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<p>Before human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, <i>COL25A1</i>. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in <i>COL25A1</i>, into <i>col-99</i>, the <i>C. elegans</i> ortholog, extended lifespan. These <i>col-99(gk694263</i>[S106L]<i>)</i> SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we find that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong <i>C. elegans</i>’ lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in <i>COL25A1</i> influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity.</p>

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A centenarian single nucleotide polymorphism in collagen gene COL25A1 promotes longevity in C. elegans

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月30日

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  • Anita Goyala,
  • Cyril Statzer,
  • Ji Young Cecilia Park,
  • Ines Neundorf,
  • Michael R. MacArthur,
  • Jan M. Gebauer,
  • Collin Y. Ewald

摘要

Before human genome sequencing, a genome-wide study of sibling centenarian pairs identified a longevity-associated locus on chromosome 4. Here, we mapped the genes in this locus and identified a collagen gene, COL25A1. Introducing an SNP linked to longevity that changes a serine predicted to be phosphorylated to leucine in COL25A1, into col-99, the C. elegans ortholog, extended lifespan. These col-99(gk694263[S106L]) SNP-mutants exhibited enhanced innate immune-related transcriptional responses, and their lifespan extension was abolished by inhibiting the p38 MAPK pathway. YAP-1, a transcriptional co-activator responsive to extracellular matrix changes, was essential for this longevity. Mechanistically, we find that this SNP modifies furin-mediated cleavage of this transmembrane collagen in vitro, and expressing the cleaved extracellular domain of COL-99 alone was sufficient to prolong C. elegans’ lifespan. These findings reveal a potential mechanism by which a human centenarian-associated SNP in COL25A1 influences furin cleavage and shedding of the collagen ectodomain to promote healthy longevity.