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Bibliography on: Telomeres

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ESP: PubMed Auto Bibliography 05 Jun 2020 at 01:50 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: 2020-06-04

Hagman M, Werner C, Kamp K, et al (2020)

Reduced telomere shortening in lifelong trained male football players compared to age-matched inactive controls.

Progress in cardiovascular diseases pii:S0033-0620(20)30117-1 [Epub ahead of print].

AIMS: Current evidence points to cellular anti-ageing effects of regular endurance training which may differ from other sport modalities. Effects of football training on markers of cell senescence have not been tested.

METHODS: One hundred and forty healthy, non-smoking men participated in the study, including young elite football players aged 18-30 years (YF, n = 35, 21.6 ± 0.5 yrs), elderly football players aged 65-80 years (EF, n = 35, 71.9 ± 0.5 yrs), untrained young controls (YC, n = 35, 24.3 ± 0.6 yrs) and elderly controls (EC, n = 35, 70.1 ± 0.7 yrs). Besides body composition (DXA scan), resting heart rate (RHR), blood pressure (BP) and selected fasting blood variables, mononuclear cells (MNC) were isolated. MNC telomere length was determined by flow-fluorescence in-situ hybridization (FISH) and polymerase chain reaction (PCR). Telomerase activity was quantified using telomerase repeat amplification protocol (TRAP) assay. mRNA expression of anti- and pro-senescent factors was measured with real-time PCR.

RESULTS: EF showed 2.5% higher (p = 0.047) granulocyte telomere length and 1.3% higher (p = 0.009) lymphocyte telomere length compared to EC. EF had 37% lower (p = 0.025) mRNA expression of the pro-senescent factor p16 compared to EC. No significant between-group differences (p > 0.050) were observed in telomerase activity or anti-senescent factors (TRF2, Ku70 and POT1a) for EF vs EC. YF had higher telomerase activity (4.2-fold, p = 0.001), telomere repeat binding factor (TRF) 2 mRNA expression (3.2-fold, p = 0.003), Ku70 mRNA expression (2.3-fold, p < 0.001) and POT1a mRNA expression (2.2-fold, p = 0.002) compared to YC, but there was no significant between-group difference in telomere length.

CONCLUSION: This study is the first cross-sectional, controlled trial showing effects of lifelong football participation on telomere shortening and senescence markers in circulating cells, suggesting that football induces cellular anti-senescence mechanisms implying positive long-term cardiovascular health effects.

RevDate: 2020-06-04

Laprade H, Querido E, Smith MJ, et al (2020)

Single-Molecule Imaging of Telomerase RNA Reveals a Recruitment-Retention Model for Telomere Elongation.

Molecular cell pii:S1097-2765(20)30306-3 [Epub ahead of print].

Extension of telomeres is a critical step in the immortalization of cancer cells. This complex reaction requires proper spatiotemporal coordination of telomerase and telomeres and remains poorly understood at the cellular level. To understand how cancer cells execute this process, we combine CRISPR genome editing and MS2 RNA tagging to image single molecules of telomerase RNA (hTR). Real-time dynamics and photoactivation experiments of hTR in Cajal bodies (CBs) reveal that hTERT controls the exit of hTR from CBs. Single-molecule tracking of hTR at telomeres shows that TPP1-mediated recruitment results in short telomere-telomerase scanning interactions, and then base pairing between hTR and telomere ssDNA promotes long interactions required for stable telomerase retention. Interestingly, POT1 OB-fold mutations that result in abnormally long telomeres in cancers act by enhancing this retention step. In summary, single-molecule imaging unveils the life cycle of telomerase RNA and provides a framework to reveal how cancer-associated mutations mechanistically drive defects in telomere homeostasis.

RevDate: 2020-06-04

Furtado CLM, Iannetta R, Ferriani RA, et al (2020)

Telomere length is not altered in girls with idiopathic central precocious puberty treated with a GnRH analog - leuprolide acetate.

Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology [Epub ahead of print].

Background: Idiopathic central precocious puberty (iCPP) presents a disproportionate advancement of bone age and maturation, as well as metabolic and endocrinological changes that may be related to effects on telomere biology.Objective: To investigate the telomere length in iCPP girls treated with GnRHa.Study design: Observational case-control study with 85 girls, including 45 iCPP treated with GnRHa and 40 controls. It was analyzed age, height, weight and body mass index (BMI), insulin, triglycerides, testosterone, insulin resistance by HOMA, and telomere length by real-time PCR. Statistical analyses were determined by Wilcoxon test and Spearman correlation was carried out.Results: Weight, BMI, insulin level and HOMA index were higher in the iCPP than in the control group (p < .01); without difference between mean ages. The telomere length did not differ between iCPP and control group. However, a negative correlation was observed between the telomere length and age in iCPP (p = .0009) and control group (p = .014), and weight in the iCPP (p = .017).Conclusions: We did not observe any difference in the telomere length in the iCPP and control group. Even though, some characteristics of the disease, such as increased weight and body fat, negatively influence the telomere biology.

RevDate: 2020-06-03

Zhang S, Li R, Yang Y, et al (2020)

Longitudinal Association of Telomere Attrition with the Effects of Antihypertensive Treatment and Blood Pressure Lowering.

Aging and disease, 11(3):494-508 pii:ad-11-3-494.

Leukocytes telomere length has been associated with hypertension, but, whether longitudinal telomeres change could serve as a useful predictive tool in hypertension remains uncertain. This study aimed to examine the longitudinal trajectory of leukocytes telomere length in a population-based prospective study of 1,108 individuals with hypertension. Leukocytes telomere length were measured at baseline and again after a median 2.2 (range 1.5-2.4) years of follow-up. Age as an independent predictor was inversely associated with baseline telomeres and follow-up telomeres. Annual telomere attrition rate was calculated as (follow-up telomeres-baseline telomeres)/follow-up years, and participants were categorized into the shorten and the lengthen groups. Results showed that telomere lengthening was significantly correlated with decreased systolic blood pressure (SBP) (β=-3.28; P=0.02) and pulse pressure (PP) (β=-2.53; P=0.02), and the differences were respectively -3.3 mmHg (95%CI, -6.2 to -0.3; P=0.03) in ∆SBP and -2.4 mmHg (95%CI, -4.9 to -0.1; P=0.04) in ∆PP between two groups after adjustment for vascular risk factors and baseline blood pressures. When stratified by age and gender, the correlations were observed in women and patients ≤60 years. Furthermore, among patients using calcium channel blocker (CCB) and angiotensin receptor blocker (ARB), those with telomeres lengthening showed a significantly lower level of ∆SBP and ∆PP. There was no correlation between telomere attrition and incidence of cardiovascular events. Our data indicated that increased telomere length of leukocytes was associated with decreased SBP and PP, particularly for patients who received CCB and ARB, supporting that telomere attrition may provide new sight in clinical intervention for hypertension.

RevDate: 2020-06-03

Nichuguti N, H Fujiwara (2020)

Essential factors involved in the precise targeting and insertion of telomere-specific non-LTR retrotransposon, SART1Bm.

Scientific reports, 10(1):8963 pii:10.1038/s41598-020-65925-x.

Telomere length maintenance is essential for most eukaryotes to ensure genome stability and integrity. A non-long terminal repeat (LTR) retrotransposon, SART1Bm, targets telomeric repeats (TTAGG)n of the silkworm Bombyx mori and is presumably involved in telomere length maintenance. However, how many telomeric repeats are required for its retrotransposition and how reverse transcription is initiated at the target site are not well understood. Here, using an ex vivo and trans-in vivo recombinant baculovirus retrotransposition system, we demonstrated that SART1Bm requires at least three (TTAGG) telomeric repeats and a longer poly(A) tail for its accurate retrotransposition. We found that SART1Bm retrotransposed only in the third (TTAGG) tract of three repeats and that the A residue of the (TTAGG) unit was essential for its retrotransposition. Interestingly, SART1Bm also retrotransposed into telomeric repeats of other species, such as human (TTAGGG)n repeats, albeit with low retrotransposition efficiency. We further showed that the reverse transcription of SART1Bm occurred inaccurately at the internal site of the 3' untranslated region (UTR) when using a short poly(A) tail but at the accurate site when using a longer poly(A) tail. These findings promote our understanding of the general mechanisms of site-specific retrotransposition and aid the development of a site-specific gene knock-in tool.

RevDate: 2020-06-03

Nanthatanti N, Tantiworawit A, Piriyakhuntorn P, et al (2020)

Leukocyte telomere length in patients with transfusion-dependent thalassemia.

BMC medical genomics, 13(1):73 pii:10.1186/s12920-020-00734-9.

BACKGROUND: Thalassemia is a hereditary hemolytic anemia with a severity ranging from mild, non-transfusion dependent to severe chronic anemia requiring lifelong transfusion. Transfusional iron overload is a major complication in patients with transfusion-dependent thalassemia (TDT). Telomeres are sequences of nucleotides forming the end caps of chromosomes that act as a DNA repair system. Iron overload in thalassemia can cause increased oxidative stress which leads to cellular damage and senescence. This may result in telomere length shortening. The degree of telomere length shortening may reflect the severity of thalassemia.

