Transcriptome-Wide Analysis of Human Liver Reveals Age-Related Differences in the Expression of Select Functional Gene Clusters and Evidence for a PPP1R10-Governed 'Aging Cascade'.

A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, pinpointing major age-related alterations in hepatic gene expression may identify ontogenetic shifts with important hepatic and systemic con-sequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of ontogeny and individual decline. By applying next-generation sequencing and subsequent statistical and bioinformatic [Ensemble Feature Selection (EFS)] analysis, we identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464; EFS score >0.3: 16 transcripts; EFS score >0.2: 28 transcripts) differ between young and old livers. Genes encoding for 25 of these highly age-related transcripts were assigned to the categories 'regulome', 'in-flammaging', 'regeneration', and 'pharmacogenes', plus two genes that did not match these cate-gories. Our results have major implications in the area of ontogeny/aging and for the age-dependently increased occurrence of non-alcoholic fatty liver, steatohepatitis, and hepatocellular carcinoma. In addition, we present a broadly substantiated and testable hypothesis on a genetical-ly governed 'aging cascade', wherein the protein phosphatase 1 regulatory subunit 10 (PPP1R10) gene acts as a putative ontogenetic master regulator, which is prominently flanked by the genes for the insulin-like growth factor-binding protein acid labile subunit (IGFALS) and dual specificity phosphatase 1 (DUSP1). The results of this transcriptome-wide analysis of human liver offer potential clues towards developing better therapeutic interventions against major liver diseases and increased insight into key mechanisms underlying aging. Overall design: Examination of differences in gene expression of human livers from 9 patients below age of 49 years and 8 patients older than 74 years.