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Bibliography on: Telomeres

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 21 Nov 2018 at 01:43 Created: 

Telomeres

Wikipedia: A telomere is a region of repetitive nucleotide sequences at each end of a chromosome, which protects the end of the chromosome from deterioration or from fusion with neighboring chromosomes. Its name is derived from the Greek nouns telos (τέλος) "end" and merοs (μέρος, root: μερ-) "part". For vertebrates, the sequence of nucleotides in telomeres is TTAGGG, with the complementary DNA strand being AATCCC, with a single-stranded TTAGGG overhang. This sequence of TTAGGG is repeated approximately 2,500 times in humans. In humans, average telomere length declines from about 11 kilobases at birth to less than 4 kilobases in old age,[3] with average rate of decline being greater in men than in women. During chromosome replication, the enzymes that duplicate DNA cannot continue their duplication all the way to the end of a chromosome, so in each duplication the end of the chromosome is shortened (this is because the synthesis of Okazaki fragments requires RNA primers attaching ahead on the lagging strand). The telomeres are disposable buffers at the ends of chromosomes which are truncated during cell division; their presence protects the genes before them on the chromosome from being truncated instead. The telomeres themselves are protected by a complex of shelterin proteins, as well as by the RNA that telomeric DNA encodes.

Created with PubMed® Query: telomere[title] OR telomeres[title] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2018-11-20

Majerska J, Feretzaki M, Glousker G, et al (2018)

Transformation-induced stress at telomeres is counteracted through changes in the telomeric proteome including SAMHD1.

Life science alliance, 1(4):e201800121 pii:LSA-2018-00121.

Telomeres play crucial roles during tumorigenesis, inducing cellular senescence upon telomere shortening and extensive chromosome instability during telomere crisis. However, it has not been investigated if and how cellular transformation and oncogenic stress alter telomeric chromatin composition and function. Here, we transform human fibroblasts by consecutive transduction with vectors expressing hTERT, the SV40 early region, and activated H-RasV12. Pairwise comparisons of the telomeric proteome during different stages of transformation reveal up-regulation of proteins involved in chromatin remodeling, DNA repair, and replication at chromosome ends. Depletion of several of these proteins induces telomere fragility, indicating their roles in replication of telomeric DNA. Depletion of SAMHD1, which has reported roles in DNA resection and homology-directed repair, leads to telomere breakage events in cells deprived of the shelterin component TRF1. Thus, our analysis identifies factors, which accumulate at telomeres during cellular transformation to promote telomere replication and repair, resisting oncogene-borne telomere replication stress.

RevDate: 2018-11-20

Wang CY (2018)

Asynchronous Shortening of Telomere Length and Cardiovascular Outcomes.

JACC. Basic to translational science, 3(5):601-603 pii:S2452-302X(18)30233-X.

RevDate: 2018-11-20

Yin H, Akawi O, Fox SA, et al (2018)

Cardiac-Referenced Leukocyte Telomere Length and Outcomes After Cardiovascular Surgery.

JACC. Basic to translational science, 3(5):591-600 pii:S2452-302X(18)30146-3.

Leukocyte telomere shortening reflects stress burdens and has been associated with cardiac events. However, the patient-specific clinical value of telomere assessment remains unknown. Moreover, telomere shortening cannot be inferred from a single telomere length assessment. The authors investigated and developed a novel strategy for gauging leukocyte telomere shortening using autologous cardiac atrial referencing. Using multitissue assessments from 163 patients who underwent cardiovascular surgery, we determined that the cardiac atrium-leukocyte telomere length difference predicted post-operative complexity. This constituted the first evidence that a single-time assessment of telomere dynamics might be salient to acute cardiac care.

RevDate: 2018-11-18

Davinelli S, Trichopoulou A, Corbi G, et al (2018)

The potential nutrigeroprotective role of Mediterranean diet and its functional components on telomere length dynamics.

Ageing research reviews pii:S1568-1637(18)30198-3 [Epub ahead of print].

The Mediterranean diet (MD) is a gold standard for nutrition and the most evidence-based diet to delay the onset of age-associated pathologies. Telomeres are the heterochromatic repeat regions found at the ends of eukaryotic chromosomes, whose length is considered a reliable hallmark of biological ageing. Telomere shortening is, at least in part, a modifiable factor and there is evidence that adherence to the MD is associated with longer telomeres. Data from several studies indicate an association between "inflammatory/oxidative status" and telomere length (TL). The MD, as a complex exposome with thousands of nutrients and phytochemicals, may positively influence telomere attrition by reducing inflammation and oxidative stress. However, it is unclear whether the protective effects on TL provided by the MD result from its individual constituents or some combination of these. Furthermore, these properties of the MD and its components are not yet fully validated by clinical endpoints in randomized trials or observational studies. Here, we summarize the data from experimental and population-based studies on the effects of the MD on TL maintenance. We will both highlight the possible role of the MD in the prevention of age-associated diseases, and attempt to identify certain aspects of the diet that are particularly important for telomere maintenance.

RevDate: 2018-11-16

Demerdash HM, Elyamany AS, E Arida (2018)

Impact of direct-acting antivirals on leukocytic DNA telomere length in hepatitis C virus-related hepatic cirrhosis.

European journal of gastroenterology & hepatology [Epub ahead of print].

BACKGROUND: Direct-acting antiviral (DAAs) represent advancement in the management of hepatitis C virus (HCV)-related hepatic cirrhosis. A high proportion of patients achieve a sustained virologic response; eradication of HCV is coupled with a decreased risk of hepatocellular carcinoma. Recent evidence suggests that shortening of the DNA telomere may be linked to cellular senescence as well as predisposition to malignant transformation.

OBJECTIVE: This study aimed to assess pretreatment leukocytic DNA telomere length in HCV-related cirrhosis and post viral eradication using DAAs.

PATIENTS AND METHODS: This study included 24 patients with HCV-related cirrhosis, Child-Pugh A. Whole-blood samples were obtained from patients before treatment and 12 weeks after the end of treatment, as well as from 24 healthy controls. Terminal restriction fragment, corresponding to telomere length, was measured using a nonradioactive Southern blot technique, detected by chemiluminescence.

RESULTS: DNA telomere length was significantly shorter before treatment compared with 12 weeks after end of treatment in HCV-related cirrhotic patients. Also, it was significantly shorter in patients before treatment compared with healthy individuals.

CONCLUSION: Telomere elongation in blood leukocytes can be considered a marker of recovery of inflammation after DAAs-induced HCV eradication. Still, the possibility of activation by cancer initiation cannot be excluded.

RevDate: 2018-11-16

de Souza MR, Kahl VFS, Rohr P, et al (2018)

Shorter telomere length and DNA hypermethylation in peripheral blood cells of coal workers.

Mutation research, 836(Pt B):36-41.

Coal is a mixture of several chemicals, mainly inorganic elements and polycyclic aromatic hydrocarbons, many of which have mutagenic and carcinogenic effects. Pneumoconiosis, fibrosis, asbestosis, silicosis, emphysema, loss of lung function and cancer are some examples of coal-related disorders. The aim of this study was to analyze coal miners with respect to telomere length (TL) and percentage (%) of global DNA methylation. The study involved 82 participants divided into two groups: 55 workers exposed to coal and 27 non-exposed individuals. DNA was isolated from peripheral blood samples from all individuals. Telomeres were measured by quantitative real time polymerase chain reaction (qPCR) and global DNA methylation levels were performed by the relative quantitation of 5-methyl-2'-deoxycytidine (5-mdC) by high-performance liquid chromatography (HPLC). TL measurements showed a mean of 9,199 bp (±4,196) for non-exposed and 7,545 bp (±2,703) for exposed groups, and% of global DNA methylation a mean of 2.78% (±0.41) for non-exposed and 3.00% (±0.37) for exposed individuals. Occupationally exposed individuals showed a significant decrease of TL (P < 0.05; Mann-Whitney test) and increase in the percentage of global DNA methylation (P < 0.05; Mann-Whitney test) when compared to the non-exposed group. This study showed that occupational exposure to coal and products of combustion is positively associated with TL and DNA methylation. Previously, we have evaluated the same individuals using comet assay, micronucleus (MN) test, oxidative stress and inorganic elements. No correlations were observed between TL and methylation with previous data in the exposed group. Further studies are needed to determine whether these alterations are associated with induced disease outcomes and if these events could be determinants to identify cancer risk.

RevDate: 2018-11-15

Mukherjee AK, Sharma S, Sengupta S, et al (2018)

Telomere length-dependent transcription and epigenetic modifications in promoters remote from telomere ends.

PLoS genetics, 14(11):e1007782 pii:PGENETICS-D-18-00930 [Epub ahead of print].

Telomere-binding proteins constituting the shelterin complex have been studied primarily for telomeric functions. However, mounting evidence shows non-telomeric binding and gene regulation by shelterin factors. This raises a key question-do telomeres impact binding of shelterin proteins at distal non-telomeric sites? Here we show that binding of the telomere-repeat-binding-factor-2 (TRF2) at promoters ~60 Mb from telomeres depends on telomere length in human cells. Promoter TRF2 occupancy was depleted in cells with elongated telomeres resulting in altered TRF2-mediated transcription of distal genes. In addition, histone modifications-activation (H3K4me1 and H3K4me3) as well as silencing marks (H3K27me3)-at distal promoters were telomere length-dependent. These demonstrate that transcription, and the epigenetic state, of telomere-distal promoters can be influenced by telomere length. Molecular links between telomeres and the extra-telomeric genome, emerging from findings here, might have important implications in telomere-related physiology, particularly ageing and cancer.

RevDate: 2018-11-14

Guha M, Srinivasan S, Johnson FB, et al (2018)

hnRNPA2 mediated acetylation reduces telomere length in response to mitochondrial dysfunction.

PloS one, 13(11):e0206897 pii:PONE-D-17-40813.

Telomeres protect against chromosomal damage. Accelerated telomere loss has been associated with premature aging syndromes such as Werner's syndrome and Dyskeratosis Congenita, while, progressive telomere loss activates a DNA damage response leading to chromosomal instability, typically observed in cancer cells and senescent cells. Therefore, identifying mechanisms of telomere length maintenance is critical for understanding human pathologies. In this paper we demonstrate that mitochondrial dysfunction plays a causal role in telomere shortening. Furthermore, hnRNPA2, a mitochondrial stress responsive lysine acetyltransferase (KAT) acetylates telomere histone H4at lysine 8 of (H4K8) and this acetylation is associated with telomere attrition. Cells containing dysfunctional mitochondria have higher telomere H4K8 acetylation and shorter telomeres independent of cell proliferation rates. Ectopic expression of KAT mutant hnRNPA2 rescued telomere length possibly due to impaired H4K8 acetylation coupled with inability to activate telomerase expression. The phenotypic outcome of telomere shortening in immortalized cells included chromosomal instability (end-fusions) and telomerase activation, typical of an oncogenic transformation; while in non-telomerase expressing fibroblasts, mitochondrial dysfunction induced-telomere attrition resulted in senescence. Our findings provide a mechanistic association between dysfunctional mitochondria and telomere loss and therefore describe a novel epigenetic signal for telomere length maintenance.

RevDate: 2018-11-14

Warny M, Helby J, Sengeløv H, et al (2018)

Bone marrow mononuclear cell telomere length in acute myeloid leukaemia and high-risk myelodysplastic syndrome.

European journal of haematology [Epub ahead of print].

OBJECTIVE: Short telomere length is a known risk factor for developing clonal hematopoietic stem cell disorders, probably due to chromosomal instability. We tested the hypotheses that bone marrow mononuclear cell telomere length change from diagnosis through chemotherapy-induced remission and relapse, and that long telomere length is associated with low risk of relapse and all-cause mortality in patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome.

METHODS: We measured telomere length in bone marrow mononuclear cells from 233 patients at diagnosis, 112 patients at chemotherapy-induced remission and 58 patients at relapse of disease.

RESULTS: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length was similar at diagnosis and relapse, but increased after chemotherapy-induced remission. Furthermore, bone marrow mononuclear cell telomere length was longer in patients with higher age at diagnosis. There was no association between telomere length at diagnosis, remission or relapse and all-cause mortality, nor did we find any association between telomere length at diagnosis or remission and risk of relapse.

CONCLUSION: In patients with acute myeloid leukaemia or high-risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length increased from diagnosis to remission. Furthermore, telomere length paradoxically was longer at higher age at diagnosis, even after adjusting for known risk factors of disease severity. Finally, we did not detect any prognostic information in telomere length. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-13

Ahvenainen TV, Mäkinen NM, von Nandelstadh P, et al (2018)

Loss of ATRX/DAXX expression and alternative lengthening of telomeres in uterine leiomyomas.

Cancer [Epub ahead of print].

BACKGROUND: Uterine leiomyomas (ULs) are the most common gynecologic tumors and affect 3 of every 4 women by the age of 50 years. The majority of ULs are classified as conventional tumors, whereas 10% represent various histopathological subtypes with features that mimic malignancy. These subtypes include cellular and mitotically active ULs and ULs with bizarre nuclei. Uterine leiomyosarcoma (ULMS), the malignant counterpart of UL, is an aggressive cancer with poor overall survival. The early diagnosis and preoperative differentiation of ULMS from UL are often challenging because their symptoms and morphology resemble one another. Recent studies have shown frequent loss of alpha-thalassemia/mental retardation syndrome X-linked (ATRX) or death domain-associated protein (DAXX) expression in ULMS, and this is often associated with an alternative lengthening of telomeres (ALT) phenotype.

METHODS: To investigate ATRX and DAXX expression and the presence of ALT in UL subtypes, immunohistochemical and telomere-specific fluorescence in situ hybridization analyses were performed. The study material consisted of 142 formalin-fixed, paraffin-embedded tissue samples representing various UL subtypes and 64 conventional ULs.

RESULTS: A loss of ATRX or DAXX and/or ALT was detected in 6.3% of the histopathological UL subtype samples (9 of 142). Two patients whose ULs showed either ATRX loss or ALT were later diagnosed with a pulmonary smooth muscle tumor. Pulmonary tumors displayed molecular alterations found in the corresponding uterine tumors, which indicated metastasis to the lungs. All conventional ULs displayed normal ATRX, DAXX, and telomeres.

CONCLUSIONS: These results highlight the differences between conventional and histopathologically atypical ULs and indicate that some UL subtype tumors may harbor long-term malignant potential.

RevDate: 2018-11-13

Faraji J, Karimi M, Soltanpour N, et al (2018)

Oxytocin-mediated social enrichment promotes longer telomeres and novelty seeking.

eLife, 7: pii:40262 [Epub ahead of print].

The quality of social relationships is a powerful determinant of lifetime health. Here, we explored the impact of social experiences on circulating oxytocin (OT) concentration, telomere length (TL) and novelty-seeking behaviour in male and female rats. Prolonged social housing raised circulating OT levels in both sexes while elongating TL only in females. Novelty-seeking behaviour in females was more responsive to social housing and increased OT levels than males. The OT antagonist (OT ANT) L-366,509 blocked the benefits of social housing in all conditions along with female-specific TL erosion and novelty-seeking deficit. Thus, females seem more susceptible than males to genetic and behavioural changes when the secretion of endogenous OT in response to social life is interrupted. Social enrichment may therefore provide a therapeutic avenue to promote stress resiliency and chances of healthy aging across generations.

RevDate: 2018-11-13

Tang H, Geng A, Zhang T, et al (2018)

Single senescent cell sequencing reveals heterogeneity in senescent cells induced by telomere erosion.

RevDate: 2018-11-12

McFarland MJ, Taylor J, McFarland CAS, et al (2018)

Perceived Unfair Treatment by Police, Race, and Telomere Length: A Nashville Community-based Sample of Black and White Men.

Journal of health and social behavior [Epub ahead of print].

Police maltreatment, whether experienced personally or indirectly through one's family or friends, represents a structurally rooted public health problem that disproportionately affects minorities. Researchers, however, know little about the physiological mechanisms connecting unfair treatment by police (UTBP) to poor health. Shortened telomeres due to exposure to this stressor represent one plausible mechanism. Using data from a community sample of black (n = 262) and white (n = 252) men residing in Nashville-Davidson County, we test four hypotheses: (1) Black men will be more likely to report UTBP than white men, (2) those reporting UTBP will have shorter telomeres than those not reporting UTBP, (3) this association will be more pronounced among black men, and (4) these hypotheses will extend to those who report vicarious UTBP. Results reveal support for all hypotheses. The implications for our findings are discussed as they pertain to debates on policing practices and health disparities research.

