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Related Experiment Video

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Enhanced C/EBPα Function Extends Healthspan and Lifespan in the African Turquoise Killifish.

Christine Müller1, Joscha S Muck1, Kirill Ustyantsev1

  • 1European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen (UMCG), University of Groningen, Groningen, the Netherlands.

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|September 19, 2025
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Summary

Disrupting a specific gene regulation mechanism in killifish extended lifespan and improved healthspan. This conserved pathway, involving CCAAT/enhancer binding protein alpha (C/EBPα) isoforms, offers insights into aging and longevity.

Keywords:
C/EBPhealthspankillifishlifespantranslation

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Area of Science:

  • Molecular Biology
  • Genetics
  • Aging Research

Background:

  • CCAAT/enhancer binding protein alpha (C/EBPα) is a crucial transcription factor regulating cell functions across various tissues.
  • Alternative translation initiation of CEBPA mRNA produces multiple C/EBPα isoforms, including antagonistic truncated variants.
  • uORF-mediated translation and mTORC1 signaling control the expression of truncated C/EBPα isoforms.

Purpose of the Study:

  • To investigate the conservation of uORF-mediated C/EBPα isoform regulation in the African turquoise killifish (Nothobranchius furzeri).
  • To determine the impact of disrupting uORF-mediated regulation on killifish lifespan and healthspan.
  • To explore the molecular pathways affected by altered C/EBPα isoform expression.

Main Methods:

  • Comparative analysis of CEBPA gene regulation in killifish.
  • Genetic disruption of the upstream open reading frame (uORF) in killifish CEBPA mRNA.
  • Lifespan and healthspan assessment of genetically modified killifish.
  • Transcriptome analysis to identify affected genes and pathways.

Main Results:

  • uORF-mediated regulation of C/EBPα isoform expression is conserved in killifish.
  • Disruption of the uORF eliminated the truncated C/EBPα isoform, enhancing full-length isoform activity.
  • Genetic modification significantly extended median and maximum lifespan and improved healthspan in male killifish.
  • Upregulation of healthspan and lifespan-associated genes and pathways was observed.

Conclusions:

  • The uORF-mediated regulation of C/EBPα is evolutionarily conserved.
  • Targeting this conserved mechanism can modulate lifespan and aging phenotypes.
  • This study provides a conserved molecular basis for lifespan extension and improved healthspan.