Open access peer-reviewed chapter

Is Senescence Important in Hepatic Diseases?

Written By

Ruth Pacheco Rivera, Jaime Arellanes Robledo and Jesús Serrano Luna

Submitted: 21 October 2016 Reviewed: 15 March 2017 Published: 30 August 2017

DOI: 10.5772/intechopen.68587

From the Edited Volume

Senescence - Physiology or Pathology

Edited by Jolanta Dorszewska and Wojciech Kozubski

Chapter metrics overview

1,251 Chapter Downloads

View Full Metrics


Aging is a condition in which a person gradually loses the ability to maintain homeostasis, due to structural alteration or dysfunction. Aging changes biological processes in many organs and tissues. The loss of regenerative capacity is the most dramatic age-associated alteration in the liver. Cellular damage, if not repaired, leads to apoptosis or senescence. The presence of permanent cell cycle arrest, the acquisition of major morphological change, and expression of senescence-associated β-galactosidase (SA-β-gal) are the characteristics of cellular senescence (CS). Interestingly, CS plays a crucial role in aging of both individual organs and the entire organism; consequently, senescent cells accumulate in organs and decline in organ function. Senescent cells have considerable influence on their microenvironment and exert both beneficial and detrimental effects through secretory associated senescent phenotype (SASP) factors. CS has attracted considerable recent interest with recognition of pathways linking aging, malignancy, and insulin resistance and the current focus on therapeutic interventions to extend healthspan. There are major implications for hepatology in the field of fibrosis and cancer, where cellular senescence of hepatocytes, cholangiocytes, stellate cells, and immune cells has been implicated in chronic liver disease progression.


  • senescence
  • aging
  • chronic liver diseases

1. Introduction

Aging is a biological process that consists of a series of structural and functional changes that appear over time and are not a consequence of diseases or accidents. In general, tissues are comprised of specific cells that determine the tissue microenvironment. Various factors affect the cellular environment, such as oxygen pressure, oxidative stress, temperature, and several growth factors secreted by cells. Sometimes the cell’s microenvironment alters the tissue homeostasis, causing a permissive environment that favors tumor promotion and development. This progressive aging is caused by multiple factors. The following nine characteristics are generally considered to contribute to the aging process: altered intracellular communication, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, stem cells exhaustion, and cellular senescence [1].


2. Cellular senescence

Cellular senescence (CS) is a stable form of cell cycle arrest that limits the proliferative potential of cells [2]. Senescence is the result of various degenerative changes characterized by shortening of the telomeres, chromosomic instability, DNA damage, oxidative stress producing reactive oxygen species (ROS), and oncogene overexpression [310]. Some researchers consider CS the natural solution to prevent cell damage, which may lead to various diseases including cancer. In contrast, with age, CS is considered to promote several chronic diseases. The pathological effects of CS may affect the health of elderly people due to the accumulation of senescent cells in several organs and tissues because CS can impair tissue regeneration. Furthermore, senescent cells can release several molecules, such as growth factors, cytokines, and chemokines that alter cellular homeostasis [11].

Up to date, two basic mechanisms have been identified to induce senescence: replicative senescence and premature senescence. Replicative senescence, or the Hayflick limit, is associated with telomere attrition; telomere exhaustion causes the limited proliferative capacity of certain types of invitro cultured cells [12]. Cells react to the loss of telomeres as if it is DNA damage, which therefore triggers the DNA damage response (DDR); the cellular response is similar to that initiated by external agents, for example, ionizing radiation and drugs.

In contrast, premature senescence is related to chromosomic instability, DNA damage, oxidative stress, oncogene overexpression, and epigenetic changes. Senescent cells have a typical morphology in culture: cells are enlarged, vacuolated, and flattened and in some cases, they are multinucleated. However, invivo senescent cells retain the normal morphology according to the tissue to which they belong. It has been found that these cells are metabolically active, and they can secrete growth factors, chemokines, and metalloproteases; this is known as the senescence associated secretor phenotype (SASP) [13].

2.1. Senescence markers

Senescent cells have several typical characteristics. First, they are positive for β-galactosidase activity at a suboptimal pH (pH 6), and this activity is based on the increment of lysosomal activity. One limitation of the β-gal assay is the need to use fresh or frozen samples [14]. Another characteristic is that senescent cells are in cellular arrest. Cellular arrest is an essential condition for senescence to occur, as senescent cells are positive for Ki67 protein or negative for the incorporation of 5-bromodeoxyuridine (Brdu) [15]. Other senescent markers are related to tumor suppressors such as p53, p16, p21, and the hypophosphorylated Rb protein. Heterochromatin bodies are known as heterochromatin foci in the nucleolus. In cells with DNA damage, it is common to find γ-H2AX histone phosphorylation which carries the DDR. Another finding is the decrease in lamin B1 levels as a common feature in many types of senescence [16, 17]. On the other hand, senescent cells have been found in biological processes other than aging as in systems such as humans, mice, and chicken embryos, suggesting that these cells are important to embryogenesis [18].

2.2. Senescence pathways

In the senescence process, there are two key tumor suppressors, the INK4/ARF locus and p53. The INK4/ARF locus allows the expression of three important proteins, p16Ink4a, p14Arf (p19Arf in mice), and p15Ink4b. Serrano et al. discovered the protein p16Ink4a. The p16Ink4a binds to CDK4/6 cyclins, preventing the phosphorylation of the Rb protein family; therefore, the cell cycle is inhibited at the G1 phase and cells enter in a cellular arrest, and this pathway is known as p16Ink4a-Rb [19]. In contrast, p53 is a transcription factor, which transcribes target genes to regulate various biological cell processes in response to stress stimuli; the biological cell processes include apoptosis, senescence, energy metabolism, and antioxidant defense. p53 is stabilized and phosphorylated by upstream kinases including ataxia telangiectasia (ATM) and Chk2 [10, 20, 21]. Phosphorylated p53 upregulates the transcription of its target gene, p21, which activates the Rb protein through the inhibition of cyclin E/Cdk2. The hypophosphorylated Rb protein inhibits the transcription of E2F genes, including cyclin A and proliferating cell nuclear antigen (PCNA), which are required for cell cycle progression [22]. On the other hand, p14Arf is directly related to p53 and is linked to the mourin double murine 2 (Mdm2) protein; therefore, p53 is stabilized, and p21 is expressed and inhibits cyclin E/Cdk2 [23]. This senescent pathway is called the p53-p21 pathway. Another senescence-signaling pathway is through the p38 protein, which is a mitogen activated protein kinase (MAPK) protein that transforms a variety of stress stimuli into a common senescence signal [24]. The inactivation of p38 delays the onset of various forms of cellular senescence including replicative, oxidative-stress-induced, and oncogene induced senescence. In contrast, enforced activation of p38 by a constitutive active form MAPK kinase (MKK6EE) of upstream kinase, MKK6, acutely induces cellular senescence [25, 26].

