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Our previous study on immune-related changes in the aged liver described immune cell infiltration and elevation of inflammation with age. Levels of interferon (IFN)-γ, a known cell cycle inhibitor, were elevated in the aging liver. Here, we determine the role played by IFN-γ in the delayed regenerative response observed in the aged livers. We observed elevated IFN signaling in both aged hepatocytes and regenerating livers post-partial hepatectomy. In vivo deletion of the major IFN-γ producers-the macrophages and the natural killer cells, leads to a reduction in the IFN-γ levels accompanied with the restoration of the DNA synthesis kinetics in the aged livers. Eighteen-month-old IFN-γ-/- mice livers, upon resection, exhibited an earlier entry into the cell cycle compared with age-matched controls. Thus, our study strongly suggests that an age-related elevation in inflammatory conditions in the liver often dubbed as "inflammaging" has a detrimental effect on the regenerative response.

Elevated Interferon Gamma Signaling Contributes to Impaired Regeneration in the Aged Liver