The Role of Senescence in the Development of Nonalcoholic Fatty Liver Disease and Progression to Nonalcoholic Steatohepatitis

Abstract

In recent years, cellular senescence has generated a lot of interest among researchers because of its involvement in both the normal aging process and common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, and genomic and mitochondrial DNA damage, leading to irreversible cell cycle arrest, and secretion of proinflammatory cytokines. Evidence suggests that the complex process of senescence is involved in the development of a plethora of chronic diseases including metabolic and inflammatory disorders and tumorigenesis. Recently, several human and animal studies have emphasized the involvement of senescence in the pathogenesis and development of liver steatosis including the progression to nonalcoholic steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning, and liver fibrosis. The development of nonalcoholic fatty liver disease (NAFLD) and its progression to NASH are commonly accompanied by several pathophysiological events including metabolic dysregulation and inflammatory phenomena occurring within the liver that may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. Conclusion: In this review, we summarize the current literature on the impact of cellular senescence in NAFLD/NASH and discuss the effectiveness and safety of novel senolytic drugs and therapeutic options available to delay or treat the disease. Finally, we identify the open questions and issues to be addressed in the near future.

Short Telomeres: Cause and Consequence in Liver Disease

“…35 However, in cirrhotic hepatocytes telomeres were found to be shorter, there was minimal telomerase activity, and there were multiple markers of cellular senescence present, such as p16 and β-galactosidase. [36][37][38][39] These findings suggest that cirrhosis is driven by impaired regeneration and accelerated progression of fibrosis, which could be the result of either genetically shortened telomeres or chronic liver disease due to a secondary etiology as previously discussed. 5 The most commonly identified genetic mutation in STSassociated cirrhosis is in TERT.…”

Aging and Chronic Liver Disease

“…88 Senescence, as a potential mechanism involved in the pathogenesis of different CLD, like MAFLD/MASH, has generated high interest among researchers. 89,90 In MAFLD, it has been shown that fat accumulation in hepatocytes promotes telomere shortening and DNA damage, which may be mediated by oxidative stress, and induces senescence in this cell type. 91 However, senescent cells also promote hepatic fat accumulation and steatosis.…”

Development of an in vitro senescent hepatic cell model for metabolic studies in aging

“…In this regard, senescent AML12 cells would be useful to identify SASPs and understand their roles in causing inflammation in hepatic cells. These cells also could be useful for understanding the pathological molecular and metabolic changes that occur in age-related chronic hepatic diseases such as NASH, hepatic cirrhosis, and HCC, as well as for screening nutraceuticals and pharmaceuticals that might be useful to treat the pathological features associated with aging and senescence, and their associated metabolic conditions [4,16,17,48,49,51,52].…”

“…Moreover, aging has been positively associated with increased risk and poor prognosis of various liver diseases including non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, hepatitis C, and negatively associated with hepatic regenerative capacity [3,4]. Thus, the study of aging and chronic hepatic diseases has been hampered by the long period of time necessary to conduct human and animal studies, and the limited relevance of non-mammalian models to human diseases.…”