RevDate: 2018-11-12

Grunst AS, Grunst ML, Gonser RA, et al (2018)

Developmental stress and telomere dynamics in a genetically polymorphic species.

Journal of evolutionary biology [Epub ahead of print].

A central objective of evolutionary biology is understanding variation in life-history trajectories and aging rate, or senescence. Senescence can be affected by tradeoffs and behavioral strategies in adults, but may also be affected by developmental stress. Developmental stress can accelerate telomere degradation, with long-term longevity and fitness consequences. Little is known regarding whether variation in developmental stress and telomere dynamics contribute to patterns of senescence during adulthood. We investigated this question in the dimorphic white-throated sparrow (Zonotrichia albicollis), a species in which adults of the two morphs exhibit established differences in behavioral strategy and patterns of senescence, and also evaluated the relationship between oxidative stress and telomere length. Tan morph females, which exhibit high levels of unassisted parental care, display faster reproductive senescence than white females, and faster actuarial senescence than all of the other morph-sex classes. We hypothesized that high oxidative stress and telomere attrition in tan female nestlings could contribute to this pattern, since tan females are small and potentially at a competitive disadvantage even as nestlings. Nestlings that were smaller than nest mates had higher oxidative stress, and nestlings with high oxidative stress and fast growth rates displayed shorter telomeres. However, we found no consistent morph-sex differences in oxidative stress or telomere length. Results suggest that oxidative stress and fast growth contribute to developmental telomere attrition, with potential ramifications for adults, but that developmental oxidative stress and telomere dynamics do not account for morph-sex differences in senescence during adulthood. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-10

Huang H, Wang Q, He X, et al (2018)

Association between polyfluoroalkyl chemical concentrations and leucocyte telomere length in US adults.

The Science of the total environment, 653:547-553 pii:S0048-9697(18)34300-6 [Epub ahead of print].

Exposure to some environmental chemicals is reportedly associated with the leucocyte telomere length (LTL), but the effects of the non-occupational exposure to polyfluoroalkyl chemical (PFCs) on the LTL are not well understood. Using data from 773 participants in the National Health and Nutrition Examination Survey (NHANES) conducted in 1999-2000, we analysed the association between blood PFC concentrations and LTL. Coefficients (betas) and 95% confidence intervals (CIs) for the blood PFC concentrations in association with the LTL were estimated using multivariate linear regression models after adjustment for age, gender, race, body mass index (BMI), poverty income ratio, educational level, white blood cell count, C-reactive protein and other PFCs. The results identified a strong positive association between the blood perfluorooctane sulfonic acid (PFOS) concentration and LTL in adults, and no associations were found between the LTL and other PFCs. In the linear regression models, each increment of one standard deviation (SD) in the base-10-logarithm-transformed PFOS concentration was associated with a 21-bp increase in the LTL in the fully adjusted model (P = 0.033). Moreover, serum PFOS was associated with the LTL mainly in females and individuals aged 40-50, as demonstrated by stratified analyses. These results provide epidemiological evidence showing that environment-related levels of serum PFOS are positively associated with the LTL in adults.

RevDate: 2018-11-10

Stefler D, Malyutina S, Maximov V, et al (2018)

Leukocyte telomere length and risk of coronary heart disease and stroke mortality: prospective evidence from a Russian cohort.

Scientific reports, 8(1):16627 pii:10.1038/s41598-018-35122-y.

Previous studies suggest that reduced leukocyte telomere length (LTL) is related to higher risk of mortality and several chronic conditions, including coronary heart disease (CHD) and stroke. However, the consistency of this association differs across populations. We investigated the relationship of LTL with CHD, stroke and all-cause mortality together with non-fatal CHD and stroke events in a Russian cohort with a mean age of 58 years at baseline. Data from 1,144 individuals in the Russian subset of the Health Alcohol and Psychosocial Factors in Eastern Europe (HAPIEE) cohort study were used. The associations between LTL at baseline and fatal/non-fatal outcomes during 12 years of follow-up were assessed using multivariable Cox regression models, which yielded adjusted hazard ratios (HR). Compared to individuals in the shortest tertile, those in the longest tertile of LTL had a 42% lower risk of death from all-causes (HR 0.58; 95% CI: 0.39-0.88) and 58% lower risk of death from CHD (HR 0.42; 95%CI: 0.19-0.97). Similar patterns of association were identified for non-fatal and combined fatal/non-fatal CHD and stroke events but the associations were weaker. Consistent with results of previous studies in Western populations, this cohort of elderly Russian adults found an inverse association between LTL and CHD and all-cause mortality. These findings reinforce the hypothesis that LTL may play (or be a marker of) an aetiological role in human health across diverse populations.

RevDate: 2018-11-08

Jordan CD, Glover LM, Gao Y, et al (2018)

Association of Psychosocial Factors with Leukocyte Telomere Length among African Americans in the Jackson Heart Study.

Stress and health : journal of the International Society for the Investigation of Stress [Epub ahead of print].

Leukocyte telomere length (LTL) is a biomarker of cellular aging. African Americans report more stress than other groups; however, the association of psychosocial stressors with biological aging among African Americans remains unclear. The current study evaluated the association of psychosocial factors (negative affect and stressors) with LTL in a large sample of African American men and women (n=2,516) from the Jackson Heart Study (JHS). Using multivariable linear regression, we examined the sex-specific associations of psychosocial factors (cynical distrust, anger-in and -out, depressive symptoms, negative affect summary scores, global stress, weekly stress, and major life events-MLEs, and stress summary scores) with LTL. Model 1 adjusted for demographics and education. Model 2 adjusted for model 1, smoking, alcohol intake, physical activity, diabetes, hypertension, and high-sensitivity C-reactive protein (hsCRP). Among women, high (vs. low) cynical distrust was associated with shorter mean LTL in model 1 (b = -0.12; p=0.039). Additionally, high (vs. low) anger-out and expressed negative affect summary scores were associated with shorter LTL among women after full adjustment (b = -0.13; p=0.011; b = -0.12, p=0.031, respectively). High levels of cynical distrust, anger out and negative affect summary scores may be risk factors for shorter LTL, particularly among African American women.

RevDate: 2018-11-08

Bianchi F, Comez L, Biehl R, et al (2018)

Structure of human telomere G-quadruplex in the presence of a model drug along the thermal unfolding pathway.

Nucleic acids research pii:5165272 [Epub ahead of print].

A multi-technique approach, combining circular dichroism spectroscopy, ultraviolet resonance Raman spectroscopy and small angle scattering techniques, has been deployed to elucidate how the structural features of the human telomeric G-quadruplex d[A(GGGTTA)3GGG] (Tel22) change upon thermal unfolding. The system is studied both in the free form and when it is bound to Actinomycin D (ActD), an anticancer ligand with remarkable conformational flexibility. We find that at room temperature binding of Tel22 with ActD involves end-stacking upon the terminal G-tetrad. Structural evidence for drug-driven dimerization of a significant fraction of the G-quadruplexes is provided. When the temperature is raised, both free and bound Tel22 undergo melting through a multi-state process. We show that in the intermediate states of Tel22 the conformational equilibrium is shifted toward the (3+1) hybrid-type, while a parallel structure is promoted in the complex. The unfolded state of the free Tel22 is consistent with a self-avoiding random-coil conformation, whereas the high-temperature state of the complex is observed to assume a quite compact form. Such an unprecedented high-temperature arrangement is caused by the persistent interaction between Tel22 and ActD, which stabilizes compact conformations even in the presence of large thermal structural fluctuations.

RevDate: 2018-11-08

Liu B, Maekawa T, Yoshida K, et al (2018)

Telomere shortening by transgenerational transmission of TNF-α-induced TERRA via ATF7.

Nucleic acids research pii:5165275 [Epub ahead of print].

Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-α, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.

RevDate: 2018-11-08

Assani G, Xiong Y, Zhou F, et al (2018)

Effect of therapies-mediated modulation of telomere and/or telomerase on cancer cells radiosensitivity.

Oncotarget, 9(79):35008-35025 pii:26150.

Cancer is one of the leading causes of death in the world. Many strategies of cancer treatment such as radiotherapy which plays a key role in cancer treatment are developed and used nowadays. However, the side effects post-cancer radiotherapy and cancer radioresistance are two major causes of the limitation of cancer radiotherapy effectiveness in the cancer patients. Moreover, reduction of the limitation of cancer radiotherapy effectiveness by reducing the side effects post-cancer radiotherapy and cancer radioresistance is the aim of several radiotherapy-oncologic teams. Otherwise, Telomere and telomerase are two cells components which play an important role in cancer initiation, cancer progression and cancer therapy resistance such as radiotherapy resistance. For resolving the problems of the limitation of cancer radiotherapy effectiveness especially the cancer radio-resistance problems, the radio-gene-therapy strategy which is the use of gene-therapy via modulation of gene expression combined with radiotherapy was developed and used as a new strategy to treat the patients with cancer. In this review, we summarized the information concerning the implication of telomere and telomerase modulation in cancer radiosensitivity.

RevDate: 2018-11-08

He L, Chen Z, Dai B, et al (2018)

Low-level lead exposure and cardiovascular disease: the roles of telomere shortening and lipid disturbance.

The Journal of toxicological sciences, 43(11):623-630.

Lead exposure contributing to cardiovascular diseases is known and recognized widely. As the deleterious effects of low lead exposure attained increasing attention over the last decades, there have been numerous studies exploring the association of low levels of lead exposure and cardiovascular diseases. Moreover, it has been observed that lead exposure could cause telomere shortening and lipid disturbance, and that telomere shortening and lipid disturbance are closely related with cardiovascular diseases. Hence, telomere shortening and lipid disturbance might play an important role in the pathophysiological process of chronic low levels of lead exposure contributing to cardiovascular diseases. This review is intended to explore views of the rarely mentioned mechanism, telomere shortening and lipid disturbance, and the cardiovascular effects of low levels of lead exposure.

RevDate: 2018-11-07

Barnard A, Moch A, S Saab (2018)

Relationship between Telomere Maintenance and Liver Disease.

Gut and liver pii:gnl18081 [Epub ahead of print].

Previous studies have established a correlation between increasing chronological age and risk of cirrhosis. This pattern raised interest in the role of telomeres and the telomerase complex in the pathogenesis of liver fibrosis and cirrhosis. This review aims to summarize and analyze the current understanding of telomere regulation in hepatocytes and lymphocytes and how this ultimately relates to the development of liver fibrosis. Notably, in chronic viral hepatitis, telomere shortening in hepatocytes and lymphocytes occurs in such a way that may promote further viral replication while also leading to liver damage. However, while telomere shortening occurs in both hepatocytes and lymphocytes and ultimately results in cellular death, the mechanisms of telomere loss appear to be initiated by independent processes. The understanding of telomere maintenance on a hepatic and immune system level in both viral and non-viral etiologies of cirrhosis may open doors to novel therapeutic strategies.

RevDate: 2018-11-07

Oliveira BS, Pirkle CM, Zunzunegui MV, et al (2018)

Leukocyte Telomere Length and Chronic Conditions in Older Women of Northeast Brazil: A Cross-Sectional Study.

Cells, 7(11): pii:cells7110193.

This study assessed whether telomere length is related to chronic conditions, cardiovascular risk factors, and inflammation in women aged 65 to 74 from Northeast Brazil. Participants were selected from two sources, a representative sample of the International Mobility in Aging Study (n = 57) and a convenience sample (n = 49) recruited at senior centers. Leukocyte telomere length was measured by quantitative polymerase chain reaction from blood samples in 83 women. Natural log-transformed telomere/single copy gene ratio was used as the dependent variable in the analysis. Blood analyses included inflammatory markers (high-sensitivity C-reactive protein and interleukin-6), total, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, glucose and glycosylated hemoglobin. Self-rated health, chronic conditions, cardiovascular risk factors and inflammatory markers were not associated with telomere length. No significant independent association was found between telomere length and anthropometric measures or blood markers, even after adjusting for age, education and adverse childhood events among these older women in Northeast Brazil. Our results did not confirm the hypothesis that chronic conditions, cardiovascular risk factors or inflammation are associated with shorter telomere length in these women who have exceptional survival relative to the life expectancy of their birth cohort.

RevDate: 2018-11-06

Ding Y, Zhou X, Wu C, et al (2018)

Telomere length, ZNF208 genetic variants and risk of chronic obstructive pulmonary disease in Hainan Li population.

The journal of gene medicine [Epub ahead of print].

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation. It is not completely reversible and progressive development. ZNF208 rs8105767 affects telomere length, the impact of telomere on COPD is still controversial. So, we want to explore impact of the ZNF208 gene polymorphism on telomere length and telomere length on the COPD in Hainan Li population.

MATERIALS AND METHODS: 270 COPD patients and 288 controls were recruited. Telomere length was measured by quantitative real time PCR. Five SNPs in ZNF208 were selected, and genotyping was performed using the MassARRAY. Differences in telomere length among the subjects with three genotypes of related genes were assessed using analysis of variance. Used unconditional logistic regression to calculate odds ratios (OR) as the indicator of association between telomere length and COPD risk.

RESULTS: RTL in COPD group and control group were 0.66 ± 0.47 and 1.44 ± 0.89, respectively. We are grouped according to the median of 0.8284 of the telomere length, and observed that the risk of COPD for individuals with a telomere length less than 0.8284 is 2.92 times longer than 0.8284 of the telomere length (OR = 2.92, 95%CI: 2.01-4.25, p = 1.91E-08). Subjects carrying the G allele of rs2188972 had the longer telomere length, subjects carrying the carrying the CA genotype of rs8103163, AC genotype of rs7248488 had the longer telomere length compared the wild-type individual.

CONCLUSION: Shorter telomeres increase COPD risk and ZNF208 polymorphism affect telomere length in COPD patients.

RevDate: 2018-11-05

Scarabino D, Veneziano L, Peconi M, et al (2018)

Leukocyte telomere shortening in Huntington's disease.

Journal of the neurological sciences, 396:25-29 pii:S0022-510X(18)30434-9 [Epub ahead of print].

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. Though symptom onset commonly occurs at midlife and inversely correlates with the CAG repeat expansion, age at clinical onset and progression rate are variable. In the present study we investigated the relationship between leukocyte telomere length (LTL) and HD development. LTL was measured by real-time PCR in manifest HD patients (HD, n = 62), pre-manifest HD patients (pre-HD, n = 38), and age-matched controls (n = 76). Significant LTL differences were observed between the three groups (p < .0001), with LTL values in the order: HD < pre-HD < controls. The relationship between LTL and age was different in the three groups. An inverse relationship between mean LTL and CAG repeat number was found in the pre-HD (p = .03). The overall data seem to indicate that after age 30 years, LT begins to shorten markedly in pre-HD patients according to CAG number and increasing age, up to the values observed in HD. This very suggestive picture allowed us to hypothesize that in pre-manifest HD, LTL could be a measure of time to clinical HD onset. The possible use of LTL as a reliable biomarker to track HD development and progression was evaluated and discussed.

RevDate: 2018-11-05

Goh F, Yang IA, Bowman RV, et al (2018)

Subtype variation and actionability of telomere length abnormality in lung cancer.

Translational lung cancer research, 7(Suppl 3):S251-S253.

RevDate: 2018-11-05

Sato S, Imaichi Y, Yoshiura Y, et al (2018)

Synthesis of peptide-human telomere DNA conjugate as fluorometric imaging reagent for biological sodium ion.

Analytical sciences : the international journal of the Japan Society for Analytical Chemistry [Epub ahead of print].

RevDate: 2018-11-05

Mangaonkar AA, MM Patnaik (2018)

In Reply-Short Telomere Syndromes, Biological Aging, and Hematopoietic Stem Cell Transplantation.

Mayo Clinic proceedings, 93(11):1685-1687.

RevDate: 2018-11-05

Testori A (2018)

Short Telomere Syndromes, Biological Aging, and Hematopoietic Stem Cell Transplantation.

Mayo Clinic proceedings, 93(11):1684-1685.

RevDate: 2018-11-03

Roy S, Roy S, Rana A, et al (2018)

The role of p38 MAPK pathway in p53 compromised state and telomere mediated DNA damage response.

