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shows fibrosis using reticulin staining (above) and hepatocyte p21 expression (below) in a patient with ALD cirrhosis in second cohort.
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Background and aimAlcohol-related liver disease (ALD) remains a leading cause of liver-related morbidity and mortality. Age, fibrosis stage, MELD score and continued alcohol consumption predict outcome in everyday clinical practice. In previous studies increased hepatocyte nuclear area and hepatocyte expression of p21, both markers of senescence, w...
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Radiation-induced liver injury (RILI) is a major complication of radiotherapy during treatment for liver cancer and other upper abdominal malignant tumors that has poor pharmacological therapeutic options. A series of pathological changes can be induced by radiation. However, the underlying mechanism of RILI remains unclear. Radiation can induce ce...
Citations
... Sublethal stresses such as oxidative stress or hypoxia induced by exogenous factors can lead to excessive cellular senescence via the excessive secretion of proinflammatory and profibrotic factors, thereby triggering degenerative processes or diseases [14][15][16]. Previous studies have shown a strong positive correlation between an increase in the degree of hepatocyte senescence and the duration of liver fibrosis [17,18]. As a key event in the genesis of liver fibrosis, hepatic stellate cell (HSC) activation results in the generation of the extracellular matrix (ECM), ultimately resulting in the accumulation of collagen fibers within the liver [19]. ...
Arsenic is an environmental pollutant that has garnered considerable attention from the World Health Organization. Liver fibrosis is an advanced pathological stage of liver injury that can be caused by chronic arsenic exposure and has the potential to be reversed to prevent cirrhosis and hepatic malignancies. However, effective treatment options are currently limited. Given the profibrogenic effect of hepatocyte senescence, we established a rat model of sub-chronic sodium arsenite exposure and investigated the ability of resveratrol (RSV), a potential anti-senescence agent, to ameliorate arsenic-induced liver fibrosis and elucidate the underlying mechanism from the perspective of hepatocyte senescence. The results demonstrated that RSV was capable of mitigating fibrosis phenotypes in rat livers, including the activation of hepatic stellate cell (HSC), the generation of extracellular matrix, and the deposition of collagen fibers in the liver vascular zone, which are all induced by arsenic exposure. Furthermore, as an activator of the longevity factor SIRT1, RSV antagonized the arsenic-induced inhibition of SIRT1 expression, thereby restoring the suppression of the senescence protein p16 by SIRT1. This prevented arsenic-induced hepatocyte senescence, manifesting as a decrease in telomere shortening and a reduction in the release of senescence-associated secretory phenotype (SASP)-related proteins. In conclusion, this study demonstrated that RSV counteracts arsenic-induced hepatocyte senescence and the release of SASP-related proteins by restoring the inhibitory effect of SIRT1 on p16, thereby suppressing the activation of fibrotic phenotypes and mitigating liver fibrosis. These findings provide new insights for understanding the mechanism of arsenic-induced liver fibrosis, and more importantly, they reveal novel potential interventional approaches.
... The observation of IGFBP-7 increased in serum in both borderline and definite NASH stages as well as during the F1C and F2 fibrosis stages, combined with its identification as a predictor by both crude and adjusted lipid models, suggests a possible role for this protein in the progression of NAFLD. We assessed cellular senescence as a mechanism mediated by IGFBP-7, which has been shown to be involved in the progression of chronic liver disease [32,33]. As expected, cellular senescence was increased during NAFLD compared with the healthy controls. ...
... In fact, they were reported as a single control group. Cellular senescence is involved in a range of chronic liver disorders, including viral hepatitis B and C [54], alcoholic liver disease [32], genetic haemochromatosis [55], and NAFLD [33]; however, the mechanisms inducing senescence in chronic liver disease remain unclear. NAFLD and its derived fibrosis occur simultaneously; however, not all subjects progress at the same rate, and fibrosis is not strictly associated with NASH [4]. ...
Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent worldwide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBPs) are a family of secreted proteins involved in senescence and scarring, mainly synthetized in the liver. Here, we aimed to study the association of IGFBPs and their induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: A total of 16-week-old male C57BL/6 mice weighing 23 ± 3 g were fed either methionine/choline-deficient (MCD) or control diet for 2, 8, or 12 weeks. Blood and liver samples were collected, and a histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in the liver and serum. Data were expressed as mean ± SD and analyzed by a one-way ANOVA followed by Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p < 0.05 was considered significant. Results: IGFBP-1 and -2 were increased in serum during NAFLD. IGFBP-7 was significantly increased in the serum in NASH compared with the controls. Senescence increased in NAFLD. Serum and liver IGFBP-7 as well as SA-β-gal activity increased as fibrosis progressed. Both IGFBP-7 and cellular senescence were significantly higher during NAFLD and fibrosis in MCD-fed mice. Conclusions: IGFBP-1, -2, and -7, through their consequent senescence, have a role in the progression of NAFLD and its associated fibrosis, being a plausible determinant in the progression from steatosis to NASH.
... The observation of IGFBP-7 increased in serum in both borderline and definite NASH stages as well as during F1C and F2 fibrosis stages combined with its consisting identification as a predictor by both crude and adjusted by lipid model, suggested a possible role for this protein in the progression of NAFLD. We assessed cellular senescence as a mechanism mediated by IGFBP-7 that has been shown to be involved in the progression of chronic liver disease [32,33]. As expected, cellular senescence was increased during NAFLD compared with healthy controls. ...
... Senescence is known to increase in aging organs and tissues [48], however we do not consider aging a factor affecting our results, since we did not observed differences in SA-β-gal activity in the livers of mice fed control diet during the 2, 8 or 12 weeks, even though they were 6-10 weeks older at sample collection, in fact they were reported as a single control group. Cellular senescence is involved in a range of chronic liver disorders including viral hepatitis B and C [49], alcoholic liver disease [32], genetic haemochromatosis [50] and NAFLD [33], however the mechanisms inducing senescence in chronic liver disease remain unclear. NAFLD and its derived fibrosis occur simultaneously; however, not all subjects progress at the same rate and fibrosis is not strictly associated to NASH [4]. ...
Background and Objectives: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent world-wide. It progresses from simple steatosis to non-alcoholic steatohepatitis (NASH). Fibrosis is often present during NAFLD progression; however, factors determining which subjects develop NASH or fibrosis are unclear. Insulin-like growth factor binding proteins (IGFBP) is a family of secreted proteins involved in senescence and scarring mainly synthetized in the liver. Here we aimed to study the association of IGFBP and its induced senescence with the progression of NAFLD and liver fibrosis. Materials and Methods: 16 weeks old male C57BL/6 mice weighing 23 ± 3 g were fed either Methionine-Choline Deficient or control diet for 2, 8 or 12 weeks. Blood and liver samples were collected; histological assessment of NAFLD and fibrosis was performed. Fat contents were measured. Cellular senescence was evaluated in the liver. IGFBP levels were assessed in liver and serum. Data was expressed as Mean ± SD and analyzed by one-way ANOVA followed Tukey’s test. Lineal regression models were applied for NAFLD and fibrosis progression. p
... [3] As the predominant liver parenchymal cells, senescent hepatocytes have received increasing attention in CLD. Accumulating evidence supports the association between increased senescent hepatocytes and more severe liver damage and fibrosis [4][5][6][7][8][9][10][11] ; however, the underlying mechanisms remain elusive. ...
... Aging reportedly increases fragility to acute liver injury and enhances susceptibility to CLD and liver fibrosis. [4][5][6] Ramirez et al [5] reported SIRT1 downregulation in hepatocytes aggravated ethanol-induced liver damage and fibrosis in aged mice, and yet, the exact mechanism is still unelucidated. Here, we found that downregulation of SIRT1 in hepatocytes induced a decline in HMGB1 deacetylation and an increase in ace-HMGB1 cytoplasmic translocation and extracellular secretion in aged mice; similar observations were found in aged human clinical samples. ...
Background
Aging increases the susceptibility to chronic liver diseases and hastens liver fibrosis deterioration, but the underlying mechanisms remain partially understood. The aim of this study was to investigate the effect of aging and chronic liver diseases on hepatocyte Sirtuin 1 (SIRT1) and LSECs and their contribution to liver fibrosis pathogeneses.
Methods
Young (8–12 wk) and aged (18–20 mo) mice were subjected to carbon tetrachloride–induced liver fibrosis. Primary HSCs and LSECs were isolated and cocultured for in vitro experiments. Liver tissues and blood samples from healthy controls and patients with liver fibrosis were analyzed.