In recent years, other elements have been incorporated into the senescence pathway regulation. Studies on genetic regulation in human fibroblasts and mice embryonic fibroblasts (MEFs) showed the presence of long noncoding RNAs (lncRNAs), which are derived from noncoding RNAs (ncRNAs). Tumor suppressors have specific lncRNAs; for example, several IncRNAs, such as focally amplified lncRNA on chromosome 1 (FAL 1), BRAF-activated non-protein coding RNA (BANCR), and long intervening noncoding RNAs (LINCRNA) p21, have been found in p21 [2730]. In the case of p53, lncRNA metastasis associated lung adenocarcinoma transcript 1 (MALAT1) as well as 7SL have been related to p53 expression [31, 32]. The INK4a-ARF locus and p16INK4amRNA are linked with lncRNAs VAD, antisense non-coding RNA in the INK4 locus (ANRIL), MIR31 host gene (MIR31), and Urothelial cancer associated 1 (UCA 1) [3338]. Another lncRNA associated with senescence is senescence-associated long non-coding RNA (SALNR), which is related to NF-9 [39]. telomeric repeat containing RNA (TERRA) is a lncRNA associated with telomere length [40]. Researchers have shown that lncRNAs are tightly regulated and tissue specific. Moreover, the dysregulation of lncRNAs has been associated with human diseases. Further studies must be performed to accurately determine the functional role of these lncRNAs in senescence and aging [41].

2.3. Chromatin alterations

Alterations in the structure of chromatin are believed to contribute to the irreversible nature of the senescent state. Narita et al. found that in DNA cells stained with 4’,6-diamidino-2-phenylindole (DAPI), chromatin bodies called foci can be observed at the nucleus [42]. It is likely that DAPI-stained foci correspond to highly compacted heterochromatin, as senescent cell chromatin is resistant to micrococcal nuclease digestion; moreover, DAPI foci contain numerous proteins characteristic of transcriptionally inactive heterochromatin, including hypoacetylated histones, methylated histone H3 on Lys 9 (H3K9 me), and heterochromatin protein 1 (HP1). The formation of heterochromatin structures known as heterochromatin foci is associated with senescence-associated heterochromatin foci (SAHF). Various forms of stress induce SAHF formation as well as other senescence phenotypes, suggesting that SAHFs can be used to identify senescent cells invivo and that SAHF formation somehow contributes to the mechanisms of cellular senescence; although, not all senescent cells exhibit SAHFs [43].


2.4. Oxidative stress and liver senescence

Under normal physiological conditions, cells are protected from oxidative stress by an array of endogenous antioxidants that maintain a balance between pro-oxidant production and antioxidant capacity. An imbalance occurs when intracellular antioxidants are unable to neutralize the pro-oxidants such as ROS, which are a number of highly reactive molecules derived from molecular oxygen [44]. ROS are mainly produced by the mitochondrial respiratory chain, cytochrome P450, and autooxidation of endogenous substrates such as heme proteins, catecholamines, quinones, among others [45]. ROS exert a broad array of biological effects, ranging from physiological regulatory functions to several oxidative modifications, which can contribute to the pathogenesis of various diseases. ROS can also impact the cell by altering physiological and biochemical processes such as gene expression, cell adhesion, cell metabolism, cell cycle, cell disease, and cell death [46, 47]. Thus, oxidative stress has been confirmed to be a common participant in several diseases including liver diseases [48]. It has been proposed that the damage induced by oxidative stress may represent a common link between different chronic liver diseases. This proposal is supported by the fact that free radicals are key players not only in normal liver function but also in the genesis and progression of liver steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [49, 50]. Therefore, a strong association is expected between oxidative stress and the pathogenesis of liver diseases. Oxidative stress is an inherent component in the liver as the activity of many enzymes involved in lipogenesis, fatty acid oxidation, cholesterol, and phospholipid metabolism is regulated by the redox status of liver parenchyma, which can influence the redox balance of the cell microenvironment [51]. Thus, following liver injury by different etiological factors [52], endogenously produced ROS may have an accumulative impact (mainly evidenced as an increase in lipid peroxidation), which plays a critical role in the progression of chronic liver diseases [53].

Several studies have proposed that ROS production is one of the main activators and stabilizers of CS. Although this is a preliminary proposal, there is evidence demonstrating a direct contribution of ROS to both the DDR and the redox-activated pathways [54, 55] and induces telomere shortening [56], which results in a DDR and senescence activation. Up to date, both experimental and clinical studies have strongly supported the association of CS with chronic liver diseases. In addition to specific parenchymal or nonparenchymal liver structures, studies have highlighted the appearance of CS in two paradoxical settings, as a tumor suppressor and as a tumor promoter, and in two physiological processes, aging and tissue repair [57, 58]. Cellular senescence is involved in multiple physiological processes; the complexity of CS may be elucidated by deciphering the mechanisms that induce its activation, such as oxidative stress. In this regard, evidence has shown that increased ROS production by mitochondrial dysfunction is triggered after a DDR and subsequent CS activation, which in turn is a consequence of p21 activation. The sequence of events maintains a dynamic feedback loop that is necessary for the stability of growth arrest during the establishment of the senescent phenotype [59]. A similar phenomenon was observed during the activation of the p16/RB pathway, which induces high intracellular levels of ROS and thereby activates protein kinase C-Δ (PKC∆); consequently, further ROS are generated to establish a positive feedback loop to sustain ROS-PKC∆ signaling [60]. Other studies have reported that activation of the RAS, p21, and p53 pathways are also closely related to elevated ROS production [61, 62]. In these reports, N-acetylcysteine treatment blocked cell cycle arrest and thereby CS, demonstrating that ROS accumulation is an important mediator of CS; furthermore, researchers proposed that ROS are a causal agent of CS. The evidence confirms that ROS play a key role in the CS process; however, it is still unclear whether ROS are a consequence or cause of CS.

