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Six Drivers of Aging Identified Among Genes Differentially Expressed With Age
Ariella Coler-Reilly1,2,3, Zachary Pincus4,5, Erica L Scheller1,2,4,6
1Division of Bone and Mineral Diseases, Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.
Aging Cell
|October 13, 2025
Summary
This study reveals six genes causally impacting lifespan by analyzing gene expression changes in aging mammals and testing their effects in C. elegans. Direction of age-related gene expression doesn't predict lifespan impact.
Area of Science:
- Genomics
- Aging Research
- Molecular Biology
Background:
- Aging is linked to chronic diseases, but gene expression studies often show associations, not causation.
- Distinguishing aging drivers from compensatory responses is crucial for understanding aging.
- Current methods struggle to identify genes with causal effects on lifespan.
Purpose of the Study:
- To develop and apply a workflow for characterizing the causal effects of differentially expressed genes on lifespan.
- To identify genes that play a conserved, causal role in the aging process.
- To investigate the relationship between age-related gene expression changes and lifespan.
Main Methods:
- Performed a meta-analysis of 25 mammalian gene expression datasets comparing young and old samples.
- Ranked genes based on consistent differential expression across multiple datasets and tissues.
- Utilized RNA interference in *C. elegans* to test the causal impact of top-ranked genes on lifespan.
Main Results:
- Identified top age-upregulated (e.g., TMEM176A, EFEMP1) and age-downregulated (e.g., CA4, SPARC) genes across mammals.
- Discovered six genes (two age-upregulated, four age-downregulated) that significantly extended *C. elegans* lifespan upon manipulation.
- Found no correlation between the direction of age-related gene expression and its effect on lifespan.
Conclusions:
- The developed workflow successfully identifies genes with causal roles in aging and lifespan.
- Six genes (CASP1, RSRC1, DIRC2, SPARC, CDC20, CA4) show conserved, causal effects on lifespan.
- The direction of differential gene expression with age is not a reliable predictor of lifespan impact.
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