Chronic oxidative stress induces a tissue-specific reduction in telomere length in CAST/Ei mice

Abstract Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance and dyslipidemia along with tissue-specific increases in ectopic lipid accumulation, oxidative stress and insulin resistance in liver and muscle of the early adult female sheep. Prenatal T increased inflammation and oxidative stress in the visceral (VAT) but not subcutaneous (SAT) adipose tissue, with no effect on insulin sensitivity in both depots. These systemic and tissue-specific metabolic changes are reminiscent of defects such as non-alcoholic fatty liver disease (NFLAD) common among aged individuals. Because it is known that gestational insults can program premature aging of reproductive organs and chronic cardiovascular abnormalities, we hypothesized that programming of premature cellular senescence is one of the ways through which gestational T induces premature aging of metabolic systems during early adulthood. To test this hypothesis, mitochondrial oxidative phosphorylation (OXPHOS) and telomere length, as measure of cellular senescence, were assessed in liver, muscle, VAT and SAT collected from control and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation) -treated female sheep at 21 months of age. Genomic DNA was subjected to TeloTAGG Telomere Length Assay (Sigma-Aldrich, St Louis, MO) and whole tissue protein lysates analyzed by immunoblot using Total OXPHOS Human WB Antibody Cocktail (ab110411, Abcam, Cambridge, MA). Data were analyzed by Student’s t test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) a trend (p = 0.09) towards a large magnitude increase in shorter telomere fragments (0.08 -3.6 KB) in the liver and 2) a non-significant large magnitude decrease in shorter telomere fragments in muscle and SAT without having any effect in the VAT. Prenatal T also induced a large magnitude increase in mitochondrial OXPHOS protein complexes II and IV in liver, without having an effect at the level of the muscle, VAT and SAT. These findings are suggestive that prenatal T-treatment induced hepatic defects may involve premature cellular senescence. The relevance of parallel increase in mitochondrial OXPHOS in the liver is unclear and remains to be explored. The defects observed in the muscle and SAT may occur independent of cellular senescence or alterations in mitochondrial function. The lack of change in telomere length and mitochondrial OXPHOS in spite of increased inflammation and oxidative stress in the VAT is suggestive of a potential protective function in play, consistent with maintenance of the insulin sensitivity in this tissue. This study, therefore, raises the possibility that metabolic defects programmed by gestational insults may involve premature aging of metabolic organs in a tissue-specific manner and have translational bearing in conditions associated with hyperandrogenic states.

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Telomere Length in Transfusion Dependent Thalassemia Patients

Blood ◽

10.1182/blood.v128.22.1291.1291 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1291-1291

Author(s):

Nithita Nanthatanti ◽

Adisak Tantiworawit ◽

Nawapong Patpan ◽

Thanawat Rattanathammethee ◽

Sasinee Hantrakool ◽

...

Keyword(s):

