Goyala, Anita, Statzer, Cyril, Park, Ji Young Cecilia, Neundorf, Ines, MacArthur, Michael R, Gebauer, Jan M and Ewald, Collin Y (2025) A centenarian single nucleotide polymorphism in collagen gene COL25A1 promotes longevity in C. elegans. npj aging, 11 (1). p. 81. ISSN 2731-6068

Abstract

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.

Item Type:	Article
Date Deposited:	14 Nov 2025 00:45
Last Modified:	14 Nov 2025 00:45
URI:	https://oak.novartis.com/id/eprint/57926