Middle-aged mice treated with GHK-Cu peptide administered intraperitoneally or intranasally show behavioral rescue but divergent hippocampal aging programs
GHK-Cu administered intranasally improved cognitive function in aged mice, while intraperitoneal administration showed only temporary benefits.
Where it sits
this study against the rest of the ghk-cu corpusSummary and findings
This study measured the effects of GHK-Cu peptide on cognitive function in aged C57BL/6J mice (20–21 months) through intraperitoneal (IP; 15 mg/kg for 5 days) and intranasal (IN; 15 mg/kg for 8 weeks) administration. The results indicated that IN GHK-Cu improved escape learning in both sexes, while IP treatment showed transient effects in males only.
Abstract
<title>Abstract</title> <p> 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 ( <italic>P</italic> < 0.05), whereas IP dosing produced a transient improvement in males during Trial 2 ( <italic>P</italic> < 0.05) without sustained effects or improvement in females. IN treatment increased synaptophysin in females ( <italic>P</italic> < 0.001) and decreased GFAP in both sexes ( <italic>P</italic> < 0.01), while IP treatment reduced TGF-β, GFAP, and MCP-1 in males ( <italic>P</italic> < 0.05) and decreased p21 in females ( <italic>P</italic> < 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. </p>
Background
This research addresses the potential effects of GHK-Cu peptide on aging-related behaviors and hippocampal function in middle-aged mice. Previous studies have suggested that GHK-Cu may influence cellular repair and regeneration, but its specific impact on behavioral and neurological outcomes in aging has not been thoroughly explored. Understanding these effects could provide insights into the mechanisms of aging and potential interventions.
Methods
The study utilized a rodent model, specifically middle-aged mice, with GHK-Cu administered via intraperitoneal or intranasal routes. The sample size and specific dosing regimen were not reported in the abstract. Primary outcomes included behavioral assessments and analyses of hippocampal aging programs, though details on secondary outcomes were not provided.
Results
Not reported in abstract.
Interpretation
The findings suggest that GHK-Cu may have a role in influencing behavioral outcomes and hippocampal aging, but the lack of detailed metrics limits the ability to assess the clinical significance of these results. The study's reliance on a rodent model introduces confounds that may affect the generalizability of the findings to human populations.
Key findings
- Behavioral improvements observed in treated mice, specific metrics not reported in abstract.
- Divergent hippocampal aging programs noted, specific details not reported in abstract.
- Not reported in abstract.
Limitations
- Rodent model may not translate to humans.
- Specific metrics and statistical analyses not detailed.
- Small sample size not reported.
- Short duration of treatment not specified.