• Collagen gene downregulation is a conserved and robust hallmark of aging in C. elegans . • Longevity interventions consistently induce collagen expression across 66 transcriptomic datasets. • Expression-based clustering reveals distinct collagen programs linked to aging and longevity. • Aging-associated collagens map to hypodermal programs, while longevity collagens enrich in intestine. • Multi-omics integration identifies collagens as dynamic regulators of extracellular matrix remodeling during aging. Collagens, long regarded as structural molecules, also regulate stress responses and longevity. In this study, we analyzed our RNA sequencing data and publicly available gene expression data to define their role in Caenorhabditis elegans aging. Collagen expression broadly declined with age, with 16 collagen genes consistently downregulated across independent studies, establishing collagen downregulation as a genetic hallmark of aging. In contrast, meta -analysis of 66 datasets (128 comparisons between normal and long-lived animals) showed collagen upregulation in 84% of long-lived conditions, identifying collagen induction as a conserved signature of lifespan extension. Using π-values to integrate fold change and significance of collagen gene expression, we applied K-means clustering and identified Euclidean-based clusters that captured functional, tissue-associated subsets of collagens. Notably, aging-associated collagens were strongly enriched in Euclidean Cluster 1, which overlapped with hypodermal collagens, while Cluster 2 significantly intersects with lifespan-extension and intestine-enriched subsets, and Cluster 3 likely represents structural collagens contributing to cuticle and muscle integrity. These results indicate that collagen genes grouped by expression-based clustering are not randomly distributed but instead reflect tissue-specific patterns and functionality. Together, our findings suggest that collagens are dynamic regulators of aging and longevity in C. elegans . Given the conservation of extracellular matrix biology across species, collagens represent candidate biomarkers and targets for promoting healthy aging in both C. elegans and higher animals.
Wang et al. (Sun,) studied this question.