The GHK-Cu delays aging in Caenorhabditis elegans via coordinated regulation of mitochondrial function and activation of DAF-16/SKN-1 pathways.

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..