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Six Drivers of Aging Identified Among Genes Differentially Expressed With Age

Ariella Coler-Reilly,Zachary Pincus,E. Scheller,Roberto Civitelli

Published 2025 in Aging Cell

ABSTRACT

Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most chronic diseases. However, these studies only identify associations without distinguishing drivers of aging from compensatory geroprotective responses or incidental downstream effects. Here, we introduce a workflow to characterize causal effects of differentially expressed genes on lifespan. First, we performed a meta‐analysis of 25 gene expression datasets comprising samples of various tissues from healthy, untreated adult mammals (humans, dogs, and rodents) at two distinct ages. Genes were ranked by the number of datasets in which they exhibited consistent differential expression with age. The top age‐upregulated genes were TMEM176A, EFEMP1, CP, and HLA‐A; the top age‐downregulated genes were CA4, SIAH, SPARC, and UQCR10. Second, the effects of the top ranked genes on lifespan were measured by applying post‐developmental RNA interference of the corresponding ortholog in Caenorhabditis elegans. Out of 10 age‐upregulated and 9 age‐downregulated genes that were tested, two age‐upregulated genes (csp‐3/CASP1 and spch‐2/RSRC1) and four age‐downregulated genes (C42C1.8/DIRC2, ost‐1/SPARC, fzy‐1/CDC20, and cah‐3/CA4) produced significant and reproducible lifespan extension. Notably, the data do not suggest that the direction of differential expression with age is predictive of the effect on lifespan. Our study provides novel insight into the relationship between differential gene expression and aging phenotypes, pilots an unbiased workflow that can be easily repeated and expanded, and pinpoints six genes with evolutionarily conserved, causal roles in the aging process for further study.

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