Network-level analysis of ageing and its relationship with diseases and tissue regeneration in the mouse liver

The liver plays a vital role in maintaining whole-body metabolic homeostasis, compound detoxification and has the unique ability to regenerate itself post-injury. Ageing leads to functional impairment of the liver and predisposes the liver to non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC). Mapping the molecular changes of the liver with ageing may help to understand the crosstalk of ageing with different liver diseases. A systems-level analysis of the ageing-induced liver changes and its crosstalk with liver-associated conditions is lacking. In the present study, we performed network-level analyses of the ageing liver using mouse transcriptomic data and a protein-protein interaction (PPI) network. A sample-wise analysis using network entropy measure was performed, which showed an increasing trend with ageing and helped to identify ageing genes based on local entropy changes. To gain further insights, we also integrated the differentially expressed genes (DEGs) between young and different age groups with the PPI network and identified core modules and nodes associated with ageing. Finally, we computed the network proximity of the ageing network with different networks of liver diseases and regeneration to quantify the effect of ageing. Our analysis revealed the complex interplay of immune, cancer signalling, and metabolic genes in the ageing liver. We found significant network proximities between ageing and NAFLD, HCC, liver damage conditions, and the early phase of liver regeneration with common nodes including NLRP12, TRP53, GSK3B, CTNNB1, MAT1 and FASN. Overall, our study maps the network-level changes of ageing and their interconnections with the physiology and pathology of the liver.