Oxidative Stress ◽

Iron Overload ◽

Telomere Length ◽

Restriction Fragment ◽

Beta Thalassemia ◽

Control Group ◽

Ineffective Erythropoiesis ◽

Chiang Mai ◽

Telomere Shortening ◽

Chronic Oxidative Stress

Abstract BACKGROUND Transfusion dependent thalassemia (TDT) patients is a group of thalassemia patients who require regular blood transfusion. Red blood cell transfusion and increased intestinal iron absorption leads to iron overload. The cellular damage associated with iron overload is mainly mediated by the state of oxidative stress and the effect of free oxygen radicals on various cell components. Telomeres are terminal protein-DNA complexes that stabilize chromosome and prevent DNA from double-stranded breaks. Chronic oxidative stress from iron overload and ineffective erythropoiesis in thalassemia may lead to shortening of telomere length. METHOD We conducted a cross-sectional study in TDT patients aged more than 18 years old who attended the adult hematology clinic at Maharaj Nakorn Chiang Mai hospital, Chiang Mai University, Thailand from 1 January 2016 to 30 April 2016. TDT was defined as thalassemia who requiring a red cell transfusion at least 3 times per year, included both beta-thalassemia and alpha-thalassemia patients. Telomere length was measured by real-time quantitative PCR and compared with matched healthy controls by age and sex. We used Pearson's correlation coefficient to test whether telomere length was associated with any factors. The threshold for statistical significance for all comparisons was chosen as P <0.05. RESULT Thirty TDT patients and 30 matched healthy control were included in this study. For TDT group, there were 19 female patients (63.3%). The median age was 29.2 (18-48) years. Baseline hemoglobin pre-transfusion 6.4 g/dL (5.3-7.4). Of these, there were 18 beta-thalassemia/Hb E disease (60%) who was the majority population. There were 11 beta-thalassemia major patients (36.4%) and 1 HbH with Constant spring patient (3.3%). The median telomeric terminal restriction fragment (TRF) length of TDT thalassemia group was 5.76 (4.94-7.13) kb. The median TRF length of control group was 6.79 (5.52-9.02) kb. TDT patients had significant shorter TRF length compared to control group (age and sex match), (p<0.0001). Telomere shortening in TDT thalassemia is aging-dependent process. The Pearson's coefficient showed the negative correlation between TRF length and age (Pearson's coefficient = 0.176), (p=0.021). There was no correlation of telomere length with other factors such as sex, hemoglobin level, transfusion requirement. CONCLUSION TDT patients had shorter telomere length compared to control group. Telomere shortening in TDT thalassemia is aging-dependent process. Chronic oxidative stress from iron overload and ineffective erythropoiesis in thalassemia may play the significant role in this accelerated telomere shortening process. Table The median telomeric terminal restriction fragment length of TDT patients compared with control group Table. The median telomeric terminal restriction fragment length of TDT patients compared with control group Disclosures No relevant conflicts of interest to declare.

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Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200131125110 ◽

2020 ◽

Vol 20 (6) ◽

pp. 498-507 ◽

Cited By ~ 4

Author(s):

Connor A.H. Thompson ◽

Judy M.Y. Wong

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Reverse Transcriptase ◽

Cancer Cells ◽

Telomere Length ◽

Telomere Maintenance ◽

Telomerase Reverse Transcriptase ◽

Alternative Mechanism ◽

Dependent Manner ◽

Mitochondrial Integrity

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

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Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging

Biology ◽

10.3390/biology10040253 ◽

2021 ◽

Vol 10 (4) ◽

pp. 253

Author(s):

Graciela Gavia-García ◽

Juana Rosado-Pérez ◽

Taide Laurita Arista-Ugalde ◽

Itzen Aguiñiga-Sánchez ◽

Edelmiro Santiago-Osorio ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Telomere Length ◽

Scientific Evidence ◽

Telomeric Dna ◽

Biochemical Alterations ◽

The Metabolic Syndrome ◽

Age Related ◽

And Function

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

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Association of Metabolically Healthy and Unhealthy Obesity Phenotypes with Oxidative Stress Parameters and Telomere Length in Healthy Young Adult Men. Analysis of the MAGNETIC Study

Antioxidants ◽

10.3390/antiox10010093 ◽

2021 ◽

Vol 10 (1) ◽

pp. 93

Author(s):

Mateusz Lejawa ◽

Kamila Osadnik ◽

Tadeusz Osadnik ◽

Natalia Pawlas

Keyword(s):

Oxidative Stress ◽

Telomere Length ◽

Quantitative Polymerase Chain Reaction ◽

Oxidative Stress Markers ◽

Metabolic Disturbances ◽

Total Oxidation ◽

Stress Markers ◽

Metabolic Dysregulation ◽

Total Antioxidant ◽

Metabolically Healthy

Obesity is a significant factor related to metabolic disturbances that can lead to metabolic syndrome (MetS). Metabolic dysregulation causes oxidative stress, which affects telomere structure. The current study aimed to evaluate the relationships between telomere length, oxidative stress and the metabolically healthy and unhealthy phenotypes in healthy young men. Ninety-eight participants were included in the study (49 healthy slim and 49 obese patients). Study participants were divided into three subgroups according to body mass index and metabolic health. Selected oxidative stress markers were measured in serum. Relative telomere length (rTL) was measured using quantitative polymerase chain reaction. The analysis showed associations between laboratory markers, oxidative stress markers and rTL in metabolically healthy and unhealthy participants. Total oxidation status (TOS), total antioxidant capacity (TAC) and rTL were significantly connected with metabolically unhealthy obesity. TAC was associated with metabolically healthy obesity. Telomeres shorten in patients with metabolic dysregulation related to oxidative stress and obesity linked to MetS. Further studies among young metabolically healthy and unhealthy individuals are needed to determine the pathways related to metabolic disturbances that cause oxidative stress that leads to MetS.