Results
Downregulated hepatocytes SIRT1 in aged mice increased high mobility group box 1 acetylation, cytoplasmic translocation, and extracellular secretion, causing LSECs dysfunction by means of the toll-like receptor 4/AK strain transforming (AKT)/endothelial nitric oxide synthase pathway, ultimately activating HSCs and increasing susceptibility to liver injury and fibrosis. Adeno-associated virus-mediated overexpression of SIRT1 in hepatocytes suppressed the abovementioned alterations and attenuated carbon tetrachloride–induced liver injury and fibrosis in liver fibrosis mice, and there were no significant differences in liver injury and fibrosis indicators between young and aged mice after SIRT1 overexpression treatment. In vitro experiments demonstrated that SIRT1 overexpression and endothelial nitric oxide synthase agonist YC-1 improved LSECs function and inhibited HSCs activation, mediated by nitric oxide. Similarly, downregulated hepatocytes SIRT1 and LSECs dysfunction were observed in the livers of aged individuals compared to young individuals and were more pronounced in aged patients with liver fibrosis.
Conclusions
Aging aggravates liver fibrosis through downregulated hepatocytes SIRT1-induced LSECs dysfunction, providing a prospective curative approach for preventing and treating liver fibrosis.
... In chronic liver disease, a close geographical correlation between hepatocyte senescence and HSC activation was found [7,37]. However, the mechanisms underlying the association between cellular senescence and the progression of liver disease are complicated and uncertain. ...
... It has been reported that inducing HSC senescence could block its activation with regression of liver fibrosis, whereby senescent cells lack their role-specific to that cell type during senescence [38]. Senescence of hepatocytes, on the other hand, has been associated with fibrosis and deterioration in persistent liver disorders [37,39]. Despite the fact that hepatocytes are the most prevalent cell type in the liver, the existence of senescent cells within the fibrotic scar in the livers of both humans and mice suggested that these cells originated from activated HSCs, which proliferate immediately after liver damage and account for much of the ECM generated during fibrosis [40]. ...
Objective: To evaluate the effect of hydroxysafflor yellow A (HSYA) on thioacetamide-induced liver fibrosis. Methods: Thioacetamide was administered to rats intraperitoneally in doses of 200 mg/kg twice a week for 12 weeks. Thioacetamide-intoxicated rats were given silymarin (50 mg/kg) or HSYA (5 mg/ kg) orally every day for 8 weeks. Liver enzymes, fibrosis markers, histological changes as well as immunohistochemistry of TNF-α, IL-6, p21, α-SMA, and caspase-3 were examined. The effect of HSYA on HSC-T6 activation/proliferation and apoptosis was also determined in vitro. Results: HSYA decreased liver enzymes, TNF-α, IL-6, and p21 expressions, hepatic PDGF-B, TIMP-1, TGF-β1, and hydroxyproline levels, as well as fibrosis score (S2 vs. S4) compared to the thioacetamide group. HSYA also downregulated α-SMA while increasing caspase-3 expression. Surprisingly, at 500 µg/mL, HSYA had only a slightly suppressive effect on HSC proliferation, with a 9.5% reduction. However, it significantly reduced TGF-β1, inhibited α-SMA expression, induced caspase-3 expression, and promoted cell senescence. Conclusions: HSYA may be a potential therapeutic agent for delaying and reversing the progression of liver fibrosis. More research on HSYA at higher doses and for a longer period is warranted.
... 97 In the peripheral blood lymphocyte subsets of healthy adults in different ages, it was found that the decreased naive CD4 and CD8 T cell number, increased memory CD4 or CD8 T cell number, and decreased CD28 expression on T cells. 70 Numerous studies have shown a close association between increased stimulation by various antigens in vitro, especially cytomegalovirus (CMV) infection, and an increase in effector memory T cells, 98 resulting in the activation of naive lymphocytes into memory lymphocytes and their long-term presence in vivo. 13,99 This process leads to an increased number of memory CD4 and CD8 T lymphocytes with age, and a decrease of TCR diversity in naive T cells, which suppresses the responsiveness of T cells to neoantigens (Fig. 2). ...
