TNFa is a trigger of aging-associated liver inflammation in mice

Tumor necrosis factor a (TNFa) has been shown to be a key regulator of inflammation in metabolic diseases and is discussed to be critical in aging associated inflammation (= inflammaging). Here, we assessed the role of TNFa on the natural course of aging-related liver inflammation and fibrosis and determined related mechanisms. First, liver histology, markers of senescence and Tnfa mRNA expression were assessed in livers of aging male C57BL/6J mice. In a second study, markers of senescence, liver damage, intestinal barrier function and intestinal microbiota composition were determined in 4 and 24 months old male TNFa-/- and wild-type mice. Moreover, effects of TNFa on small intestinal barrier function was assessed. Aging was related with the development of inflammatory alterations in liver tissue and a significant increase in p16 and p21 as well as Tnfa mRNA expression in liver tissue. When compared to age-matched wild-type mice, 24 months old TNFa-/- mice were significantly protected from the increase in markers of senescence and inflammation as well as fibrosis in liver. This protection was related with a protection from the increase in small intestinal permeability and bacterial endotoxin. Old age TNFa-/- mice showed no loss of intestinal stem cell markers and decrease in a-diversity of microbiota in small intestine compared to age-matched wild-type mice. Employing an ex vivo small intestinal everted sac model, it was further shown, that TNFa alters permeability and tight junction protein levels through c-jun n-terminal kinases (JNK)-dependent signaling pathways. Taken together, our results suggest that TNFa is critical in the development of aging-related liver decline .