Molecular Basis of Accelerated Aging with Immune Dysfunction-Mediated Inflammation (Inflamm-Aging) in Patients with Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.

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A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1− mice is correlated to increased cellular senescence

Redox Biology ◽

10.1016/j.redox.2016.10.014 ◽

2017 ◽

Vol 11 ◽

pp. 30-37 ◽

Cited By ~ 63

Author(s):

Yiqiang Zhang ◽

Archana Unnikrishnan ◽

Sathyaseelan S. Deepa ◽

Yuhong Liu ◽

Yan Li ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Accelerated Aging

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Link between increased cellular senescence and extracellular matrix changes in COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00028.2020 ◽

2020 ◽

Vol 319 (1) ◽

pp. L48-L60 ◽

Cited By ~ 3

Author(s):

Roy R. Woldhuis ◽

Maaike de Vries ◽

Wim Timens ◽

Maarten van den Berge ◽

Marco Demaria ◽

...

Keyword(s):

Oxidative Stress ◽

Extracellular Matrix ◽

Dna Damage ◽

Lung Tissue ◽

Cellular Senescence ◽

Accelerated Aging ◽

Lung Fibroblasts ◽

Copd Patients ◽

And Oxidative Stress ◽

P16 Expression

Chronic obstructive pulmonary disease (COPD) is associated with features of accelerated aging, including cellular senescence, DNA damage, oxidative stress, and extracellular matrix (ECM) changes. We propose that these features are particularly apparent in patients with severe, early-onset (SEO)-COPD. Whether fibroblasts from COPD patients display features of accelerated aging and whether this is also present in relatively young SEO-COPD patients is unknown. Therefore, we aimed to determine markers of aging in (SEO)-COPD-derived lung fibroblasts and investigate the impact on ECM. Aging hallmarks and ECM markers were analyzed in lung fibroblasts from SEO-COPD and older COPD patients and compared with fibroblasts from matched non-COPD groups ( n = 9–11 per group), both at normal culture conditions and upon Paraquat-induced senescence. COPD-related differences in senescence and ECM expression were validated in lung tissue. Higher levels of cellular senescence, including senescence-associated β-galactosidase (SA-β-gal)-positive cells (19% for COPD vs. 13% for control) and p16 expression, DNA damage (γ-H2A.X-positive nuclei), and oxidative stress ( MGST1) were detected in COPD compared with control-derived fibroblasts. Most effects were also different in SEO-COPD, with SA-β-gal-positive cells only being significant in SEO-COPD vs. matched controls. Lower decorin expression in COPD-derived fibroblasts correlated with higher p16 expression, and this association was confirmed in lung tissue. Paraquat treatment induced cellular senescence along with clear changes in ECM expression, including decorin. Fibroblasts from COPD patients, including SEO-COPD, display higher levels of cellular senescence, DNA damage, and oxidative stress. The association between cellular senescence and ECM expression changes may suggest a link between accelerated aging and ECM dysregulation in COPD.

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Role of Cellular Senescence and NOX4-Mediated Oxidative Stress in Systemic Sclerosis Pathogenesis

Current Rheumatology Reports ◽

10.1007/s11926-014-0473-0 ◽

2014 ◽

Vol 17 (1) ◽

Cited By ~ 27

Author(s):

Sonsoles Piera-Velazquez ◽

Sergio A. Jimenez

Keyword(s):

Oxidative Stress ◽

Systemic Sclerosis ◽

Cellular Senescence

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Chromosome Instability, Aging and Brain Diseases

Cells ◽

10.3390/cells10051256 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1256

Author(s):

Ivan Y. Iourov ◽

Yuri B. Yurov ◽

Svetlana G. Vorsanova ◽

Sergei I. Kutsev

Keyword(s):

Brain Aging ◽

Chromosome Instability ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Accelerated Aging ◽

Brain Diseases ◽

Aging Brain ◽

Ontogenetic Changes ◽

Health And Disease

Chromosome instability (CIN) has been repeatedly associated with aging and progeroid phenotypes. Moreover, brain-specific CIN seems to be an important element of pathogenic cascades leading to neurodegeneration in late adulthood. Alternatively, CIN and aneuploidy (chromosomal loss/gain) syndromes exhibit accelerated aging phenotypes. Molecularly, cellular senescence, which seems to be mediated by CIN and aneuploidy, is likely to contribute to brain aging in health and disease. However, there is no consensus about the occurrence of CIN in the aging brain. As a result, the role of CIN/somatic aneuploidy in normal and pathological brain aging is a matter of debate. Still, taking into account the effects of CIN on cellular homeostasis, the possibility of involvement in brain aging is highly likely. More importantly, the CIN contribution to neuronal cell death may be responsible for neurodegeneration and the aging-related deterioration of the brain. The loss of CIN-affected neurons probably underlies the contradiction between reports addressing ontogenetic changes of karyotypes within the aged brain. In future studies, the combination of single-cell visualization and whole-genome techniques with systems biology methods would certainly define the intrinsic role of CIN in the aging of the normal and diseased brain.

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Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Nutrients ◽

10.3390/nu13010041 ◽

2020 ◽

Vol 13 (1) ◽

pp. 41

Author(s):

Nouf Aljobaily ◽

Michael J. Viereckl ◽

David S. Hydock ◽

Hend Aljobaily ◽

Tsung-Yen Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Methylation ◽

Body Weight ◽

Liver Fibrosis ◽

Liver Damage ◽

Cellular Senescence ◽

Weight Ratio ◽

Mrna Levels ◽

Body Weight Ratio ◽

Chromosomal Stability

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

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Uric acid promotes oxidative stress and enhances vascular endothelial cell apoptosis in rats with middle cerebral artery occlusion

Bioscience Reports ◽

10.1042/bsr20170939 ◽

2018 ◽

Vol 38 (3) ◽

Cited By ~ 12

Author(s):

Chengfu Song ◽

Xiangdong Zhao

Keyword(s):

Oxidative Stress ◽

Uric Acid ◽

Endothelial Cell ◽

Cell Apoptosis ◽

Vascular Endothelial Cell ◽

Artery Occlusion ◽

Vascular Endothelial ◽

Endothelial Cell Apoptosis ◽

Related Factors ◽

Cerebral Artery Occlusion

In patients with cerebral infarction (CI), elevated serum uric acid (UA) level may exacerbate the occurrence and development of carotid atherosclerosis (AS). Our study intended to explore the underlying mechanism. We enrolled 86 patients with CI, and divided them into four groups: Non-AS, AS-mild, AS-moderate, and AS-severe groups; the levels of UA and oxidative stress-related factors in serum were detected. The middle cerebral artery occlusion (MCAO) model was used to stimulate CI in rats, and different doses of UA were administrated. The levels of oxidative stress-related factors in serum were detected. Hematoxylin & eosin (H&E) staining was used to observe the morphological alterations, and the apoptotic cell death detection kit was used to detect apoptotic cells. Increased UA concentration and enhanced oxidative stress were found in AS patients. H&E staining results showed that UA treatment exacerbated morphological damage in rats with MCAO, promoted oxidative stress, and enhanced vascular endothelial cell apoptosis in rats with MCAO.

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