Aging is characterized by systemic chronic inflammation, which is accompanied by cellular senescence, immunosenescence, organ dysfunction, and age-related diseases. Given the multidimensional complexity of aging, there is an urgent need for a systematic organization of inflammaging through dimensionality reduction. Factors secreted by senescent cells, known as the senescence-associated secretory phenotype (SASP), promote chronic inflammation and can induce senescence in normal cells. At the same time, chronic inflammation accelerates the senescence of immune cells, resulting in weakened immune function and an inability to clear senescent cells and inflammatory factors, which creates a vicious cycle of inflammation and senescence. Persistently elevated inflammation levels in organs such as the bone marrow, liver, and lungs cannot be eliminated in time, leading to organ damage and aging-related diseases. Therefore, inflammation has been recognized as an endogenous factor in aging, and the elimination of inflammation could be a potential strategy for anti-aging. Here we discuss inflammaging at the molecular, cellular, organ, and disease levels, and review current aging models, the implications of cutting-edge single cell technologies, as well as anti-aging strategies. Since preventing and alleviating aging-related diseases and improving the overall quality of life are the ultimate goals of aging research, our review highlights the critical features and potential mechanisms of inflammation and aging, along with the latest developments and future directions in aging research, providing a theoretical foundation for novel and practical anti-aging strategies.
... Cellular senescence is a consequence of mitochondrial oxidative dysfunction and ethanol exposure and AH result in increased senescence markers in different cell types. [39][40][41] We report enrichment of senescence pathways including genes regulating telomere length on scRNAseq from PBMC in AH compared to HC and HD, suggesting immune senescence. The most changes were noted in pDC despite their constituting only a small percentage of the PBMC pool. ...
Background:
Patients with acute alcohol-associated hepatitis (AH) have immune dysfunction. Mitochondrial function is critical for immune cell responses and regulates senescence. Clinical translational studies using complementary bioinformatics-experimental validation of mitochondrial responses were performed in peripheral blood mononuclear cells (PBMC) from patients with AH, healthy controls (HC), and heavy drinkers without evidence of liver disease (HD).
Methods:
Feature extraction for differentially expressed genes (DEG) in mitochondrial components and telomere regulatory pathways from single-cell RNAseq (scRNAseq) and integrated 'pseudobulk' transcriptomics from PBMC from AH and HC (n = 4 each) were performed. After optimising isolation and processing protocols for functional studies in PBMC, mitochondrial oxidative responses to substrates, uncoupler, and inhibitors were quantified in independent discovery (AH n = 12; HD n = 6; HC n = 12) and validation cohorts (AH n = 10; HC n = 7). Intermediary metabolites (gas-chromatography/mass-spectrometry) and telomere length (real-time PCR) were quantified in subsets of subjects (PBMC/plasma AH n = 69/59; HD n = 8/8; HC n = 14/27 for metabolites; HC n = 13; HD n = 8; AH n = 72 for telomere length).
Results:
Mitochondrial, intermediary metabolite, and senescence-regulatory genes were differentially expressed in PBMC from AH and HC in a cell type-specific manner at baseline and with lipopolysaccharide (LPS). Fresh PBMC isolated using the cell preparation tube generated optimum mitochondrial responses. Intact cell and maximal respiration were lower (p ≤ .05) in AH than HC/HD in the discovery and validation cohorts. In permeabilised PBMC, maximum respiration, complex I and II function were lower in AH than HC. Most tricarboxylic acid (TCA) cycle intermediates in plasma were higher while those in PBMC were lower in patients with AH than those from HC. Lower telomere length, a measure of cellular senescence, was associated with higher mortality in AH.
Conclusion:
Patients with AH have lower mitochondrial oxidative function, higher plasma TCA cycle intermediates, with telomere shortening in nonsurvivors.
... Indeed, aging is associated with the severity and poor prognosis of various liver diseases including nonalcoholic fatty liver disease, alcoholic liver disease, hepatitis C, and liver transplantation [28,29]. In addition, as this organ has the capacity for regeneration, process that declines with age, fibrotic response is also altered during aging [30,31]. ...
Oxygen is vital for life as it is required for many different enzymatic reactions involved in intermediate metabolism and xenobiotic biotransformation. Moreover, oxygen consumption in the electron transport chain of mitochondria is used to drive the synthesis of ATP to meet the energetic demands of cells. However, toxic free radicals are generated as byproducts of molecular oxygen consumption. Oxidative stress ensues not only when the production of reactive oxygen species (ROS) exceeds the endogenous antioxidant defense mechanism of cells, but it can also occur as a consequence of an unbalance between antioxidant strategies. Given the important role of hepatocytes in the biotransformation and metabolism of xenobiotics, ROS production represents a critical event in liver physiology, and increasing evidence suggests that oxidative stress contributes to the development of many liver diseases. The present review, which is part of the special issue “Oxidant stress in Liver Diseases”, aims to provide an overview of the sources and targets of ROS in different liver diseases and highlights the pivotal role of oxidative stress in cell death. In addition, current antioxidant therapies as treatment options for such disorders and their limitations for future trial design are discussed.