2.5. Reactive oxygen species and hepatic diseases

A variety of free radicals are found in the liver and can be classified as mitochondrial, principally from complexes I and III, and extra mitochondrial, such as cytochrome P450, xanthine oxidase, nitric oxide synthase, and nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase. Where neutrophils and Kupffer cells primarily produce free radicals, the cytochrome P450 system and mitochondria are the major sites of ROS release in hepatocytes. An important mechanistic source of ROS is lipid metabolism, which is dependent on the redox balance of the liver, and its alteration is closely linked to both alcoholic and nonalcoholic steatohepatitis [51, 63]. The above-mentioned sources of ROS are strictly controlled in normal hepatocytes; however, in hepatic diseases, an overproduction of free radicals can overcome the antioxidant defenses and induce liver injury [51]. Consequently, the liver is a continuous target of oxidative stress and redox balance. It is not surprising that an increasing number of findings have shown a close association between liver diseases and ROS production [63]. Clinical and experimental reports have suggested that CS onset may be an intrinsic phenomenon from the beginning of liver injury, such as the appearance of neoplastic nodules [64, 65]. This proposal is supported by the presence of replicative and premature senescence in both parenchymal and nonparenchymal liver cells [58, 66, 67]. Using a liver injury model to mimic sequential HCC progression (from fibrosis to cirrhosis and HCC) [68], we recently confirmed that CS appearance is intrinsic to the initiation of liver injury, as a chronological increase of CS alongside HCC progression was observed [69]. We did not determine ROS levels in this investigation; however, HCC was induced with continuous diethylnitrosamine administration, a hepatotoxic and potent ROS producer [70], suggesting that the chronological appearance of CS was accompanied by persistent ROS induction. In a recent study, the role of hepatocyte senescence in the development of insulin resistance was investigated [71]. Using HepG2 cells, they demonstrated that H2O2 treatment induced CS despite insulin stimulation. This phenomenon was accompanied by a persistent nuclear localization of FoxO1, a transcription factor that, among others, promotes the expression of genes involved in cell cycle arrest and detoxification of ROS. Moreover, an increase and decrease in the expression of glucose transporters 2 and 4 (GLUT2 and GLUT4), respectively, were proposed as senescence markers, as this pattern was found in senescent HepG2, in human cirrhotic liver tissue, and in publicly available liver disease datasets. In a different study by the same research group, gene expression profiles of HepG2 cells subjected to oxidative stress were compared with public microarray datasets obtained from human cirrhotic samples. The results showed that the gene upregulation profile of senescent HepG2 cells induced by H2O2 treatment was similar to that in human cirrhotic livers. Interestingly, gene expression profile patterns of senescent hepatocytes were markedly linked to alterations in cell cycle regulation, morphology, metabolism, and stellate cell activation, which occur alongside impaired synthetic function in senescence [72]. Although these results suggest a close relationship between hepatocyte senescence and ROS action, the use of an external stressor agent to induce CS may be a key factor to work in an asynchronous manner in the sequence of molecular events involved in intrinsic ROS production. More direct evidence has demonstrated a strong interconnection between senescence, ROS, and TGF-β signaling in chronic liver diseases. Borkham-Kamphorst et al. showed that the overexpression of cysteine-rich protein 61 (CCN1/CYR61) significantly inhibited the production of collagen type I and induced ROS, leading to CS and apoptosis invivo and invitro. This effect was associated with an attenuation of TGF-β signaling; as a result, CCN1/CYR61 overexpression mitigated liver fibrogenesis in a bile duct ligation model. This analysis is a clear example of ROS and CS induction as a potential molecular mechanism for tissue repair and remodeling promoted by the manipulation of CCN1/CYR61 during hepatic injury [73]. In a similar study with contrasting reports, dioscin, a saponin plant steroid, promoted CS but decreased the oxidative stress induced by CCl4 in activated hepatic stellated cells (HSC). Among others, this antifibrotic effect was associated with the attenuation of TGF-β/Smad, Wnt/β-catenin, MAPK, and mitochondrial signaling pathways [74]. Recent investigations have shown that Sir2 enzyme members, collectively called sirtuins, are involved in CS associated with liver diseases. Sirtuin 6 (SIRT6), an enzyme that promotes resistance to DNA damage and oxidative stress, plays a central role in the CS induced by ROS and TGF-β signaling in HCC cells [75]. In this report, ROS and TGF-β upregulated SIRT6 expression by inducing sustained activation of extracelular signal-regulated kinase (ERK) and Smad pathways. Upregulated SIRT6 not only abrogated the inducing effect of TGF-β and ROS on CS but was also required for the ERK pathway to suppress p16 and p21 expression. Additionally, upregulation of SIRT6 promoted HCC cell tumorigenicity and contributed to the inhibitory effect of the ERK pathway on cellular senescence. This feedback loop activation integrated by SIRT6 and TGF-β has the potential to modulate both tumorigenicity and senescence and represents a clear example of the molecular complexity around senescence activation. Another investigation group demonstrated that SIRT1, an enzyme that deacetylates nonhistone proteins and allows mammalian cell survival under oxidative stress, is downregulated in aged and middle-aged mice. This condition increased mice susceptibility to the effect produced by chronic alcohol consumption and exacerbated alcoholic liver injury and fibrosis in hepatocytes and hepatic stellate cells [76]. This evidence clearly reveals that the senescence and ROS pair in the liver of elderly patients boosts alcohol liver disease, likely by the modification of liver metabolic functions. This proposal is in accordance with a recent report of Cyp2e1 as a central player in aging-dependent hepatic steatosis, apoptosis, and fibrosis. The investigation demonstrated that Cyp2e1 increased the production of reactive nitrogen species and ROS in aged mice; as a result, high levels of lipid peroxidation, oxidative protein modifications, oxidative DNA damage, and inflammation were found. These changes were absent or decreased in aged Cyp2e1-null mice [77]. In the serum of patients with nonalcoholic steatohepatitis (NASH) and NASH-related HCC, oxidative stress correlated with the levels of NASH activity markers, while the antioxidative function was preserved in younger patients as well as in patients with a well-preserved liver function; in contrast, patients with NASH-related HCC tended to be older and exhibited a diminished antioxidative function [78]. In addition to the complexities involved with senescence and ROS in liver diseases, there is evidence of SIRT1 and Cyp2e1 as possible targets for preventing aging-related liver disease.