Mutation research, 836(Pt A):89-97.

There is an intricate balance of DNA damage response and repair which determines the homeostasis of human genome function. p53 protein is widely known for its role in cell cycle regulation and tumor suppressor activity. In case of several cancers where function of p53 gene gets compromised either by mutation or partial inactivation, the role of p53 in response to DNA damage needs to be supplemented by another molecule or pathway. Due to sedentary lifestyle and exposure to genotoxic agents, genome is predisposed to chronic stress, which ultimately leads to unrepaired or background DNA damage. p38 MAPK signaling pathway is strongly activated in response to various environmental and cellular stresses. DNA damage response and the repair options have crucial links with chromosomal integrity. Telomere that regulates integrity of genome is protected by a six member shielding unit called shelterin complex which communicates with other pathways for functionality of telomeres. There are evidences that p38 gets activated through ATM in response to DNA damage. Dysfunctional telomere leads to activation of ATM which subsequently activates p38 suggesting a crosstalk between p38, ATM and shelterin complex. This review focuses on activation of p38 in response to genotoxic stress induced DNA damage in p53 mutated or compromised state and its possible cross talk with telomere shelterin proteins. Thus p38 may act as an important target to treat various diseases and in majority of cancers in p53 mutated state.

RevDate: 2018-11-03

Chatterjee D, Adak S, Banerjee N, et al (2018)

Evaluatıon of health effects, genetıc damage and telomere length ın children exposed to arsenic in West Bengal, İndia.

Mutation research, 836(Pt A):82-88.

Increasing evidence of arsenic contamination in ground water and its associated adverse health outcomes affects millions of people worldwide. However, arsenic toxicity studies in children have gained impetus very recently due to the non-prominence of the hallmarks of arsenic toxicity i.e skin lesions. We recognized the need to evaluate the status of genetic damage brought about by early life exposure to arsenic in children as measured by micronucleus (MN) assay for three cell types namely buccal mucosa, urothelial cells and lymphocytes. A thorough health checkup and complete haematogram of the study participants was performed to measure overall health effects and changes in the blood profile in children exposed to arsenic through drinking water in West Bengal, India. Since telomere length alteration has been identified as a good indicator of arsenic toxicity in adults, we measured the telomere length of the arsenic exposed and unexposed children. We found that all the three cell types had significantly higher (P < 0.0001) MN frequency in the arsenic exposed children when compared to the unexposed. Blood profiling showed significantly altered neutrophil, eosinophil, lymphocyte and haemoglobin levels in the arsenic exposed children than their unexposed counterparts. Telomere length in the arsenic exposed children was slightly higher than the unexposed. This is a firsthand report of the genetic damage observed in children exposed to arsenic through drinking water in West Bengal, India.

RevDate: 2018-11-02

Boccardi V, Cari L, Nocentini G, et al (2018)

Telomeres Increasingly Develop Aberrant Structures in Aging Humans.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5154976 [Epub ahead of print].

Telomeres progressively shorten with age, and it has been proposed that critically short and dysfunctional telomeres contribute to aging and aging-associated diseases in humans. For many years it was thought that telomere erosion was strictly a consequence of the "end replication problem", or the inability of replicative polymerases to completely duplicate linear DNA ends. It is becoming increasingly evident, however, that telomere shortening of cultured human cells is also caused due to other replication defects in telomeric repeats, those that cause fragile telomeres and other aberrant telomeric structures that can be detected on metaphase chromosomes. Whether these replication defects contribute to telomere erosion also in human tissues is currently unknown. By analyzing peripheral blood mononuclear cells from a total of 35 healthy subjects ranging in age from 23 to 101 years, we demonstrated that telomeres increasingly display aberrant structures with advancing donor age. While the percentages of fragile telomeres increased only until adulthood, the percentages of chromosomes displaying sister telomere loss and sister telomere chromatid fusions increased consistently throughout the entire human lifespan. Our data, therefore, suggest that telomeric replication defects other than the end replication problem contribute to aging associated-telomere erosion in humans.

RevDate: 2018-11-02

Gil D, Alfonso-Iñiguez S, Pérez-Rodríguez L, et al (2018)

Harsh conditions during early development influence telomere length in an altricial passerine: links with oxidative stress and corticosteroids.

Journal of evolutionary biology [Epub ahead of print].

Stress during early development can induce substantial long-term effects in organisms. In the case of birds, despite growth compensations, nestlings reared under harsh conditions typically show reduced survival chances in adulthood. It has been proposed that environmental early-life stressors could affect longevity via effects on telomere length, possibly mediated through oxidative stress. However, the link between these processes is not clear. In this study, we experimentally manipulated brood size in spotless starlings (Sturnus unicolor) to test the causal relationship between early stress, oxidative and corticosterone-mediated stress and telomere shortening. Our results show that experimentally enlarged brood sizes led to a reduction in morphometric development on nestlings, the effect being stronger for females than males. Additionally, basal corticosterone levels increased with increasing brood size in female nestlings. Neither plasma antioxidant status nor malondialdehyde levels (a marker of lipid peroxidation) were affected by experimental brood size, although the levels of a key intracellular antioxidant (glutathione) decreased with increasing brood size. We found that the treatment showed a quadratic effect on nestling telomere lengths, that were shortened either by increases or decreases of the original brood size. Our study provides experimental evidence for a link between developmental stress and telomere length, but does not support a direct causal link of this reduction with corticosterone or oxidative stress. We suggest that future studies should focus on how telomere length responds to additional markers of allostatic load. This article is protected by copyright. All rights reserved.

RevDate: 2018-11-01

Shivakumar V, Kalmady SV, Rajasekaran A, et al (2018)

Telomere length and its association with hippocampal gray matter volume in antipsychotic-naïve/free schizophrenia patients.

Psychiatry research. Neuroimaging, 282:11-17 pii:S0925-4927(17)30294-9 [Epub ahead of print].

Accelerated ageing processes are postulated to underlie schizophrenia pathogenesis. This postulate is supported by observations of reduced telomere length in schizophrenia patients. Hippocampus, one of the most important brain regions implicated in schizophrenia, is shown to atrophy at a faster rate in aging. In this study, telomere length (TL) was measured in 30 antipsychotic-naive/free schizophrenia patients and 60 healthy controls using quantitative PCR assay. Hippocampus volume was measured using voxel-based morphometry. Schizophrenia was associated with differential TL between sexes [Status × Sex; F(1,85) = 5.9, p = 0.017, η2 = 0.065]. Male schizophrenia patients had significantly lower relative TL than female patients [F(1,85) = 7.38, p = 0.008], while such sex difference was not observed in healthy controls [F(1,85) = 0.16, p = 0.69]. Schizophrenia patients showed a significant sex-by-telomere interaction with both right & left hippocampus, with male patients showing positive association of telomere length with volume, while female patients showed negative association. Telomere shortening and the positive association of telomere length with hippocampus volume was observed only in male patients with schizophrenia. Since correlational observations in this cross-sectional study does not necessarily support definitive causal relationship, further longitudinal studies examining hippocampus volume and telomere in schizophrenia patients are needed.

RevDate: 2018-11-01

Xavier G, Spindola LM, Ota VK, et al (2018)

Effect of male-specific childhood trauma on telomere length.

Journal of psychiatric research, 107:104-109 pii:S0022-3956(18)30722-2 [Epub ahead of print].

Child maltreatment (CM) is a global issue with serious lifelong consequences. In fact, maltreatment during childhood might be an important risk factor for the development of psychiatric disorders. Furthermore, previous studies showed a strong relationship between telomere length (TL) and early life stress. Considering that only a few studies have evaluated this relationship in children and that even fewer considered the sex as a possible moderator, we investigated whether TL in the blood of both children and adolescents was associated with psychopathology and with a history of CM, and whether these associations were moderated by the sex. In this cross-sectional study, 561 individuals (ranging between 6 and 14 years of age) from a large prospective community school-based study, i.e., the Brazilian High-Risk Cohort (HRC), were evaluated. The Child Behavior Checklist (CBCL) score was used to assess psychopathology, whereas a latent variable encompassing some questions about history of adverse environment and trauma was employed to determine the CM history. TL was measured in blood cells using a multiplex quantitative polymerase chain reaction. Additionally, TL was inserted in two moderation models, in which the CBCL score/CM, TL and sex were the independent variables, the outcome, and the moderator variable, respectively. Although an association between psychiatric symptoms and TL was not observed, a relation between CM and TL moderated by the sex was seen, indicating that males with higher CM scores presented with shorter telomeres than did females. Our results suggest that child maltreatment could influence telomere length in both children and adolescents and that this effect is mediated by the sex.

RevDate: 2018-11-01

Miri M, Nazarzadeh M, Alahabadi A, et al (2018)

Air pollution and telomere length in adults: A systematic review and meta-analysis of observational studies.

Environmental pollution (Barking, Essex : 1987), 244:636-647 pii:S0269-7491(18)31073-X [Epub ahead of print].

Telomere length (TL) has been suggested to be a surrogate for cellular ageing, and a record of cumulative inflammation and oxidative stress over life. An emerging body of evidence has associated exposure to air pollution to changes in TL. To date there is no available systematic review of literature on this association. We aimed to systematically review and conduct meta-analysis of published studies on the relationship between air pollution and TL in adults. Electronic databases were systematically searched for available English language studies on the association between air pollution and TL published up to 1 July 2018. Meta-analyses were conducted following MOOSE guidelines. The heterogeneity in the reported associations was assessed using Cochran's Q test and quantified as I2 index. Publication bias was assessed using Egger's regression. Our search identified 19 eligible studies including 11 retrospective and eight prospective studies of which, four had excellent quality, ten had good quality and five had fair quality. Meta-analysis result of two studies on long-term exposure to PM2.5 showed an inverse association between these exposures and TL (for 5 μg/m3 PM2.5-0.03 95% CI; -0.05, -0.01). Meta-analysis of short-term exposure to PM2.5 with three studies and Polychlorinated Biphenyls (PCBs) with two studies revealed a direct association between these exposures and TL (0.03 95% CI; 0.02, 0.04 and 0.10 95% CI; 0.06, 0.15 respectively). No statistically significant relationship between exposure to PM10 and polycyclic aromatic hydrocarbons (PAHs) exposure and TL were observed. We observed suggestive evidence for associations between air pollution and TL with potentially different direction of associations for short- and long-term exposures.

RevDate: 2018-11-01

Fletcher JM (2018)

Spousal concordance in telomere length: New evidence from older adults in the US.

PloS one, 13(11):e0202388 pii:PONE-D-18-15206.

Telomere length (TL) has been associated with a range of aging outcomes as well as mortality. Recent research has shown both high heritability (~70%) of TL as well as moderate spousal similarity (r~0.3) using European datasets. This paper explores the level of spousal concordance in telomere length in the Health and Retirement Study, a national sample of adults in the US. The results show that the spousal correlations are lower (r~0.11). Regression-based associations in TL in the US are low (beta~0.08) and also vary by the number of times respondents have been married, where spouses married a single time have higher associations in TL (beta~.12) than spouses married more once (beta~0.03). I also find variation in spousal TL association levels based on husband's education level. These findings suggest the possibility of both assortative mating patterns related to telomere length as well as likelihood of shared environmental factors that cause TL similarity in people who are socially connected.

RevDate: 2018-10-31

Gramatges MM, Morton LM, Yasui Y, et al (2018)

Telomere length-associated genetic variants and the risk of thyroid cancer in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS).

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-18-0972 [Epub ahead of print].

BACKGROUND: Given the inverse relationship previously described between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length and thyroid SMN among survivors.

METHODS: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the hazard ratio for thyroid SMN among 5,324 genotyped survivors.

RESULTS: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically-estimated leukocyte telomere length and risk for thyroid SMN was identified.

CONCLUSIONS: Our results suggest that variation in common SNPs influencing leukocyte telomere length is not strongly associated with risk for thyroid SMN in survivors of childhood cancer.

IMPACT: The previously-observed inverse relationship between leukocyte telomere length and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms, and warrants further study.

RevDate: 2018-10-30

Yuan X, Kronström M, Hellenius ML, et al (2018)

Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men.

Aging pii:101611 [Epub ahead of print].

Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.

RevDate: 2018-10-29

Schöttker B, Hagen L, Zhang Y, et al (2018)

Serum 25-hydroxyvitamin D levels as an ageing marker. Strong associations with age and all-cause mortality independent from telomere length, epigenetic age acceleration and 8-isoprostane levels.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5146062 [Epub ahead of print].

Background: A strong association of serum 25-hydroxyvitamin-D levels (25(OH)D) with all-cause mortality has been shown previously and 25(OH)D could be a useful ageing marker.

Methods: The analysis was performed in a population-based, cohort study from Germany with 9,940 participants, aged 50-74 years at baseline. A general linear model was used to assess associations of 25(OH)D levels with chronological age and the ageing markers leukocyte telomere length, epigenetic age acceleration, and 8-isoprostane levels. A multivariate Cox regression model was applied to explore the independent and combined associations of these biomarkers with all-cause mortality (2,204 deaths occurred during a median follow-up of 14.3 years).

Results: On average, study participants lost 2.9 nmol/L 25(OH)D each 10 years of age. Increasing 25(OH)D levels were significantly associated with decreasing levels of 8-isoprostane levels but neither with leukocyte telomere length nor epigenetic age acceleration. The association of 25(OH)D quartiles with mortality was almost unchanged after adjusting for all ageing markers (1.6-fold increased mortality in bottom quartile compared to top quartile). All ageing markers were independent mortality predictors and subjects with unfavorable values for 4, 3, 2 and 1 ageing marker(s) had 4.3-, 2.9-, 2.2, and 1.4-fold increased mortality, respectively.

Conclusions: The 25(OH)D level can be regarded as an ageing marker because it is linearly associated with age and an independent mortality predictor. Mechanisms linking vitamin D to healthy ageing are unique and can neither be fully explained by ageing of the epigenome, loss of telomeres or anti-oxidative effects of vitamin D metabolites.

RevDate: 2018-10-29

Deng T, Huang Y, Weng K, et al (2018)

TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance.

Nucleic acids research pii:5146193 [Epub ahead of print].

In human cells, telomeres are elongated by the telomerase complex that contains the reverse transcriptase hTERT and RNA template TERC/hTR. Poly(A)-specific ribonuclease (PARN) is known to trim hTR precursors by removing poly(A) tails. However, the precise mechanism of hTR 3' maturation remains largely unknown. Target of Egr1 (TOE1) is an Asp-Glu-Asp-Asp (DEDD) domain containing deadenylase that is mutated in the human disease Pontocerebella Hypoplasia Type 7 (PCH7) and implicated in snRNA and hTR processing. We have previously found TOE1 to localize specifically in Cajal bodies, where telomerase RNP complex assembly takes place. In this study, we showed that TOE1 could interact with hTR and the telomerase complex. TOE1-deficient cells accumulated hTR precursors, including oligoadenylated and 3'-extended forms, which was accompanied by impaired telomerase activity and shortened telomeres. Telomerase activity in TOE1-deficient cells could be rescued by wild-type TOE1 but not the catalytically inactive mutant. Our results suggest that hTR 3' end processing likely involves multiple exonucleases that work in parallel and/or sequentially, where TOE1 may function non-redundantly as a 3'-to-5' exonuclease in conjunction with PARN. Our study highlights a mechanistic link between TOE1 mutation, improper hTR processing and telomere dysfunction in diseases such as PCH7.

RevDate: 2018-10-28

Olsson M, Friesen CR, Rollings N, et al (2018)

Long term effects of superoxide and DNA repair on lizard telomeres.

Molecular ecology [Epub ahead of print].

Telomeres are the non-coding protein-nucleotide 'caps' at chromosome ends that contribute to chromosomal stability by protecting the coding parts of the linear DNA from shortening at cell division, and from erosion by reactive molecules. Recently, there has been some controversy between molecular and cell biologists, on the one hand, and evolutionary ecologists on the other, regarding whether reactive molecules erode telomeres during oxidative stress. Many studies of biochemistry and medicine have verified these relationships in cell culture, but other researchers have failed to find such effects in free-living vertebrates. Here we use a novel approach to measure free radicals (superoxide), mitochondrial 'content' (a combined measure of mitochondrial number and size in cells), telomere length and DNA damage at two primary time points during the mating season of an annual lizard species (Ctenophorus pictus). Superoxide levels early in the mating season vary widely and elevated levels predict shorter telomeres both at that time as well as several months later. These effects are likely driven by mitochondrial content, which significantly impacts late season superoxide (cells with more mitochondria have more superoxide), but superoxide effects on telomeres are counteracted by DNA repair as revealed by 8-hydroxy-2'-deoxyguanosine assays. We conclude that reactive oxygen species and DNA repair are fundamental for both short- and long-term regulation of lizard telomere length with pronounced effects of early-season cellular stress detectable on telomere length near lizard death. This article is protected by copyright. All rights reserved.

