Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

SummaryShort telomeres are thought to trigger senescence, most likely through a single -or a group of few -critically shortened telomeres. Such short telomeres are thought to result from a combination of gradual linear shortening resulting from the end replication problem, reflecting the division history of the cell, superimposed by a more stochastic mechanism, suddenly causing a significant shortening of a single telomere. Previously, studies that have tried to explore the role of critically shortened telomeres have been hampered by methodological problems. With the method presented here, Universal STELA, we have a tool that can directly investigate the relationship between senescence and the load of short telomeres. The method is a variant of the chromosome-specific STELA method but has the advantage that it can demonstrate short telomeres regardless of chromosome. With Universal STELA, we find a strong correlation between the load of short telomeres and cellular senescence. Further we show that the load of short telomeres is higher in senescent cells compared to proliferating cells at the same passage, offering an explanation of premature cell senescence. This new method, Universal STELA, offers some advantages compared to existing methods and can be used to explore many of the unanswered questions in telomere biology including the role that telomeres play in cancer and aging.

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“…, 1995), although contradictory results have been published on this matter (von Zglinicki et al. , 2000; Britt‐Compton et al. , 2009).…”

Section: Discussionmentioning

confidence: 99%

The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells

et al. 2010

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“…Recently, Liang et al reported that aging increases the susceptibility of MSCs to ROS and impairs their therapeutic potency [35]. Britt-Compton et al indicated that more intense ROS-generating stressors can induce senescence through the generation of telomere-independent DNA damage [36]. It has been reported that an antioxidant is an indicator inhibiting oxidative stress [37,38].…”

Section: Discussionmentioning

confidence: 99%

Curcumin Affects Adipose Tissue-Derived Mesenchymal Stem Cell Aging Through TERT Gene Expression

et al. 2017

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Aging and losing cell survival is one of the main problems in cell therapy. Aging of Mesenchymal Stem Cells (MSCs) is associated with a rise in intracellular reactive oxygen species, decrease in telomerase reverse transcriptase (TERT) expression and finally eroded telomere ends. Given that the production of free radicals in the aging process is effective, the use of antioxidants can help in scavenging free radicals and prevent the aging of cells. The aim of this study is to evaluate the effects of curcumin on proliferation, aging and TERT expression of rat adipose tissue-derived stem cells (rADSC). rADSCs were isolated from inguinal rat adipose tissue and their viabilities were assessed by MTT after exposure to different concentrations of curcumin. Flow-cytometry was performed for investigating the cell surface markers. Adipogenic and osteogenic differentiation were carried out to evaluate the pluripotency of rADSCs. Telomerase expression and percentage of senescent cells were evaluated using real-time PCR and senescence-associated β-galactosidase activity, respectively. The results demonstrated significant proliferation of rADSCs after 48 h treatment with 1 and 5 µM curcumin. Additionally, these concentrations could significantly reduce the population doubling time and aging of rADSCs at different passages. The findings of SA-ß-gal staining showed that curcumin significantly decreased the number of senescent cells in the 5 and 7 cell passages. Moreover, expression levels of TERT increased in the presence of 1 and 5 µM curcumin than control group (P<0.001). As a conclusion, curcumin may be a good candidate to improve lifespan of rADSCs through promoting TERT gene expression.

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“…Mammalian cells cultured in 21% oxygen enter replicative senescence with longer telomeres and at earlier population doublings compared to cells grown in the presence of antioxidants or in 2% oxygen atmosphere (Chen et al ., 1995; von Zglinicki et al ., 2000; Betts et al ., 2008; Britt-Compton et al ., 2009). The cause for skin fibroblast senescence in either oxygen tension is telomere dysfunction (d'Adda di Fagagna et al ., 2003; Gire et al ., 2004; Herbig et al ., 2004).…”

Section: Discussionmentioning

confidence: 99%

Stn1 is critical for telomere maintenance and long‐term viability of somatic human cells

et al. 2015

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Disruption of telomere maintenance pathways leads to accelerated entry into cellular senescence, a stable proliferative arrest that promotes aging-associated disorders in some mammals. The budding yeast CST complex, comprising Cdc13, Stn1, and Ctc1, is critical for telomere replication, length regulation, and end protection. Although mammalian homologues of CST have been identified recently, their role and function for telomere maintenance in normal somatic human cells are still incompletely understood. Here, we characterize the function of human Stn1 in cultured human fibroblasts and demonstrate its critical role in telomere replication, length regulation, and function. In the absence of high telomerase activity, shRNA-mediated knockdown of hStn1 resulted in aberrant and fragile telomeric structures, stochastic telomere attrition, increased telomere erosion rates, telomere dysfunction, and consequently accelerated entry into cellular senescence. Oxidative stress augmented the defects caused by Stn1 knockdown leading to almost immediate cessation of cell proliferation. In contrast, overexpression of hTERT suppressed some of the defects caused by hStn1 knockdown suggesting that telomerase can partially compensate for hStn1 loss. Our findings reveal a critical role for human Stn1 in telomere length maintenance and function, supporting the model that efficient replication of telomeric repeats is critical for long-term viability of normal somatic mammalian cells.

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Telomere dynamics during replicative senescence are not directly modulated by conditions of oxidative stress in IMR90 fibroblast cells

Cited by 23 publications

References 45 publications

The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells

The load of short telomeres, estimated by a new method, Universal STELA, correlates with number of senescent cells

Curcumin Affects Adipose Tissue-Derived Mesenchymal Stem Cell Aging Through TERT Gene Expression

Stn1 is critical for telomere maintenance and long‐term viability of somatic human cells

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