Senescence explains age- and obesity-related liver steatosis

Abstract

Cellular senescence, the irreversible loss of replicative potential of somatic cells, was first described in fibroblasts cultured in vitro by Leonard Hayflick more than 50 years ago. Since then, the field of cellular senescence has witnessed a meteoric rise, with multiple studies highlighting its importance in varied physiological contexts such as cancer, development and ageing. A major recent development in the senescence field has been the creation of mouse models which allow the specific elimination of senescent cells. These genetic tools have allowed scientists, for the first time, to conduct proof-of-principle investigations into the causal impact of senescence during the ageing process and in the context of several age-related diseases. Furthermore, these experiments provided the rationale for the development of a new class of drugs named "senolytics", that can specifically kill senescent cells, which are now of great interest to academics and pharma companies alike. Non-alcoholic fatty liver disease (NAFLD) is more prevalent in the older and obese population and unrelated to alcohol consumption. It can be characterized by simple liver fat accumulation (steatosis) but it can progress to more severe stages such as non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Previous studies have demonstrated that during ageing and NAFLD, hepatocytes accumulate markers of cellular senescence. However, until now, it was unclear whether senescence was a cause or consequence of liver disease.

Keywords: NAFLD; ageing; senescence; senolytic.

Figure 1. FIGURE 1: Treatment scheme for obese and ageing animals.

(A) db/db mice were treated with D+Q for 2 months until 6 months of age. (B) Wild-type mice underwent several dietary restriction regimes. (C) Ink-ATTAC mice under high fat diet were treated with AP20187 for 4 months and (D) ageing Ink-ATTAC mice were treated for 3 months wit AP20187 or D+Q.

Figure 2. FIGURE 2: Impaired fatty acid oxidation in senescent cells leads to increased fat storage. Induction of cellular senescence induces mitochondrial dysfunction and impaired fatty acid oxidation, thus contributing to increased cytosolic fat accumulation (lipid droplets).