RevDate: 2018-10-28

Sanei B, Zavar Reza J, Momtaz M, et al (2018)

Occupational exposure to particulate matters and telomere length.

Environmental science and pollution research international pii:10.1007/s11356-018-3486-9 [Epub ahead of print].

Little is known about the possible association between occupational exposure to mineral particulate matters and change in leukocyte telomere length (LTL) as a hallmark of aging. The present study studied the relationship between occupational exposures to mineral dust and LTL in the exposed group of workers and compared to non-exposed workers. One hundred and ten male workers (80 exposed and 30 non-exposed) from different units of a ceramic factory were recruited in the study. Personal air samples were collected in the breathing zone of the workers for inhalable and respirable fractions. Relative LTL was measured in blood genomic DNA using the quantitative real-time PCR method and expressed as telomere/single copy gene ratio. Exposure to inhalable and respirable dusts in the exposed group was 22.66 ± 52.38 and 2.54 ± 9.34 mg/m3 respectively. Inhalable and respirable exposure values were highly correlated (r2 = 0.43; p < 0.001). Exposure to respirable and inhalable particles in 38.75% and 8.75% of exposed workers was higher than threshold limit value respectively. Mean LTL in the exposed workers (0.64 ± 0.06) was significantly shorter than the non-exposed workers (0.73 ± 0.07) (p < 0.001). Despite the significant difference in exposure intensity according to working units in the exposed group, there was no significant difference in LTL according to the working units (p = 0.60). In the adjusted regression models, but not crude models, marginally significant and positive association was found between both size fractions and LTL. The observed effect size for respirable particles was five times of that found for the inhalable fraction (beta 0.005 and 0.001 respectively). Mineral dust-and not only traffic-related air pollutant exposure-could be regarded as a risk factor in the process of cell aging. Our findings imply that early biological aging, as reflected in telomere shortening, may mediate the effects of occupational air pollution exposure on human health.

RevDate: 2018-10-26

Parolini M, Possenti CD, Romano A, et al (2018)

Physiological increase of yolk testosterone level does not affect oxidative status and telomere length in gull hatchlings.

PloS one, 13(10):e0206503 pii:PONE-D-18-04034.

Conditions experienced during early-life can cause the onset of oxidative stress, resulting in pervasive effects on diverse life-history traits, including lifespan. In birds, maternally-transferred egg substances may exert positive or negative influence over the offspring phenotype. Among these, testosterone can upregulate the bioavailability of certain antioxidants but simultaneously promotes the production of pro-oxidants, leading to an oxidative stress situation, which is one of the main forces causing telomere attrition However, no study has investigated the role of this androgen on telomere dynamics in birds and little is known about the effects of yolk testosterone on oxidative status in early-life of these species. We physiologically increased the levels of yolk testosterone by in ovo injections in yellow-legged gull (Larus michahellis) to evaluate the effects induced by this androgen on hatchlings plasma total antioxidant capacity, amount of pro-oxidant molecules and telomere length at hatching. Testosterone supplementation did not increase hatchling body growth, did not result in the overproduction of pro-oxidant molecules nor a reduction of antioxidant capacity. Accordingly, telomere length at hatching was not affected by testosterone treatment, although hatchlings from the third-laid eggs showed shorter telomeres than their siblings from first- and second-laid eggs, independently of testosterone treatment. Our results suggest that injection of physiological levels of testosterone does not induce oxidative stress to hatchlings and, consequently do not affect telomere dynamics during early post-natal periods.

RevDate: 2018-10-25

Ivanyi-Nagy R, Ahmed SM, Peter S, et al (2018)

The RNA interactome of human telomerase RNA reveals a coding-independent role for a histone mRNA in telomere homeostasis.

eLife, 7: pii:40037 [Epub ahead of print].

Telomerase RNA (TR) provides the template for DNA repeat synthesis at telomeres and is essential for genome stability in continuously dividing cells. We mapped the RNA interactome of human TR (hTR) and identified a set of non-coding and coding hTR-interacting RNAs, including the histone 1C mRNA (HIST1H1C). Disruption of the hTR-HIST1H1C RNA association resulted in markedly increased telomere elongation without affecting telomerase enzymatic activity. Conversely, over-expression of HIST1H1C led to telomere attrition. By using a combination of mutations to disentangle the effects of histone 1 RNA synthesis, protein expression, and hTR interaction, we show that HIST1H1C RNA negatively regulates telomere length independently of its protein coding potential. Taken together, our data provide important insights into a surprisingly complex hTR-RNA interaction network and define an unexpected non-coding RNA role for HIST1H1C in regulating telomere length homeostasis, thus offering a glimpse into the mostly uncharted, vast space of non-canonical messenger RNA functions.

RevDate: 2018-10-25

Martínez P, MA Blasco (2018)

Heart-Breaking Telomeres.

Circulation research, 123(7):787-802.

Telomeres, the protective ends of linear chromosomes, shorten throughout an individual's lifetime. Accumulation of critically short telomeres is proposed to be a primary molecular cause of aging and age-associated diseases. Mutations in telomere maintenance genes are associated with pathologies referred to as or telomeropathies. The rate of telomere shortening throughout life is determined by endogenous (genetic) and external (nongenetic) factors. Therapeutic strategies based on telomerase activation are being developed to treat and prevent telomere-associated diseases, namely aging-related diseases and telomeropathies. Here, we review the molecular mechanisms underlying telomere driven diseases with particular emphasis on cardiovascular diseases.

RevDate: 2018-10-24

Maeda T, Horiuchi T, N Makino (2018)

Shorter somatic telomere can be an increased risk for hospitalization.

Molecular and cellular biochemistry pii:10.1007/s11010-018-3465-y [Epub ahead of print].

Somatic telomere DNA length is known to shorten with certain disease states and senescence. Furthermore, we have reported that the telomere length of a sub-healthy population also correlates with the blood data of laboratory tests. These facts suggest that patients with shorter telomere length tend to be hospitalized more easily than patients with longer telomere length. And such hospitalization tendencies can also be reflected in differences in clinical laboratory data. To address this issue, we evaluated and compared the telomere length and clinical laboratory data of outpatients and inpatients. In this study, 35 inpatients with chronic illness and 38 outpatients with one or more weeks without hospitalization experience were enrolled. Telomere length was shorter in hospitalized patients than outpatients. Inpatients and outpatients showed significant differences in some laboratory test results. Male outpatients showed higher values of fast blood sugar, HbA1c, blood urea nitrogen, creatinine, C-reactive protein, red blood cell count, and hemoglobin. Among female outpatients, the values of aspartate aminotransferase, alanine aminotransferase, albumin, creatine kinase, red blood cell count and hemoglobin were high. Of these, only albumin levels showed a positive correlation with telomere length in both sexes. Unexpectedly, all the other clinical data distinguishing outpatients and inpatients showed no significant association with telomere length. These items appeared to be related to hospital risk independently of TL. Having a shorter somatic telomere length appeared to be at a higher risk of hospitalization. This risk can be augmented by further complications such as deterioration of nutritional status and anemia. Maintaining sufficiently high nutritional status and erythropoietic potential may lead to avoidance of clinical events that require hospitalization.

RevDate: 2018-10-24

Wang Y, Savage SA, Alsaggaf R, et al (2018)

Telomere Length Calibration from qPCR Measurement: Limitations of Current Method.

Cells, 7(11): pii:cells7110183.

Telomere length (TL) comparisons from different methods are challenging due to differences in laboratory techniques and data configuration. This study aimed to assess the validity of converting the quantitative polymerase chain reaction (qPCR) telomere/single copy gene (T/S) ratio to TL in kilobases (kb). We developed a linear regression equation to predict TL from qPCR T/S using flow cytometry with fluorescence in situ hybridization (flow FISH) TL data from 181 healthy donors (age range = 19⁻53) from the National Marrow Donor Program (NMDP) biorepository. TL measurements by qPCR and flow FISH were modestly correlated (R² = 0.56, p < 0.0001). In Bland-Altman analyses, individuals with the shortest (≤10th percentile) or longest (≥90th) flow FISH TL had an over- or under-estimated qPCR TL (bias = 0.89 and -0.77 kb, respectively). Comparisons of calculated TL from the NMDP samples and 1810 age- and sex-matched individuals from the National Health and Nutrition Examination Survey showed significant differences (median = 7.1 versus 5.8 kb, respectively, p < 0.0001). Differences in annual TL attrition were also noted (31 versus 13 bp/year, respectively, p = 0.02). Our results demonstrate that TL calculated in kb from qPCR T/S may yield biased estimates for individuals with the shortest or longest TL, those often of high clinical interest. We also showed that calculated TL in kb from qPCR data are not comparable across populations and therefore are not necessarily useful.

RevDate: 2018-10-22

Gao D, Zhang R, Ji G, et al (2018)

Relative Telomere Length and Stroke Risk in a Chinese Han Population.

Journal of molecular neuroscience : MN pii:10.1007/s12031-018-1160-9 [Epub ahead of print].

This study aimed to further understand the role of relative telomere length (RTL) in susceptibility to stroke and investigate the association regulator of telomere elongation helicase 1 (RETL1) gene polymorphisms and RTL. RTL was measured using the real-time quantitative polymerase chain reaction (qPCR) from 300 stroke patients and 299 healthy controls. Genotyping was performed using the Sequenom MassARRAY platform. The results indicated that stroke patients had significantly shorter median RTL than controls (P < 0.001). Compared with the longer RTL (≥ 0.766), the shorter RTL (< 0.766) was significantly increased the risk of stroke (odds ratio [OR] = 8.44, 95% confidence interval [CI] 5.42-13.14, P < 0.001). The RTL was categorized into tertiles, we found that the shorter RTL (0.515-1.366) (OR = 16.27, 95% CI 7.72-34.29, P < 0.001) and lowest RTL (< 0.515) (OR = 30.63, 95% CI 14.27-65.75, P < 0.001) were significantly increased stroke risk compared with the highest RTL (> 1.366). Stratified analysis showed that the shorter RTL was also significantly increased the risk of stroke compared with the longer RTL in male, age < 60 years and ≥ 60 years, except the female participants. In addition, individuals with the genotypes AA (rs2297441) and GG (rs6089953) have shorter telomeres than the genotypes GG (P = 0.031) and AA (P = 0.032), respectively. Our results suggested that shorter RTL was associated with an increased risk of stroke. The association was found between the genotypes AA (rs2297441) and GG (rs6089953) and shorter RTL in case group. Further studies in larger sample size and biological functional assays are warranted to validate our findings.

RevDate: 2018-10-22

Lin J, Smith DL, Esteves K, et al (2018)

Telomere length measurement by qPCR - Summary of critical factors and recommendations for assay design.

Psychoneuroendocrinology pii:S0306-4530(18)30778-9 [Epub ahead of print].

Research in the last decade has explored the length of telomeres, the protective ends of eukaryotic chromosomes, as a biomarker for the cumulative effects of environmental exposures and life experiences as well as a risk factor for major diseases. With a growing interest in telomere biology across biomedical, epidemiological and public health research, it is critical to ensure that the measurement of telomere length is performed with high precision and accuracy. Of the several major methods utilized to determine telomere length, quantitative PCR (qPCR) remains the most cost-effective and suitable method for large-scale epidemiological and population studies. However, inconsistencies in recent reports utilizing the qPCR method highlight the need for a careful methodological analysis of each step of this process. In this review, we summarize each critical step in qPCR telomere length assay, including sample type selection, sample collection, storage, processing issues and assay procedures. We provide guidance and recommendations for each step based on current knowledge. It is clear that a collaborative and rigorous effort is needed to characterize and resolve existing issues related to sample storage, both before and after DNA extraction, as well as the impact of different extraction protocols, reagents and post extraction processing across all tissue types (e.g. blood, saliva, buccal swabs, etc.) to provide the needed data upon which best practices for TL analyses can be agreed upon. Additionally, we suggest that the whole telomere research community be invited to collaborate on the development and implementation of standardized protocols for the assay itself as well as for reporting in scientific journals. The existing evidence provides substantial support for the continuation of telomere research across a range of different exposures and health outcomes. However, as with any technological or methodologic advance in science, reproducibility, reliability and rigor need to be established to ensure the highest quality research.

RevDate: 2018-10-20

Cao DW, Jiang CM, Wan C, et al (2018)

Upregulation of MiR-126 Delays the Senescence of Human Glomerular Mesangial Cells Induced by High Glucose via Telomere-p53-p21-Rb Signaling Pathway.

Current medical science, 38(5):758-764.

Diabetic kidney disease (DKD) is a microvascular complication of type 2 diabetes. The study of DKD mechanisms is the most important target for the prevention of DKD. Renal senescence is one of the important pathogeneses for DKD, but the mechanism of renal and cellular senescence is unclear. Decreased expression of circulating miR-126 is associated with the development of DKD and may be a promising blood-based biomarker for DKD. This study is to probe the effect and mechanism of miR-126 on the aging of human glomerular mesangial cells (HGMCs) induced by high glucose. HGMCs were cultured with Roswell Park Memorial Institute (RPMI-1640) in vitro. The effect of high glucose on morphology of HGMCs was observed 72 h after intervention. The cell cycle was examined by flow cytometry. The telomere length was measured by Southern blotting. The expression levels of p53, p21 and Rb proteins in p53-p21-Rb signaling pathway and p-stat1, p-stat3 in JAK/STAT signaling pathway were detected by Western blotting respectively. The expression of miR-126 was examined by qRT-PCR. MiR-126 mimics was transfected into HGMCs. The effects of miR-126 mimics transfection on cell morphology, cell cycle, telomere length, p53, p21, Rb, p-stat1 and p-stat3 were observed. The results showed that high glucose not only arrested the cell cycle in G1 phase but also shortened the telomere length. High glucose led to high expression of p53, p21, Rb, p-stat1 and p-stat3 and premature senescence of HGMCs by activating the telomere-p53-p21-Rb and JAK/STAT signaling pathways. Moreover, the miR-126 was decreased in HGMCs induced by high glucose. It was suggested that the transfection of miR-126 mimics could inhibit the telomere-p53-p21-Rb and JAK/STAT signaling pathway activity in vitro and delay the senescence of HGMCs. The results may serve as a new strategy for the treatment of DKD.

RevDate: 2018-10-20

Solana C, Pereira D, R Tarazona (2018)

Early Senescence and Leukocyte Telomere Shortening in SCHIZOPHRENIA: A Role for Cytomegalovirus Infection?.

Brain sciences, 8(10): pii:brainsci8100188.

Schizophrenia is a severe, chronic mental disorder characterized by delusions and hallucinations. Several evidences support the link of schizophrenia with accelerated telomeres shortening and accelerated aging. Thus, schizophrenia patients show higher mortality compared to age-matched healthy donors. The etiology of schizophrenia is multifactorial, involving genetic and environmental factors. Telomere erosion has been shown to be accelerated by different factors including environmental factors such as cigarette smoking and chronic alcohol consumption or by psychosocial stress such as childhood maltreatment. In humans, telomere studies have mainly relied on measurements of leukocyte telomere length and it is generally accepted that individuals with short leukocyte telomere length are considered biologically older than those with longer ones. A dysregulation of both innate and adaptive immune systems has been described in schizophrenia patients and other mental diseases supporting the contribution of the immune system to disease symptoms. Thus, it has been suggested that abnormal immune activation with high pro-inflammatory cytokine production in response to still undefined environmental agents such as herpesviruses infections can be involved in the pathogenesis and pathophysiology of schizophrenia. It has been proposed that chronic inflammation and oxidative stress are involved in the course of schizophrenia illness, early onset of cardiovascular disease, accelerated aging, and premature mortality in schizophrenia. Prenatal or neonatal exposures to neurotropic pathogens such as Cytomegalovirus or Toxoplasma gondii have been proposed as environmental risk factors for schizophrenia in individuals with a risk genetic background. Thus, pro-inflammatory cytokines and microglia activation, together with genetic vulnerability, are considered etiological factors for schizophrenia, and support that inflammation status is involved in the course of illness in schizophrenia.