Senescence induction has also been another means for researchers to determine the efficiency of chemotherapeutic agents against cancer. Most of these agents are strong oxidative stress inducers such as cisplatin. In a recent study, this compound promoted a senescent phenotype in HCC cell lines dependent on p53 and p21 activation and intracellular ROS generation [79]. Although senescence activation appears to be a natural consequence of oxidative stress induction, ROS generation may dictate different cellular consequences depending on the overall concentration at steady-state levels and site of generation [80]. In support of this, an advanced investigation has conferred an important role for ROS production and its participation as a decisive factor in the progression and aggressiveness of cancer [81], and has also raised the complexity of the senescence and ROS pair. Investigators reported that the normally high potential for melanoma cells to form subcutaneous tumors is limited after intravenous or intrasplenic transplantation; this occurs because metastatic cells experience a charge of oxidative stress in the blood and visceral organs, which is not present in established subcutaneous tumors. To overcome that barrier, cells undergo reversible metabolic changes during metastasis that increase their capability to withstand oxidative stress. It was found that mitochondrial membrane potential, mass, and ROS levels declined more in circulating metastatic cells compared to subcutaneous tumors, raising the possibility that mitochondrial function is reduced in circulating melanoma cells in an effort to reduce ROS generation [81]. During the normal aging process, mitochondrial metabolic changes are implicated in the induction and maintenance of CS [82]. While the investigation did not show whether oxidative stress also limits the initiation and early growth of primary cutaneous cancer cells [81], it is reasonable to hypothesize that senescence activation and/or ROS generation are determinant factors of the appearance and progression of different multifocal HCC types. This intriguing hypothesis stems from a proposal that multifocal HCCs are either from an HCC of multicentric origin or HCC of intrahepatic metastasis [83]. Thus, in this scenario, ROS may modulate CS activation in the HCC microenvironment. As a result, senescence and ROS may be the decisive molecular pair to establish the outcome of multifocal HCC. This hypothetical proposal also raises the question of whether the appearance of senescence/ROS is a transitory, sporadic, or specific event of a determined HCC development stage. We have recently shown that, concomitant to the HCC development induced by diethylnitrosamine, there is also a chronological appearance of CS [69]; however, its association with ROS generation and effect on the outcome of multifocal HCC type has not been investigated. This is an interesting and comprehensive proposal worth investigating.


3. Is cellular senescence important in the development of hepatic diseases?

Aging changes the biological processes in many organs and tissues of mammalians, leading to the development of age-associated diseases and aberrant body homeostasis. Nearly 13% of the population in the United States is over the age of 65 years; this percentage and the number of elderly people will increase substantially over the next 50 years [84]. Although the aging process does not cause death, elderly people appear to be predisposed to a variety of diseases; therefore, aging facilitates the onset and/or progression of various pathologies including diseases of the liver [84]. The ability to withstand hepatic insult decreases each decade, including those associated with high triglyceride levels, nonalcoholic fatty liver diseases, and HCC [8587]. The percentage of deaths caused by liver diseases increases dramatically in humans over the age of 45 years. Accordingly, age is a critical determinant in the outcome of hepatitis C infection [88] and liver transplantation [89]. However, the most dramatic effect of aging on the liver is its delayed and/or reduced proliferation after a loss of mass from a surgical or chemical injury [9092]. Based on these correlations, it has been suggested that elderly people are predisposed to liver diseases. The livers of young individuals regenerate after these treatments and maintain homeostasis; conversely, there is a dramatically reduced regeneration of the livers of older people. The clinical outcome of human acute liver injury is also partially dependent on the potential for hepatic regeneration. In older people, there is a higher incidence of acute liver failure and a higher mortality with acute hepatitis A [93, 94]. In a cohort of patients with acute liver failure secondary to viral hepatitis, age was an independent predictor of a poor outcome, with the worst outcomes in people over the age of 50 years [95]. Wong et al. and Poynard et al. were among the first to demonstrate that age at infection was a major risk factor for subsequent fibrosis progression and that the rate of fibrosis progression accelerated with increasing age [96, 97]. Studies of other liver diseases have demonstrated similar findings. Age is an independent risk factor for poor outcomes in primary biliary cirrhosis (PBC) in addition to the presence of portal hypertension and impaired liver function [98]. Similarly, age, independent of bilirubin, prothrombin time, and renal function, predicted the outcome in patients with alcoholic hepatitis [99]. There is some evidence that age may influence disease progression in nonalcoholic fatty liver disease (NAFLD) [100, 101].

The role of CS in diverse chronic liver diseases has come into recent research. The structure of hepatocytes changes with age. The volume of hepatocytes increases with development and maturation but declines with senescence [84]. The relative volumes of hepatocyte organelles also change during aging. The universal change in diagnostic liver biopsy specimens is the age-related cytoplasmic accumulation of highly oxidized insoluble protein lipofuscin or age pigment, which in turn reflects a concomitant increase in the volume of the dense body compartment [102]. Accelerated hepatocyte aging and the accumulation of senescent hepatocytes have been found in diverse chronic liver disorders [103108]. Furthermore, the studies have shown that the increased proportion of senescent hepatocytes is associated independently with increased fibrosis stage, impaired hepatic function, and an adverse liver-related outcome including liver-related death [103109]. However, it is still unknown whether hepatocyte senescence contributes causally to fibrosis progression, declining hepatic function, or the increased risk of an adverse liver-related outcome.

3.1. Hepatic fibrosis

Hepatic fibrosis is a common pathological consequence of chronic liver diseases and results from the progressive accumulation of an excess quantity of extracellular matrix (ECM) tissue. In many patients, continuous liver parenchyma insult ultimately leads to cirrhosis [110]. The ECM accumulation during chronic liver injury is caused by a heterogeneous population of myofibroblasts derived mainly from hepatic stellate cells and from resident fibroblasts. Myofibroblasts are highly proliferative cells with enhanced survival that migrate and accumulate at sites of liver damage in response to a liver insult that caused a wide variety of growth factors, cytokines, and lipid mediators. Recently, many studies have observed that the presence of an increased proportion of senescent hepatocytes is associated with an increased fibrosis stage. This results in impaired hepatic function and an adverse liver-related outcome, including liver-related death [103, 104, 106108].

