Middle-aged mice treated with GHK-Cu peptide administered intraperitoneally or intranasally show behavioral rescue but divergent hippocampal aging programs
This mouse study investigated whether the endogenous copper-binding peptide GHK-Cu could improve age-related cognitive decline, and whether outcomes differed based on how the compound was delivered. Aged C57BL/6J mice (20–21 months old) received GHK-Cu either intraperitoneally (IP) for 5 days or intranasally (IN) for 8 weeks. Researchers assessed hippocampal-dependent spatial learning, along with hippocampal tissue markers and bulk RNA sequencing. Both delivery routes were associated with improvements in escape learning, though IN administration showed broader and more sustained benefits across both sexes, while IP dosing produced a more limited effect, primarily in males. Immunohistochemistry revealed route-dependent changes in markers of synaptic density (synaptophysin), neuroinflammation (GFAP, MCP-1, TGF-β), and cellular senescence (p21). Transcriptomic analysis showed striking divergence: IN treatment was associated with suppression of oxidative phosphorylation and MYC target pathways, while IP treatment activated stress-response, DNA repair, and mitochondrial metabolic pathways. The authors conclude that GHK-Cu can improve cognitive outcomes through mechanistically distinct biological programs depending on the route and duration of administration. Key limitations include use of a single rodent strain, lack of human data, and preprint status (not yet peer-reviewed).
Why this grade: All experimental subjects were aged mice; no human participants were included, and the work has not yet undergone peer review.
Age-related cognitive decline (ARCD) is driven by conserved biological mechanisms of aging, yet no gerotherapeutic directly targets these processes in the brain. Glycyl-L-histidyl-L-lysine complexed with copper (GHK-Cu) is an endogenous peptide with regenerative and anti-inflammatory properties that declines with age. Whether its effects on cognitive aging depend on delivery route or exposure duration remains unclear. Aged C57BL/6J mice (20-21 months) received GHK-Cu (15 mg/kg) via short-term intraperitoneal (IP; 5 days) or longer-term intranasal (IN; 8 weeks) administration. Hippocampal-dependent escape learning was assessed using a spatial navigation task. Molecular effects were evaluated using hippocampal immunohistochemistry and bulk RNA sequencing. Differential gene expression was analyzed using DESeq2 with false discovery rate (FDR) correction, and pathway-level changes were assessed via gene set enrichment analysis (GSEA). IN GHK-Cu improved escape latency across Trials 2-4 in both sexes ( P < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 ( P < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females ( P < 0.001) and decreased GFAP in both sexes ( P < 0.01), while IP treatment reduced TGF-β, GFAP, and MCP-1 in males ( P < 0.05) and decreased p21 in females ( P < 0.0001). Transcriptomic analysis revealed distinct molecular programs. IN GHK-Cu induced coordinated suppression of oxidative phosphorylation (male NES -5.44, female NES -4.20; FDR < 0.0001) and MYC target pathways (female NES -4.31, FDR < 0.0001), with additional attenuation of PI3K-AKT-mTOR signaling in females (NES -3.15, FDR = 0.062). In contrast, IP treatment activated oxidative phosphorylation (female NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002), indicating engagement of acute stress-response and repair pathways. GHK-Cu improves hippocampal-dependent learning in aged mice through distinct biological modes: IP exposure activates repair and stress-response pathways, whereas IN delivery induces sustained suppression of growth and mitochondrial metabolic signaling associated with aging biology. These findings demonstrate that functional cognitive improvement can arise from divergent molecular states and identify administrative route and exposure duration as key determinants of gerotherapeutic response.
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