METHODS: This research aimed to study the leukocyte telomere length in patients with TDT in comparison to non-thalassemic individuals and to identify the clinical and laboratory parameters that are associated with telomere length. We conducted a cross-sectional study in patients with TDT aged ≥18 years. Leukocyte telomere length was measured by real-time quantitative PCR.

RESULTS: Sixty-five patients with TDT were enrolled onto the study. There were 37 female patients (54.4%). The median age was 27 (18-57) years, and mean pre-transfusion hemoglobin level was 7.1 (± 1.07) g/dL. The mean telomere to single copy gene (T/S) ratios of patients with TDT and the controls were 0.72 ± 0.18 and 0.99 ± 0.25, respectively (p < 0.0001). There was a significant correlation between the T/S ratio and age (p = 0.0002), and hemoglobin level (p = 0.044). There was no correlation between telomere length and other factors.

CONCLUSIONS: Our study showed that TDT patients had shorter leukocyte telomere length compared with controls. Leukocyte telomere shortening in TDT was an aging-dependent process and associated with lower hemoglobin level.

RevDate: 2020-06-03

Toupance S, Stathopoulou MG, Petrelis AM, et al (2020)

TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.

Cells, 9(6): pii:cells9061360.

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

RevDate: 2020-06-02

Brenner KA, J Nandakumar (2020)

Small Molecules Restore Telomeres in Patient Stem Cells.

Trends in pharmacological sciences pii:S0165-6147(20)30127-9 [Epub ahead of print].

Genetic defects in telomere maintenance result in stem cell exhaustion and a spectrum of telomere biology diseases. Systemic treatments beyond organ transplantation are lacking for these diseases. Nagpal and colleagues identified small molecules that restore telomere maintenance in patient-derived stem cells, offering a promising therapy for telomere biology diseases.

RevDate: 2020-06-01

Thierry AD (2020)

Association between telomere length and neighborhood characteristics by race and region in US midlife and older adults.

Health & place, 62:102272.

Disadvantaged neighborhoods are correlated with worse health outcomes, particularly among US Blacks. However, less is known about the link between neighborhood characteristics and biomarkers of cellular age, such as telomere length (TL), which may be implicated in racial health inequities. Moreover, this relationship may vary across US region given patterns of racial segregation across the US. Therefore, this study analyzed 2008 Health and Retirement Study data on 3,869 US-born white and Black adults >50 years old to examine race differences in the relationship between salivary TL and (1) neighborhood safety, cleanliness, and social cohesion and (2) interactions between neighborhood characteristics and US region. Neighborhood characteristics were not associated with TL in whites. However, significant associations were found among Blacks with variation by region. Blacks living in less clean neighborhoods in the Northeast (b = -0.03, SE = 0.01, p < 0.05), Midwest (b = -0.04, SE = 0.01, p < 0.01), and South (b = -0.05, SE = 0.01, p < 0.01) as well as those reporting less neighborhood safety and social cohesion in the Midwest (b = -0.03, SE = 0.02, p < 0.05 and b = -0.03, SE = 0.01, p < 0.05) and South (b = -0.03, SE = 0.01, p < 0.05 for both characteristics) had shorter TL than Blacks in the West. Therefore, exposure to neighborhood level historical discrimination and neglect may be detrimental to TL in Blacks. Future research should further examine how neighborhoods contribute to aging disparities.

RevDate: 2020-05-31

Lee AG, Cowell W, Kannan S, et al (2020)

Prenatal particulate air pollution and newborn telomere length: Effect modification by maternal antioxidant intakes and infant sex.

Environmental research, 187:109707 pii:S0013-9351(20)30600-9 [Epub ahead of print].

BACKGROUND: Evidence links gestational exposure to particulate matter with an aerodynamic diameter of less than 2.5 μm (PM2.5) with changes in leukocyte telomere length in cord blood with some studies showing sex-specific effects. PM2.5 exposure in utero increases oxidative stress, which can impact telomere biology. Thus, maternal antioxidant intakes may also modify the particulate air pollution effects.

METHODS: We examined associations among prenatal PM2.5 exposure and newborn relative leukocyte telomere length (rLTL), and the modifying effects of maternal antioxidant intake and infant sex. We estimated daily PM2.5 exposures over gestation using a validated spatiotemporally resolved satellite-based model. Maternal dietary and supplemental antioxidant intakes over the prior three months were ascertained during the second trimester using the modified Block98 food frequency questionnaire; high and low antioxidant intakes were categorized based on a median split. We employed Bayesian distributed lag interaction models (BDLIMs) to identify both sensitive windows of exposure and cumulative effect estimates for prenatal PM2.5 exposure on newborn rLTL, and to examine effect modification by maternal antioxidant intakes. A 3-way interaction between PM2.5, maternal antioxidant intake and infant sex was also explored.

RESULTS: For the main effect of PM2.5, BDLIMs identified a sensitive window at 12-20 weeks gestation for the association between increased prenatal PM2.5 exposure and shorter newborn rLTL and a cumulative effect of PM2.5 over gestation on newborn telomere length [cumulative effect estimate (CEE) = -0.29 (95% CI -0.49 to -0.10) per 1μg/m3 increase in PM2.5]. In models examining maternal antioxidant intake effects, BDLIMs found that children born to mothers reporting low antioxidant intakes were most vulnerable [CEE of low maternal antioxidant intake = -0.31 (95% CI -0.55 to -0.06) vs high maternal antioxidant intake = -0.07 (95% CI -0.34 to 0.17) per 1μg/m3 increase in PM2.5]. In exploratory models examining effect modification by both maternal antioxidant intakes and infant sex, the cumulative effect remained significant only in boys whose mothers reported low antioxidant intakes [CEE = -0.38 (95% CI -0.80 to -0.004)]; no sensitive windows were identified in any group.

CONCLUSIONS: Prenatal PM2.5 exposure in mid-gestation was associated with reduced infant telomere length. Higher maternal antioxidant intakes mitigated these effects.

RevDate: 2020-05-30

de Krijger I, van der Torre J, Peuscher MH, et al (2020)

H3K36 dimethylation by MMSET promotes classical non-homologous end-joining at unprotected telomeres.

Oncogene pii:10.1038/s41388-020-1334-0 [Epub ahead of print].

The epigenetic environment plays an important role in DNA damage recognition and repair, both at DNA double-strand breaks and at deprotected telomeres. To increase understanding on how DNA damage responses (DDR) at deprotected telomeres are regulated by modification and remodeling of telomeric chromatin we screened 38 methyltransferases for their ability to promote telomere dysfunction-induced genomic instability. As top hit we identified MMSET, a histone methyltransferase (HMT) causally linked to multiple myeloma and Wolf-Hirschhorn syndrome. We show that MMSET promotes non-homologous end-joining (NHEJ) at deprotected telomeres through Ligase4-dependent classical NHEJ, and does not contribute to Ligase3-dependent alternative NHEJ. Moreover, we show that this is dependent on the catalytic activity of MMSET, enabled by its SET-domain. Indeed, in absence of MMSET H3K36-dimethylation (H3K36me2) decreases, both globally and at subtelomeric regions. Interestingly, the level of MMSET-dependent H3K36me2 directly correlates with NHEJ-efficiency. We show that MMSET depletion does not impact on recognition of deprotected telomeres by the DDR-machinery or on subsequent recruitment of DDR-factors acting upstream or at the level of DNA repair pathway choice. Our data are most consistent with an important role for H3K36me2 in more downstream steps of the DNA repair process. Moreover, we find additional H3K36me2-specific HMTs to contribute to NHEJ at deprotected telomeres, further emphasizing the importance of H3K36me2 in DNA repair.

RevDate: 2020-05-29

He S, Li J, Wang Z, et al (2020)

Early-life exposure to famine and late-life depression: Does leukocyte telomere length mediate the association?.

Journal of affective disorders, 274:223-228 pii:S0165-0327(20)30726-6 [Epub ahead of print].

BACKGROUND: A positive association between early-life famine exposure and depression has been demonstrated. However, the mechanisms by which famine exposure in early life leads to late-life depression remains unclear. The present study examines the impact of leukocyte telomere length (LTL) and/or religiosity on the relationship between early-life famine exposure and late-life depression in a Chinese minority sample.

METHODS: A cross-sectional study of community-dwelling adults aged 55 or older was conducted in the Ningxia province of western China from 2013 to 2016. Multivariate ordinal logistic regression was used to examine the association between famine exposure and depression status, and a series mediation model was constructed to identify the mediation role of LTL and religiosity.