3.2. Cirrhosis and HCC

In humans, cirrhosis is induced by a variety of liver diseases. Regardless of its etiology, cirrhosis evolves slowly over many years, and chronic hepatocyte death and renewal are major predisposing factors [111]. Cirrhosis is associated with life-threatening complications due to a decreased functional parenchymal reserve and altered hepatic blood flow. A recent report by WHO indicates that cirrhosis accounts for 170,000 deaths in Europe per year [110]. The cellular growth arrest and CS appear to be in a pro-fibrotic state. There is existing research on the relation between cirrhosis and telomere shortening, showing that telomere shortening is a marker of cirrhosis and correlates with senescence-associated β-galactosidase in 84% of cirrhosis samples, specifically in hepatocytes [110]. CS contributes to age-related tissue dysfunction, macroH2A1, and a variant of histone H2A. CS is also a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. MacroH2A1, a variant of histone H2A, is a marker of senescence-associated heterochromatic foci that synergizes with DNA methylation to silence tumor-suppressor genes in human fibroblasts. In a recent study, Borghesan et al. investigated the relationship between macroH2A1 splice variants, macroH2A1.1 and macroH2A1.2, and liver carcinogenesis. It was found that protein levels of both macroH2A1 isoforms were increased in the livers of very elderly rodents and humans, and were strong immunohistochemical markers of human cirrhosis and HCC [112].

3.3. Chronic hepatitis B

Chronic hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis, and HCC. HBV infection is associated with age, cell cycle arrest, and CS. In a recent study, the authors assessed the HBV antigen production in relation to cell cycle arrest and CS invitro using hepG2 and hepG2.2.15 cell lines [113].The authors found that cell cycle arrest induced invitro by the addition of H2O2 caused increased levels of supernatant HBsAg and HBV DNA and increased expression of HBcAg. In contrast, there was no observed effect on HBsAg or HBV DNA production in senescent cells, with only a minor increase in cytoplasmic HBcAg staining [113].Widespread telomere shortening is consistent with accelerated aging in chronic HBV [114].

3.4. Chronic hepatitis C

Chronic infection with hepatitis C virus (HCV) affects approximately 170 million people around the world. Moreover, 20% of these affected people develop cirrhosis and are at great risk to develop HCC. An increased risk of HCV-related cirrhosis is associated with hepatic steatosis, older age, and higher alcohol consumption [88, 115]. It has been reported that during chronic HCV infection, telomere shortening is present in liver tissue [116], likely due to increased hepatocyte turnover. Critically short telomeres trigger replicative senescence. Marshall et al. found a strong correlation between hepatocyte G1 arrest, dysfunctional hepatic regeneration, and increased cirrhosis in patients with chronic HCV. They showed increased hepatocyte cell cycle arrest measured by the expression of the mini-chromosome maintenance protein 2 (Mcm-2) in liver biopsy samples. The researchers also found that p21 expressed predominantly in hepatocytes and it was correlated with the stage of fibrosis [107].

3.5. Nonalcohol-related fatty liver disease (NAFLD)

NAFLD is a leading cause of chronic liver disease worldwide [117], which presents a wide range of liver disorders including simple steatosis, steatohepatitis, cirrhosis, and HCC [117]. In ob/ob mice, NAFLD is associated with an increased expression of the cell cycle inhibitor p21 and impaired liver regeneration [118]. The combination of impaired regeneration and increased incidence of cancer in NAFLD suggests accelerated aging. In the literature, NAFLD has been separately described by the appearance of premature telomere shortening, increased hepatocyte nuclear area, advanced fibrosis, and p21 expression [103, 104]. Recently, Aravinthan et al. performed a study on 105 archived formalin-fixed paraffin-embedded liver needle biopsy specimens from 70 patients within the spectrum of NAFLD, and 43 liver needle biopsies at the time of liver transplantation from age- and sex-matched donor livers served as controls. In this study, the authors found a close correlation between hepatic steatosis and short telomeres; additionally, the proportion of hepatocytes with DNA damage identified by the presence of γ-H2AX increased in parallel with steatosis grade. The authors suggested that the accumulation of fat in hepatocytes causes DNA damage and telomere erosion, possibly mediated by oxidative stress. A critically short telomere and a break in double-stranded DNA lead to CS and permanent cell cycle arrest. The authors also found a pattern of predominant hepatocyte G1/S phase cell cycle arrest in NAFLD, with an increased expression of Mcm-2 compared to a normal liver. Furthermore, there was increased expression of the p21 protein. A striking feature was the association of p21 expression with the fibrosis stage, which suggests an accumulation of senescent hepatocytes with disease progression [105].

3.6. Alcohol-related liver disease

Alcohol-related liver disease (ALD) is one of the leading causes of liver-related morbidity and mortality in the world. ALD encompasses a broad spectrum of liver injury from simple steatosis to alcohol-related hepatitis, cirrhosis, and HCC. The pathophysiology of ALD is a complex phenomenon; however, oxidative stress is an important factor in the disease since alcohol consumption increases the production of ROS and diminishes cellular antioxidant levels [119]. The validity of clinical criteria in predicting outcomes in ALD has been studied. In one study, it was shown that the increase of the hepatocyte nuclear area was related to hepatic dysfunction and suggests hepatocyte senescence, since nuclear enlargement is a recognized morphological characteristic of CS [120]. In contrast, irreversible cell arrest that limits the proliferative potential of cell is a hallmark of CS and is mediated by p21 [121]. Thus, p21 has a vital role in the stability of cell cycle arrest and the induction of senescence [121].

3.7. Senolytic drugs

The accumulation of senescent cells in tissues and organs contributes to age-related diseases; however, the presence of radiations or genotoxic agents may contribute to the development of senescence phenotype. This accumulation is important because senescent cells contribute to alterations in the microenvironment. This can support conditions for diseases such as cancer to develop, but senescent cell quantity is important for organ function in the case of aging.

Senolytic agents may be used for clearance of senescent cells in the organs. Chang et al. used ABT263, a specific inhibitor of apoptosis genes BCL2 and BCL2L1, to selectively induce apoptosis in senescent cells in culture. They carried out experiments using a mouse model with known p16-3 MR and administered ABT263 to mice and observed that p16-positive senescent cells were depleted in bone marrow, lung, and muscle tissue via apoptosis. The data demonstrate that ABT263 is a senolytic drug that acts in a highly specific manner on various tissues to target senescent cells both in culture and invivo. These findings significantly advance clinical targeting of cell senescence [122].


4. Conclusion

Until now, the role of CS is poorly understood and little studied in hepatology. There are major implications for hepatology in the field of fibrosis and cancer, and liver chronic diseases. Further investigation into the molecular basis of senescence in liver diseases is necessary, and the collaboration between basic and clinical researchers is fundamental to arrive to better diagnosis and treatment.



