The GHK-Cu delays aging in Caenorhabditis elegans via coordinated regulation of mitochondrial function and activation of DAF-16/SKN-1 pathways.
This study investigated whether GHK-Cu (the tripeptide Glycine-Histidine-Lysine complexed with copper, naturally found in human plasma and urine) could delay aging using the roundworm Caenorhabditis elegans as a model organism. The researchers measured lifespan, stress resistance (oxidative and thermal), physical function (motility, pharyngeal pumping, defecation rhythm), and markers of cellular aging such as lipofuscin and lipid accumulation. They also examined mitochondrial health and key longevity signaling pathways. The study found that GHK-Cu extended worm lifespan, improved multiple age-related functional measures, and reduced aging biomarkers. At the mechanistic level, GHK-Cu appeared to preserve mitochondrial function—maintaining membrane potential, reducing age-related mitochondrial fragmentation, promoting mitochondrial fusion (via regulation of drp-1 and fzo-1), and increasing ATP production. Additionally, GHK-Cu activated the DAF-16 and SKN-1 longevity pathways and upregulated downstream target genes including sod-3, gst-4, gcs-1, lys-7, and lys-8. A key limitation is that all experiments were conducted in C. elegans; whether these findings translate to mammals or humans remains unknown.
Why this grade: All experiments were conducted exclusively in the invertebrate model organism C. elegans; no mammalian or human data were generated.
Aging is a complex biological process characterized by progressive functional decline across tissues and increased susceptibility to age-related diseases, with oxidative stress being a key contributing factor. Glycine-Histidine-Lysine (GHK), a naturally occurring tripeptide present in human plasma and urine, possesses potent antioxidant properties; however, its broader anti-aging potential remains inadequately explored. In this study, we employed the model organism Caenorhabditis elegans to systematically investigate the anti-aging effects of GHK-Cu (GHK complexed with copper) and elucidate its underlying molecular mechanisms. Our results demonstrated that GHK-Cu significantly extended lifespan of C. elegans and ameliorated mutiple aging-related phenotypes, including enhanced resistance to oxidative and thermal stress, improved motility, pharyngeal pumping, defecation rhythm, and reduced lipofuscin/lipid accumulation. Mechanistically, GHK-Cu preserved mitochondrial function by increasing mitochondrial membrane potential, alleviating age-related mitochondrial network fragmentation, shifting mitochondrial dynamics toward fusion via regulating drp-1 and fzo-1 expression, and promoting ATP biosynthesis. Meanwhile, GHK-Cu activating DAF-16 and SKN-1 pathway, and upregulating sod-3, gst-4, gcs-1, lys-7 and lys-8. This study provides the first mechanistic evidence that GHK-Cu delays aging through coordinated regulation of mitochondrial function and activation of both DAF-16 and SKN-1 pathways. Our findings identify novel molecular targets for developing anti-aging interventions and underscore the potential of GHK-Cu's as a multifaceted geroprotective compound.
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