TNFα is a trigger of aging-associated liver inflammation in mice.

Tumor necrosis factor α (TNFα) regulates inflammation in metabolic diseases and probably aging-associated inflammation. Here, TNFα´s role in aging-related liver inflammation and fibrosis and underlying mechanisms was assessed in mice. In male C57BL/6J mice, aging increased hepatic inflammation, senescence markers p16 and p21 and Tnfa mRNA expression in liver tissue. In a second study, 4 and 24-month-old TNFα(-/-) and wild-type (WT) mice were compared for senescence, liver damage, intestinal barrier function, and microbiota composition. 24-month-old TNFα(-/-) mice were significantly protected from the aging-associated increase in hepatic senescence, inflammation and fibrosis found in WT mice. This protection was related with preserved stem cell marker expression, maintained small intestinal barrier function and lower bacterial endotoxin in portal blood. While differing from young mice, intestinal microbiota composition of old TNFα(-/-) mice differed markedly from age-matched WT mice. Also, TNFα was found to alter permeability and tight junction protein levels being reversed by the presence of an JNK inhibitor in an ex vivo intestinal tissue model. Taken together, our results suggest that TNFα plays a key role in the development of aging-related liver decline in male mice.