RevDate: 2018-10-18

Brosnan-Cashman JA, Graham MK, CM Heaphy (2018)

Genetic alterations associated with ALTered telomeres.

Oncotarget, 9(73):33739-33740 pii:26111.

RevDate: 2018-10-18

Ye X, He Z, Deng P, et al (2018)

[Characteristics of distribution and changes of telomere length in human].

Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences, 43(9):945-949.

OBJECTIVE: To explore the relationship between telomere length changes and age, and to provide data and reference for further study of geriatric medical problems.
 Methods: The healthy people over 20 years old were chosen as subject from several hospitals by random sampling method, and their peripheral blood samples were collected. The relative length of telomere was detected by quantitative real-time PCR, and the relationship between age and telomere length was analyzed by statistical software.
 Results: A total of 1 022 samples were obtained. There were significant differences in the relative telomere length among different age groups (F=21.492, P<0.001). Telomere length and age showed negative correlation (r=-0.325, P<0.001), the regression equation was y=-0.008x+1.772 (x for age, y for the average telomere length, P<0.001).
 Conclusion: The telomere length for peripheral blood leukocytes in healthy people varies between different age groups, suggesting that telomere length gradually decreases with age.

RevDate: 2018-10-17

Peacock SD, Massey TE, Vanner SJ, et al (2018)

Telomere length in the colon is related to colorectal adenoma prevalence.

PloS one, 13(10):e0205697 pii:PONE-D-18-11874.

Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.

RevDate: 2018-10-17

Jiménez KM, Pereira-Morales AJ, Adan A, et al (2018)

Telomere length and childhood trauma in Colombians with depressive symptoms.

Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) pii:S1516-44462018005007112 [Epub ahead of print].

OBJECTIVE: Childhood trauma and telomere length (TL) are important risk factors for major depressive disorder. We examined whether there was an association between childhood trauma and TL in a sample of Colombians who were assessed for depressive symptoms.

METHODS: We applied the Center for Epidemiologic Studies Depression scale, the Patient Health Questionnaire-9, the Hospital Anxiety and Depression scale and the Childhood Trauma Questionnaire to 92 Colombian subjects (mean age = 21). TL was measured with quantitative PCR. Spearman's correlation coefficient (rs) was used to analyze the relationship between childhood trauma scores and TL.

RESULTS: We found a significant correlation between TL and sexual abuse scores (rs = 0.428, p = 0.002) in individuals with higher depressive symptom scores.

CONCLUSION: This is the first report of a significant association between TL and sexual abuse in a Latin American sample and provides additional evidence about the role of childhood trauma and TL in neuropsychiatric disorders.

RevDate: 2018-10-17

Caria P, Dettori T, Frau DV, et al (2018)

Characterizing the three-dimensional organization of telomeres in papillary thyroid carcinoma cells.

Journal of cellular physiology [Epub ahead of print].

The relationship between the three-dimensional (3D) nuclear telomere architecture and specific genetic alterations in papillary thyroid carcinoma (PTC), in particular in cancer stem-like cells (CSLCs), has not yet been investigated. We isolated thyrospheres containing CSLCs from B-CPAP, K1, and TPC-1 PTC-derived cell lines, representative of tumors with different genetic backgrounds within the newly identified BRAFV600E -like PTC subgroup, and used immortalized normal human thyrocytes (Nthy-ori 3.1) as control. We performed quantitative fluorescence in situ hybridization, 3D imaging, and 3D telomere analysis using TeloView software to examine telomere dysfunction in both parental and thyrosphere cells. Among the 3D telomere profile, a wide heterogeneity was observed, except for telomere intensity. Our findings indicate that CSLCs of each cell line had longer telomeres than parental cells, according to telomere intensity values, which correlate with telomere length. Indeed, the thyrosphere cells had lower numbers of lower-intensity telomeres (≤5,000 arbitrary fluorescent units, a.u.), compared with parental cancer cells, as well as parental control cells, (p < 0.0001). The B-CPAP thyrospheres showed a decreased number of higher intensity telomeres (>17,000 a.u.) than K1 and TPC-1 cells, as well as control cells (p < 0.0001). By selecting PTC-derived cell lines with different genetic backgrounds characteristic of BRAFV600E -like PTC subgroups, we demonstrate that thyrosphere cells with BRAFV600E and TP53 mutations show shorter telomeres than those harboring RET/PTC or BRAFV600E and wild-type TP53. Hence, our data reveal a trend towards a decrease in telomere shortening in CSLCs, representing the early cancer-promoting subpopulation, as opposed to parental cells representing the tumor bulk cells.

RevDate: 2018-10-17

Gamal RM, Hammam N, Zakary MM, et al (2018)

Telomere dysfunction-related serological markers and oxidative stress markers in rheumatoid arthritis patients: correlation with diseases activity.

Clinical rheumatology pii:10.1007/s10067-018-4318-5 [Epub ahead of print].

Rheumatoid arthritis (RA) is an inflammatory autoimmune polyarthritis with progressive destruction of the synovial joints associated with systemic manifestations. RA is characterized by infiltration of the synovial joints with inflammatory immune cells with premature immunosenescence. Shorter telomere length in the peripheral blood cells and increase in the oxidative stress have been detected in patients with RA. The aim of the present study was to study the association of markers of telomere shortening and oxidative stress with RA disease activity. Sixty-one RA patients and 15 healthy controls were enrolled in the study. Demographic data, clinical examination, and disease activity status were evaluated for the RA patients. Serum levels of chitinase and NAG (telomere markers) were determined by biochemical reactions using colloidal chitin and NAG as substrates, respectively. Nitric oxide and superoxide dismutase (oxidative stress markers) were determined colometrically and spectrophotometrically, respectively, in the sera of RA patients and controls. Results were correlated with disease activity. Indices of telomere shortening and oxidative markers were significantly higher in RA patients compared to controls. These indices were correlated with signs of disease activity (including number of swollen and tender joints, DAS-28, and inflammatory markers). Rheumatoid arthritis is a disease in which markers of telomere shortening and elevated oxidant stress correlate with disease activity.

RevDate: 2018-10-17

Harpaz T, Abumock H, Beery E, et al (2018)

The Effect of Ethanol on Telomere Dynamics and Regulation in Human Cells.

Cells, 7(10): pii:cells7100169.

Telomeres (TLs) protect chromosome ends from chromosomal fusion and degradation, thus conferring genomic stability, and play crucial roles in cellular aging and disease. Recent studies have found a correlation between environmental, physiological and even mental stresses on TL dynamics in humans. However, the causal relationship between stress and TL length and the molecular mechanisms underlying that relationship are far from being understood. This study describes the effect of moderate concentrations of ethanol, equivalent to social drinking, on human TL dynamics and partially elucidates the mechanism mediating this effect. The exposure of Immortalized human foreskin fibroblast, primary human foreskin fibroblast and human hepatocellular carcinoma cells to 25 mM ethanol for one week moderately shortened telomeres in all cells. Similar TL shortening was obtained following cells' exposure to 25 µM acetaldehyde (AcH) and to a much lower extent after exposure to 4-methylpyrazolean, an inhibitor of alcoholdehydrogenase, suggesting that AcH plays a key role in ethanol-dependent telomere shortening. Telomerase activity was not involved in this effect. TRF2 and several TRF2 binding proteins increased their binding to TLs after ethanol treatment, implying their involvement in this effect. The methylation status of several sub-telomeric regions increased in response to EtOH exposure. Gene expression profiling showed distinct patterns in cells treated with EtOH and in cells recovered from EtOH. In addition to cellular ageing, the described telomere shortening may contribute to the carcinogenic potential of acute alcohol consumption; both are associated with the shortening of TLs and provide new insights regarding the moderate consumption of alcohol referred to as "social drinking."

RevDate: 2018-10-16

Eissenberg JC (2013)

Telomeres, Cancer & Aging: Live Long & Prosper?.

Missouri medicine, 110(1):10-16.

Like our clothes, our chromosomes fray at the edges with age. Some believe that if we could discover a molecular tailor to patch our age-abraded chromosome ends, we could become modern Methuselahs. Notably, cancer cells achieve immortality by protecting their chromosome ends. Drugs that selectively fray the ends of cancer cell chromosomes would be potent and general anti-cancer therapies. Here, I summarize data on the role of chromosome ends in cellular and organismal aging.

RevDate: 2018-10-16

Campa D, Matarazzi M, Greenhalf W, et al (2018)

Genetic determinants of telomere length and risk of pancreatic cancer: a PANDoRA study.

International journal of cancer [Epub ahead of print].

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54x10-10) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87x10-6 , ptrend = 3.27x10-7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98x10-9 for highest vs. lowest quintile; p = 1.82x10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer. This article is protected by copyright. All rights reserved.

RevDate: 2018-10-15

Planas-Cerezales L, Arias-Salgado EG, Buendia-Roldán I, et al (2018)

Predictive factors and prognostic effect of telomere shortening in pulmonary fibrosis.

Respirology (Carlton, Vic.) [Epub ahead of print].

BACKGROUND AND OBJECTIVE: The abnormal shortening of telomeres is a mechanism linking ageing to idiopathic pulmonary fibrosis (IPF) that could be useful in the clinical setting. The objective of this study was to identify the IPF patients with higher risk for telomere shortening and to investigate the outcome implications.

METHODS: Consecutive Spanish patients were included at diagnosis and followed up for 3 years. DNA blood samples from a Mexican cohort were used to validate the results found in Spanish sporadic IPF. Prior to treatment, telomere length was measured through quantitative polymerase chain reaction (qPCR) and Southern blot. Outcome was assessed according to mortality or need for lung transplantation. A multivariate regression logistic model was used for statistical analysis.

RESULTS: Family aggregation, age of <60 years and the presence of non-specific immunological or haematological abnormalities were associated with a higher probability of telomere shortening. Overall, 66.6% of patients younger than 60 years with telomere shortening died or required lung transplantation, independent of functional impairment at diagnosis. By contrast, in patients older than 60 years with telomere shortening, the negative impact of telomere shortening in outcome was not significant.

CONCLUSION: Our data indicate that young sporadic IPF patients (<60 years) with some non-specific immunological or haematological abnormalities had higher risk of telomere shortening, and furthermore, they presented a poorer prognosis.

RevDate: 2018-10-13

Rodriguez-Brenes IA, Komarova NL, D Wodarz (2018)

The role of telomere shortening in carcinogenesis: A hybrid stochastic-deterministic approach.

Journal of theoretical biology pii:S0022-5193(18)30433-8 [Epub ahead of print].

Genome instability is a characteristic of most cancers, contributing to the acquisition of genetic alterations that drive tumor progression. One important source of genome instability is linked to telomere dysfunction in cells with critically short telomeres that lack p53-mediated surveillance of genomic integrity. Here we research the probability that cancer emerges through an evolutionary pathway that includes a telomere-induced phase of genome instability. To implement our models we use a hybrid stochastic-deterministic approach, which allows us to perform large numbers of simulations using biologically realistic population sizes and mutation rates, circumventing the traditional limitations of fully stochastic algorithms. The hybrid methodology should be easily adaptable to a wide range of evolutionary problems. In particular, we model telomere shortening and the acquisition of two mutations: Telomerase activation and p53 inactivation. We find that the death rate of unstable cells, and the number of cell divisions that p53 mutants can sustain beyond the normal senescence setpoint determine the likelihood that the first double mutant originates in a cell with telomere-induced instability. The model has applications to an influential telomerase-null mouse model and p16 silenced human cells. We end by discussing algorithmic performance and a measure for the accuracy of the hybrid approximation.

RevDate: 2018-10-11

Tahara H (2018)

[Risk assessment of age-associated diseases using telomere and microRNA technologies].

[Rinsho ketsueki] The Japanese journal of clinical hematology, 59(10):1880-1885.

Prevention and early detection of age-associated diseases are critical to achieve healthy longevity among the super-aged individuals. To this end, technology that can assess the risk of diseases before onset and that can detect diseases at an early stage for early treatment intervention is essential. Technology that measures telomere G-tail length can be used to examine the risk of age-associated diseases, while miRNAs may serve as a novel diagnostic marker for the early detection of diseases, such as cancer and dementia. In this review, the potential of telomere and microRNA technologies as disease risk assessment tools is explored.

RevDate: 2018-10-10

Wang S, Qu F, Han W, et al (2018)

A resonance Rayleigh scattering sensor for sensitive differentiation of telomere DNA length and monitoring special motifs (G-quadruplex and i-motif) based on the Ag nanoclusters and NAND logic gate responding to chemical input signals.

Journal of nanobiotechnology, 16(1):78 pii:10.1186/s12951-018-0407-5.

BACKGROUND: Differentiation of telomere length is of vital importance because telomere length is closely related with several deadly diseases such as cancer. Additionally, G-quadruplex and i-motif formation in telomeric DNA have been shown to act as a negative regulator of telomere elongation by telomerase in vivo and are considered as an attractive drug target for cancer chemotherapy.

RESULTS: In this assay, Ag nanoclusters templated by hyperbranched polyethyleneimine (PEI-Ag NCs) are designed as a new novel resonance Rayleigh scattering (RRS) probe for sensitive differentiation of telomere length and monitoring special motifs (G-quadruplex and i-motif). In this assay, free PEI-Ag NC probe or DNA sequence alone emits low intensities of RRS, while the formation of PEI-Ag NCs/DNA complexes yields greatly enhanced RRS signals; however, when PEI-Ag NCs react with G-quadruplex or i-motif, the intensities of RRS exhibit slight changes. At the same concentration, the enhancement of RRS signal is directly proportional to the length of telomere, and the sensitivity of 64 bases is the highest with the linear range of 0.3-50 nM (limit of detection 0.12 nM). On the other hand, due to the conversion of telomere DNA molecules among multiple surrounding conditions, a DNA logic gate is developed on the basis of two chemical input signals (K+ and H+) and a change in RRS intensity as the output signal.

CONCLUSION: Our results indicate that PEI-Ag NCs can serve as a novel RRS probe to identify DNA length and monitor G-quadruplex/i-motif through the different increasing degrees of RRS intensity. Meanwhile, the novel attributes of the nanoprobe stand superior to those involving dyes or labeled DNA because of no chemical modification, low cost, green, and high efficiency.

RevDate: 2018-10-09

Arias-Sosa LA (2018)

Understanding the Role of Telomere Dynamics in Normal and Dysfunctional Human Reproduction.

Reproductive sciences (Thousand Oaks, Calif.) [Epub ahead of print].

In modern society, fertility problems and demand of treatment seem to be on the rise, which led to an increased interest in research regarding human reproduction. Among these efforts, the study of the molecular senescence process has gain notorious popularity as aging is one of the most important variables involved in reproductive capacity and since the comprehension of telomere dynamics has become an important and influential theme. This new knowledge regarding the reproductive aging process is expected to offer new tools to understand the acquisition, maintenance, and loss of fertility potential. Therefore, this review seeks to clarify the relevance of molecular aging (evaluated by telomere shortening) in human reproduction, showing that it is a dynamic and variable process modulated according to the specific tissue and stage of development. As well, it is discussed how telomere status influence the development and progression of some fertility pathologies, the outcome of assisted reproductive treatments, and programming of aging in the offspring.

RevDate: 2018-10-06

Jimenez Villarreal J, Murillo Ortiz B, Martinez Garza S, et al (2018)

Telomere length analysis in residents of a community exposed to arsenic.

Journal of biochemical and molecular toxicology [Epub ahead of print].

Differentiated cells telomere length is an indicator of senescence or lifespan; however, in peripheral blood leukocytes the relative shortening of the telomere has been considered as a biological marker of aging, and lengthening telomere as an associated risk to cancer. Individual's age, type of tissue, lifestyle, and environmental factors make telomere length variable. The presence of environmental carcinogens such as arsenic (As) influence as causal agents of these alterations, the main modes of action for As described are oxidative stress, reduction in DNA repair capacity, overexpression of genes, alteration of telomerase activity, and damage to telomeres. The telomeres of leukocytes resulting a finite capacity of replication due to the low or no activity of the telomerase enzyme, therefore, elongation telomere in this kind of cells is a potential biological marker associated with the development of chronic diseases and carcinogenesis.

