scholarly journals Telomere shortening rate predicts species life span

2019 ◽  
Vol 116 (30) ◽  
pp. 15122-15127 ◽  
Author(s):  
Kurt Whittemore ◽  
Elsa Vera ◽  
Eva Martínez-Nevado ◽  
Carola Sanpera ◽  
Maria A. Blasco
Keyword(s):  
Dna Damage ◽  
Life Span ◽  
Telomere Length ◽  
Rangifer Tarandus ◽  
Critical Length ◽  
Capra Hircus ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Gyps Fulvus ◽  
Shortening Rate

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin’s gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

scholarly journals Stochastic Variation in Telomere Shortening Rate Causes Heterogeneity of Human Fibroblast Replicative Life Span

2004 ◽  
Vol 279 (17) ◽  
pp. 17826-17833 ◽  
Author(s):  
Carmen Martin-Ruiz ◽  
Gabriele Saretzki ◽  
Joanne Petrie ◽  
Juliane Ladhoff ◽  
Jessie Jeyapalan ◽  
...  
Keyword(s):  
Life Span ◽  
Human Fibroblast ◽  
Stochastic Variation ◽  
Telomere Shortening ◽  
Replicative Life Span ◽  
Shortening Rate

scholarly journals Functional Diversification of Replication Protein A Paralogs and Telomere Length Maintenance in Arabidopsis

Genetics ◽  
2020 ◽  
Vol 215 (4) ◽  
pp. 989-1002
Author(s):  
Behailu B. Aklilu ◽  
François Peurois ◽  
Carole Saintomé ◽  
Kevin M. Culligan ◽  
Daniela Kobbe ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Telomere Length ◽  
Protein A ◽  
Replication Protein A ◽  
Telomerase Activity ◽  
Replication Protein ◽  
Telomeric Dna ◽  
Telomere Shortening ◽  
Replication Group

Replication protein A (RPA) is essential for many facets of DNA metabolism. The RPA gene family expanded in Arabidopsis thaliana with five phylogenetically distinct RPA1 subunits (RPA1A-E), two RPA2 (RPA2A and B), and two RPA3 (RPA3A and B). RPA1 paralogs exhibit partial redundancy and functional specialization in DNA replication (RPA1B and RPA1D), repair (RPA1C and RPA1E), and meiotic recombination (RPA1A and RPA1C). Here, we show that RPA subunits also differentially impact telomere length set point. Loss of RPA1 resets bulk telomeres at a shorter length, with a functional hierarchy for replication group over repair and meiosis group RPA1 subunits. Plants lacking RPA2A, but not RPA2B, harbor short telomeres similar to the replication group. Telomere shortening does not correlate with decreased telomerase activity or deprotection of chromosome ends in rpa mutants. However, in vitro assays show that RPA1B2A3B unfolds telomeric G-quadruplexes known to inhibit replications fork progression. We also found that ATR deficiency can partially rescue short telomeres in rpa2a mutants, although plants exhibit defects in growth and development. Unexpectedly, the telomere shortening phenotype of rpa2a mutants is completely abolished in plants lacking the RTEL1 helicase. RTEL1 has been implicated in a variety of nucleic acid transactions, including suppression of homologous recombination. Thus, the lack of telomere shortening in rpa2a mutants upon RTEL1 deletion suggests that telomere replication defects incurred by loss of RPA may be bypassed by homologous recombination. Taken together, these findings provide new insight into how RPA cooperates with replication and recombination machinery to sustain telomeric DNA.

The Telomerase Inhibitor RHPS4 Induces Telomere Shortening, DNA-Damage and Cell Death in AML Cells and Chemosensitises Cells to Daunorubicin.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2760-2760
Author(s):  
Monica Pallis ◽  
Dotun Ojo ◽  
Jaineeta Richardson ◽  
John Ronan ◽  
Malcolm Stevens ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Telomere Length ◽  
Progenitor Cells ◽  
Cell Lines ◽  
Dna Damage Response ◽  
Cell Types ◽  
Telomere Shortening ◽  
Damage Response

