Cellular Senescence and Their Role in Liver Metabolism in Health and Disease: Overview and Future Directions

Abstract

Chronic liver disease has globally risen mainly due to a prevalent hepatitis C virus (HCV) infection rate and an epidemic of obesity. It is estimated by the year 2030, 2.2 billion people around the world will be overweight and 1.1 billion people will be obese. Diabetes and obesity are the main risk factors for the development of the metabolic syndrome and in the liver of non-alcoholic fatty liver disease (NAFLD) which could progress to non-alcoholic fatty steatohepatitis (NASH) related cirrhosis and liver malignancy. At present there is not effective therapy for NASH besides loss of weight and exercise. Furthermore, optimal management of HCC with curative intent includes resection or liver transplantation. Nevertheless, these therapies are limited because the degree of liver dysfunction or the medical conditions at the time of diagnosis and the scarcity of available liver grafts. The role of cellular lipid management and metabolism in human health and disease is taking a center stage. The present overview articulates the current pathophysiology of fatty liver disease under the aging processes, potential biological markers of liver disease diagnosis and progression and future therapies.

Ferroptosis resistance cooperates with cellular senescence in the overt stage of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis

“… 41 However, the accumulation of senescent cells in a tissue is associated with the onset and progression of many degenerative and chronic diseases, such as Parkinson’s disease, atherosclerosis, and osteoporosis. 5 , 12 , 17 In line with this data, the use of senolytic drugs is a promising therapeutic strategy to treat these pathologies. 42 Senescence is induced by endogenous and exogenous stimuli that cause DNA damage, culminating in irreversible cell cycle arrest and senescence initiation.…”

“…In this context, it is increasingly accepted that senescence is associated with other events, including ferroptosis, a newly-discovered form of irondependent programmed cell death. Although it is well-known that both senescence and ferroptosis are involved in the progression of aging or age-related pathologies, including NAFLD/NASH, 2 , 17 , 32 , 40 the true relationship between these two processes is still poorly characterized, especially in the overt stage of liver degeneration and NASH. In this paper, we describe the ferroptotic-resistant phenotype of the senescent cells in the NAFLD/NASH background, thus refuting the hypothesis of ferroptosis activation, at least in the context of the overt NAFLD/NASH stage.…”

“…15,16 Lipid storage in hepatocytes is able to induce an increase in reactive oxygen species (ROS), accelerating apoptosis and senescence, thereby contributing to progressive organ decline and the development of disease. 17 Additionally, ROS accumulation is associated with a recentlyidentified form of non-apoptotic cell death, known as ferroptosis. This process is mechanistically and biochemically distinct from apoptosis, necrosis and autophagic cell death.…”

“… 15 , 16 Lipid storage in hepatocytes is able to induce an increase in reactive oxygen species (ROS), accelerating apoptosis and senescence, thereby contributing to progressive organ decline and the development of disease. 17 …”

Late-life isoleucine restriction promotes physiological and molecular signatures of healthy aging

“…Cellular senescence plays a large role in promoting several aging phenotypes of the liver, including fibrosis and non-alcoholic fatty liver disease (Matthew et al, 2017). To characterize the molecular remodeling that occurs in the aged liver induced by the two dietary interventions, we performed real time quantitative PCR (rt-qPCR) for gene expression level changes of well-established senescence-associated markers in male mice.…”