RevDate: 2018-10-07

Fujiwara C, Muramatsu Y, Nishii M, et al (2018)

Cell-based chemical fingerprinting identifies telomeres and lamin A as modifiers of DNA damage response in cancer cells.

Scientific reports, 8(1):14827 pii:10.1038/s41598-018-33139-x.

Telomere maintenance by telomerase activity supports the infinite growth of cancer cells. MST-312, a synthetic telomerase inhibitor, gradually shortens telomeres at non-acute lethal doses and eventually induces senescence and apoptosis of telomerase-positive cancer cells. Here we report that MST-312 at higher doses works as a dual inhibitor of telomerase and DNA topoisomerase II and exhibits acute anti-proliferative effects on cancer cells and xenografted tumours in vivo. Our cell-based chemical fingerprinting approach revealed that cancer cells with shorter telomeres and lower expression of lamin A, a nuclear architectural protein, exhibited higher sensitivity to the acute deleterious effects of MST-312, accompanied by formation of telomere dysfunction-induced foci and DNA double-strand breaks. Telomere elongation and lamin A overexpression attenuated telomeric and non-telomeric DNA damage, respectively, and both conferred resistance to apoptosis induced by MST-312 and other DNA damaging anticancer agents. These observations suggest that sufficient pools of telomeres and a nuclear lamina component contribute to the cellular robustness against DNA damage induced by therapeutic treatment in human cancer cells.

RevDate: 2018-10-04

Salihu HM, Adegoke KK, King LM, et al (2018)

Effects of Maternal Carbohydrate and Fat Intake on Fetal Telomere Length.

Southern medical journal, 111(10):591-596.

OBJECTIVES: Telomere length can be affected by dietary factors in adults. We investigated the association between maternal carbohydrate and fat intake during pregnancy and telomere length in neonatal cord blood leukocytes. We hypothesized that high fat consumption and high carbohydrate consumption would be associated with shortened fetal telomere length.

METHODS: We collected umbilical cord blood at delivery from women admitted for labor and delivery in a university hospital (N = 62) and extracted genomic DNA using quantitative polymerase chain reaction. We quantified telomere length using the telomere-to-single copy gene ratio method (T:S ratio). High carbohydrate intake was defined as consumption of >175 g/day and high fat intake as >35 g/day. We performed generalized linear regression modeling and bootstrap statistical analyses to derive precise estimates of association.

RESULTS: Of the 62 maternal-fetal dyads included in this study, 79% were classified as high carbohydrate consumers and 37% were classified as high fat consumers. High fat consumption had a significant negative effect on T:S ratio (P < 0.05). Although high carbohydrate consumption was associated with a decreased T:S ratio, this relation did not attain statistical significance.

CONCLUSIONS: To our knowledge, this study is the first evidence of an association between maternal high fat consumption and shortened fetal telomere length. These findings could enhance our understanding of the role of maternal diet in fetal programming.

RevDate: 2018-10-04

Lopes AC, Oliveira PF, M Sousa (2018)

Shedding light into the relevance of telomeres in human reproduction and male factor infertility.

Biology of reproduction pii:5114555 [Epub ahead of print].

Sperm telomere length (STL) is a promising new parameter for sperm quality analysis that may elucidate the molecular mechanisms underlying the idiopathic cases of male factor infertility, which represent almost half of all the male factor infertility cases worldwide. Telomeres consist of nucleoprotein structures present at the ends of eukaryotic chromosomes, whose protective functions maintain the genomic stability. Their role in reproduction includes an active intervention during gametogenesis, fertilization and preimplantation embryo development. In consonance, studies have shown that compromised telomere homeostasis is associated with male infertility. Since critically short telomeres have their function affected, assessing STL may be a fast and economic method for sperm quality analysis and expectantly contribute to improve the success of fertility treatments. This hypothesis is supported by several reports associating STL with seminal parameters, genome integrity and clinical outcomes. However, there are other studies in the literature that do not demonstrate these associations. Additionally, it is still not clear whether the lengthening mechanisms of telomeres occurring during early embryo development resume the inherited telomere length. Further research it is essential to clarify the suitability of STL as a biomarker for male infertility, before it could be routinely implemented in medically assisted reproduction centers. Understanding the molecular mechanisms underlying STL function and dynamics will provide us new insights into the origins of male infertility and a new useful tool as an outcome predictor for assisted reproduction.

RevDate: 2018-10-03

Kazemi Noureini S, Fatemi L, M Wink (2018)

Telomere shortening in breast cancer cells (MCF7) under treatment with low doses of the benzylisoquinoline alkaloid chelidonine.

PloS one, 13(10):e0204901 pii:PONE-D-18-10381.

Telomeres, the specialized dynamic structures at chromosome ends, regularly shrink with every replication. Thus, they function as an internal molecular clock counting down the number of cell divisions. However, most cancer cells escape this limitation by activating telomerase, which can maintain telomere length. Previous studies showed that the benzylisoquinoline alkaloid chelidonine stimulates multiple modes of cell death and strongly down-regulates telomerase. It is still unknown if down-regulation of telomerase by chelidonine boosts substantial telomere shortening. The breast cancer cell line MCF7 was sequentially treated with very low concentrations of chelidonine over several cell passages. Telomere length and telomerase activity were measured by a monochrome multiplex quantitative PCR and a q-TRAP assay, respectively. Changes in population size and doubling time correlated well with telomerase inhibition and telomere shortening. MCF7 cell growth was arrested completely after three sequential treatments with 0.1 μM chelidonine, each ending after 48 h, while telomere length was reduced to almost 10% of the untreated control. However, treatment with 0.01 μM chelidonine did not have any apparent consequence. In addition to dose and time dependent telomerase inhibition, chelidonine changed the splicing pattern of hTERT towards non-enzyme coding isoforms of the transcript. In conclusion, telomere length and telomere stability are strongly affected by chelidonine in addition to microtubule formation.

RevDate: 2018-10-03

Gurung RL, Yiamunaa M, Liu S, et al (2018)

Ethnic disparities in relationship of obesity indices and telomere length in Asians with type 2 diabetes.

Journal of diabetes [Epub ahead of print].

BACKGROUND: Obesity and shorter telomeres increase the risk for diabetes complications and mortality. However, the relationship of obesity and telomere length in diverse Asian population with type 2 diabetes (T2D) is not well understood. In this study, we examine the association of the baseline and changes in obesity indices, with telomere length in multi-ethnic Asian populations with T2D.

METHODS: Leukocyte telomere length (LTL) was measured by qPCR assay in SMART2D cohort (n=1431 at baseline, n= 1039 after 3.2 years median follow-up). Associations between obesity indices and LTL were assessed after adjusting for age, gender, diabetes condition, hypertension, obesity and inflammation markers.

RESULTS: Compared to Chinese, LTL was longer in Malays (P<0.0001) and similar in Indians. Cross-sectionally, body mass index (BMI) (β = -0.016, P=0.087), BMI adjusted (residual) visceral fat area (VFA) (β = -0.004, P=0.006) and waist-to-hip ratio (WHR) (β = -1.95, P=0.030) were significantly associated with LTL in Chinese but not in Malays and Indians. Changes in BMI (r= -0.080; P=0.053) and VFA (r= -0.126; P=0.002) were inversely correlated with changes in LTL only in Chinese. Furthermore, 1-SD incremental changes in BMI (β= -0.070; P=0.040) and VFA (β = -0.088, P=0.028) were significantly associated with larger telomere attrition, independent of age, gender, diabetes condition, baseline LTL, obesity and inflammation markers in Chinese.

CONCLUSIONS: 3-year changes in BMI and VFA were associated with telomere dynamics in Chinese but not in Malays and Indians with T2D. Reducing obesity may reduce the risk of diabetes complications associated with shorter LTL, in Chinese population.

RevDate: 2018-10-05

Swapna G, Yu EY, NF Lue (2018)

Single telomere length analysis in Ustilago maydis, a high-resolution tool for examining fungal telomere length distribution and C-strand 5'-end processing.

Microbial cell (Graz, Austria), 5(9):393-403 pii:MIC0178E133.

Telomeres play important roles in genome stability and cell proliferation. Telomere lengths are heterogeneous and because just a few abnormal telomeres are sufficient to trigger significant cellular response, it is informative to have accurate assays that reveal not only average telomere lengths, but also the distribution of the longest and shortest telomeres in a given sample. Herein we report for the first time, the development of single telomere length analysis (STELA) - a PCR-based assay that amplifies multiple, individual telomeres - for Ustilago maydis, a basidiomycete fungus. Compared to the standard telomere Southern technique, STELA revealed a broader distribution of telomere size as well as the existence of relatively short telomeres in wild type cells. When applied to blm∆, a mutant thought to be defective in telomere replication, STELA revealed preferential loss of long telomeres, whose maintenance may thus be especially dependent upon efficient replication. In comparison to blm∆, the trt1∆ (telomerase null) mutant exhibited greater erosion of short telomeres, consistent with a special role for telomerase in re-lengthening extra-short telomeres. We also used STELA to characterize the 5' ends of telomere C-strand, and found that in U. maydis, they terminate preferentially at selected nucleotide positions within the telomere repeat. Deleting trt1 altered the 5'-end distributions, suggesting that telomerase may directly or indirectly modulate C-strand 5' end formation. These findings illustrate the utility of STELA as well as the strengths of U. maydis as a model system for telomere research.

RevDate: 2018-10-03

Zhang LL, Wu Z, JQ Zhou (2018)

Tel1 and Rif2 oppositely regulate telomere protection at uncapped telomeres in Saccharomyces cerevisiae.

Journal of genetics and genomics = Yi chuan xue bao pii:S1673-8527(18)30164-4 [Epub ahead of print].

It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2 (MRX) activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At uncapped telomeres, whether Tel1 or Rif2 plays any role remains largely unknown. In this work, we examined the roles of Tel1 and Rif2 at uncapped telomeres in yku70Δ and/or cdc13-1 mutant cells cultured at non-permissive temperature. We found that deletion of TEL1 exacerbates the temperature sensitivity of both yku70Δ and cdc13-1 cells. Further epistasis analysis indicated that MRX and Tel1 function in the same pathway in telomere protection. Consistently, TEL1 deletion increases accumulation of Exo1-dependent telomeric single-stranded DNA (ssDNA) at uncapped telomeres, which stimulates checkpoint-dependent cell cycle arrest. Moreover, deletion of TEL1 in yku70Δ and yku70Δ tlc1Δ cells facilitates Rad51-dependent Y' recombination, allowing yku70Δ tlc1Δ cells to bypass senescence. In contrast, RIF2 deletion in yku70Δ cells decreases the accumulation of telomeric ssDNA after 8 h of incubation at the non-permissive temperature of 37 °C and suppresses the temperature sensitivity of yku70Δ cells, likely due to the increase of Mre11 association at telomeres. Collectively, our findings indicate that Tel1 and Rif2 regulate telomere protection at uncapped telomeres via their roles in balancing MRX activity in telomere resection.

RevDate: 2018-10-16
CmpDate: 2018-10-16

Jin X, Pan B, Dang X, et al (2018)

Relationship between short telomere length and stroke: A meta-analysis.

Medicine, 97(39):e12489.

BACKGROUND: Several epidemiological studies had been carried out in different population cohorts to estimate the relationship between the shortened telomere length and stroke. However, the results still remained dispute. Consequently, we conducted this meta-analysis to estimate the relationship between them.

METHODS: PubMed, EMBASE, and Web of Science were systematically searched for related articles to evaluate the association between "stroke" and "telomere length. STATA 12.0 software was used to perform the meta-analysis. The Cochran Q test and inconsistency index (I) were used to assess the heterogeneity. Begg funnel plot and Egger test were used to assess publication bias.

RESULTS: The meta-analysis was composed of 11 studies, consisting of 25,340 participants. We found a significant relationship between shortened telomere length and stroke (OR: 1.50, 95% CI: 1.13-2.0; P = .005); however, in the prospective and retrospective study subgroup, we did not find a statistical significant relationship between shortened telomere length and stroke (the prospective subgroup: OR: 1.41, 95% CI: 1-1.98; P = .051) (the retrospective subgroup: OR: 1.89, 95% CI: 0.96-3.72; P = .067).

RevDate: 2018-10-11

Wai KM, Umezaki M, Kosaka S, et al (2018)

Impact of prenatal heavy metal exposure on newborn leucocyte telomere length: A birth-cohort study.

Environmental pollution (Barking, Essex : 1987), 243(Pt B):1414-1421 pii:S0269-7491(18)32939-7 [Epub ahead of print].

Arsenic, cadmium and lead are toxic environmental contaminants. They were shown to be associated with telomere length (TL) in adults. Although they can cross the placental barrier, the effect of prenatal exposure of these metals on newborn TL is unknown. The aim of this study was to examine whether prenatal exposure to heavy metals has an impact on newborn leucocyte TL. A birth-cohort study was conducted with 409 pregnant women and their newborns in Myanmar. During the first visit, face-to-face interviews were conducted, and maternal spot urine sampling was performed. Cord blood samples were collected during follow-up. Urinary heavy metal concentration was measured by ICP-MS and adjusted for creatinine. Relative TL was measured by quantitative real-time polymerase chain reaction. The extent of prenatal arsenic, cadmium and lead exposure and their associations with newborn leucocyte TL were assessed using multivariate linear regression. The median values of maternal urinary arsenic, cadmium, and lead concentrations were 73.9, 0.9, and 1.8 μg/g creatinine, respectively. Prenatal arsenic and cadmium exposure was significantly associated with newborn TL shortening (lowest vs highest quartile, coefficient = - 0.13, 95% CI: - 0.22, - 0.03, p = 0.002, and coefficient = - 0.17, 95% CI: - 0.27, - 0.07, p = 0.001, respectively), and the associations remained robust after adjusting for confounders. There was no significant association between prenatal lead exposure and newborn TL. The present study identified the effect of arsenic and cadmium exposure on TL shortening, even in utero exposure at a lower concentration.

RevDate: 2018-10-02

Li J, Zhang L, Zhu H, et al (2018)

Leukocyte Telomere Length and Clinical Outcomes of Advanced Lung Adenocarcinoma Patients with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Treatment.

DNA and cell biology [Epub ahead of print].

Gefitinib is currently one of the mostly used epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) recommended for treating nonsmall cell lung cancer. However, drug resistance is observed among the majority of patients after initial treatment. Factors that predict treatment prognosis and drug resistance to EGFR-TKIs remain elusive. The objective of this study is to investigate whether leukocyte relative telomere length (RTL) can be used as a prognostic biomarker of EGFR-TKIs therapy. In this study, 369 patients with stage IIIB or IV lung adenocarcinoma were recruited and treated with gefitinib as first-line monotherapy. Leukocyte RTL of each patient was measured using quantitative polymerase chain reaction protocol and calculated according to Cawthon's formula. Finally, we examined the association between leukocyte RTL and prognosis or drug resistance of advanced lung adenocarcinoma to gefitinib treatment. Our results indicated that compared with long RTL, short leukocyte RTL was significantly associated with poor prognosis in all patients after gefitinib treatment (overall survival [OS]: 12.9 months vs. 17.8 months, p = 1.2 × 10-4; progression-free survival: 7.8 months vs. 13.0 months, p = 0.043). In addition, statistically significant association between short leukocyte RTL and short OS still existed among the EGFR mutant patients (hazards ratio [HR] = 1.65, 95% confidence interval [CI] = 1.28-2.12; p = 0.006). Besides EGFR mutation status, short RTL also contributed to remarkably elevated risk of gefitinib primary resistance (HR = 1.50, 95% CI = 1.05-2.15, p = 0.027). Our results highlight the clinical potential of leukocyte RTL as a novel biomarker in advanced lung adenocarcinoma treated with EGFR-TKIs.

RevDate: 2018-10-02

Rocca MS, Foresta C, A Ferlin (2018)

Telomere length: lights and shadows on their role in human reproduction.

Biology of reproduction pii:5113454 [Epub ahead of print].