Abstract Abstract 2760 Poster Board II-736 The quadruplex ligand RHPS4 is the lead compound in a drug discovery program at the University of Nottingham. It has been shown to bind to telomeres and inhibit telomerase, and subsequently induces growth arrest in progenitor cells from cancer cell lines whilst sparing normal haematopoietic progenitor cells. We explored its in vitro effects in AML cells, which are reported generally to have considerably shorter telomeres than normal CD34+ cells. AML cell lines were grown for 21 days in suspension culture. Primary samples were cultured for 14 days in semi-solid medium. Telomere length was measured by Southern blotting. γH2A.X was used to identify a DNA damage response, and cell viability was measured flow cytometrically with 7-amino actinomycin D. As reported in other tumour cell types, sensitivity to RHPS4 was found to be greatest in those AML cells with the shortest telomeres. In the OCI-AML3 cell line 0.3 μM RHPS4 inhibited cell growth by 50% in a 21 day clonogenic assay, accompanied by shortening of telomeres from 2.6 Kb to <1 Kb. Molm 13 cells (initial telomere length 3.2kB) also underwent telomere shortening in the presence of 0.3 μM RHPS4 (2.8Kb), whereas TF1a and U937 (both with initial telomere lengths approximately 6.5 kB) were insensitive at that concentration. After 6 days at 0.3 μM, RHPS4 was cytostatic, but at higher concentrations (1 μM) the drug was found to induce a substantial DNA damage response and loss of viability to OCI-AML3 cells. Moreover 0.3 μM RHPS4 enhanced the γH2A.X expression and cell death induced by the chemotherapy drug daunorubicin in these cells. Using 14 day clonogenic assays in primary AML samples (n=6), we found that the IC50 for RHPS4 alone was 0.7 μM. However, in the presence of 0.3 μM RHPS4, the median IC50 to daunorubicin was reduced from 19 nM to 5.5 nM. In conclusion we have determined that RHPS4 has telomere-shortening, cytostatic, cytotoxic and chemosensitising properties in AML cells. Disclosures: Stevens: Pharminox Ltd: director and shareholder of Pharminox Ltd which has a financial interest in RHPS4.

RHPS4, An Anti-Telomere Agent, Specifically Targets the Subgroup of AML Cells with Loss or Gain of Parts of Chromosomes.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1195-1195
Author(s):  
Monica Pallis ◽  
Simone Clarke ◽  
Martin Grundy ◽  
Jaineeta Richardson ◽  
Dotun Ojo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Telomere Length ◽  
Conflicts Of Interest ◽  
Poor Response ◽  
Damage Mechanism ◽  
Additional Material ◽  
Telomere Shortening ◽  
Growth And Survival ◽  
Exact Test

Abstract Abstract 1195 Cytogenetic abnormalities vary greatly in AML and those with gains and losses of chromosome parts, terminal deletions and whole chromosome losses could theoretically derive from telomere dysfunction. Cells with these abnormalities are characterised by telomere shortening and abnormal function characterised by activation of both the negative telomere regulator TRF1 and also of hTERT. The G quadruplex ligand RHPS4 (Pharminox Ltd, Biocity, Nottingham, UK) binds telomeres and induces DNA damage at higher doses in the short term and critical telomere shortening in longer term growth assays. We have previously reported cytostatic and cytotoxic effects for this agent in AML cell lines, whilst others have found that normal haematopoietic progenitor cells are not targeted. We have now examined effects of RHPS4 on the in vitro growth and survival of primary AML cells, comprising 9 samples with normal and 8 with abnormal karyotypes (5 complex, one -7, one 5q- and one with additional material on chromosomes 2 and 9). Cells were incubated with RHPS4 in standard 14 day colony assays and for 7 and 21 days in a novel suspension culture medium supplemented with supernatant from cultured normal human osteoblasts. In the 7 day cultures, no effects were observed on cell survival. In the longer term growth assays, a submicromolar IC50 for RHPS4 was observed in 7/8 samples with aberrant cytogenetics in contrast with only 1/9 with normal cytogenetics (P=0.003, Fisher's exact test). Furthermore, RHPS4 significantly sensitised samples with abnormal cytogenetics to daunorubicin reducing the median IC50 from 27nM to 10nM (n=8, p<0.05). A qPCR method was used to measure telomere length of untreated DNA from 15 of the samples; the qPCR assay had previously been performed in a separate patient cohort alongside a Southern technique and comparable values were attained for the two different methods. There were no significant differences in telomere lengths between the normal and abnormal cytogenetic groups suggestive that telomere length is not a determinant of RHPS4 sensitivity in these assays. Samples with adverse cytogenetics have previously been associated with an up-regulation of basal DNA damage markers and may therefore be sensitive to compounds that can exacerbate levels of damage. We therefore studied the levels of p-ATM by immunocytochemistry in RHPS4-treated cells and found a significant increase compared to untreated cells - hence RHPS4 may be acting via a DNA damage mechanism. We conclude that telomere targeting has exciting potential as therapy for a subset of AML patients including those with adverse cytogenetics who have a poor response to conventional chemotherapeutics. Disclosures: No relevant conflicts of interest to declare.

