Cellular senescence drives age-dependent hepatic steatosis
By M. Ogrodnik, Satomi Miwa, T. Tchkonia, D. Tiniakos, Caroline L. Wilson, Albert Lahat, C. Day, A. Burt, Allyson K. Palmer, Q. Anstee and 10 more. Nature Communications, 2017
924 citations recorded by the source corpus.
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 p16Ink4a-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.
Subfields: Cancer Research, Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/24bd5124ada35500a9ff5d26b022ac9f0237c3fe
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Citations in the corpus
- Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “The elimination of senescent cells using INK-ATTC mice reduces liver fat accumulation (Ogrodnik et al., 2017).”
- Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Loomba et al. found that a set of 152 differentially methylated CpG islands in the peripheral blood-DNA of NASH patients correlate with the severity of hepatic fibrosis and that this DNA methylation signature is associated with the age-related acceleration of NASH in patients.74 However, demethylati”