Journal Article

Cellular senescence drives age-dependent hepatic steatosis

Tchkonia, Tamar, Palmer, Allyson, Grellscheid, Sushma Nagaraja, Day, Christoper P., Burt, Alastair, Miwa, Satomi, Bird, Thomas G., von Zglinicki, Thomas, Anstee, Quentin M., Ogrodnik, Mikolaj, Wilson, Caroline L., Hoeijmakers, Jan H J., Kirkland, James L., Barnhoorn, Sander, Mann, Derek A., Lahat, Albert, Passos, João F., Tiniakos, Dina, Jurk, Diana, Vermeij, Wilbert P.

2017

Overview

The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16 Ink4a -expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis. Conversely, inducing hepatocyte senescence promotes fat accumulation in vitro and in vivo . Mechanistically, we show that mitochondria in senescent cells lose the ability to metabolize fatty acids efficiently. Our study demonstrates that cellular senescence drives hepatic steatosis and elimination of senescent cells may be a novel therapeutic strategy to reduce steatosis. Non-alcoholic fatty liver disease is more common among older individuals. Here, the authors show that senescent cells in the liver promote fat accumulation and steatosis in the liver, and that clearance of senescent cells reduces hepatic steatosis in old, obese or diabetic mice.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/51 / 14/32 / 14/63 / 631/443/7 / 631/80/509 / 64/60 / 692/699/1503/1607/2751 / 96/34 / Ablation / Accumulation / Age / Animals / Apoptosis - drug effects / Cells, Cultured / Cellular Senescence - drug effects / Correlation / Cyclin-Dependent Kinase Inhibitor p16 - metabolism / Cytokines / Dasatinib - chemistry / Degeneration / Drugs / Fatty acids / Fatty liver / Fatty Liver - metabolism / Fatty Liver - pathology / Fibroblasts - metabolism / Hepatocytes - cytology / Humanities and Social Sciences / In vitro methods and tests / Incidence / Inflammation / INK4a protein / Liver / Liver - metabolism / Liver diseases / Male / Markers / Mice / Mice, Inbred C57BL / Mice, Transgenic / Mitochondria / Mitochondria - metabolism / multidisciplinary / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - pathology / p16 Protein / Quercetin / Quercetin - chemistry / Rodents / Science / Science (multidisciplinary) / Senescence / Steatosis / Suicide / Suicide genes