Effect of intensive lipid-lowering therapy on telomere erosion in endothelial progenitor cells obtained from patients with coronary artery disease

2009 ◽  
Vol 116 (11) ◽  
pp. 827-835 ◽  
Author(s):  
Mamoru Satoh ◽  
Yoshitaka Minami ◽  
Yuji Takahashi ◽  
Tsuyoshi Tabuchi ◽  
Tomonori Itoh ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Dna Damage ◽  
Telomere Length ◽  
Oxidative Dna Damage ◽  
Lipid Lowering ◽  
Lipid Lowering Therapy ◽  
Telomere Shortening ◽  
Lowering Therapy ◽  
Artery Disease ◽  
Telomere Erosion

Telomere erosion of EPCs (endothelial progenitor cells) may be a key factor in endothelial cell senescence and is highly dependent on cellular oxidative damage. The aim of the present study was to investigate whether LLT (lipid-lowering therapy) with statins could attenuate EPC telomere erosion in patients with CAD (coronary artery disease). The study included 100 patients with stable CAD and 25 subjects without CAD as controls. CAD patients were randomized to 12 months of intensive LLT with atorvastatin or moderate LLT with pravastatin. EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Telomere length in EPCs was measured by FISH (fluorescence in situ hybridization) and oxidative DNA damage by flow cytometry of oxidized DNA bases. EPC telomere length was shorter in the CAD group than in the controls, and oxidative DNA damage to EPCs was higher in the CAD group compared with controls. After 12 months of therapy, changes in lipid profiles were greater in the intensive LLT group than in the moderate LLT group. Intensive LLT markedly increased EPC number and decreased oxidative DNA damage in EPCs (both P<0.05), with no change in telomere length. In contrast, moderate LLT did not change EPC counts or oxidative DNA damage, but showed telomere shortening (P<0.05). There was a weak negative correlation between changes in EPC number and LDL (low-density lipoprotein)-cholesterol levels after intensive LLT, whereas there was no correlation between them after moderate LLT. With in vitro culturing of EPCs subjected to oxidative stress, atorvastatin led to the prevention of EPC telomere shortening compared with pravastatin. In conclusion, the present study has demonstrated that intensive LLT may prevent EPC telomere erosion in patients with CAD, possibly contributing to the beneficial effects of intensive LLT in this disorder.

scholarly journals Population differences in the length, early-life dynamics, and heritability of telomeres among European pied flycatchers

2021 ◽  
Author(s):  
Tiia Karkkainen ◽  
Toni Laaksonen ◽  
Malcolm Burgess ◽  
Alejandro Cantarero ◽  
Jesus Martinez-Padilla ◽  
...  
Keyword(s):  
Telomere Length ◽  
Early Life ◽  
Large Scale ◽  
Later Life ◽  
Sub Saharan Africa ◽  
Pied Flycatcher ◽  
Breeding Period ◽  
Population Differences ◽  
Telomere Shortening ◽  
Shortening Rate

Telomere length and shortening rate are increasingly used as biomarkers for long-term costs in ecological and evolutionary studies because of their relationships with survival and fitness. Telomere length can be heritable, but both early-life conditions and later-life stressors can create variation in telomere shortening rate. Studies on between-population telomere length and dynamics are mostly lacking, despite the expectation that populations exposed to varying environmental constraints would present divergent telomere length patterns. Pied flycatcher (Ficedula hypoleuca) is a passerine bird spending the non-breeding period in sub-Saharan Africa but breeding across Eurasia (from Spain to western Siberia). Populations show marked differences in migration distance, genetics, breeding parameters, and egg components. We studied the large-scale variation of telomere length, early-life dynamics and heritability in the pied flycatcher by comparing six European populations across a north-south gradient (Finland, Estonia, England and Spain). There were clear population differences in telomere length, with English birds having the longest telomeres, followed by Spanish and lastly by Estonian and Finnish birds. Early-life telomere shortening rate tended to vary between populations, and faster nestling growth affected telomeres more negatively in northern than southern populations. The heritability of telomere length was moderate (h2 = 0.34 - 0.40), with stronger heritability to paternal than maternal telomere length. There was also evidence indicating that the level of paternal heritability could differ between populations. While the sources of between-population differences in telomere-related biology remain to be identified (i.e. genetics, environmental factors), our study illustrates the need to expand telomere studies at the between-population level.

