Many studies have compared gene expression in young and old samples to gain insights on aging, the primary risk factor for most major chronic diseases. However, these studies only describe associations, failing to distinguish drivers of aging from compensatory geroprotective responses and incidental downstream effects. Here, we introduce a workflow to characterize the 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. We ranked each gene according to the number of distinct datasets in which the gene was differentially expressed with age in a consistent direction. 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 the nematode C. elegans (two trials, with roughly 100 animals per genotype per trial). Out of 10 age-upregulated and 9 age-downregulated genes that were tested, two age-upregulated genes (

Six drivers of aging identified among genes differentially expressed with age