RESULTS: Compared with famine exposure during adulthood, fetal famine exposure was associated with a higher risk of late-life depression (adjusted odds ratio of 3.17, 95% CI: 1.36-7.38). A cumulative effect of fetal famine exposure on the risk of late-life depression was observed. Participants born in 1961 (the third year of the famine) had the strongest association with late-life depression. LTL played a mediating role in the association between famine exposure and depression which accounted for 21% of the total effect.

LIMITATIONS: The cross-sectional design prevents causal inferences regarding the relationships between famine and depression.

CONCLUSIONS: Fetal famine exposure was associated with an increased risk of late-life depression in a Chinese minority community-dwelling population. Telomere shortening partially mediated this association.

RevDate: 2020-05-29

Savoy CD, Schmidt LA, McGowan PO, et al (2020)

Extremely low birth weight influences the relationship between stress and telomere length in adulthood.

Journal of developmental origins of health and disease pii:S2040174420000409 [Epub ahead of print].

This study examined the link between two biological markers of stress vulnerability at 22-26 years of age and telomere length at 30-35 among extremely low birth weight (ELBW; <1000 g) survivors and normal birth weight (NBW; >2500 g) control participants. Sixteen ELBW and 22 NBW participants provided baseline afternoon salivary cortisol samples and resting frontal electroencephalogram (EEG) alpha asymmetry data at 22-26 years. Buccal cells were assayed for telomere length at 30-35 years. Analyses controlled for sex, postnatal steroid exposure, childhood socioeconomic status, time of cortisol sample collection, and body mass index at 22-26 years. Salivary cortisol and frontal asymmetry at age 22-26 independently predicted telomere length at age 30-35, such that relatively higher cortisol and greater relative right frontal asymmetry at rest predicted telomere shortening among NBW controls, but not among ELBW survivors. However, similar associations were not noted in ELBW survivors, suggesting that ELBW survivors may have different mechanisms of stress coping as a result of their early-life exposures. These findings offer preliminary evidence in support of the role of stress in the genesis of cellular senescence at least among those born at NBW, but that these links may differ in those born preterm.

RevDate: 2020-05-29

Park MK, Lee JC, Lee JW, et al (2020)

Effects of fermented rice bran on DEN-induced oxidative stress in mice: GSTP1, LINE-1 methylation, and telomere length ratio.

Journal of food biochemistry [Epub ahead of print].

N-diethylnitrosamine (DEN), a well-known carcinogen, not only induces excessive reactive oxygen species but also suppresses DNA methylation. This study investigated the effect of fermented rice bran (FRB) treatment on DEN-induced oxidative stress through DNA methylation and telomere length analysis. To evaluate the potential protective role of FRB in oxidative stress, two different doses of FRB, DEN, and their combination were administered to mice that were preadapted or not to FRB. Glutathione-S-transferase P1 (GSTP1) methylation levels significantly decreased at 2 and 24 hr after FRB and DEN co-administration in mice with and without pre-adaptation. Moreover, GSTP1 mRNA was upregulated under DEN-induced oxidative stress. Furthermore, changes in long interspersed nuclear element-1 methylation were observed from the viewpoint of genomic instability. In addition, FRB preadapted mice displayed a lower telomere length ratio than the non-adapted mice, suggesting that FRB adaptation offers advantages over the non-adapted conditions in terms of inflammation suppression. PRACTICAL APPLICATIONS: DEN induces excessive ROS, which is associated with oxidative stress on DNA and other cellular components, resulting in inflammation. This study shows that FRB may alleviate DEN-triggered oxidative stress, based on changes in GSTP1, LINE-1 methylation, and telomere length ratios, thereby, revealing the potential of dietary intervention during inflammation. Furthermore, this study furthers the current understanding of DNA methylation mechanisms underlying the antioxidant and anti-inflammatory effects of functional food components. These results indicate that dietary inclusion of FRB may help decrease oxidative DNA damage and its associated inflammation at early stages of a disease.

RevDate: 2020-05-29

Wu J, DL Crowe (2020)

Telomere DNA damage signaling regulates prostate cancer tumorigenesis.

Molecular cancer research : MCR pii:1541-7786.MCR-19-1129 [Epub ahead of print].

Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant progression of the prostate gland. We reasoned that reduced TRF2 expression in prostate epithelium, by activating the telomere DNA damage response, would allow us to model both benign and malignant prostate disease. Prostate glands with reduced epithelial TRF2 expression developed age- and p53-dependent hypertrophy, senescence, ductal dilation, and smooth muscle hyperplasia similar to human BPH. Prostate tumors with reduced TRF2 expression were classified as high grade androgen receptor negative adenocarcinomas which exhibited decreased latency, increased proliferation, and distant metastases. Prostate cancer stem cells with reduced TRF2 expression were highly tumorigenic and maintained telomeres both by telomerase and alternative lengthening (ALT). Telomerase inhibition in prostate glands with reduced TRF2 expression produced significant reduction in prostate tumor incidence by halting progression at intraepithelial neoplasia (PIN). These lesions were highly differentiated, exhibited low proliferation index, and high apoptotic cell fraction. Prostate tumors with reduced TRF2 expression and telomerase inhibition failed to metastasize and did not exhibit ALT. Implications: Our results demonstrate that the telomere DNA damage response regulates BPH, PIN, and prostate cancer and may be therapeutically manipulated to prevent prostate cancer progression.

RevDate: 2020-05-28

Kosebent EG, Uysal F, S Ozturk (2020)

The altered expression of telomerase components and telomere-linked proteins may associate with ovarian aging in mouse.

Experimental gerontology pii:S0531-5565(20)30323-5 [Epub ahead of print].

Telomeres are repetitive DNA sequences localized at the ends of eukaryotic chromosomes, and shorten during ovarian aging. The molecular background of telomere shortening during ovarian aging is not fully understood. As the telomerase components (TERT and Terc) and telomere-associated proteins (TRF1, TRF2, and POT1a) play key roles in the elongation and maintenance of telomeres, we aimed to determine their spatial and temporal expression and cellular localization in the mouse ovaries at the different ages of postnatal life. For this purpose, five groups were generated based on the ovarian histological changes in the postnatal mouse ovaries as follows: young (1- and 2-week-old; n = 3 from each week), prepubertal (3- and 4-week-old; n = 3 from each week), pubertal (5- and 6-week-old; n = 3 from each week), postpubertal (16- and 18-week-old; n = 3 from each week) and aged (52-, 60- and 72-week-old, n = 3 from each week). We found significant changes for the Tert, Terc, Trf1, Trf2, and Pot1a genes expression in the postnatal ovary groups from young to aged (P < 0.05) as well as in the follicles from primordial to antral stages and their oocytes and granulosa cells. Also, we have detected gradually decreasing telomere length from young to aged groups (P < 0.001). In conclusion, the altered Tert, Terc, Trf2, and Pot1a genes expression compatible with telomere shortening may be associated with ovarian aging.

RevDate: 2020-05-28

Benati M, Montagnana M, Danese E, et al (2020)

Aberrant Telomere Length in Circulating Cell-Free DNA as Possible Blood Biomarker with High Diagnostic Performance in Endometrial Cancer.

Pathology oncology research : POR pii:10.1007/s12253-020-00819-x [Epub ahead of print].

To investigate the diagnostic performance of relative telomere length (RTL) in cell-free DNA (cfDNA) for endometrioid endometrial cancer (EC). We measured RTL in cfDNA of 40 EC patients (65 ± 12 years) and 31 healthy controls (HC) (63 ± 13 years), excluding in both groups other oncologic and severe non-oncologic diseases to limit confounders. Circulating cfDNA was extracted from serum using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany). After the quantitative real-time polymerase chain reaction, telomere repeat copy number to single-gene copy number ratio was calculated. RTL in cfDNA was found to be significantly lower in EC patients than in HC (p < 0.0001). The diagnostic performance of cfDNA RTL was estimated with receiver operating characteristics (ROC) curve analysis, which showed a diagnostic accuracy for EC of 0.87 (95% CI: 0.79-0.95, p < 0.0001). The cutoff cfDNA RTL value of 2.505 (T/S copy ratio) reported a sensitivity of 80.0% (95% CI: 64.35-90.95) and a specificity of 80.65% (95% CI: 62.53-92.55). Significant differences of RTL among EC stages or grades (p = 0.85 and p = 0.89, respectively) were not observed. Our results suggest that cfDNA RTL analysis may be a diagnostic tool for EC detection since the early stage, whilst its diagnostic performance seems unsatisfactory for cancer progression, staging, and grading. However, further studies are needed to confirm these preliminary findings. In particular, future investigations should focus on high-risk patients (such as those with atypical endometrial hyperplasia) that may benefit from this tool, because TL shortening is not specific for EC and is influenced by other oncologic and non-oncologic diseases.

RevDate: 2020-05-27

Viblanc VA, Schull Q, Stier A, et al (2020)

Foster rather than biological parental telomere length predicts offspring survival and telomere length in king penguins.

Molecular ecology [Epub ahead of print].