... Accumulation of senescent hepatocytes is well described in chronic liver disease, irrespective of aetiology [6][7][8][9][10]. Most studies demonstrated a strong positive association between the proportion of senescent hepatocytes and liver fibrosis stage [6][7][8]10]. ...
... Accumulation of senescent hepatocytes is well described in chronic liver disease, irrespective of aetiology [6][7][8][9][10]. Most studies demonstrated a strong positive association between the proportion of senescent hepatocytes and liver fibrosis stage [6][7][8]10]. However, it is not clear whether progression of liver fibrosis is a consequence of the accumulation of senescent hepatocytes or whether accumulation of senescent hepatocytes and liver fibrosis progression are unrelated consequences of liver injury. ...
... During initiation, changes occur in gene expression which leads to th perpetuation phase, where HSCs become pro-inflammatory and fibrogenic. Previou studies demonstrated a strong positive association between the proportion of senescen hepatocytes and liver fibrosis stage, irrespective of aetiology, but did not address a causa association [6,[8][9][10]. The current study demonstrated that senescent hepatocytes influ ence their microenvironment through secretion of senescence-associated secretory fac tors; incubation of HSCs in cell-free conditioned media derived from senescent HepG cells led to changes in their gene expression profile. ...
Hepatocyte senescence is associated with liver fibrosis. However, the possibility of a direct, causal relation between hepatocyte senescence and hepatic stellate cell (HSC) activation was the subject of this study. Liver biopsy specimens obtained from 50 patients with non-alcoholic fatty liver disease and a spectrum of liver fibrosis stages were stained for p16, αSMA, and picrosirius red (PSR). Primary human HSCs were cultured in conditioned media derived from senescent or control HepG2 cells. Expression of inflammatory and fibrogenic genes in HSCs cultured in conditioned media were studied using RT-PCR. ELISAs were undertaken to measure factors known to activate HSCs in the conditioned media from senescent and control HepG2 cells and serum samples from healthy volunteers or patients with biopsy-proven cirrhosis. There was a strong association between proportion of senescent hepatocytes and hepatic stellate cell activation. Both proportion of hepatocyte senescence and hepatic stellate cell activation were closely associated with fibrosis stage. Inflammatory and fibrogenic genes were up-regulated significantly in HSCs cultured in conditioned media from senescent HepG2 cells compared with control HepG2 cells. PDGF levels were significantly higher in the conditioned media from senescent hepatocytes than control HepG2-conditioned media, and in serum samples from patients with cirrhosis than healthy volunteers. In conclusion, this ‘proof of concept’ study revealed activation of human HSCs by media from senescent HepG2 cells, indicating direct involvement of factors secreted by senescent hepatocytes in liver fibrosis.
... During advanced aging, microglia obtain an arrested growth state that is accompanied by enhanced production of proinflammatory cytokines and associated neurodegeneration and cognitive dysfunction (Angelova & Brown, 2019). Ethanol exposure promotes cellular senescence in peripheral organs, yet the influence of ethanol exposure on inflammation and cellular senescence, including microglia senescence, in the aged brain is not well characterized (Aravinthan et al., 2013). To address these gaps in the literature, they examined senescence and inflammation markers in the hippocampi of young and aged mice after chronic binge ethanol exposure. ...
On November 19th, 2021, the annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held at Loyola University Chicago Health Sciences Campus in Maywood, Illinois. The 2021 meeting focused on how alcohol misuse is linked to immune system derangements, leading to tissue and organ damage, and how this research can be translated into improve alcohol-related disease. This meeting was divided into three plenary sessions: first session focused on how alcohol misuse affects different parts of the immune systems; second session presented research on mechanisms of organ damage from alcohol misuse; the final session highlighted research on potential therapeutic targets for treating alcohol mediated tissue damage. Diverse areas of alcohol research were covered during the meeting, from alcohol’s effect on pulmonary systems and neuroinflammation to epigenetic changes, senescence markers and microvesicle particles. What yielded from all these presentations is a thoughtful discussion on how the findings can lead to therapeutic treatments for people suffering from alcohol-related diseases.
