Cellular senescence drives age-dependent hepatic steatosis

Abstract

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.

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…The senolytic activities and efficacies of some drugs have already been confirmed in mouse disease models (Childs et al, 2016; Farr et al, 2017; Jeon et al, 2017; Ogrodnik et al, 2017; Roos et al, 2016; Schafer et al, 2017). We used the anti‐apoptotic Bcl‐2 family inhibitor, ABT‐263, in the PPE‐induced emphysema model.…”

“…The targeting of senescent cells through a semi‐genetic approach extends the health span by ameliorating the aging‐associated phenotypes of kidney, eye, heart, bone, and lung tissues in wild‐type or progeria model mice (Baar et al, 2017; Baker et al, 2016; Farr et al, 2017; Hashimoto et al, 2016). In addition, senescent cell elimination alleviates pathologies in disease models, which include those of atherosclerosis, idiopathic pulmonary fibrosis (IPF), hepatic steatosis, and osteoarthritis (Childs et al, 2016; Jeon et al, 2017; Ogrodnik et al, 2017; Schafer et al, 2017). As the removal of senescent cells has beneficial effects on the maintenance of tissue homeostasis and the prevention of diseases in mice, senescent cells are expected to have potential as therapeutic targets for these diseases.…”

“…The efficacy of drugs that induce senescent cell death, namely senolytic drugs, has been demonstrated in several mouse disease models. The combination of dasatinib and quercetin, which inhibits pro‐survival kinase pathways, ameliorates cardiovascular and vasomotor functions (Roos et al, 2016; Zhu et al, 2015), hepatic steatosis (Ogrodnik et al, 2017), and IPF (Schafer et al, 2017), similar to the semi‐genetic elimination of senescent cells. The anti‐apoptotic bcl‐2 family protein inhibitors ABT‐263/737 are effective in atherosclerosis and osteoarthritis models (Childs et al, 2016; Jeon et al, 2017) and improve stem cell functions and other aging‐associated phenotypes (Chang et al, 2016; Yosef et al, 2016).…”

Tau protein aggregation is associated with cellular senescence in the brain

“…Control and tau NFT ‐Mapt 0/0 mice aged 19–20 months were randomized to receive DQ senolytic (5 mg/kg dasatinib [LC Laboratories, Woburn, MA] with 50 mg/kg quercetin [Sigma‐Aldrich]) or vehicle (60% Phosal 50 PG, 30% PEG 400%, and 10% ethanol) via oral gavage as described previously (Ogrodnik et al, 2017). Mice were weighed and fasted for 2 hr prior to treatment.…”

Oxidation resistance 1 is a novel senolytic target

“…This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age‐related diseases and disorders in both progeroid and naturally aged mice (Baker et al., 2011, 2016). Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti‐aging strategy and a new treatment for chemotherapy‐ and radiotherapy‐induced side effects (Baar et al., 2017; Chang et al., 2016; Childs et al., 2016; Demaria et al., 2017; Jeon et al., 2017; Ogrodnik et al., 2017; Pan et al., 2017; Schafer et al., 2017; Yosef et al., 2016; Zhu et al., 2015). …”