Are Senescent Cells an Important Cause of Non-Alcoholic Fatty Liver Disease Pathology?

Raised levels of senescent cells are found in the liver of patients and animal models exhibiting non-alcoholic fatty liver disease (NAFLD), which progresses to the more serious nonalcoholic steatohepatitis (NASH). These conditions are a consequence of obesity, which is also correlated with a higher burden of senescent cells throughout the body, and particularly in fat deposits. Senescent cells secrete signals that provoke chronic inflammation and disrupt tissue structure and function. They are an important contributing cause of aging and age-related disease. In this sense, we might think of many of the consequences of obesity as literally accelerated aging. In conditions like NAFLD and NASH, however, it is less clear that senescence is a major cause of pathology, versus being a downstream consequence that produces further harms. That will most likely be settled by studies and trials in which animals and patients are given senolytic drugs to clear senescent cells; any major improvement or prevention will argue for an important role for senescent cells in this condition.

Data from studies in rodents and humans have shown that NAFLD is accompanied by an increase in senescent cells in the liver, and that the number of senescent cells is associated with a more advanced disease state. Despite the strong associations between senescence and NAFLD in humans and the work derived from in vitro studies and rodents, it remains to be determined if hepatic senescence is a mere consequence of the metabolic dysregulation and inflammatory phenomena in NAFLD or a causal player in the development of this disease.

Although a causal role of cellular senescence must be further substantiated and subsequently established in humans, this pathophysiological process holds great potential, particularly when bearing in mind that there is currently no effective treatment for NAFLD. Targeting senescence has emerged as an attractive therapeutic target for NAFLD since senescence might be involved in the full spectrum of the disease (i.e. from early steatosis to cirrhosis). Moreover, senolytic drugs can be administrated intermittently, thereby minimising potential toxic effects and increasing adherence in the individual often affected by multiple morbidities and thus treated with multiple medications.

Nevertheless, clinical trials conducted in individuals with NAFLD using senolytics have not been performed. Such trials are needed to better define the benefits and potential risks of these drugs. To increase efficacy and accuracy of these clinical trials, new or composite assays are needed, and development of these assays should be a top priority for the field.


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