Middle-aged mice treated with GHK-Cu peptide administered intraperitoneally or intranasally show behavioral rescue but divergent hippocampal aging programs

This preclinical study investigated whether the endogenous copper-binding peptide GHK-Cu (glycyl-L-histidyl-L-lysine–copper complex) could mitigate age-related cognitive decline in middle-aged to old C57BL/6J mice (20–21 months). Two delivery routes were compared: short-term intraperitoneal (IP) administration over 5 days and longer-term intranasal (IN) administration over 8 weeks. Hippocampal-dependent spatial learning was assessed via an escape latency task; molecular changes were examined through hippocampal immunohistochemistry and bulk RNA sequencing, with differential gene expression analyzed using DESeq2 and gene set enrichment analysis (GSEA). Both delivery routes were associated with improved escape latency performance in treated mice of both sexes compared to controls, suggesting behavioral rescue of age-related learning deficits. However, the two routes produced divergent hippocampal transcriptomic profiles, implying that delivery method and exposure duration engage distinct molecular aging programs. Key limitations include the exclusive use of a mouse model, the absence of human data, variability in statistical power across outcome measures, and preprint status meaning the findings have not yet undergone formal peer review. The study does not establish causality in humans and is hypothesis-generating for future translational research.

Why this grade: All experiments were conducted exclusively in aged mice with no human participants, and the work is currently a preprint without peer review, limiting the strength and generalizability of its conclusions.