Telomeres are repeated DNA sequences whose main function is to preserve genome stability, protecting chromosomes ends from shortening caused by progressive loss during each cell replication or DNA damage. Telomere length regulation is normally achieved by telomerase enzyme, whose activity is progressively shut off during embryonic differentiation in somatic tissues, whereas it is maintained in germ cells, activated lymphocytes, and certain types of stem cell populations. The maintenance of telomerase activity for a longer time is necessary for germ cells to delay telomere erosion, avoiding thus chromosome segregation defects that could contribute to aneuploid or unbalanced gametes. Over the last few years, telomere biology has become an important topic in the field of human reproduction, encouraging several studies to focus on the relation between telomere length and spermatogenesis and male fertility, embryo development and quality during assisted reproductive treatment, and female pathologies as polycystic ovary, premature ovarian insufficiency and endometriosis. This review analyses whether telomere length in germ cells is related to reproduction fitness, whether telomere length is related to pathologies associated with male and female fertility and whether measurement of telomere length could represent a biomarker of germ cell and embryo quality. Telomere length could be considered a molecular marker of spermatogenesis and sperm quality and is somewhat related to male fertility potential. Fewer evidence, although promising, is available for oocytes, female (in)fertility and embryo quality. The increasing evidence for a role of telomeres and telomere length in human reproduction, indeed, has expanded the historical view of considering them just a marker of aging. Telomere length might have in the future a prognostic potential in couple infertility, especially useful to select best germ cells with the greatest potential of fertilization.

RevDate: 2018-10-05

Liu Y, Lei T, Zhang N, et al (2018)

Leukocyte telomere length and risk of gastric cardia adenocarcinoma.

Scientific reports, 8(1):14584 pii:10.1038/s41598-018-32954-6.

As a chromosome stabilizer, telomeres play an essential part in maintaining the stability and integrity of human genome. Shortened telomeres have been associated with the development of cancers but it is still largely unclear whether leukocyte telomere length contributes to predisposition of gastric cardia adenocarcinoma (GCA). We conducted a case-control study consisting of 524 GCA cases and 510 controls to assess the association between telomere length in peripheral blood leukocytes and GCA risk in a Chinese Han population. The GCA patients had significantly overall shorter relative leukocyte telomere length (RTL) (median ± SD: 1.10 ± 0.54) when compared with the controls (1.24 ± 0.58). Individuals with the shortest quartile of RTL performed a doubled GCA risk (OR = 2.18; 95% CI = 1.47-3.22, P = 9.90 × 10-5) when compared with those with the highest quartile. We also found that telomere shortening and smoking have a significantly synergistic effect in intensifying risk of GCA (OR = 7.03, 95% CI = 4.55-10.86, P = 1.43 × 10-18). These findings indicate that short RTL contributes to increased susceptibility of gastric cardia adenocarcinoma and might be a promising marker to identify high-risk individuals combined with lifestyle risk factors.

RevDate: 2018-10-02

Autsavapromporn N, Klunklin P, Threeratana C, et al (2018)

Short Telomere Length as a Biomarker Risk of Lung Cancer Development Induced by High Radon Levels: A Pilot Study.

International journal of environmental research and public health, 15(10): pii:ijerph15102152.

Long-term exposure to radon has been determined to be the second leading cause of lung cancer after tobacco smoking. However, an in-depth study of this topic has not been explicitly carried out in Chiang Mai (Thailand). This paper presents the results of an indoor radon level measurement campaign in dwellings of Chiang Mai using total of 110 detectors (CR-39) during one year. The results show that the average radon levels varied from 35 to 219 Bq/m³, with an overall average of 57 Bq/m³. The finding also shows that the average value is higher than the global average value of 39 Bq/m³. In addition, to examine the cause of lung cancer development among people with risk of chronic exposure to radon during their lifetime, 35 non-smoker lung cancer patients and 33 healthy nonsmokers were analyzed for telomere length. As expected, telomere length was significantly shorter in lung cancer patients than in healthy nonsmokers. Among healthy nonsmokers, the telomere length was significantly shorter in a high radon group than in an unaffected low radon group. To the best of our knowledge, our research provides the first attempt in describing the shortened telomeres in areas with high levels of environmental radon that might be related to lung cancer development.

RevDate: 2018-10-15

Gallicchio L, Gadalla SM, Murphy JD, et al (2018)

The Effect of Cancer Treatments on Telomere Length: A Systematic Review of the Literature.

Journal of the National Cancer Institute, 110(10):1048-1058.

Background: It has been hypothesized that cancer treatments cause accelerated aging through a mechanism involving the shortening of telomeres. However, the effect of cancer treatments on telomere length is unclear.

Methods: We systematically reviewed the epidemiological evidence evaluating the associations between cancer treatment and changes in telomere length. Searches were performed in PubMed for the period of January 1966 through November 2016 using the following search strategy: telomere AND (cancer OR tumor OR carcinoma OR neoplasm) AND (survivor OR patient). Data were extracted and the quality of studies was assessed.

Results: A total of 25 studies were included in this review. Ten were solid cancer studies, 11 were hematological malignancy studies, and 4 included a mixed sample of both solid and hematological cancers. Three of the 10 solid tumor studies reported a statistically significant association between cancer treatment and telomere length shortening, and one reported longer telomere length after treatment. Among the hematological cancer studies, three showed statistically significant decreases in telomere length with treatment, and two showed elongation. When these studies were rated using quality criteria, most of the studies were judged to be of moderate quality.

Conclusions: The findings from this review indicate that the effect of cancer treatment on telomere length may differ by cancer type and treatment as well as other factors. Definitive conclusions cannot be made based on the published literature, because sample sizes tended to be small; treatments, cancer types, and biospecimens were heterogenous; and the length of follow-up times differed greatly.

RevDate: 2018-10-01

Kosebent EG, Uysal F, S Ozturk (2018)

Telomere length and telomerase activity during folliculogenesis in mammals.

The Journal of reproduction and development [Epub ahead of print].

Telomeres are repetitive non-coding DNA sequences located at the end of chromosomes in eukaryotic cells. Their most important function is to protect chromosome ends from being recognized as DNA damage. They are also implicated in meiosis and synapse formation. The length of telomeres inevitably shortens at the end of each round of DNA replication and, also, as a consequence of the exposure to oxidative stress and/or genotoxic agents. The enzyme telomerase contributes to telomere lengthening. It has been reported that telomerase is exclusively expressed in germ cells, granulosa cells, early embryos, stem cells, and various types of cancerous cells. Granulosa cells undergo many mitotic divisions and either granulosa cells or oocytes are exposed to a variety of genotoxic agents throughout folliculogenesis; thus, telomerase plays an important role in the maintenance of telomere length. In this review article, we have comprehensively evaluated the studies focusing on the regulation of telomerase expression and activity, as well as telomere length, during folliculogenesis from primordial to antral follicles, in several mammalian species including mice, bovines, and humans. Also, the possible relationships between female infertility caused by follicular development defects and alterations in the telomeres and/or telomerase activity are discussed.

RevDate: 2018-10-16

Grun LK, Teixeira NDR, Mengden LV, et al (2018)

TRF1 as a major contributor for telomeres' shortening in the context of obesity.

Free radical biology & medicine, 129:286-295 pii:S0891-5849(18)31552-1 [Epub ahead of print].

Obesity is a prevalent multifactorial chronic disorder characterized by metabolic dysregulation. Sustained pro-oxidative mediators trigger harmful consequences that reflect at systemic level and contribute for the establishment of a premature senescent phenotype associated with macromolecular damage (DNA, protein, and lipids). Telomeres are structures that protect chromosome ends and are associated with a six-protein complex called the shelterin complex and subject to regulation. Under pro-oxidant conditions, telomere attrition and the altered expression of the shelterin proteins are central for the establishment of many pathophysiological conditions such as obesity. Thus, considering that individuals with obesity display a systemic oxidative stress profile that may compromise the telomeres length or its regulation, the aim of this study was to investigate telomere homeostasis in patients with obesity and explore broad/systemic associations with the expression of shelterin genes and the plasma redox state. We performed a cross-sectional study in 39 patients with obesity and 27 eutrophic subjects. Telomere length (T/S ratio) and gene expression of shelterin components were performed in peripheral blood mononuclear cells by qPCR. The oxidative damage (lipid peroxidation and protein carbonylation) and non-enzymatic antioxidant system (total radical-trapping antioxidant potential/reactivity, sulfhydryl and GSH content) were evaluated in plasma. Our results demonstrate that independently of comorbidities, individuals with obesity had significantly shorter telomeres, augmented expression of negative regulators of the shelterin complex, increased lipid peroxidation and higher oxidized protein levels associated with increased non-enzymatic antioxidant defenses. Principal component analysis revealed TRF1 as a major contributor for firstly telomeres shortening. In conclusion, our study is first showing a comprehensive analysis of telomeres in the context of obesity, associated with dysregulation of the shelterin components that was partially explained by TRF1 upregulation that could not be reversed by the observed adaptive non-enzymatic antioxidant response.

RevDate: 2018-09-29

Helby J, Petersen SL, Kornblit B, et al (2018)

Title: Mononuclear cell telomere attrition is associated with overall survival after non-myeloablative allogeneic hematopoietic cell transplantation for hematologic malignancies.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(18)30592-5 [Epub ahead of print].

After allogeneic hematopoietic cell transplantation (allo-HCT), transplanted cells rapidly undergo multiple rounds of division. This may cause extensive telomere attrition, which could potentially prohibit further cell division and lead to increased mortality. We therefore characterized the development in telomere length after non-myeloablative allo-HCT in 240 consecutive patients transplanted due to hematologic malignancies and tested the hypothesis that extensive telomere attrition post-transplant is associated with low overall survival. Telomere length was measured using quantitative polymerase chain reaction in mononuclear cells obtained from donors and recipients pre-transplant and in follow-up samples from recipients post-transplant. Telomere attrition at 9 to 15 months post-transplant was calculated as the difference between recipient telomere length at 9 to 15 months post-transplant and donor-pre-transplant telomere length, divided by donor pre-transplant telomere length. Although allo-HCT led to shorter mean telomere length in recipients when compared to donors, recipients had longer mean telomere length 9 to 15 months post-transplant than they had pre-transplant. When compared to donor telomeres, recipients with extensive telomere attrition at 9 to 15 months post-transplant had low overall survival (10-year survival from 9 to 15 months post-transplant and onwards 68% in the tertile with least telomere attrition, 57% in the middle tertile, and 39% in the tertile with most attrition;log-rank p=0.01). Similarly, after adjusting for potential confounders, recipients with extensive telomere attrition had high all-cause mortality (multivariable adjusted hazard ratio 1.84 per standard deviation of telomere attrition at 9 to 15 months post-transplant;95% confidence interval 1.25-2.72;p=0.002) and high relapse-related mortality (sub-hazard ratio 2.07;1.14-3.76;p=0.02). Taken together, telomere attrition may be a clinically relevant marker for identifying patients at high risk of mortality.

RevDate: 2018-09-29

Puterman E, Weiss J, Lin J, et al (2018)

Aerobic exercise lengthens telomeres and reduces stress in family caregivers: A randomized controlled trial - Curt Richter Award Paper 2018.

Psychoneuroendocrinology pii:S0306-4530(18)30773-X [Epub ahead of print].

STUDY DESIGN: Family members caring for chronically ill relatives are typically sedentary, chronically stressed, and at high risk of disease. Observational reports suggest caregivers have accelerated cellular aging as indicated by shorter leukocyte telomere lengths. We performed a randomized controlled trial to examine the effect of aerobic exercise on changes in telomerase levels (primary outcome) and telomere lengths (secondary outcome) in inactive caregivers.

METHODS: 68 female and male community dwelling dementia caregivers who reported high stress and physical inactivity were randomly assigned to a highly supervised aerobic exercise intervention vs. waitlist control group for 24 weeks. Average leukocyte telomere lengths and peripheral blood mononuclear cells' telomerase activity were measured pre- and post-intervention. All staff completing blood draws, fitness testing and bioassays were blinded to group assignment.

RESULTS: The intervention group completed approximately 40 min of aerobic exercise 3-5 times per week, verified by actigraphy. There was high (81%) adherence to 120 min/week of aerobic exercise. Groups did not significantly differ in telomerase activity changes across time, but had significant different telomere length changes across time (67.3 base pairs, 95%CI 3.1, 131.5). There were also significant reductions in body mass index and perceived stress and an increase in cardiorespiratory fitness (i.e., VO2peak) in the exercising caregivers versus controls.

CONCLUSION: In the context of a highly controlled intervention, exercise can induce apparent telomere lengthening, though the mechanisms remain elusive. Our study underscores the importance of increasing participation in aerobic exercise to improve markers of health and attenuate cellular aging in high-risk samples.

RevDate: 2018-09-28

Fasching CL (2018)

Telomere length measurement as a clinical biomarker of aging and disease.

Critical reviews in clinical laboratory sciences [Epub ahead of print].

Telomere length measurement is increasingly recognized as a clinical gauge for age-related disease risk. There are several methods for studying blood telomere length (BTL) as a clinical biomarker. The first is an observational study approach, which directly measures telomere lengths using either cross-sectional or longitudinal patient cohorts and compares them to a population of age- and sex-matched individuals. These direct traceable measurements can be considered reflective of an individual's current health or disease state. Escalating interest in personalized medicine, access to high-throughput genotyping and resulting acquisition of large volumes of genetic data corroborates the second method, Mendelian randomization (MR). MR employs telomere length-associated genetic variants to indicate predisposition to disease risk based on the genomic composition of the individual. When assessed from cells in the bloodstream, telomeres can show variation from their genetically predisposed lengths due to environmental-induced changes. These alterations in telomere length act as an indicator of cellular health, which, in turn, can provide disease risk status. Overall, BTL measurement is a dynamic marker of biological health and well-being that together with genetically defined telomere lengths can provide insights into improved healthcare for the individual.

RevDate: 2018-09-27

Fujishiro K, Needham BL, Landsbergis PA, et al (2018)

Selected occupational characteristics and change in leukocyte telomere length over 10 years: The Multi-Ethnic Study of Atherosclerosis (MESA).

PloS one, 13(9):e0204704 pii:PONE-D-18-18922.

Telomere length (TL) is considered as a marker of cell senescence, but factors influencing the rate of TL attrition are not well understood. While one previous study reported the association of occupation and TL, many subsequent studies have failed to find the association. This may be due to heterogeneity within the samples and cross-sectional designs. This longitudinal study examines two occupational characteristics, occupational complexity and hazardous conditions, as predictors of TL attrition in gender- and race/ethnicity-stratified analysis. Leukocyte TL (expressed as T/S ratio) was measured twice over a 10-year period in a multi-racial sample (n = 914). Linear mixed effect models were used to estimate TL attrition associated with occupational complexity and hazardous conditions. Analysis was stratified by gender and race/ethnicity (white, African American, and Latino) and controlled for baseline age, baseline TL, and time since baseline. Higher occupational complexity was associated with slower rates of TL attrition only among white men. Hazardous conditions were not associated with TL attrition for any gender-and-race/ethnicity stratified group. Occupational complexity may influence TL attrition, but the different findings for white men and other groups suggest that a more comprehensive framework is needed to better understand the potential link between occupational characteristics and biological aging.

RevDate: 2018-09-26

Lonardo A, Lugari S, F Nascimbeni (2018)

Telomere shortening: An innocent bystander at the crossroad of NASH with ageing and cardiometabolic risk?.

Liver international : official journal of the International Association for the Study of the Liver, 38(10):1730-1732.

RevDate: 2018-09-26

Gisselsson D, Lichtenzstejn D, Kachko P, et al (2018)

Clonal evolution through genetic bottlenecks and telomere attrition: potential threats to in vitro data reproducibility.

Genes, chromosomes & cancer [Epub ahead of print].

Tissue cultures of immortalized human cells, also known as established cell lines, are broadly accessible and cost-efficient tools for biomedical research. We here review potential genetic sources of systematic error in cell line experiments due to clonal evolution in vitro. In particular, we highlight alterations in telomere function over prolonged culture and population bottlenecks, respectively, as two commonly overlooked phenomena that can result in significant alterations in cell line genotypes over just one or a few passages in vitro. These alterations may include changes in mutation status of oncogenes and large scale chromosomal imbalances. We introduce a simple list of factors to be avoided in order to reduce the risk of data misinterpretation due to clonal evolution, including unacknowledged in vitro selection pressures, prolonged culture per se, harsh population size reductions, experiments at early phases after establishment, and the employment of cell lines not sufficiently analyzed by high resolution genetic techniques. This article is protected by copyright. All rights reserved.

