Age-related proteomic profiling of livers from Caspase-2 deficient mice

Caspase-2 function in liver homeostasis is influenced by its important role in mitotic catastrophe to prevent survival and accumulation of aneuploid and polyploid cells. While loss of caspase-2 promotes hepatocyte polyploidy, it is unclear how this influences liver homeostasis with ageing. To address this, this project examined age-related liver proteomic changes, in caspase-2 deficient mice (knockout and catalytic cytsteine mutant- C320S), comparing protein abundance in young (3-month-old) and ageing (12 and 18-month-old) mice. We describe changes in several cell-cycle related and inflammation-related proteins that are associated with early hepatocyte hyperpolyploidy in young caspase-2- deficient mice, as well as increased liver disease in ageing caspase-2 deficient mice. These findings demonstrate that caspase-2 catalytic activity is critical for age-related liver homeostasis by preventing pathogenic hyperpolyploidy, tissue inflammation, tissue damage and survival of pre-neoplastic cells.