Because telomere length and dynamics relate to individual growth, reproductive investment and survival, telomeres have emerged as possible markers of individual quality. Here, we tested the hypothesis that, in species with parental care, parental telomere length can be a marker of parental quality that predicts offspring phenotype and survival. In king penguins, we experimentally swapped the single egg of 66 breeding pairs just after egg laying to disentangle the contribution of pre-laying parental quality (e.g. genetics, investment in the egg) and/or post-laying parental quality (e.g. incubation, postnatal feeding rate) on offspring growth, telomere length and survival. Parental quality was estimated through the joint effects of biological and foster parent telomere length on offspring traits, both soon after hatching (day 10) and at the end of the pre-winter growth period (day 105). We expected that offspring traits would be mostly related to the telomere lengths (i.e. quality) of biological parents at day 10 and to the telomere lengths of foster parents at day 105. Results show that chick survival up to 10 days was negatively related to biological fathers' telomere length whereas survival up to 105 days was positively related to foster fathers' telomere lengths. Chick growth was neither related to biological nor to foster parents' telomere length. Chick telomere length was positively related to foster mothers' telomere length at both 10 and 105 days. Overall, our study shows that, in a species with bi-parental care, parents' telomere length is foremost a proxy of post-laying parental care quality, supporting the "telomere - parental quality hypothesis".

RevDate: 2020-05-26

Lyu L, He S, Zhang H, et al (2020)

TNFα Mediates the Interaction of Telomeres and Mitochondria Induced by Hyperglycemia: A Rural Community-Based Cross-Sectional Study.

Oxidative medicine and cellular longevity, 2020:8235873.

This study is aimed at evaluating the relationship between leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn) in a noninterventional rural community of China with different glucose tolerance statuses. In addition, we investigate whether the indicators of oxidative stress and inflammation were involved and identify mediators among them. A total of 450 subjects in rural China were included and divided into two groups according to a 75 g oral glucose tolerance test (OGTT): the abnormal glucose metabolism (AGM, n = 257, 57.1%) group and the normal glucose tolerance (NGT, n = 193, 42.9%) group. Indicators of oxidative stress (superoxide dismutase (SOD) and glutathione reductase (GR)) and inflammatory indices (tumor necrosis factor α (TNFα) and interleukin-6 (IL-6)) were all determined by ELISA. LTL and mtDNAcn were measured using a real-time PCR assay. Linear regressions were used to adjust for covariates that might affect the relationship between LTL and mtDNAcn. Mediation analyses were utilized to evaluate the mediators. In the AGM, LTL was correlated with mtDNAcn (r = 0.214, p = 0.001), but no correlation was found in the NGT. The association between LTL and mtDNAcn was weakened after adjusting for inflammatory factors in the AGM (p = 0.087). LTL and mtDNAcn were both inversely related to HbA1c, IL-6, TNFα, and SOD activity. Mediation analysis demonstrated that TNFα was a significant mediator in the telomere-mitochondrial interactome in the AGM. This result suggests that inflammation and oxidative stress may play a vital role in telomere shortening as well as mitochondrial dysfunction. In the subjects with hyperglycemia, a significant positive correlation is observed between LTL and mtDNAcn, which is probably mediated by TNFα. TNFα may be considered a potential therapeutic target against aging-related disease in hyperglycemia.

RevDate: 2020-05-25

Gao YY, Guo JY, Zhang Z, et al (2020)

[Relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension in coal miners].

Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi, 41(5):727-732.

Objective: To explore the relationship of telomere length, mitochondrial DNA copy number of peripheral blood with hypertension and the interaction between telomere length and mtDNA-CN on hypertension in coal miners. Methods: A case control study was conducted in a coal mine of Shanxi province from July to December of 2013, in which 325 healthy workers were selected as the control group and 378 workers with hypertension as the case group. The information about general demographic characteristics and life behavior habits of the subjects were collected through questionnaire. Levels of telomere length and mtDNA-CN in peripheral blood were detected by real-time PCR. Unconditional logistic regression was used to examine the association between hypertension and telomere length, mtDNA-CN. The interaction test between telomere length and mtDNA-CN on hypertension was performed by adding the interaction term in the corresponding model. Results: The mean telomere length of the workers in the case group was (1.50±0.55) kb, and that of the control group was (2.01±0.62) kb, the difference between two groups was significant (t=11.68, P<0.001). The correlation analysis showed that telomere length was positively correlated with mtDNA-CN (r=0.157, P=0.002) in the case group. Multivariate analysis showed that telomere length (OR=4.408, 95%CI: 3.012-6.452), age (OR=0.417, 95%CI: 0.284-0.613), BMI (OR=1.357, 95%CI: 1.162-1.584), monthly household income level (OR=0.656, 95%CI: 0.553-0.778) and work duration (OR=1.249, 95%CI: 1.100-1.417) were influencing factors of hypertension. The multiply interaction between telomere length and mtDNA-CN was significant on hypertension (OR=1.267, 95%CI: 1.094-1.468). Conclusions: The results suggest shorter telomere length is a risk factor of hypertension. There is a multiply interaction between telomere length and mtDNA-CN on hypertension. However, the association between mtDNA-CN and hypertension was not found.

RevDate: 2020-05-24

Vita GL, Aguennouz M, Sframeli M, et al (2020)

Effect of exercise on telomere length and telomere proteins expression in mdx mice.

Molecular and cellular biochemistry pii:10.1007/s11010-020-03761-3 [Epub ahead of print].

In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the mdx mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in mdx muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in mdx an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.

RevDate: 2020-05-23

Vinayagamurthy S, Ganguly A, S Chowdhury (2020)

Extra-telomeric impact of telomeres: Emerging molecular connections in pluripotency or stemness.

The Journal of biological chemistry pii:REV119.009710 [Epub ahead of print].

Telomeres comprise specialized nucleic acid-protein complexes that help protect chromosome ends from DNA damage. Moreover, telomeres associate with sub-telomeric regions through looping. This results in altered expression of sub-telomeric genes. Recent observations further reveal telomere length dependent gene regulation and epigenetic modifications at sites spread across the genome and distant from telomeres. This regulation is mediated through the telomere-binding protein telomeric repeat-binding factor 2 (TRF2). These observations suggest a role of telomeres in extra-telomeric functions. Most notably, telomeres have a broad impact on pluripotency and differentiation. For example, cardiomyocytes differentiate with higher efficacy from pluripotent cells (iPSC) having long telomeres, and differentiated cells obtained from human embryonic stem cells (hESCs) with relatively long telomeres have a longer life-span. Here, we first highlight reports on these two seemingly distinct research areas: the extra-telomeric role of telomere-binding factors and the role of telomeres in pluripotency/stemness. On the basis of the observations reported in these studies, we draw attention to potential molecular connections between extra-telomeric biology and pluripotency. Finally, in the context of the non-local influence of telomeres on pluripotency and stemness, we discuss major opportunities for progress in molecular understanding of aging-related disorders and neurodegenerative diseases.

RevDate: 2020-05-23

Pasquier E, RJ Wellinger (2020)

In vivo chromatin organization on native yeast telomeric regions is independent of a cis-telomere loopback conformation.

Epigenetics & chromatin, 13(1):23 pii:10.1186/s13072-020-00344-w.

BACKGROUND: DNA packaging into chromatin regulates all DNA-related processes and at chromosomal ends could affect both essential functions of telomeres: protection against DNA damage response and telomere replication. Despite this primordial role of chromatin, little is known about chromatin organization, and in particular about nucleosome positioning on unmodified subtelomere-telomere junctions in Saccharomyces cerevisiae.

RESULTS: By ChEC experiments and indirect end-labeling, we characterized nucleosome positioning as well as specialized protein-DNA associations on most subtelomere-telomere junctions present in budding yeast. The results show that there is a relatively large nucleosome-free region at chromosome ends. Despite the absence of sequence homologies between the two major classes of subtelomere-telomere junctions (i.e.: Y'-telomeres and X-telomeres), all analyzed subtelomere-telomere junctions show a terminal nucleosome-free region just distally from the known Rap1-covered telomeric repeats. Moreover, previous evidence suggested a telomeric chromatin fold-back structure onto subtelomeric areas that supposedly was implicated in chromosome end protection. The in vivo ChEC method used herein in conjunction with several proteins in a natural context revealed no evidence for such structures in bulk chromatin.

CONCLUSIONS: Our study allows a structural definition of the chromatin found at chromosome ends in budding yeast. This definition, derived with direct in vivo approaches, includes a terminal area that is free of nucleosomes, certain positioned nucleosomes and conserved DNA-bound protein complexes. This organization of subtelomeric and telomeric areas however does not include a telomeric cis-loopback conformation. We propose that the observations on such fold-back structures may report rare and/or transient associations and not stable or constitutive structures.

RevDate: 2020-05-22

Davis SK, Xu R, Khan RJ, et al (2020)

Modifiable mediators associated with the relationship between adiposity and leukocyte telomere length in US adults: The National Health and Nutrition Examination Survey.

Preventive medicine pii:S0091-7435(20)30157-2 [Epub ahead of print].