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Telomere Shortening and Psychiatric Disorders: A Systematic Review

Cells ◽

10.3390/cells10061423 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1423

Author(s):

Pedro A. Pousa ◽

Raquel M. Souza ◽

Paulo Henrique M. Melo ◽

Bernardo H. M. Correa ◽

Tamires S. C. Mendonça ◽

...

Keyword(s):

Oxidative Stress ◽

Psychological Distress ◽

Mental Disorders ◽

Psychiatric Disorders ◽

Telomere Length ◽

Traumatic Stress ◽

Molecular Mechanisms ◽

Cochrane Library ◽

Telomere Shortening ◽

Anxiety Depression

Telomeres are aging biomarkers, as they shorten while cells undergo mitosis. The aim of this study was to evaluate whether psychiatric disorders marked by psychological distress lead to alterations to telomere length (TL), corroborating the hypothesis that mental disorders might have a deeper impact on our physiology and aging than it was previously thought. A systematic search of the literature using MeSH descriptors of psychological distress (“Traumatic Stress Disorder” or “Anxiety Disorder” or “depression”) and telomere length (“cellular senescence”, “oxidative stress” and “telomere”) was conducted on PubMed, Cochrane Library and ScienceDirect databases. A total of 56 studies (113,699 patients) measured the TL from individuals diagnosed with anxiety, depression and posttraumatic disorders and compared them with those from healthy subjects. Overall, TL negatively associates with distress-related mental disorders. The possible underlying molecular mechanisms that underly psychiatric diseases to telomere shortening include oxidative stress, inflammation and mitochondrial dysfunction linking. It is still unclear whether psychological distress is either a cause or a consequence of telomere shortening.

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Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study

Journal of Clinical Medicine ◽

10.3390/jcm10071349 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1349

Author(s):

Kamila Czubak-Prowizor ◽

Jacek Trelinski ◽

Paulina Stelmach ◽

Piotr Stelmach ◽

Agnieszka Madon ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Myeloid Leukemia ◽

Exploratory Study ◽

Myeloid Leukemia ◽

Thiobarbituric Acid ◽

Red Blood Cell Transfusion ◽

Packed Red Blood Cells ◽

Chronic Oxidative Stress ◽

Total Antioxidant ◽

Acute Myeloid

Chronic oxidative stress (OS) can be an important factor of acute myeloid leukemia (AML) progression; however, there are no data on the extent/consequence of OS after transfusion of packed red blood cells (pRBCs) and platelet concentrates (PCs), which are commonly used in the treatment of leukemia-associated anemia and thrombocytopenia. We aimed to investigate the effects of pRBC/PC transfusion on the OS markers, i.e., thiol and carbonyl (CO) groups, 3-nitrotyrosine (3-NT), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGE), total antioxidant capacity (TAC), SOD, GST, and LDH, in the blood plasma of AML patients, before and 24 h post-transfusion. In this exploratory study, 52 patients were examined, of which 27 were transfused with pRBCs and 25 with PCs. Age-matched healthy subjects were also enrolled as controls. Our results showed the oxidation of thiols, increased 3-NT, AGE levels, and decreased TAC in AML groups versus controls. After pRBC transfusion, CO groups, AGE, and 3-NT significantly increased (by approximately 30, 23, and 35%; p < 0.05, p < 0.05, and p < 0.01, respectively) while thiols reduced (by 18%; p < 0.05). The PC transfusion resulted in the raise of TBARS and AGE (by 45%; p < 0.01 and 31%; p < 0.001), respectively). Other variables showed no significant post-transfusion changes. In conclusion, transfusion of both pRBCs and PCs was associated with an increased OS; however, transfusing the former may have more severe consequences, since it is associated with the irreversible oxidative/nitrative modifications of plasma proteins.

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