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<p>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&#xa0;the model organism <i>Caenorhabditis elegans</i> 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&#xa0;lifespan of <i>C. elegans</i> 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 <i>drp-1</i> and <i>fzo-1</i> expression, and promoting ATP biosynthesis. Meanwhile, GHK-Cu activating DAF-16 and SKN-1 pathway, and upregulating&#xa0;<i>sod-3</i>,&#xa0;<i>gst-4</i>,&#xa0;<i>gcs-1</i>, <i>lys-7</i> and <i>lys-8</i>. 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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月5日

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  • Huijun Wen,
  • Keshu Zhao,
  • Xiangjian Luo,
  • Jian Pu,
  • Yixin Li,
  • Yi Dou,
  • Jie He,
  • Xinyu Nie,
  • Yuan Ke,
  • Wenhui Zhou

摘要

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.