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Aging/HIV & Senescence; NASH
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Aging itself, induces cellular senescence leading to development and disease progression of NAFLD through several pathways(1,4,43). Age-related mitochondrial dysfunction and elevated oxidative stress trigger fatty liver disease in aged mice on a HFD(44).
The term "senescence" derives from the Latin word "senex" meaning a man of old age. Cellular senescence describes a decline in cell division capacity whereby normal diploid differentiated cells enter a state of cell cycle arrest and lose their ability to proliferate (1,2). It is triggered by DNA damage in chromosomes and telomeres, provoked by internal or external stimuli such as aging, oncogene expression and reactive oxygen species(ROS) accumulation or radiation and chemotherapies respectively (3,4).
Cellular senescence is a complex process that has a dual function, both beneficial and detrimental in human health. Under physiological conditions, senescence eliminates damaged cells and is involved in tissue restoration upon acute stress or injury.
Metabolic dysregulation is thought to favor cellular senescence in metabolic tissues, such as the AT and the pancreas, further perpetuating a status of metabolic dyshomeostasis of these tissues.
Whereas, at first glance, senolytic agents may seem as a propitious therapeutic opportunity for several chronic senescence-related diseases, we should bear in mind that cellular senescence is a normal and sometimes beneficial process. Potential side effects such as rampant cell proliferation and tumorigenesis may prohibit their applicability to human patients. Thus, the therapeutic potential of senescence remains elusive and although senescence has a vast clinical significance, more studies should be conducted in order to clarify its role not only in NAFLD but also in most clinical medical specialties.
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The role of senescence in the development of non-alcoholic fatty liver disease and progression to non-alcoholic steatohepatitis
Hepatology June 23 2019 - Alkistis-Maria Papatheodoridi1,*, Lampros Chrysavgis1,*, Michael Koutsilieris1,# and Antonios Chatzigeorgiou1,2,#
1Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527, Athens, Greece
2Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
full text
Abstract
In recent years cellular senescence has generated a lot of interest among researchers due to its involvement in normal aging process and also in common human diseases. During senescence, cells undergo alterations that include telomere shortening, nuclear area enlargement, 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 Non-Alcoholic Steatohepatitis (NASH) as characterized by the additional emergence of inflammation, hepatocyte ballooning and liver fibrosis. The development of Non-Alcoholic 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 which may contribute to or derive from cellular senescence, implying that the latter may be both a stimulus and a consequence of the disease. 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.
Abbreviations
1. NASH: Non Alcoholic Steatohepatitis
2. NAFLD: Non Alcoholic Fatty Liver Disease
3. ROS: Reactive oxygen species
4. ATM: Ataxia-telangiectasia mutated
5. SA-β-GAL: senescence-associated β-galactosidase
6. SASP: senescence associated secretory phenotype
7. IL: interleukins
8. AT: Adipose tissue
9. HFD: high fat diet
10. HCC: hepatocellular carcinoma
11. HSC: hepatic stellate cells
1. Introduction: Molecular characteristics of senescence
The term "senescence" derives from the Latin word "senex" meaning a man of old age. Cellular senescence describes a decline in cell division capacity whereby normal diploid differentiated cells enter a state of cell cycle arrest and lose their ability to proliferate (1,2). It is triggered by DNA damage in chromosomes and telomeres, provoked by internal or external stimuli such as aging, oncogene expression and reactive oxygen species(ROS) accumulation or radiation and chemotherapies respectively (3,4). More specifically, there are two major mechanisms of cellular senescence; one is replicative senescence which depends on telomere shortening or erosion, predominantly upon aging, and the other is stress-induced premature senescence which is mostly telomere-independent and refers to intracellular or environmental stress factors leading to DNA damage (1,2). Both mechanisms induce a complex multigenic pathway known as DNA damage response(DDR) which can either activate a repair mechanism or lead to the inhibition of cell cycle(5). In the latter case, DDR triggers ataxia-telangiectasia mutated(ATM) and Radd3-related protein kinases leading to p53 phosphorylation and subsequent activation of p21 resulting to cell cycle arrest(6,7). Concurrently p21 and p16 inhibit the phosphorylation of the retinoblastoma factor(Rb) allowing it to bind to E2F transcription factor and stop the progression of the cell cycle(8).
Cells undergoing senescence appear enlarged and flattened with enlarged nuclei under light microscope observation, while biochemical assessment of senescent cells shows the presence of the senescence biomarker senescence-associated β-galactosidase(SA-β-GAL)(9). Senescence-associated heterochromatin foci (SAHF) constitute another senescence biomarker. SAHFs consist of heterochromatin and a group of proteins that contribute to senescence by repressing the expression of proliferation-promoting genes (10). Importantly, the senescence-associated secretory phenotype(SASP), a complex mixture of molecular mediators secreted by senescent cells, serves as an important molecular signature for senescence(3). SASP includes proinflammatory cytokines, such as interleukin-1b(IL-1b), IL-6, IL-8, chemokines such as Monocyte Chemoattractant Protein-1(MCP-1), growth factors such as Human Growth Factor (HGF) and Fibroblast Growth Factor(FGF), proteases such as matrix Metalloproteinases (MMPs), fibronectin, ROS and nitric oxide(3,11). These factors alter the tissue microenvironment as they induce inflammation, attract immune cells to remove senescent cells and induce senescence in neighboring cells in a paracrine manner (12,13)(Figure 1).
