# Six Drivers of Aging Identified Among Genes Differentially Expressed With Age

## TL;DR

This study identifies six genes that consistently change with age and shows they have causal roles in aging by testing their effects on lifespan in worms.

## Contribution

A novel workflow combining meta-analysis and functional testing in C. elegans to identify evolutionarily conserved aging drivers.

## Key findings

- 45 genes were consistently differentially expressed with age across 25 datasets.
- Six genes showed significant lifespan extension when tested in C. elegans.
- Age-related gene expression direction does not predict lifespan effects.

## 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.

A meta‐analysis of 25 transcriptomic datasets from mammalian tissues revealed 45 genes consistently upregulated or downregulated with age. Orthologs of these genes were functionally evaluated using
Caenorhabditis elegans
lifespan screens to reveal those with causal roles in the aging process, thus identifying six evolutionarily conserved drivers of aging.