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

In aged mice, GHK-Cu improved hippocampal-dependent learning whether given by short intraperitoneal or longer intranasal dosing, but the two routes produced opposite hippocampal gene-expression programs. Intranasal delivery suppressed oxidative phosphorylation and growth signaling, while intraperitoneal delivery activated oxidative phosphorylation, DNA repair, and MYC targets. The authors conclude that delivery route and exposure duration shape how a gerotherapeutic peptide affects the aging brain.

Journal article — Preclinical interventional study in aged mice. Population: Aged C57BL/6J mice (20-21 months). Follow-up: 5 days (IP) or 8 weeks (IN). Interventions: GHK-Cu 15 mg/kg intraperitoneally (5 days); GHK-Cu 15 mg/kg intranasally (8 weeks).

Intranasal GHK-Cu improved escape latency across Trials 2-4 in both sexes (P < 0.0001). Transcriptomically, intranasal GHK-Cu suppressed oxidative phosphorylation in males (NES -5.44; FDR < 0.0001) and females (NES -4.20; FDR < 0.0001), plus MYC targets in females (NES -4.31; FDR < 0.0001) and PI3K-AKT-mTOR signaling in females (NES -3.15; FDR = 0.062). Intraperitoneal GHK-Cu instead activated oxidative phosphorylation in females (NES 4.97; FDR < 0.001), DNA repair (NES 5.58; FDR < 0.001), and MYC targets (NES 4.34; FDR = 0.002). The authors concluded that both routes improved learning while producing divergent molecular states.

Researchers studying GHK-Cu would care because this paper shows the peptide can improve a hippocampus-dependent behavior in aged mice while producing route-dependent, even opposite, hippocampal transcriptional programs. It does not establish the causal mechanism of cognitive rescue, the optimal dose or delivery schedule, or whether the effects extend beyond aged mice.

Key findings

• Intranasal GHK-Cu improved escape latency across Trials 2-4 in both sexes (P < 0.0001).
• Intranasal GHK-Cu suppressed oxidative phosphorylation in males (NES -5.44) and females (NES -4.20), both FDR < 0.0001.
• Intranasal GHK-Cu suppressed MYC targets in females (NES -4.31, FDR < 0.0001) and attenuated PI3K-AKT-mTOR signaling in females (NES -3.15, FDR = 0.062).
• Intraperitoneal GHK-Cu activated oxidative phosphorylation in females (NES 4.97, FDR < 0.001), DNA repair (NES 5.58, FDR < 0.001), and MYC targets (NES 4.34, FDR = 0.002).
• The two GHK-Cu delivery routes produced divergent hippocampal transcriptomic programs, with intranasal suppression and intraperitoneal activation of overlapping pathways.

Limitations

• The two routes also differed in exposure duration, so route and duration are confounded.
• No control or vehicle group is described in the abstract, so specificity of the behavioral effect to GHK-Cu cannot be assessed.
• The study is a preprint and has not been peer-reviewed.
• The abstract reports no sample size, so the precision of the effect estimates cannot be evaluated.

The record

• Journal: Research square: rs.3.rs-9520102
• Published: 2026-05-26
• PMID: 42245779 — DOI: 10.21203/rs.3.rs-9520102/v1

Peptide profiles: GHK-Cu.

All indexed evidence: GHK-Cu trials & papers.

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