This review aims at providing a synopsis on the current literature dealing with cellular and molecular aspects influencing cellular senescence during non-alcoholic fatty liver disease (NAFLD), as well as during its progression to non-alcoholic steatohepatitis(NASH).
2. Senescence in health and disease
2.1: General aspects
Cellular senescence is a complex process that has a dual function, both beneficial and detrimental in human health. Under physiological conditions, senescence eliminates damaged cells and is involved in tissue restoration upon acute stress or injury. The secretion of chemokines and cytokines such as IL-1b, IL8 and MCP-1 through SASP attracts immune cells leading to immunological clearance of the senescent cells (14,15). Consistently, aging and chronic stress induce telomere attrition and excessive SASP, leading to accumulation of senescent cells and insufficient tissue regeneration (14,16). Concurrently, hematopoietic stem cells decrease with age leading in fewer immune cells and a decline in the immune response, provoking a vicious cycle of defective clearance of senescent cells(17). The combination of ineffective regeneration, excessive SASP and inefficient clearance may explain the accumulation of senescent cells in aged organisms, thus increasing the risk for chronic age-related diseases such as dementia, osteoarthritis, metabolic dysregulation and carcinogenesis(16,18).
2.2: Senescence and metabolic dysregulation
Metabolic dysregulation refers to a complex wide range of alterations in glucose and lipids' metabolism, taking place mainly during diabetes and the metabolic syndrome, which can lead to several secondary complications such as NAFLD and cardiometabolic disease(19). Importantly, the expansion of the adipose tissue(AT) and in particular the increase of adipocyte size during obesity leads to upregulation of leptin and downregulation of adiponectin production by the AT(20,21). Besides, the increased adipocyte size leads to hypoxia-induced oversecretion of cytokines and chemokines such as Tumor Necrosis Factor(TNF), IL-6 and MCP-1 by the adipocytes as well as by the inflammatory immune cells that accumulate in the obese AT(19,22). When reaching the liver, the aforementioned mediators together with the increased levels of free fatty acids and apolipoproteins, observed during metabolic dysregulation, lead to liver injury and development of NAFLD/NASH(20,21).
Metabolic dysregulation is thought to favor cellular senescence in metabolic tissues, such as the AT and the pancreas, further perpetuating a status of metabolic dyshomeostasis of these tissues. For instance, obesity induces excessive ROS production, increased production of cytokines and high expression of SA-β-GAL as well as p53, p16 and p21 in the AT of both mice and humans (23,24). Along this line, p53 ablation in mice ameliorated insulin resistance under obese conditions (24). Consistently, high expression of p14 has been reported in subcutaneous AT from diabetic individuals, having also a positive correlation with p21 in the same tissue(25). Consistently, SA-β-GAL was more abundant in preadipocytes and endothelial cells isolated from obese rats and humans as compared to that of lean ones(26). Senescence-related phenomena are also implicated in pancreatic islet dysfunction during obesity. Deletion of p27 in Irs2-deficient or db/db diabetic mice improved hyperglycaemia by inducing compensatory insulin production due to improved maintenance of their islet mass (27). Besides, senescent endothelial cells express p16INK4a and SA-β-GAL at atherosclerotic plaques and gene polymorphisms in p21 affect the risk of development coronary artery disease and myocardial infraction (28,29).
3. The role of senescence in NAFLD/NASH
NAFLD is one of the most common chronic liver diseases affecting approximately 25% of the population worldwide and its prevalence increases along with aging, obesity and diabetes (30). Its diagnosis depends on clinical and histological criteria which include triglyceride accumulation in hepatocytes, defined as steatosis, in individuals that do not consume excessive amounts of alcohol. NAFLD frequently progresses to NASH which is characterized by the presence of steatosis, inflammation, necrosis and fibrosis (30,31). Advanced fibrosis observed in some NASH patients may lead to cirrhosis in 10-15% of these patients or even to hepatocellular carcinoma(HCC) (30). Currently there is increasing interest in the association between NAFLD/NASH and senescence.
Conclusion and future perspectives
Steatotic hepatocytes often display severe DNA damage and express markers of cell cycle arrest, indicating that they have entered a senescent state and implying that senescence is involved in NAFLD/NASH pathogenesis(figure 2)(32,47). Taken that hepatic senescence is causally induced by HFD and aging, both well-established risk factors for NAFLD development, it could be considered as a secondary phenomenon during NAFLD emergence and progression. Nevertheless, depletion of senescent cells in vivo attenuated steatosis, while senescence induction in vitro and in vivo promoted hepatocyte lipid deposition, suggesting that senescence plays indeed an important role in NAFLD pathogenesis(32). Notably, a vicious cycle of cytokine-induced senescence during NAFLD cannot be excluded(78). However, intriguingly, NAFLD-associated senescence may also have beneficial impacts on NAFLD to NASH progression. For instance, senescent HSCs produce less extracellular matrix components and more MMPs, thereby alleviating fibrosis advancement(71). Concurrently, hepatocyte senescence is required for damaged, pre-cancerous cells' detection and clearance, preventing thus liver carcinogenesis(60).
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