scholarly journals Interrogating accessibility of telomeric sequences with FRET-PAINT: evidence for length-dependent telomere compaction

2021 ◽  
Author(s):  
Golam Mustafa ◽  
Sajad Shiekh ◽  
Keshav GC ◽  
Sanjaya Abeysirigunawardena ◽  
Hamza Balci
Keyword(s):  
Dna Damage ◽  
Telomere Length ◽  
Dna Damage Response ◽  
Single Molecule ◽  
Telomeric Repeat ◽  
Dna Molecules ◽  
Telomeric Dna ◽  
Telomeric Sequences ◽  
G Quadruplex ◽  
Damage Response

Abstract Single-stranded telomeric overhangs are ∼200 nucleotides long and can form tandem G-quadruplex (GQ) structures, which reduce their accessibility to nucleases and proteins that activate DNA damage response. Whether these tandem GQs further stack to form compact superstructures, which may provide better protection for longer telomeres, is not known. We report single-molecule measurements where the accessibility of 24–144 nucleotide long human telomeric DNA molecules is interrogated by a short PNA molecule that is complementary to a single GGGTTA repeat, as implemented in the FRET-PAINT method. Binding of the PNA strand to available GGGTTA sequences results in discrete FRET bursts which were analyzed in terms of their dwell times, binding frequencies, and topographic distributions. The binding frequencies were greater for binding to intermediate regions of telomeric DNA compared to 3′- or 5′-ends, suggesting these regions are more accessible. Significantly, the binding frequency per telomeric repeat monotonically decreased with increasing telomere length. These results are consistent with telomeres forming more compact structures at longer lengths, reducing accessibility of these critical genomic sites.

scholarly journals Oxidative Stress Induced Damage and Early Senescence in Preterm Placenta

2021 ◽  
Vol 2021 ◽  
pp. 1-6
Author(s):  
Yudianto Budi Saroyo ◽  
Noroyono Wibowo ◽  
Rima Irwinda ◽  
Ani Retno Prijanti ◽  
Evy Yunihastuti ◽  
...  
Keyword(s):  
Preterm Birth ◽  
Telomere Length ◽  
Clinical Signs ◽  
High Mobility ◽  
Critical Length ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Telomere Shortening ◽  
Maternal Characteristics ◽  
Term Birth

Introduction. Senescent cells have been demonstrated to release High Mobility Group Box 1 (HMGB1) which induces labor through an inflammatory pathway. This research is aimed at demonstrating whether telomere shortening, proinflammatory HMGB1, and oxidative damage marker 8-OHdG play a role in the placenta of preterm birth in comparison to term birth. Method. A cross-sectional study on 67 full thickness of the placenta obtained from mothers with term and preterm birth. Mothers with clinical signs of infection ( fever > 38 ° C , leukocytosis > 18000 / μ L , or abnormal vaginal discharge) and other pregnancy complications were excluded. Real-time polymerase chain reaction was performed to measure T/S ratio and ELISA quantification to measure the amount of HMGB1 and 8-OHdG. Result. A total of 34 placentas from preterm and 33 placentas from term birth were examined. Maternal characteristics were comparable between the two groups. There were no statistical difference of T/S ratio ( p = 0.181 ), HMGB1 ( p = 0.119 ), and 8-OHdG ( p = 0.144 ) between the preterm and term groups. HMGB1 was moderately correlated with 8-OHdG ( r = 0.314 ). Telomere T/S ratio of the placenta did not differ between preterm and term labor despite difference in gestational age, suggesting earlier shortening in the preterm group. It is possible that critical telomere length has been achieved in both term and preterm placenta that warrants labor through senescence process. The result of our study also showed that HMGB1 was not correlated to telomere length, due to the fact that HMGB1 is not upregulated until the critical length of telomere for senescence is exhibited. Conclusion. Similar telomere length might be exhibited due to early telomere shortening in preterm birth that mimics the term placenta. The relationship between placental telomere shortening and HMGB1 release remains to be uncovered. Further research is needed to discover the factors leading to early telomere shortening in the placenta of preterm birth.

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