人类肝脏的转录组范围分析揭示了所选功能基因簇表达的年龄相关差异以及PPP1R10控制的“衰老级联”的证据。

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.