RevDate: 2018-09-26

Wu Z, He MH, Zhang LL, et al (2018)

Rad6-Bre1 mediated histone H2Bub1 protects uncapped telomeres from exonuclease Exo1 in Saccharomyces cerevisiae.

DNA repair pii:S1568-7864(18)30106-X [Epub ahead of print].

Histone H2B lysine 123 mono-ubiquitination (H2Bub1), catalyzed by Rad6 and Bre1 in Saccharomyces cerevisiae, modulates chromatin structure and affects diverse cellular functions. H2Bub1 plays roles in telomeric silencing and telomere replication. Here, we have explored a novel role of H2Bub1 in telomere protection at uncapped telomeres in yku70Δ and cdc13-1 cells. Deletion of RAD6 or BRE1, or mutation of H2BK123R enhances the temperature sensitivity of both yku70Δ and cdc13-1 telomere capping mutants. Consistently, BRE1 deletion increases accumulation of telomeric single-stranded DNA (ssDNA) in yku70Δ and cdc13-1 cells, and EXO1 deletion improves the growth of yku70Δ bre1Δ and cdc13-1 bre1Δ cells and decreases ssDNA accumulation. Additionally, deletion of BRE1 exacerbates the rate of entry into senescence of yku70Δ mre11Δ cells with telomere defects, and increases the recombination of subtelomeric Y' element that is required for telomere maintenance and survivor generation. Furthermore, Exo1 contributes to the abrupt senescence of yku70Δ mre11Δ bre1Δ cells, and Rad51 is essential for Y' recombination to generate survivors. Finally, deletion of BRE1 or mutation of H2BK123R results in nucleosome instability at subtelomeric regions. Collectively, this study provides a mechanistic link between H2Bub1-mediated chromatin structure and telomere protection after telomere uncapping.

RevDate: 2018-10-04

Wang Q, Zhan Y, Pedersen NL, et al (2018)

Telomere Length and All-Cause Mortality: A Meta-analysis.

Ageing research reviews, 48:11-20 pii:S1568-1637(18)30123-5 [Epub ahead of print].

Telomere attrition is associated with increased morbidity and mortality of various age-related diseases. Reports of association between telomere length (TL) and all-cause mortality remain inconsistent. In the present study, a meta-analysis was performed using published cohort studies and un-published data from the Swedish Twin Registry (STR). Twenty-five studies were included: four STR cohorts (12,083 individuals with 2517 deaths) and 21 published studies. In the STR studies, one standard deviation (SD) decrement of leukocyte TL corresponded to 13% increased all-cause mortality risk (95% confidence interval [CI]: 7%-19%); individuals in the shortest TL quarter had 44% higher hazard (95% CI: 27%-63%) than those in the longest quarter. Meta-analysis of all eligible studies (121,749 individuals with 21,763 deaths) revealed one SD TL decrement-associated hazard ratio of 1.09 (95% CI: 1.06-1.13); those in the shortest TL quarter had 26% higher hazard (95% CI: 15%-38%) compared to the longest quarter, although between-study heterogeneity was observed. Analyses stratified by age indicated that the hazard ratio was smaller in individuals over 80 years old. In summary, short telomeres are associated with increased all-cause mortality risk in the general population. However, TL measurement techniques and age at measurement contribute to the heterogeneity of effect estimation.

RevDate: 2018-10-17

Glustrom LW, Lyon KR, Paschini M, et al (2018)

Single-stranded telomere-binding protein employs a dual rheostat for binding affinity and specificity that drives function.

Proceedings of the National Academy of Sciences of the United States of America, 115(41):10315-10320.

ssDNA, which is involved in numerous aspects of chromosome biology, is managed by a suite of proteins with tailored activities. The majority of these proteins bind ssDNA indiscriminately, exhibiting little apparent sequence preference. However, there are several notable exceptions, including the Saccharomyces cerevisiae Cdc13 protein, which is vital for yeast telomere maintenance. Cdc13 is one of the tightest known binders of ssDNA and is specific for G-rich telomeric sequences. To investigate how these two different biochemical features, affinity and specificity, contribute to function, we created an unbiased panel of alanine mutations across the Cdc13 DNA-binding interface, including several aromatic amino acids that play critical roles in binding activity. A subset of mutant proteins exhibited significant loss in affinity in vitro that, as expected, conferred a profound loss of viability in vivo. Unexpectedly, a second category of mutant proteins displayed an increase in specificity, manifested as an inability to accommodate changes in ssDNA sequence. Yeast strains with specificity-enhanced mutations displayed a gradient of viability in vivo that paralleled the loss in sequence tolerance in vitro, arguing that binding specificity can be fine-tuned to ensure optimal function. We propose that DNA binding by Cdc13 employs a highly cooperative interface whereby sequence diversity is accommodated through plastic binding modes. This suggests that sequence specificity is not a binary choice but rather is a continuum. Even in proteins that are thought to be specific nucleic acid binders, sequence tolerance through the utilization of multiple binding modes may be a broader phenomenon than previously appreciated.

RevDate: 2018-09-24

Ghosh M, M Singh (2018)

RGG-box in hnRNPA1 specifically recognizes the telomere G-quadruplex DNA and enhances the G-quadruplex unfolding ability of UP1 domain.

Nucleic acids research pii:5105846 [Epub ahead of print].

hnRNPA1 is a member of heteronuclear ribonucleoproteins that has been shown to promote telomere elongation apart from its roles in RNA transport and alternative splicing. It is a modular protein with an N-terminal domain called UP1 that consists of two RNA Recognition Motifs (RRM1 and RRM2 domains) and a C-terminal region that harbors functional motifs such as RGG-box, a prion-like domain, and a nuclear shuttling sequence. UP1 has been reported to bind and destabilize telomeric DNA G-quadruplexes and thereby participate in DNA telomere remodeling. An RGG-box motif that consists of four RGG repeats (containing arginine and glycine residues) is located C-terminal to the UP1 domain and constitutes an additional nucleic acid and protein-binding domain. However, the precise role of the RGG-box of hnRNPA1 in telomere DNA recognition and G-quadruplex DNA unfolding remains unexplored. Here, we show that the isolated RGG-box interacts specifically with the structured telomere G-quadruplex DNA but not with the single-stranded DNA. Further the interaction of the RGG-box with the G-quadruplex DNA is dependent on the loop nucleotides of the G-quadruplex. Finally, we show that the RGG-box enhances the G-quadruplex unfolding activity of the adjacent UP1 domain. We propose that UP1 and RGG-box act synergistically to achieve complete telomere G-quadruplex DNA unfolding.

RevDate: 2018-09-23

Razdan N, Vasilopoulos T, U Herbig (2018)

Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts.

Aging cell [Epub ahead of print].

Cells that had undergone telomere dysfunction-induced senescence secrete numerous cytokines and other molecules, collectively called the senescence-associated secretory phenotype (SASP). Although certain SASP factors have been demonstrated to promote cellular senescence in neighboring cells in a paracrine manner, the mechanisms leading to bystander senescence and the functional significance of these effects are currently unclear. Here, we demonstrate that TGF-β1, a component of the SASP, causes telomere dysfunction in normal somatic human fibroblasts in a Smad3/NOX4/ROS-dependent manner. Surprisingly, instead of activating cellular senescence, TGF-β1-induced telomere dysfunction caused fibroblasts to transdifferentiate into α-SMA-expressing myofibroblasts, a mesenchymal and contractile cell type that is critical for wound healing and tissue repair. Despite the presence of dysfunctional telomeres, transdifferentiated cells acquired the ability to contract collagen lattices and displayed a gene expression signature characteristic of functional myofibroblasts. Significantly, the formation of dysfunctional telomeres and downstream p53 signaling was necessary for myofibroblast transdifferentiation, as suppressing telomere dysfunction by expression of hTERT, inhibiting the signaling pathways that lead to stochastic telomere dysfunction, and suppressing p53 function prevented the generation of myofibroblasts in response to TGF-β1 signaling. Furthermore, inducing telomere dysfunction using shRNA against TRF2 also caused cells to develop features that are characteristic of myofibroblasts, even in the absence of exogenous TGF-β1. Overall, our data demonstrate that telomere dysfunction is not only compatible with cell functionality, but they also demonstrate that the generation of dysfunctional telomeres is an essential step for transdifferentiation of human fibroblasts into myofibroblasts.

RevDate: 2018-10-17

Huang YC, Wang LJ, Tseng PT, et al (2018)

Leukocyte telomere length in patients with bipolar disorder: An updated meta-analysis and subgroup analysis by mood status.

Psychiatry research, 270:41-49 pii:S0165-1781(18)30247-6 [Epub ahead of print].

The purpose of the present meta-analysis was to compare leukocyte telomere length (LTL), a proposed marker for cell aging, between patients with bipolar disorder (BD) and healthy controls and explore potential moderators for the LTL difference. We searched for the major research databases up to May 2018 for studies that examined LTL in patients with BD and healthy controls. The effect sizes (ESs) of LTL differences from the included studies were pooled using a random-effects model. Furthermore, we adopted subgroup analysis to investigate whether mood status of BD patients or methods for measuring telomere length may influence such differences. We included 10 studies, with a total of 579 patients and 551 controls, in the current meta-analysis and observed significantly shorter LTL in BD patients compared to control subjects. Such differences were found in studies with patients in all mood statuses and in studies using different methods for measuring telomere length. Late-stage BD patients demonstrated more significant LTL shortening than early-stage BD patients. Our current results support the hypothesis of accelerated aging in BD patients. In the future, further properly controlled longitudinal studies are warranted to determine whether LTL changes with disease status or medication use in BD patients.

RevDate: 2018-10-09

Kresovich JK, Parks CG, Sandler DP, et al (2018)

Reproductive history and blood cell telomere length.

Aging, 10(9):2383-2393.

Telomeres are repetitive nucleotide sequences that protect against chromosomal shortening. They are replenished by telomerase, an enzyme that may be activated by estrogen. Women have longer telomeres than men; this difference might be due to estrogen exposure. We hypothesized that reproductive histories reflecting greater estrogen exposure will be associated with longer blood cell telomeres. Among women in the Sister Study (n= 1,048), we examined telomere length in relation to self-reported data on reproductive history. The difference between age at menarche and last menstrual period was used to approximate the reproductive period. Relative telomere length (rTL) was measured using qPCR. After adjustment, rTL decreased with longer reproductive period (β= -0.019, 95% CI: -0.04, -0.00, p= 0.03). Premenopausal women had shorter rTL than postmenopausal women (β= -0.051, 95% CI: -0.12, 0.01, p= 0.13). Longer breastfeeding duration was associated with longer rTL (β= 0.027, 95% CI: 0.01, 0.05, p=0.01); increasing parity was associated with shorter rTL (β = -0.016, 95% CI: -0.03, 0.00, p=0.07). Duration of exogenous hormone use was not associated with rTL. Reproductive histories reflecting greater endogenous estrogen exposure were associated with shorter rTL. Our findings suggest that longer telomeres in women are unlikely to be explained by greater estrogen exposure.

RevDate: 2018-09-23

Rathore M, J Abraham (2018)

Implication of Asana, Pranayama and Meditation on Telomere Stability.

International journal of yoga, 11(3):186-193.

Telomeres, the repetitive sequences that protect the ends of chromosomes, help to maintain genomic integrity and are of key importance to human health. Telomeres progressively shorten throughout life and a number of studies have shown shorter telomere length to be associated with lifestyle disorders. Previous studies also indicate that yoga and lifestyle-based intervention have significant role on oxidative DNA damage and cellular aging. However, very few publications investigate telomere stability and its implication from the point of view of asana, pranayama, and meditation. In this context, a review was conducted to systematically assess the available data on the effectiveness of asana, pranayama, and meditation in maintaining telomere and telomerase. Literature search was performed using the following electronic databases: Cochrane Library, NCBI, PubMed, Google Scholar, EMBASE, and Web of Science. We explored the possible mechanisms of how asana, pranayama, and meditation might be affecting telomere length and telomerase. Moreover, results showed that asana and pranayama increase the oxygen flow to the cells and meditation reduces the stress level by modulating the hypothalamic-pituitary-adrenal axis. Summing up the result, it can be concluded that practice of asana, pranayama, and meditation can help to maintain genomic integrity and are of key importance to human health and lifestyle disorders.

RevDate: 2018-09-19

Zhu Y, Liu X, Ding X, et al (2018)

Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction.

Biogerontology pii:10.1007/s10522-018-9769-1 [Epub ahead of print].

Aging is a biological process characterized by a progressive functional decline in tissues and organs, which eventually leads to mortality. Telomeres, the repetitive DNA repeat sequences at the end of linear eukaryotic chromosomes protecting chromosome ends from degradation and illegitimate recombination, play a crucial role in cell fate and aging. Due to the mechanism of replication, telomeres shorten as cells proliferate, which consequently contributes to cellular senescence and mitochondrial dysfunction. Cells are the basic unit of organismal structure and function, and mitochondria are the powerhouse and metabolic center of cells. Therefore, cellular senescence and mitochondrial dysfunction would result in tissue or organ degeneration and dysfunction followed by somatic aging through multiple pathways. In this review, we summarized the main mechanisms of cellular senescence, mitochondrial malfunction and aging triggered by telomere attrition. Understanding the molecular mechanisms involved in the aging process may elicit new strategies for improving health and extending lifespan.

RevDate: 2018-10-09

Brosnan-Cashman JA, Yuan M, Graham MK, et al (2018)

ATRX loss induces multiple hallmarks of the alternative lengthening of telomeres (ALT) phenotype in human glioma cell lines in a cell line-specific manner.

PloS one, 13(9):e0204159 pii:PONE-D-18-12176.

Cancers must maintain their telomeres at lengths sufficient for cell survival. In several cancer subtypes, a recombination-like mechanism termed alternative lengthening of telomeres (ALT), is frequently used for telomere length maintenance. Cancers utilizing ALT often have lost functional ATRX, a chromatin remodeling protein, through mutation or deletion, thereby strongly implicating ATRX as an ALT suppressor. Herein, we have generated functional ATRX knockouts in four telomerase-positive, ALT-negative human glioma cell lines: MOG-G-UVW, SF188, U-251 and UW479. After loss of ATRX, two of the four cell lines (U-251 and UW479) show multiple characteristics of ALT-positive cells, including ultrabright telomeric DNA foci, ALT-associated PML bodies, and c-circles. However, telomerase activity and overall telomere length heterogeneity are unaffected after ATRX loss, regardless of cellular context. The two cell lines that showed ALT hallmarks after complete ATRX loss also did so upon ATRX depletion via shRNA-mediated knockdown. These results suggest that other genomic or epigenetic events, in addition to ATRX loss, are necessary for the induction of ALT in human cancer.

RevDate: 2018-09-20

Pepper GV, Bateson M, D Nettle (2018)

Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis.

Royal Society open science, 5(8):180744 pii:rsos180744.

Telomeres have been proposed as a biomarker that integrates the impacts of different kinds of stress and adversity into a common currency. There has as yet been no overall comparison of how different classes of exposure associate with telomeres. We present a meta-analysis of the literature relating telomere measures to stresses and adversities in humans. The analysed dataset contained 543 associations from 138 studies involving 402 116 people. Overall, there was a weak association between telomere variables and exposures (greater adversity, shorter telomeres: r = -0.15, 95% CI -0.18 to -0.11). This was not driven by any one type of exposure, because significant associations were found separately for physical diseases, environmental hazards, nutrition, psychiatric illness, smoking, physical activity, psychosocial and socioeconomic exposures. Methodological features of the studies did not explain any substantial proportion of the heterogeneity in association strength. There was, however, evidence consistent with publication bias, with unexpectedly strong negative associations reported by studies with small samples. Restricting analysis to sample sizes greater than 100 attenuated the overall association substantially (r = -0.09, 95% CI -0.13 to -0.05). Most studies were underpowered to detect the typical association magnitude. The literature is dominated by cross-sectional and correlational studies which makes causal interpretation problematic.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

Administrator

Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

Publisher

While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

Speaker

Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

Facilitator

Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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Although multicellular eukaryotes (MCEs) are the most visible component of the biosphere, they represent a highly derived and constrained evolutionary subset of the biosphere, unrepresentative of the vast, mostly unseen, microbial world of prokaryotic life that comprises at least half of the planet's biomass and most of its genetic diversity. The existence of telomeres is one component of the specialized biology of eukaryotes. R. Robbins

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

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