human Genome to Health

The human tripeptide GHK has a long history of safe use in wound healing and skin care; it is naturally occurring, nontoxic, and is active at a very low nanomolar concentration. It readily forms complexes with copper, regulating its metabolism and improving its bioavailability. It possesses antioxidant, anti-inflammatory, and regenerative properties, improves circulation, supports stem cell functions, and promotes nerve outgrown and synthesis of neurotrophic factors. Recent studies demonstrated its ability to regulate a large number of human genes. At 1 micromolar it was able to suppress 70% of genes overexpressed in metastatic colon cancer. It upregulates p63 and integrins in epidermal stem cells, increases collagen, glycosaminoglycans, and decorin expression. Our studies with the Broad Institute’s Connectivity Map revealed its ability to regulate a large number of human genes including those that are involved in nervous system physiology, development, and maintenance.

Even though it is not always possible to distinguish between activity of GHK peptide and its copper complex GHK-Cu, we strongly believe that for the future therapeutical applications GHK-Cu should be used. Numerous studies demonstrating pleiotropic health promoting and antiage activity of the GHK-Cu peptide together with recent studies revealing gene regulating activity of GHK suggest that this compound may belong to a class of epigenetic modifiers capable of exhibiting broad protective and restorative actions, reducing harmful epigenetic changes caused by environmental perturbagens. The GHK-Cu peptide should be considered a promising neuroprotective agent capable of preventing the development of common age-associated neurodegenerative disorders. [10]

◉ The number of human genes stimulated or suppressed by GHK with a change greater than or equal to 50% is 31.2%. GHK increases gene expression in 59% of the genes, while suppressing it in 41%. For our studies, we used the gene expression results from 50% . This gave the best correlation with our biological data. Table 1 presents an estimate of the number of genes affected by GHK at variouscutoff points. [1]

Table 1 ~ Estimate of number of genes affected by glycyl-L-histidyl-L-lysine (GHK) [5].

The human tripeptide GHK has a long history of safe use in wound healing and skin care; it is naturally occurring, nontoxic, and is active at a very low nanomolar concentration.

The Lethal Dose of GHK-Cu for 50% of mice (LD50) deaths was 8 mg for a 25-gram mouse or about 23 grams for a 70 kg human. A possible explanation of lethal effects of high doses of GHK-Cu is dropping of blood pressure. There are no reports for an LD50 for GHK without copper, so it must be very nontoxic. [5]

▶︎ GHK is readily available at low cost and can be easily incorporated into a wide range of skin products such as sunscreens and protective cosmetic creams, as well as medicated ointments. It penetrates the stratum corneum and can be incorporated into liposomes or skin patches [61,62,63,64]. The molecule is very safe and no issues have ever arisen during its use as a skin cosmetic or in human wound healing studies.◀︎[18]

GHK-Cu is sold in various skin creams and topical ointments (shown below). The beneficial effects of this route have been know almost since its discovery, 40 years ago. Pure GHK-Cu is available as a tripeptide bound to copper from multiple sources online. It should be noted that there are no standard or quality controls for may of these online vendors of GHK-Cu. There are also multiple products in development that are seeking to optimize the full spectrum of biological activities that this dramatic discovery provides.

Skin renewal

Neel Copper Peptide Skin Gel

Neutrogena Visibly Firm Night Cream®

Neutrogena Visibly Firm Eye Cream®

Blue Copper Firming Elasticity Repair®

Climate Extreme Body Repair with Copper Peptide®

Blue Razor Aftershave®

Neova® Eye TherapyNeova®

Neova® Night Therapy Cream®

Neova® Body Therapy Lotion®

Neova® Cuticle TherapyNeova®

Neova® Cleansing BarNeova®