This book chapter was supported by grant No 83710 from CONACyT.


  1. 1. Lopez-Otin C, et al. The hallmarks of aging. Cell. 2013;153(6):1194-1217
  2. 2. Campisi J, d'Adda di Fagagna F. Cellular senescence: When bad things happen to good cells. Nature Reviews Molecular Cell Biology. 2007;8(9):729-740
  3. 3. Sahin E, DePinho RA. Axis of ageing: Telomeres, p53 and mitochondria. Nature Reviews Molecular Cell Biology. 2012;13(6):397-404
  4. 4. Sedelnikova OA, et al. Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks. Nature Cell Biology. 2004;6(2):168-170
  5. 5. Chen QM, et al. Uncoupling the senescent phenotype from telomere shortening in hydrogen peroxide-treated fibroblasts. Experimental Cell Research. 2001;265(2):294-303
  6. 6. Parrinello S, et al. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nature Cell Biology. 2003;5(8):741-747
  7. 7. Cheung AL, Deng W. Telomere dysfunction, genome instability and cancer. Frontiers in Bioscience. 2008;13:2075-2090
  8. 8. Sarkisian CJ, et al. Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis. Nature Cell Biology. 2007;9(5):493-505
  9. 9. Blagosklonny MV. Cell senescence and hypermitogenic arrest. European Molecular Biology Organization Reports. 2003;4(4):358-362
  10. 10. Serrano M, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593-602
  11. 11. Degirmenci U, Lei S. Role of lncRNAs in cellular aging. Frontiers in Endocrinology (Lausanne). 2016;7:151
  12. 12. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Experimental Cell Research. 1961;25:585-621
  13. 13. Coppe JP, et al. The senescence-associated secretory phenotype: The dark side of tumor suppression. Annual Review of Pathology. 2010;5:99-118
  14. 14. Dimri GP, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(20):9363-9367
  15. 15. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends in Cell Biology. 2001;11(11):S27-31
  16. 16. Shimi T, et al. The role of nuclear lamin B1 in cell proliferation and senescence. Genes & Development. 2011;25(24):2579-2593
  17. 17. Freund A, et al. Inflammatory networks during cellular senescence: Causes and consequences. Trends in Molecular Medicine. 2010;16(5):238-246
  18. 18. Munoz-Espin D, Serrano M. Cellular senescence: From physiology to pathology. Nature Reviews Molecular Cell Biology. 2014;15(7):482-496
  19. 19. Kim WY, Sharpless NE. The regulation of INK4/ARF in cancer and aging. Cell. 2006;127(2):265-275
  20. 20. Webley KM, Shorthouse AJ, Royds JA. Effect of mutation and conformation on the function of p53 in colorectal cancer. The Journal of Pathology. 2000;191(4):361-367
  21. 21. d'Adda di Fagagna F, et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature. 2003;426(6963):194-198
  22. 22. Dyson N. The regulation of E2F by pRB-family proteins. Genes & Development. 1998;12(15):2245-2262
  23. 23. Haupt Y, et al. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387(6630):296-299
  24. 24. Wang L, et al. Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. Journal of Biological Chemistry. 2002;277(49):47257-47262
  25. 25. Iwasa H, Han J, Ishikawa F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells. 2003;8(2):131-144
  26. 26. Ishikawa Y, et al. Regulation of Bax translocation through phosphorylation at Ser-70 of Bcl-2 by MAP kinase in NO-induced neuronal apoptosis. Molecular and Cellular Neuroscience. 2003;24(2):451-459
  27. 27. Hu X, et al. A functional genomic approach identifies FAL1 as an oncogenic long noncoding RNA that associates with BMI1 and represses p21 expression in cancer. Cancer Cell. 2014;26(3):344-357
  28. 28. Zhong X, Hu X, Zhang L. Oncogenic long noncoding RNA FAL1 in human cancer. Molecular and Cellular Oncology. 2015;2(2):e977154
  29. 29. Shi Y, et al. Downregulated long noncoding RNA BANCR promotes the proliferation of colorectal cancer cells via downregualtion of p21 expression. PLoS One. 2015;10(4):e0122679
  30. 30. Dimitrova N, et al. LincRNA-p21 activates p21 in cis to promote polycomb target gene expression and to enforce the G1/S checkpoint. Molecular Cell. 2014;54(5):777-790
  31. 31. Tripathi V, et al. The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation. Molecular Cell. 2010;39(6):925-938
  32. 32. Abdelmohsen K, et al. 7SL RNA represses p53 translation by competing with HuR. Nucleic Acids Research. 2014;42(15):10099-10111
  33. 33. Lazorthes S, et al. A vlincRNA participates in senescence maintenance by relieving H2AZ-mediated repression at the INK4 locus. Nature Communications. 2015;6:5971
  34. 34. Kotake Y, et al. Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene. Oncogene. 2011;30(16):1956-1962
  35. 35. Yap KL, et al. Molecular interplay of the noncoding RNA ANRIL and methylated histone H3 lysine 27 by polycomb CBX7 in transcriptional silencing of INK4a. Molecular Cell. 2010;38(5):662-674
  36. 36. Montes M, et al. The lncRNA MIR31HG regulates p16(INK4A) expression to modulate senescence. Nature Communications. 2015;6:6967
  37. 37. Kumar PP, et al. Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex. Elife. 2014;3:1-28
  38. 38. Xue M, Chen W, Li X. Urothelial cancer associated 1: A long noncoding RNA with a crucial role in cancer. Journal of Cancer Research and Clinical Oncology. 2016;142(7):1407-1419
  39. 39. Wu CL, et al. Senescence-associated long non-coding RNA (SALNR) delays oncogene-induced senescence through NF90 regulation. Journal of Biological Chemistry. 2015;290(50):30175-30192
  40. 40. Arnoult N, Van Beneden A, Decottignies A. Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1alpha. Nature Structural & Molecular Biology. 2012;19(9):948-956
  41. 41. Taft RJ, et al. Non-coding RNAs: Regulators of disease. The Journal of Pathology. 2010;220(2):126-139
  42. 42. Beausejour CM, et al. Reversal of human cellular senescence: Roles of the p53 and p16 pathways. European Molecular Biology Organization Journal. 2003;22(16):4212-4222
  43. 43. Narita M, et al. A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation. Cell. 2006;126(3):503-514
  44. 44. Ye ZW, et al. Oxidative stress, redox regulation and diseases of cellular differentiation. Biochimica et Biophysica Acta. 2015;1850(8):1607-1621
