• Neurodegenerative diseases of aging (e.g., Alzheimer’s, Parkinson’s) cause early debilitation and dependency.

Key processes:

• Oxidative stress.
• Metal homeostasis disruption.
• Neuroinflammation.

• Environmental/dietary factors may cause epigenetic damage.
• Antioxidants (vitamin E, melatonin, resveratrol) show mixed clinical results.
• Metal chelators and dietary restrictions investigated but limited.

GHK-Cu:

• Safe, natural peptide with diverse regenerative actions.
• Shown to regulate a large number of human genes.

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• Discovered in plasma in 1973.
• Levels: ~200 µg/L at age 20–25 → ~80 µg/L by age 60–80.
• High copper affinity → forms stable GHK-Cu.
• Role: delivers nontoxic copper for cellular functions.

Structural studies show:

• Cu(II) binds to histidine, glycine amino group, and peptide bond nitrogen.
• Stable binary/ternary structures possible.
• Can acquire copper from plasma albumin.
• Prevents oxidative damage by silencing redox activity.

• Copper is essential but excess free copper may cause oxidative stress.
• Copper deficiency → severe neurological issues in humans and mice.

Alzheimer’s disease (AD):

• Copper role debated (cause vs. consequence).
• Some evidence: copper deficiency may be linked to AD.

Clinical trials:

• 8 mg/day copper supplementation improved AD markers.
• Suggests copper supplementation may be protective.
• GHK: forms nontoxic copper complexes, increases bioavailability.

• Brain vulnerable: high oxygen use, rich in unsaturated fatty acids, few antioxidants.
• SOD1 (superoxide dismutase) requires copper/zinc.
• Copper deficiency reduces activity → more oxidative damage.

GHK-Cu:

• Restores SOD activity.
• Inhibits lipid peroxidation (e.g., ferritin-bound iron).
• Quenches toxic lipid peroxidation products (HNE, acrolein).

Anti-inflammatory effects:

• Lowers TNF-alpha and TGF-beta cytokines.
• Improves ischemic wound healing.

• Brain health depends on vascular integrity.

GHK-Cu promotes:

• Angiogenesis.
• Anticoagulation.
• Vasodilation.
• Increases VEGF and bFGF.
• SPARC protein: contains GHK sequence; released during tissue damage.
• Stimulates vessel growth until blood flow restored.

• Neurotrophic factors reduce oxidative damage and support neurons.

Evidence:

• GHK stimulates nerve outgrowth in culture.
• In collagen implants, increased NGF, NT-3, NT-4.
• Boosted axon count and Schwann cell proliferation.

Epigenetic factors influence neurodegeneration.

GHK-Cu effects:

• Accelerates wound healing.
• Stimulates synthesis and breakdown of collagen/glycosaminoglycans.
• Modulates metalloproteinases (MMPs) and inhibitors (TIMPs).
• Increases mRNA for ECM components (collagen, decorin).
• Upregulates integrins and p63 (epidermal stem cell markers).

Connectivity Map studies:

• 268 genes upregulated, 167 suppressed.

Cancer studies:

• Suppressed RNA in 70% of metastatic colorectal cancer genes.

Connectivity Map data:

• 76 genes upregulated, 6 downregulated at 1 μM GHK.

Nervous system genes stimulated:

• SIGMAR1 (dementia-linked).
• EPM2A (Lafora disease).
• NAIP (anti-apoptotic).
• FGFR2 (embryonic brain development).
• SLIT2 (nervous system development).

Demonstrates potential neuroprotective gene regulation.

• Age 20–25: peak health → decline later.
• Epigenetic silencing increases inflammation, cancer risk.
• HDAC enzymes implicated in neurodegeneration.
• GHK: strong HDAC inhibitor.
• Suggests potential in reversing gene silencing → protective effects.

• Advantages of GHK-Cu over GHK: prevents copper deficiency, safe delivery.
• Likely able to cross blood-brain barrier.

Delivery methods:

• Intravenous.
• Oral (liposome-encapsulated).
• Effective systemic wound healing at 1.1 mg/kg in pigs (~75 mg in humans).
• Therapeutic window far below toxic dose.
• Effective at nanomolar concentrations.

Cognitive decline involves multiple mechanisms: oxidative stress, inflammation, copper imbalance, poor circulation, epigenetics.

GHK-Cu is:

• Natural and safe.
• Antioxidant and anti-inflammatory.
• Supports circulation, stem cells, neurotrophins.
• Regulates genes and reverses harmful epigenetic changes.
• Proposed as a promising neuroprotective agent for age-associated disorders.