Obesity is associated with age-related health conditions and telomere attrition - a marker of cellular aging. Obesity is attributable to adverse modifiable lifestyle factors. Little is known about the mediation effect of lifestyle factors associated with the relationship between obesity and telomere length. Our objective was to examine this association in the US. Pack years smoked, drinking level per day, physical activity (PA) per week and diet based on Healthy Eating Index (HEI) were assessed as mediators associated with the relationship between adiposity measures and leukocyte telomere length (LTL); adiposity measures included body mass index (BMI), % total body fat (TBF) and waist circumference (WC). Separate adjusted linear regressions and mediation analysis were conducted on a total of 4919 respondents aged 20-84 years using cross-sectional 1999-2002 data from the US National Health and Nutrition Examination Survey. Inadequate PA correlated with 1.28% shorter LTL and was a factor accounting for 35% of the relationship between BMI and LTL (β = -0.0128, 95% CI = 0.0259, 0.0004, p = .05). Smoking 30-≥59 pack years correlated with 4% shorter LTL and accounted for 21% of the relationship between %TBF and LTL (β = -0.0386, 95% CI = -0.0742, -0.0030, p = .03). Improvement in diet correlated with 0.11% longer LTL and contributed 25% of the association between %TBF and LTL (β = 0.0011, 95%CI =0.0004, 0.0018, p = .01). Diet correlated with 0.11% longer LTL and correspond to 28% of the relationship between WC and LTL (β = 0.0011, 95%CI = 0.0004, 0.0018, p = .03). Interventions to improve modifiable behaviors may ameliorate cellular aging and aging related health conditions due to obesity among US adults.

RevDate: 2020-05-22

Kang JI, Mueller SG, Wu GWY, et al (2020)

Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume.

Biological psychiatry. Cognitive neuroscience and neuroimaging pii:S2451-9022(20)30076-8 [Epub ahead of print].

BACKGROUND: Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined.

METHODS: Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging.

RESULTS: A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates.

CONCLUSIONS: These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.

RevDate: 2020-05-20

Li Y, Gu J, Ding Y, et al (2020)

A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.

RevDate: 2020-05-20

Vecoli C, Borghini A, MG Andreassi (2020)

The molecular biomarkers of vascular aging and atherosclerosis: telomere length and mitochondrial DNA4977 common deletion.

Mutation research, 784:108309.

Age is the dominant risk factor for the most prevalent atherosclerotic vascular diseases, including coronary artery disease, myocardial infarction, cerebrovascular disease and stroke. In human, telomere erosion and mitochondrial DNA (mtDNA) damage play a central role in the mechanisms leading to cellular aging decline. This review summarizes the most relevant findings on the role of telomere shortening and the common mtDNA4977 deletion in the progression and evolution of atherosclerosis by combining insight from experimental models and human clinical studies. The current evidence shows a link between telomere erosion and compromised mitochondrial function and provides a new perspective regarding their potential role as clinical biomarkers and therapeutic targets.

RevDate: 2020-05-20

Noguera JC, A Velando (2020)

Gull chicks grow faster but lose telomeres when prenatal cues mismatch the real presence of sibling competitors.

Proceedings. Biological sciences, 287(1927):20200242.

During embryonic life, individuals should adjust their phenotype to the conditions that they will encounter after birth, including the social environment, if they have access to (social) cues that allow them to forecast future conditions. In birds, evidence indicates that embryos are sensitive to cues from clutch mates, but whether embryos adjust their development to cope with the expected level of sibling competition has not hitherto been investigated. To tackle this question, we performed a 'match versus mismatch' experimental design where we manipulated the presence of clutch mates (i.e. clutch size manipulation) and the real (postnatal) level of sibling competition (i.e. brood size manipulation) in the yellow-legged gull (Larus michahellis). We provide evidence that the prenatal cues of sibling presence induced developmental changes (such as epigenetic profiles) that had programming effects on chick begging behaviour and growth trajectories after hatching. While receiving mismatching information favoured chick begging and growth, this came at the cost of reduced antioxidant defences and a premature loss of telomeres. Our findings highlight the role of the prenatal social environment in developmental plasticity and suggest that telomere attrition may be an important physiological cost of phenotype-environment mismatch.

RevDate: 2020-05-19

Gerritsen L, Hägg S, Reynolds CA, et al (2020)

The association of individual changes in stressful life events and telomere length over time in twins aged 50 years and above.

Psychosomatic medicine [Epub ahead of print].

OBJECTIVE: Exposure to adverse stressors has been associated with shortening of leukocyte telomere length(LTL). The present longitudinal study investigates the time course of exposure to life events and LTL to determine whether increases in exposure to life events are related to subsequent accelerated LTL shortening.

METHODS: In the Swedish Adoption Twin Study of Aging (SATSA) we assessed late-life stressful events and LTL in 543 individual participants (mean age 68.4 and 40% men, including 48 complete monozygotic twin pairs and 167 complete dizygotic twin pairs) in up to 5 separate measurements over a period of 25 years. LTL was measured using qPCR. Longitudinal analyses were conducted using time-varying mixed modeling, corrected for lifestyle factors and depressive symptoms.

RESULTS: When adjusting for differences in genetic makeup by looking only in monozygotic twins, we found that an increase in life stressors within an individual was related to decreased LTL over time (B=-0,02; 95%CI=-0,04 to 0,01; p=0,002). None of the findings were significant when only looking at dizygotic twins (all p values > 0.05).

CONCLUSION: Our findings in an older population show a causal relation between increase in life stress on accelerated LTL shortening by using intra-individual time-varying analysis.

RevDate: 2020-05-19

Aviv A (2020)

Telomeres and COVID-19.

FASEB journal : official publication of the Federation of American Societies for Experimental Biology [Epub ahead of print].

The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.

RevDate: 2020-05-20

El Maï M, Marzullo M, de Castro IP, et al (2020)

Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish.

eLife, 9: pii:54935.

Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced SOD2 expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.

RevDate: 2020-05-19

van der Spek A, Warner SC, Broer L, et al (2020)

Exome Sequencing Analysis Identifies Rare Variants in ATM and RPL8 That Are Associated With Shorter Telomere Length.

Frontiers in genetics, 11:337.

Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family (ERF) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based ERF study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length (p-value < 1.42 × 10-7, minor allele frequency of 0.2-0.5%) in the ERF study. Eight of these variants (in C11orf65, ACAT1, NPAT, ATM, KDELC2, and EXPH5) were located on chromosome 11q22.3 that contains ATM, a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS (p-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in RPL8 (p-value = 1.48 × 10-6), which has previously been associated with age. Additionally, a novel rare variant in the known RTEL1 locus showed suggestive evidence for association (p-value = 1.18 × 10-4) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

RevDate: 2020-05-18

Morais M, Dias F, Resende T, et al (2020)

Leukocyte telomere length and hTERT genetic polymorphism rs2735940 influence the renal cell carcinoma clinical outcome.

Future oncology (London, England) [Epub ahead of print].

Aim: Analysis of the genetic hTERT-1327 C>T (rs2735940) influence on leukocyte telomere length (LTL) and tumor development, progression and overall survival in renal cell carcinoma (RCC) patients. Materials & methods: Using leukocyte DNA of RCC patients and healthy individuals, LTL measurement and allelic discrimination of rs2735940 was performed by real-time PCR. Results: RCC patients showed shorter LTL than healthy individuals and LTL increased with clinical stage. CC+TC genotypes healthy carriers' presented shorter LTL. However, no statistical association between the different genotypes and RCC risk. Nevertheless, CC homozygous presented a reduced time to disease progression and a lower overall survival. The use of hTERT-1327 single nucleotide polymorphism information increased the capacity to predict risk for RCC progression. Conclusion: In fact, in healthy individuals, hTERT-1327 CC+TC genotypes were associated with shorter LTL, and this single nucleotide polymorphism was associated with time to disease progression, being a promising potential prognosis biomarker to be used in the future.

RevDate: 2020-05-17

Wang C, Wolters PJ, Calfee CS, et al (2020)

Long-term ozone exposure is positively associated with telomere length in critically ill patients.

Environment international, 141:105780 pii:S0160-4120(19)34845-7 [Epub ahead of print].

RATIONALE: Chronic air pollutant exposure has been associated with development of Acute Respiratory Distress Syndrome (ARDS) in patients at risk, particularly from severe trauma. We recently reported that shorter peripheral blood leukocyte (PBL) telomere length (TL) was associated with worse outcomes and higher severity of ARDS in critically ill patients. Since most major air pollutants are potent oxidants that can induce cellular oxidative stress, and oxidative stress can accelerate telomere shortening, we hypothesized that higher levels of chronic air pollutant exposure would be associated with shorter telomere length in critically ill patients including patients with ARDS.