  45. 45. Sid B, Verrax J, Calderon PB. Role of oxidative stress in the pathogenesis of alcohol-induced liver disease. Free Radical Research. 2013;47(11):894-904
  46. 46. Yang HY, Lee TH. Antioxidant enzymes as redox-based biomarkers: A brief review. BMB Reports. 2015;48(4):200-208
  47. 47. Bouayed J, Bohn T. Exogenous antioxidants-double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxidative Medicine and Cellular Longevity. 2010;3(4):228-237
  48. 48. Alfadda AA, Sallam RM. Reactive oxygen species in health and disease. Journal of Biomedicine and Biotechnology. 2012;2012:936486
  49. 49. Ha HL, et al. Oxidative stress and antioxidants in hepatic pathogenesis. World Journal of Gastroenterology. 2010;16(48):6035-6043
  50. 50. Mari M, et al. Redox control of liver function in health and disease. Antioxidants & Redox Signaling. 2010;12(11):1295-1331
  51. 51. Serviddio G, Bellanti F, Vendemiale G. Free radical biology for medicine: Learning from nonalcoholic fatty liver disease. Free Radical Biology and Medicine. 2013;65:952-968
  52. 52. Parola M, Robino G. Oxidative stress-related molecules and liver fibrosis. Journal of Hepatology. 2001;35(2):297-306
  53. 53. Nair J, et al. High urinary excretion of lipid peroxidation-derived DNA damage in patients with cancer-prone liver diseases. Mutation Research. 2010;683(1-2):23-28
  54. 54. Lu T, Finkel T. Free radicals and senescence. Experimental Cell Research. 2008;314(9):1918-1922
  55. 55. Chen Q, et al. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(10):4337-4341
  56. 56. von Zglinicki T, Oxidative stress shortens telomeres. Trends in Biochemical Sciences. 2002;27(7):339-344
  57. 57. Rodier F, Campisi J. Four faces of cellular senescence. Journal of Cell Biology. 2011;192(4):547-556
  58. 58. Krizhanovsky V, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657-667
  59. 59. Passos JF, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology. 2010;6:347
  60. 60. Takahashi A, et al. Mitogenic signalling and the p16INK4a-Rb pathway cooperate to enforce irreversible cellular senescence. Nature Cell Biology. 2006;8(11):1291-1297
  61. 61. Lee AC, et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. Journal of Biological Chemistry. 1999;274(12):7936-7940
  62. 62. Macip S, et al. Influence of induced reactive oxygen species in p53-mediated cell fate decisions. Molecular and Cellular Biology. 2003;23(23):8576-8585
  63. 63. Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis. Free Radical Biology and Medicine. 2012;52(1):59-69
  64. 64. Paradis V, et al. Replicative senescence in normal liver, chronic hepatitis C, and hepatocellular carcinomas. Human Pathology. 2001;32(3):327-332
  65. 65. Ramakrishna G, et al. From cirrhosis to hepatocellular carcinoma: New molecular insights on inflammation and cellular senescence. Liver Cancer. 2013;2(3-4):367-383
  66. 66. Schnabl B, et al. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology. 2003;37(3):653-664
  67. 67. Kang TW, et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature. 2011;479(7374):547-551
  68. 68. Schiffer E, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005;41(2):307-314
  69. 69. Pacheco-Rivera R, et al. Double staining of beta-galactosidase with fibrosis and cancer markers reveals the chronological appearance of senescence in liver carcinogenesis induced by diethylnitrosamine. Toxicology Letters. 2016;241:19-31
  70. 70. Verna L, Whysner J, Williams GM. N-nitrosodiethylamine mechanistic data and risk assessment: Bioactivation, DNA-adduct formation, mutagenicity, and tumor initiation. Pharmacology & Therapeutics. 1996;71(1-2):57-81
  71. 71. Aravinthan A, et al. Selective insulin resistance in hepatocyte senescence. Experimental Cell Research. 2015;331(1):38-45
  72. 72. Aravinthan A, et al. The senescent hepatocyte gene signature in chronic liver disease. Experimental Gerontology. 2014;60:37-45
  73. 73. Borkham-Kamphorst E, et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-beta signaling. Biochimica et Biophysica Acta. 2014;1843(5):902-914
  74. 74. Zhang X, et al. Potent effects of dioscin against liver fibrosis. Scientific Reports. 2015;5:9713
  75. 75. Feng XX, et al. Sirtuin 6 promotes transforming growth factor-beta1/H2O2/HOCl-mediated enhancement of hepatocellular carcinoma cell tumorigenicity by suppressing cellular senescence. Cancer Science. 2015;106(5):559-566
  76. 76. Ramirez T, et al. Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. Journal of Hepatology. 2017;66(3):601-609
  77. 77. Abdelmegeed MA, et al. Cytochrome P450-2E1 promotes aging-related hepatic steatosis, apoptosis and fibrosis through increased nitroxidative stress. Free Radical Biology and Medicine. 2016;91:188-202
  78. 78. Shimomura Y, et al. The serum oxidative/anti-oxidative stress balance becomes dysregulated in patients with non-alcoholic steatohepatitis associated with hepatocellular carcinoma. Internal Medicine. 2017;56(3):243-251
  79. 79. Qu K, et al. Reactive oxygen species generation is essential for cisplatin-induced accelerated senescence in hepatocellular carcinoma. Frontiers in Medicine. 2014;8(2):227-235
  80. 80. Panieri E, et al. Reactive oxygen species generated in different compartments induce cell death, survival, or senescence. Free Radical Biology and Medicine. 2013;57:176-187
  81. 81. Piskounova E, et al. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature. 2015;527(7577):186-191
  82. 82. Correia-Melo C, Passos JF. Mitochondria: Are they causal players in cellular senescence? Biochimica et Biophysica Acta. 2015;1847(11):1373-1379
  83. 83. Feo F, Pascale RM. Multifocal hepatocellular carcinoma: Intrahepatic metastasis or multicentric carcinogenesis? Annals of Translational Medicine. 2015;3(1):4
  84. 84. Schmucker DL. Age-related changes in liver structure and function: Implications for disease ? Experimental Gerontology. 2005;40(8-9):650-659
  85. 85. Cuadrado A, et al. Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. Obesity Surgery. 2005;15(3):442-446
