Hepatic senescence, the good and the bad

Abstract

Gradual alterations of cell's physiology and functions due to age or exposure to various stresses lead to the conversion of normal cells to senescent cells. Once becoming senescent, the cell stops dividing permanently but remains metabolically active. Cellular senescence does not have a single marker but is characterized mainly by a combination of multiple markers, such as, morphological changes, expression of cell cycle inhibitors, senescence associated β-galactosidase activity, and changes in nuclear membrane. When cells in an organ become senescent, the entire organism can be affected. This may occur through the senescence-associated secretory phenotype (SASP). SASP may exert beneficial or harmful effects on the microenvironment of tissues. Research on senescence has become a very exciting field in cell biology since the link between age-related diseases, including cancer, and senescence has been established. The loss of regenerative and homeostatic capacity of the liver over the age is somehow connected to cellular senescence. The major contributors of senescence properties in the liver are hepatocytes and cholangiocytes. Senescent cells in the liver have been implicated in the etiology of chronic liver diseases including cirrhosis and hepatocellular carcinoma and in the interference of liver regeneration. This review summarizes recently reported findings in the understanding of the molecular mechanisms of senescence and its relationship with liver diseases.

Keywords: Cell cycle arrest; Cholangiocyte; DNA damage; Hepatic stellate cell; Hepatocyte; Senescence; Senescence associated secretory phenotype.

Figure 1

Stress-induced senescence. Both external and internal stresses can induce DNA damage and the activation of p16^INK4A and/or p15^INK4B. DNA damage can activate p53 ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) pathway. Activated p53 induces p21 ^Cip1 expression. Expression of p21^Cip1 can also be regulated by p53-independent mechanisms. The Cyclin dependent kinases activate Rb but are inhibited by p15^INK4B/ p16^INK4A and p21^Cip1 which leads to cell cycle arrest and senescence. The senescent cells express senescence-associated secretory phenotype (SASP). The SASP factors may induce senescence in neighboring cells in a paracrine fashion. ATM: Ataxia telangiectasia mutated; SASP: Senescence-associated secretory phenotype.

Figure 2

Senescence-associated secretory phenotype signaling pathways. Nuclear factor kappa light chain enhancer of activated B cells can be activated via multiple signaling pathways such as the GATA binding protein 4, cyclic GMP-AMP synthase-stimulator of interferon genes, and nicotinamide adenine dinucleotide -nicotinamide phosphoribosyltransferase NAD⁺-NAMT pathways, which lead to the expression of senescence-associated secretory phenotype (SASP) proteins. SASP can be positively regulated through C-X-C motif chemokine receptor 2, or negatively by NOTCH via CCAAT-enhancer-binding proteins. SASP can induce senescence in both autocrine and paracrine manners. SASP can be anti-tumorigenic in the early phase of senescence, but can be pro-tumorigenic in the late phase of senescence. NF-κB: Nuclear factor kappa light chain enhancer of activated B cells; GATA4: GATA binding protein 4; cGAS-STING: Cyclic GMP-AMP synthase-stimulator of interferon genes; SASP: Senescence-associated secretory phenotype; CXCR2: C-X-C motif chemokine receptor 2; C/EBP: CCAAT-enhancer-binding protein.