METHODS: PBL-TL was measured in genomic DNA collected on the morning of ICU day 2 in 772 critically ill patients enrolled in a prospective observational study. Exposures to air pollutants including ozone (warm-season only), particulate matter < 2.5 µm (PM2.5), particulate matter < 10 µm (PM10), CO, NO2 and SO2, were estimated by weighted average of daily levels from all monitors within 50 km of each patient's residential address for the 3 years prior to admission. Associations of each air pollutant exposure and PBL-TL were investigated by multivariable linear regression models adjusting for age, ethnicity, sex, smoking history, alcohol abuse, insurance status, median household income, history of malignancy and APACHE II.

RESULTS: Contrary to our hypothesis, TL increased across exposure quartiles in both ozone and PM2.5 analyses (p < 0.05). In a regression model controlling for potential confounders, long term ozone exposure was significantly associated with an increase in TL in the entire cohort (0.31 kb per 10 ppb), as well as in subgroups with sepsis, trauma and ARDS (all p < 0.05). In multivariable models, entire-year exposure to PM2.5, PM10, CO, NO2 and SO2 was not associated with TL after adjustment for potential confounders. In an analysis restricted to warm-season levels to assess the effect of seasonality, higher warm-season PM2.5 and CO exposures were independently associated with longer TL.

CONCLUSIONS: Long-term exposure to ozone is associated with longer peripheral blood TL in critically ill patients. Further studies are needed to investigate the potential underlying mechanisms for this unexpected positive association between telomere length and air pollution exposure in critical illness.

RevDate: 2020-05-16

Ren JC, Liu H, Zhang GH, et al (2020)

Interaction effects of environmental response gene polymorphisms and benzene exposure on telomere length in shoe-making workers.

Chemosphere, 255:126841 pii:S0045-6535(20)31034-1 [Epub ahead of print].

Benzene is a globally occurring environmental and occupational pollutant that causes leukemia. To better understand telomere length (TL) as a function of benzene toxicity, we recruited 294 shoe-making workers and 102 controls from Wenzhou, China in 2011. Biomarkers of TL, cytokinesis-block micronucleus (MN) frequency, and white blood cells (WBC) were measured. In total, 18 polymorphic sites in environmental response genes, including metabolic and DNA repair genes, were analyzed. Results indicate that benzene exposure led to a longer TL at a threshold of 32 mg/m3-year of cumulative exposure dose (CED). Furthermore, the TL was longer in members of the damaged group, when evaluated for MN frequency (P < 0.001) and reduced WBC (P < 0.001), than in those of the normal group. Workers carrying genotype TT (β = 0.32, P = 0.042) in rs3212986 of ERCC1 and genotype TC (β = 0.24, P = 0.082) in rs1051740 of mEH exon3 were associated with a longer TL as compared to the wild-type group. TA (β = -0.53, P < 0.001) in rs6413432 of CYP2E1 was associated with a shorter TL. Benzene exposure interacted with the TA type in rs6413432 (β = 0.003, 95% CI: 0, 0.006, P = 0.042) and the CC type in rs1051740 (β = 0.007, 95% CI: 0.001, 0.013, P = 0.015) after adjusting for confounding factors. Our results indicate that benzene induces an increase in TL at a threshold of CED ≥32mg/m3-year. Rs1051740, rs3212986, and rs6413432 were found to be involved in benzene-induced telomere growth; in particular, rs1051740 and rs6413432 interacted with the benzene exposure, resulting in an extended TL.

RevDate: 2020-05-15

Lee CY, Bisig CG, Conrad MN, et al (2020)

Telomere-led meiotic chromosome movements: recent update in structure and function.

Nucleus (Austin, Tex.) [Epub ahead of print].

Telomere-led chromosome movement or Rapid Prophase Movements (RPM) occur in meiotic prophase and is a conserved process required for proper homologous chromosome interactions. This type of active movements originates in the cytoplasm and is translated to the telomeres through the nuclear membrane. We highlight our recent advances in the engine generating RPMs in S. cerevisiae, with special emphasis in exonuclear components of the machinery. We demonstrate that Mps2 protein participates as a LINC complex component; we identify Myo2 motor protein, which interacts with Mps2 connecting telomeres to the actin cytoskeleton; and show that Csm4 is a regulator of the Mps2-Myo2 interaction and function. In this article we extend our observations regarding to the functional interaction of Mps2 and Csm4. We show that the Mps2-Csm4 fusion protein complement deficient sporulation and anaphase I entrance of a csm4 deletion strain, and partially complement RPM function. Overall, our results allow the construction of a complete model for the primary mechanism generating chromosome movements in budding yeast. Malfunction of this machinery results in impaired meiotic progression in different experimental models indicating its requirement for successful haploidization of the genome and species survival.

RevDate: 2020-05-15

Huang YQ, Liu L, Lo K, et al (2020)

The relationship between mean telomere length and blood pressure: results from the National Health and Nutrition Examination Surveys.

Annals of translational medicine, 8(8):535.

Background: Recent studies have shown that telomere length has significantly relationship with different age-related diseases. However, the relationship between mean telomere length (MTL) and elevated blood pressure (BP) has been unclear. Therefore, the aim of the recent study was tried to explore the association of MLT with BP.

Methods: There were 5,981 subjects from the National Health and Nutrition Examination Surveys (NHANES, 1999-2002) was included in analysis. The MTL was measured using the quantitative polymerase chain reaction (PCR) method and expressed in telomere-to-single copy gene (T/S) ratio and grouped into quartiles. Multivariate linear [expressed in beta and 95% confidence interval (CI)], logistic regression [odds ratios (ORs) and 95% CI] analyses and smooth curve fitting were performed to evaluate the relationship between MTL, BPs and the likelihood of hypertension.

Results: The mean age of the participants was 45.2±17.3 years, including 2,923 (48.9%) males. After adjusting for potential confounders, MLT was significantly related to the prevalence of hypertension (OR: 0.12, 95% CI: 0.02, 0.94; P=0.04). Smooth curve fitting found a non-linear relationship between MTL, the levels of systolic and diastolic blood pressure (SBP/DBP) and the prevalence of hypertension. The inflection points for the smooth curve of MLT were at 0.86, 1.02 and 0.80 (T/S ratio) respectively. The betas (95% CIs) for SBP [-12.58 (-20.07, -5.09), P<0.01 and 2.25 (0.07, 4.43), P=0.04] and DBP [4.88 (1.29, 8.47), P<0.01 and -3.30 (-5.54, -1.06), P<0.01], and ORs (95% CIs) for the prevalence of hypertension [0.02 (0.001, 9.71), P=0.15 and 0.26 (0.026, 2.60), P=0.25] on the left and right of the inflection point, respectively.

Conclusions: Our findings revealed that MTL was related with SBP, DBP and the odds of hypertension in a non-linear manner.

RevDate: 2020-05-15

Oko Y, Ito N, T Sakamoto (2020)

The mechanisms and significance of the positional control of centromeres and telomeres in plants.

Journal of plant research pii:10.1007/s10265-020-01202-2 [Epub ahead of print].

The centromere and telomere are universal heterochromatic domains; however, the proper positioning of those domains in nuclear space during the mitotic interphase differs among eukaryotes. Consequently, the question arises how and why this difference occurs. Studies over the past 2 decades have identified several nuclear membrane proteins, nucleolar proteins, and the structural maintenance of a chromosome complex as factors involved in the positional control of centromeres and/or telomeres during the mitotic interphase in yeasts, animals, and plants. In this review, with a primary focus on plants, the roles of those factors are summarized, and the biological significance of proper centromere and telomere positionings during the mitotic interphase is discussed in an effort to provide guidance for this question.

RevDate: 2020-05-15

da Cruz I, Brochier-Armanet C, R Benavente (2020)

The TERB1-TERB2-MAJIN complex of mouse meiotic telomeres dates back to the common ancestor of metazoans.

BMC evolutionary biology, 20(1):55 pii:10.1186/s12862-020-01612-9.

BACKGROUND: Meiosis is essential for sexual reproduction and generates genetically diverse haploid gametes from a diploid germ cell. Reduction of ploidy depends on active chromosome movements during early meiotic prophase I. Chromosome movements require telomere attachment to the nuclear envelope. This attachment is mediated by telomere adaptor proteins. Telomere adaptor proteins have to date been identified in fission yeast and mice. In the mouse, they form a complex composed of the meiotic proteins TERB1, TERB2, and MAJIN. No sequence similarity was observed between these three mouse proteins and the adaptor proteins of fission yeast, raising the question of the evolutionary history and significance of this specific protein complex.

RESULT: Here, we show the TERB1, TERB2, and MAJIN proteins are found throughout the Metazoa and even in early-branching non-bilateral phyla such as Cnidaria, Placozoa and Porifera. Metazoan TERB1, TERB2, and MAJIN showed comparable domain architecture across all clades. Furthermore, the protein domains involved in the formation of the complex as well as those involved for the interaction with the telomere shelterin protein and the LINC complexes revealed high sequence similarity. Finally, gene expression in the cnidarian Hydra vulgaris provided evidence that the TERB1-TERB2-MAJIN complex is selectively expressed in the germ line.

