GHK (Glycyl-L-Histidyl-L-Lysine)

GHK (Glycyl-L-Histidyl-L-Lysine) is a naturally occurring human tripeptide with the sequence Gly-His-Lys and a molecular weight of approximately 340 Da (or approximately 403 Da as the copper complex GHK-Cu). It was discovered in 1973 by Dr. Loren Pickart when he observed that albumin fractions from the plasma of young adults (age 20-25) stimulated aged liver cells (from donors over 60) to synthesize proteins at rates characteristic of young cells. The active factor responsible for this rejuvenating effect was isolated and identified as GHK.

GHK circulates in human plasma at approximately 200 ng/ml at age 20, declining to approximately 80 ng/ml by age 60, a 60% reduction that correlates temporally with declining wound healing capacity, increased fibrosis, and reduced tissue regenerative potential. This age-related decline suggests that GHK functions as a systemic youth-associated signal, and that its loss contributes directly to the aging phenotype.

The mechanism of action was dramatically illuminated by genome-wide expression studies using the Connectivity Map (CMap) database at the Broad Institute. Analysis revealed that GHK modulates the activity of 4,048 human genes, representing approximately 31% of the human genome. It upregulates 2,024 genes associated with tissue repair, stem cell function, antioxidant defense, ubiquitin/proteasome pathways, and DNA repair, while downregulating 2,024 genes associated with inflammation (NF-kB pathway), fibrosis (TGF-beta pathway), tissue destruction (MMPs), and cancer metastasis. The net effect is a broad reset of gene expression toward patterns seen in younger, healthier tissue. This gene-regulatory profile was published in BioMed Research International and Genome Medicine.

GHK has high affinity for copper(II) ions, forming the complex GHK-Cu with a binding constant (log K) of approximately 16.2. The copper complex is the most commonly studied form and is the predominant circulating species in plasma (where copper concentrations are 10-25 umol/L). However, the peptide backbone itself has significant biological activity independent of copper binding, particularly in gene regulation. The copper serves as a cofactor for copper-dependent enzymes (lysyl oxidase for collagen cross-linking, superoxide dismutase for antioxidant defense, tyrosinase for melanin synthesis) and as a catalytic center for antioxidant activity.

In wound healing studies, GHK-Cu accelerated wound closure by 30-40% in animal models, reduced scarring, increased collagen deposition (types I, III, and V), promoted angiogenesis (new blood vessel formation), stimulated glycosaminoglycan synthesis (decorin, dermatan sulfate), and attracted macrophages and mast cells to wound sites, coordinating the inflammatory-to-proliferative phase transition. These effects have been documented in over 150 peer-reviewed publications spanning 50+ years since its discovery.

Pharmacokinetically, GHK is a small tripeptide that is absorbed through multiple routes: subcutaneous injection (rapid absorption, peak at 15-30 min), topical application (penetrates skin, especially when formulated with penetration enhancers), and potentially oral (though peptidase degradation limits oral bioavailability). Plasma half-life is estimated at 30-60 minutes. The peptide is degraded by tissue peptidases into its constituent amino acids, all of which are naturally occurring and non-toxic.

For storage, GHK powder should be stored at -20C for long-term stability or 2-8C for up to 60 days. The copper complex (GHK-Cu) is more stable than the free peptide. Reconstitute with sterile water or bacteriostatic water. Solutions should be stored at 2-8C and used within 21 days. Stable at pH 5-7. Protect from strong light as the copper complex can undergo photoreduction.

Safety is well-characterized through 50+ years of research and extensive cosmetic industry use (GHK-Cu is a major active ingredient in premium skincare products). No systemic toxicity, immunogenicity, mutagenicity, or carcinogenicity has been reported. GHK is a naturally occurring human molecule, and exogenous administration simply restores declining endogenous levels. Topical GHK-Cu causes no irritation or sensitization in standard dermatological testing. Subcutaneous injection produces only mild, transient injection site reactions.