  86. 86. Cankurtaran M, et al. Serum vitamin-E levels and its relation to clinical features in nonalcoholic fatty liver disease with elevated ALT levels. Acta Gastroenterolgica Belgica. 2006;69(1):5-11
  87. 87. Blouin K, et al. Contribution of age and declining androgen levels to features of the metabolic syndrome in men. Metabolism. 2005;54(8):1034-1040
  88. 88. Poynard T, et al. Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis c. Journal of Hepatology. 2001;34(5):730-739
  89. 89. Keswani SC, Rosenberg B, Hoke A. The use of GAP-43 mRNA quantification in high throughput screening of putative neuroprotective agents in dorsal root ganglion cultures. Journal of Neuroscience Methods. 2004;136(2):193-195
  90. 90. Fry M, et al. Delayed and reduced cell replication and diminishing levels of DNA polymerase-alpha in regenerating liver of aging mice. Journal of Cellular Physiology. 1984;118(3):225-232
  91. 91. Timchenko NA, et al. Regenerating livers of old rats contain high levels of C/EBPalpha that correlate with altered expression of cell cycle associated proteins. Nucleic Acids Research. 1998;26(13):3293-3299
  92. 92. Iakova P, Awad SS, Timchenko NA. Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest. Cell. 2003;113(4):495-506
  93. 93. Forbes A, Williams R. Increasing age--an important adverse prognostic factor in hepatitis A virus infection. Journal of the Royal College of Physicians of London. 1988;22(4):237-239
  94. 94. Forbes A, Williams R. Changing epidemiology and clinical aspects of hepatitis A. British Medical Bulletin. 1990;46(2):303-318
  95. 95. Dhiman RK, et al. Early indicators of prognosis in fulminant hepatic failure: An assessment of the Model for End-Stage Liver Disease (MELD) and King's College Hospital criteria. Liver Transplantation. 2007;13(6):814-821
  96. 96. Wong V, et al. Importance of age in chronic hepatitis C virus infection. Journal of Viral Hepatitis. 1997;4(4):255-264
  97. 97. Poynard T. Interferon alpha in hepatitis C: A cytokine for reducing fibrosis progression. European Cytokine Network. 1997;8(3):319-320
  98. 98. Goudie BM, et al. Risk factors and prognosis in primary biliary cirrhosis. The American Journal of Gastroenterology. 1989;84(7):713-716
  99. 99. Forrest EH, et al. Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut. 2005;54(8):1174-1179
  100. 100. Ratziu V, et al. Liver fibrosis in overweight patients. Gastroenterology. 2000;118(6):1117-1123
  101. 101. Angulo P, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30(6):1356-1362
  102. 102. Schmucker DL, Sachs H. Quantifying dense bodies and lipofuscin during aging: A morphologist's perspective. Archives of Gerontology and Geriatrics. 2002;34(3):249-261
  103. 103. Nakajima T, et al. Premature telomere shortening and impaired regenerative response in hepatocytes of individuals with NAFLD. Liver international. 2006;26(1):23-31
  104. 104. Richardson MM, et al. Progressive fibrosis in nonalcoholic steatohepatitis: Association with altered regeneration and a ductular reaction. Gastroenterology. 2007;133(1):80-90
  105. 105. Aravinthan A, et al. Hepatocyte expression of the senescence marker p21 is linked to fibrosis and an adverse liver-related outcome in alcohol-related liver disease. PLoS One. 2013;8(9):e72904
  106. 106. Aravinthan A, et al. Hepatocyte senescence predicts progression in non-alcohol-related fatty liver disease. Journal of Hepatology. 2013;58(3):549-556
  107. 107. Marshall A, et al. Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology. 2005;128(1):33-42
  108. 108. Wood MJ, et al. Ductular reaction in hereditary hemochromatosis: The link between hepatocyte senescence and fibrosis progression. Hepatology. 2014;59(3):848-857
  109. 109. Gonzalez-Reimers E, et al. Hepatocyte and nuclear areas and fatty infiltration of the liver in chronic alcoholic liver disease. Drug and Alcohol Dependence. 1988;22(3):195-203
  110. 110. Mallat A, Lotersztajn S. Cellular mechanisms of tissue fibrosis. 5. Novel insights into liver fibrosis. American Journal of Physiology Cell Physiology. 2013;305(8):C789-799
  111. 111. Friedman SL. Liver fibrosis - from bench to bedside. Journal of Hepatology. 2003;38 Suppl 1:S38-S53
  112. 112. Borghesan M, et al. DNA hypomethylation and histone variant macroH2A1 synergistically attenuate chemotherapy-induced senescence to promote hepatocellular carcinoma progression. Cancer Research. 2016;76(3):594-606
  113. 113. Tachtatzis PM, et al. Correction: Chronic hepatitis B virus infection: The relation between hepatitis B antigen expression, telomere length, senescence, inflammation and fibrosis. PLoS One. 2015;10(7):e0134315
  114. 114. Kim H, et al. Large liver cell change in hepatitis B virus-related liver cirrhosis. Hepatology. 2009;50(3):752-762
  115. 115. Adinolfi LE, et al. Steatosis accelerates the progression of liver damage of chronic hepatitis C patients and correlates with specific HCV genotype and visceral obesity. Hepatology. 2001;33(6):1358-1364
  116. 116. Miura N, et al. Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. Cancer Genetics and Cytogenetics. 1997;93(1):56-62
  117. 117. de Alwis NM, Day CP. Non-alcoholic fatty liver disease: The mist gradually clears. Journal of Hepatology. 2008;48 Suppl 1:S104-112
  118. 118. Torbenson M, et al. STAT-3 overexpression and p21 up-regulation accompany impaired regeneration of fatty livers. The American Journal of Pathology. 2002;161(1):155-161
  119. 119. O'Shea RS, Dasarathy S, McCullough AJ. Alcoholic liver disease. The American Journal of Gastroenterology. 2010;105(1):14-32. quiz 33.
  120. 120. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. The International Journal of Biochemistry & Cell Biology. 2005;37(5):961-976
  121. 121. d'Adda di Fagagna F. Living on a break: Cellular senescence as a DNA-damage response. Nature Reviews Cancer. 2008;8(7):512-522
  122. 122. Chang J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nature Medicine. 2016;22(1):78-83

Written By

Ruth Pacheco Rivera, Jaime Arellanes Robledo and Jesús Serrano Luna

Submitted: 21 October 2016 Reviewed: 15 March 2017 Published: 30 August 2017