CONCLUSION: Our results indicate that the TERB1-TERB2-MAJIN complex has an ancient origin in metazoans, suggesting conservation of meiotic functions.

RevDate: 2020-05-13

Ustaoglu M, Bektas A, Bedir A, et al (2020)

The telomere length of gastric mucosal samples and peripheral blood lymphocytes in patients who have undergone Billroth II distal gastrectomy.

Archives of medical science : AMS, 16(3):577-583 pii:40439.

Introduction: Telomeres play an important role in maintaining chromosomal integrity. Functional loss of telomeres increases the risk of cancer by causing genomic instability. Telomere length abnormalities have been reported in several precancerous lesions. There is no study that evaluates telomere length in Billroth II distal gastrectomy, which is known as a risk factor for gastric stump carcinogenesis, in the literature. The aim of this study was to assess the relationship between the telomere length of residual gastric mucosal samples, peripheral blood lymphocytes, and other clinicopathological parameters of patients who had undergone Billroth II distal gastrectomy.

Material and methods: There were two groups: a control group (n = 15) and a patient group (n = 15). In all cases, upper gastrointestinal endoscopy was performed, and biopsies were taken during endoscopy. Telomere lengths were measured by qRT-PCR.

Results: It was observed that the lengths of the telomeres were shortened as the time of postoperative period increased in the patient group (r = -0.126) (p > 0.05). Also, the lengths of the telomeres were shortened in chronic inflammation, neutrophil activity, glandular atrophy, and intestinal metaplasia.

Conclusions: The telomere length was shortened as the time of postoperative period increased in the patient group. The telomeres were also shorter in chronic inflammation, neutrophil activity, intestinal metaplasia, and glandular atrophy, in all of the study groups. Telomere length abnormalities in gastric stump carcinogenesis process may be a guide for early diagnosis and treatment.

RevDate: 2020-05-11

Braz MG, Silva MAP, Figueiredo DBS, et al (2020)

Genetic instability assessed by telomere length and micronucleus in physicians exposed to anesthetics.

Environmental and molecular mutagenesis [Epub ahead of print].

This study evaluated both telomere length (TL) and micronucleus (MN) as indicators of genome instability in 40 anesthesiologists occupationally exposed to anesthetics and in 40 physicians without occupational exposure to anesthetics who were matched by age, sex and lifestyle. Blood and buccal samples were collected from both groups at the same period. Anesthetic exposure assessment was performed. The studied groups were assessed regarding relative TL by quantitative polymerase chain reaction and MN by buccal MN assay. Mean trace concentrations of anesthetics were below two parts per million. No significant differences between groups were found for both biomarkers. However, MN frequency was slightly increased (1.9-fold; P=0.094) in the exposed group compared to the control group and in the exposed males (2.4-fold; P=0.090) compared to unexposed males. TL and age showed a significant negative correlation. Anesthetic occupational exposure below recommended levels is not associated with changes in TL and MN in anesthesiologists. This article is protected by copyright. All rights reserved.

RevDate: 2020-05-11

Heaphy CM, Haffner MC, Graham MK, et al (2020)

Telomere lengths differ significantly between small cell neuroendocrine prostate carcinoma and adenocarcinoma of the prostate.

Human pathology pii:S0046-8177(20)30086-1 [Epub ahead of print].

BACKGROUND: Small cell neuroendocrine carcinoma (SCNC) of the prostate is an aggressive subtype with frequent TP53 mutation and RB1 inactivation, however the molecular phenotype remains an area of investigation. Here, we compared telomere lengths in prostatic SCNC and usual-type prostatic adenocarcinoma (AdCa).

METHODS: We studied 32 cases of prostatic SCNC (including 11 cases with concurrent AdCa) and 347 cases of usual-type AdCa on tissue microarrays. Telomere lengths in tumor cells were qualitatively compared to that in normal cells using a telomere-specific fluorescence in situ hybridization assay. ERG, PTEN and TP53 status were assessed in a proportion of cases using genetically validated immunohistochemistry protocols. Clinical-pathologic and molecular characteristics of cases were compared between telomere groups using the chi-square test.

RESULTS: A significantly higher proportion of prostatic SCNC cases (50%, 16/32) showed normal/long telomeres compared to AdCa cases (11%, 39/347; p<0.0001). In 82% (9/11) of cases with concurrent SCNC and AdCa, the paired components were concordant for telomere length status. Among AdCa cases, the proportion of cases with normal/long telomeres significantly increased with increasing tumor Grade Group (p=0.01) and pathologic stage (p=0.02). Cases with normal/long telomeres were more likely to be ERG positive (p=0.04) and to have TP53 missense mutation (p=0.01) compared to cases with short telomeres.

CONCLUSIONS: Normal or long telomere lengths are significantly more common in prostatic SCNC compared to AdCa and are similar between concurrent SCNC and AdCa tumors supporting a common origin. Among AdCa cases, longer telomere lengths are significantly associated with high risk pathologic and molecular features.

RevDate: 2020-05-11

Harari Y, Gershon L, Alonso-Perez E, et al (2020)

Telomeres and stress in yeast cells: When genes and environment interact.

Fungal biology, 124(5):311-315.

Telomeres are structures composed of simple DNA repeats and specific proteins that protect the eukaryotic chromosomal ends from degradation, and facilitate the replication of the genome. They are central to the maintenance of the genome integrity, and play important roles in the development of cancer and in the process of aging in humans. The yeast Saccharomyces cerevisiae has greatly contributed to our understanding of basic telomere biology. Our laboratory has carried out systematic screen for mutants that affect telomere length, and identified ∼500 genes that, when mutated, affect telomere length. Remarkably, all ∼500 TLM (Telomere Length Maintenance) genes participate in a very tight homeostatic process, and it is enough to mutate one of them to change the steady-state telomere length. Despite this complex network of balances, it is also possible to change telomere length in yeast by applying several types of external stresses. We summarize our insights about the molecular mechanisms by which genes and environment interact to affect telomere length.

RevDate: 2020-05-11

Chen XX, Y Sun (2020)

[A review and update of the potential impact of early life adversity on telomere length].

Zhonghua yu fang yi xue za zhi [Chinese journal of preventive medicine], 54(5):581-585.

Early life adversity is a risk factor for many diseases, but the related mechanism is not clear. Some research clues suggest that early life adversity is related to biological aging, and at present, the more recognized biological aging index is telomere length. Therefore, exploring the relationship between early life adversity and telomere length is of great significance to reveal the related mechanism of adversity. Through a review of previous literature, this paper discusses the possible effects of different adversity types, exposure time and research design on the relationship between early life adversity and telomere length, so as to provide a basis for the intervention of early life adversity.

RevDate: 2020-05-09

Jurikova K, Gajarsky M, Hajikazemi M, et al (2020)

Role of folding kinetics of secondary structures in telomeric G-overhangs in the regulation of telomere maintenance in Saccharomyces cerevisiae.

The Journal of biological chemistry pii:RA120.012914 [Epub ahead of print].

The ends of eukaryotic chromosomes typically contain a 3' single-stranded DNA G-rich protrusion (G-overhang). This overhang must be protected against detrimental activities of nucleases and of the DNA damage response machinery and participates in the regulation of telomerase, a ribonucleoprotein complex that maintains telomere integrity. These functions are mediated by DNA-binding proteins, such as Cdc13 in Saccharomyces cerevisiae and the propensity of G-rich sequences to form various non-B DNA structures. Using CD and NMR spectroscopies we show here that G-overhangs of S. cerevisiae form distinct Hoogsteen pairing-based secondary structures depending on their length. Whereas short telomeric oligonucleotides form a G-hairpin, their longer counterparts form parallel and/or anti-parallel G-quadruplexes (G4s). Regardless of their topologies, non-B DNA structures exhibited impaired binding to Cdc13 in vitro as demonstrated by electrophoretic mobility shift assays. Importantly, whereas G4 structures formed relatively quickly, G-hairpins folded extremely slowly, indicating that short G-overhangs, which are typical for most of the cell cycle, are present predominantly as single-stranded oligonucleotides and are suitable substrates for Cdc13. Using chromatin immunoprecipitation we show that the occurrence of G4 structures peaks at the late S phase, thus correlating with the accumulation of long G-overhangs. We present a model of how time- and length-dependent formation of non-B DNA structures at chromosomal termini participates in telomere maintenance.

RevDate: 2020-05-08

Cherska M, Krasnienkov D, Tronko N, et al (2020)

TELOMERE LENGTH, TELOMERASE ACTIVITY, HEART RATE VARIABILITY, OR OXIDATIVE STRESS: WHICH ONE IS MOST ASSOCIATED WITH THE ATHEROTHROMBOTIC STROKE IN THE ELDERLY?.

Georgian medical news.

