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’
Thomas Schreiter,
Robert K. Gieseler,
Ramiro Vílchez-Vargas,
Ruy Jauregui,
Jan-Peter Sowa,
Susanne Klein-Scory,
Ruth Broering,
Roland S. Croner,
Jürgen W. Treckmann,
Alexander Link,
Ali Canbay
Affiliations
Thomas Schreiter
Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
Robert K. Gieseler
Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
Ramiro Vílchez-Vargas
Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany
Ruy Jauregui
Data Science Grasslands, Grasslands Research Centre, AgResearch, Palmerston North 4410, New Zealand
Jan-Peter Sowa
Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
Susanne Klein-Scory
Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
Ruth Broering
Department of Gastroenterology and Hepatology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Roland S. Croner
Department of General, Visceral, Vascular and Transplantation Surgery, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany
Jürgen W. Treckmann
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Alexander Link
Department of Gastroenterology, Hepatology, and Infectious Diseases, Medical Faculty, Otto-von-Guericke University, 39120 Magdeburg, Germany
Ali Canbay
Department of Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44892 Bochum, Germany
A transcriptome-wide analysis of human liver for demonstrating differences between young and old humans has not yet been performed. However, identifying major age-related alterations in hepatic gene expression may pinpoint ontogenetic shifts with important hepatic and systemic consequences, provide novel pharmacogenetic information, offer clues to efficiently counteract symptoms of old age, and improve the overarching understanding of individual decline. Next-generation sequencing (NGS) data analyzed by the Mann–Whitney nonparametric test and Ensemble Feature Selection (EFS) bioinformatics identified 44 transcripts among 60,617 total and 19,986 protein-encoding transcripts that significantly (p = 0.0003 to 0.0464) and strikingly (EFS score > 0.3:16 transcripts; EFS score > 0.2:28 transcripts) differ between young and old livers. Most of these age-related transcripts were assigned to the categories ‘regulome’, ‘inflammaging’, ‘regeneration’, and ‘pharmacogenes’. NGS results were confirmed by quantitative real-time polymerase chain reaction. Our results have important implications for the areas of ontogeny/aging and the age-dependent increase in major liver diseases. Finally, we present a broadly substantiated and testable hypothesis on a genetically governed ‘aging cascade’, wherein PPP1R10 acts as a putative ontogenetic master regulator, prominently flanked by IGFALS and DUSP1. This transcriptome-wide analysis of human liver offers potential clues towards developing safer and improved therapeutic interventions against major liver diseases and increased insights into key mechanisms underlying aging.