The objective of this study - to evaluate the impact of the markers of oxidative stress and HRV to stroke. The comprehensive clinical and instrumental study involved 84 patients with the diagnosis "Cerebral Atherosclerosis" (CA). Study design: simple, prospective, non-randomized, with sequential inclusion of patients. All patients underwent generally accepted clinical, laboratory and instrumental examination. All patients received antihypertensive drugs and metformin if they had DM and didn't receive any statins. Patients were divided into the 2 groups: I - those who underwent ischemic stroke (IS), II - with CA of 1-2 degrees. Mean age was 65.5±10.2 and 66.0±9.3 years, respectively. The number of patients with type 2 diabetes and the average fasting glucose was comparable in both groups. The LF/HF indicator reflects the state of the sympatho-parasympathetic balance of the ANS. Large values of this indicator indicate the predominance of the tone of the sympathetic ANS, which was observed (p <0.05) in patients of the 2nd group, while HF, LF and VLF were also higher (p>0.05) in the group of patients with cerebral atherosclerosis of 1-2 stages and above normal international values. Both groups were comparable in terms of telomere length and telomerase activity, as well as markers of oxidative stress, with the exception of GSH, which was higher in post-stroke patients (p>0.05). Our findings show that markers of oxidative stress together with HRV indices are useful for the atherothrombotic stroke risk assessment in the elderly. Future longitudinal study with bigger sample size and, probably wide panel of markers required for clarifying links between oxidative stress, HRV and stroke.

RevDate: 2020-05-07

Bai Y, Fu W, Guan X, et al (2020)

Co-exposure to multiple metals, TERT-CLPTM1L variants, and their joint influence on leukocyte telomere length.

Environment international, 140:105762 pii:S0160-4120(19)34753-1 [Epub ahead of print].

OBJECTIVE: Telomere is required for maintaining chromosome stability and genome integrity, while telomere length is sensitive to environmental stressors. We aimed to identify the effects of multiple metals co-exposure as well as their joint effects with TERT-CLPTM1L variants on leukocyte telomere length (LTL).

METHODS: This study included 842 workers from a coke-oven plant, of whom plasma concentrations of 23 metals and LTL were determined. Genetic variations in TERT-CLPTM1L were genotyped by using the Global Screening Array. Multipollutant-based statistical methods, including the Bonferroni-correction, backward elimination procedure, and LASSO penalized regression analysis, were used to select the LTL-associated metals. Generalized linear regression models were used to evaluate the joint effects of TERT-CLPTM1L variants with positive metal on LTL.

RESULTS: Each 1% increase in plasma concentration of manganese (Mn) was significantly associated with a 0.153% increase in LTL [β(95%CI) = 0.153(0.075, 0.230), P < 0.001] in single-metal models after Bonferroni-correction. The multiple-metal models and the LASSO penalized regression analysis both indicated Mn as the sole significant predictor for LTL. Furthermore, 5 tagSNPs (rs33954691, rs6554759, rs465498, rs2455393, and rs31489) in TERT-CLPTM1L with high plasma Mn (>4.21 μg/L) showed joint effects on increasing LTL.

CONCLUSIONS: Our study revealed the independent and positive association between plasma Mn and LTL when accounting for co-exposure to other metals. This effect can be further enhanced by TERT-CLPTM1L variants. These results may advance our understanding of the complex interplay between genetic and environmental factors on telomere length. Further experimental studies are warranted to elucidate the underlying mechanisms.

RevDate: 2020-05-07

Jacome-Burbano MS, E Gilson (2020)

Long-lived post-mitotic cell aging: is a telomere clock at play?.

Mechanisms of ageing and development pii:S0047-6374(20)30052-X [Epub ahead of print].

Senescence is a cellular response to stress for both dividing and post-mitotic cells. Noteworthy, long-lived post-mitotic cells (collectively named LLPMCs), which can live for decades in the organism, can exhibit a distinct type of cellular aging characterized by a progressive functional decline not associated to an overt senescence phenotype. The age-related drivers of senescence and aging in LLPMCs remain largely unknown. There is evidence that an increased production of reactive oxygen species (ROS) due to dysfunctional mitochondria, coupled with an inherent inability of cellular-degradation mechanisms to remove damaged molecules, is responsible for senescence and aging in LLPMC. Although telomeric DNA shortening, by nature linked to cell division, is generally not considered as a driver of LLPMC aging and senescence, we discuss recent reports revealing the existence of age-related telomere changes in LLPMC. These findings reveal unexpected roles for telomeres in LLPMC function and invite us to consider the hypothesis of a complex telomere clock involved in both dividing and non-dividing cell aging.

RevDate: 2020-05-07

Shi G, Hu Y, Zhu X, et al (2020)

A critical role of telomere chromatin compaction in ALT tumor cell growth.

Nucleic acids research pii:5831760 [Epub ahead of print].

ALT tumor cells often contain abundant DNA damage foci at telomeres and rely on the alternative lengthening of telomeres (ALT) mechanism to maintain their telomeres. How the telomere chromatin is regulated and maintained in these cells remains largely unknown. In this study, we present evidence that heterochromatin protein 1 binding protein 3 (HP1BP3) can localize to telomeres and is particularly enriched on telomeres in ALT cells. HP1BP3 inhibition led to preferential growth inhibition of ALT cells, which was accompanied by telomere chromatin decompaction, increased presence of C-circles, more pronounced ALT-associated phenotypes and elongated telomeres. Furthermore, HP1BP3 appeared to participate in regulating telomere histone H3K9me3 epigenetic marks. Taken together, our data suggest that HP1BP3 functions on telomeres to maintain telomere chromatin and represents a novel target for inhibiting ALT cancer cells.

RevDate: 2020-05-07

George SL, Parmar V, Lorenzi F, et al (2020)

Novel therapeutic strategies targeting telomere maintenance mechanisms in high-risk neuroblastoma.

Journal of experimental & clinical cancer research : CR, 39(1):78 pii:10.1186/s13046-020-01582-2.

The majority of high-risk neuroblastomas can be divided into three distinct molecular subgroups defined by the presence of MYCN amplification, upstream TERT rearrangements or alternative lengthening of telomeres (ALT). The common defining feature of all three subgroups is altered telomere maintenance; MYCN amplification and upstream TERT rearrangements drive high levels of telomerase expression whereas ALT is a telomerase independent telomere maintenance mechanism. As all three telomere maintenance mechanisms are independently associated with poor outcomes, the development of strategies to selectively target either telomerase expressing or ALT cells holds great promise as a therapeutic approach that is applicable to the majority of children with aggressive disease.Here we summarise the biology of telomere maintenance and the molecular drivers of aggressive neuroblastoma before describing the most promising therapeutic strategies to target both telomerase expressing and ALT cancers. For telomerase-expressing neuroblastoma the most promising targeted agent to date is 6-thio-2'-deoxyguanosine, however clinical development of this agent is required. In osteosarcoma cell lines with ALT, selective sensitivity to ATR inhibition has been reported. However, we present data showing that in fact ALT neuroblastoma cells are more resistant to the clinical ATR inhibitor AZD6738 compared to other neuroblastoma subtypes. More recently a number of additional candidate compounds have been shown to show selectivity for ALT cancers, such as Tetra-Pt (bpy), a compound targeting the telomeric G-quadruplex and pifithrin-α, a putative p53 inhibitor. Further pre-clinical evaluation of these compounds in neuroblastoma models is warranted.In summary, telomere maintenance targeting strategies offer a significant opportunity to develop effective new therapies, applicable to a large proportion of children with high-risk neuroblastoma. In parallel to clinical development, more pre-clinical research specifically for neuroblastoma is urgently needed, if we are to improve survival for this common poor outcome tumour of childhood.

RevDate: 2020-05-06

Pisanu C, Congiu D, Manchia M, et al (2020)

Differences in telomere length between patients with bipolar disorder and controls are influenced by lithium treatment.

Pharmacogenomics [Epub ahead of print].

Aim: To assess the role of lithium treatment in the relationship between bipolar disorder (BD) and leukocyte telomere length (LTL). Materials & methods: We compared LTL between 131 patients with BD, with or without a history of lithium treatment, and 336 controls. We tested the association between genetically determined LTL and BD in two large genome-wide association datasets. Results: Patients with BD with a history lithium treatment showed longer LTL compared with never-treated patients (p = 0.015), and similar LTL compared with controls. Patients never treated with lithium showed shorter LTL compared with controls (p = 0.029). Mendelian randomization analysis showed no association between BD and genetically determined LTL. Conclusion: Our data support previous findings showing that long-term lithium treatment might protect against telomere shortening.

RevDate: 2020-05-05

Rubio Galisteo JM, Fernández L, Gómez Gómez E, et al (2020)

Telomere-based risk models for the early diagnosis of clinically significant prostate cancer.

Prostate cancer and prostatic diseases pii:10.1038/s41391-020-0232-4 [Epub ahead of print].

BACKGROUND: The objective of this study was to explore telomere-associated variables (TAV) as complementary biomarkers in the early diagnosis of prostate cancer (PCa), analyzing their application in risk models for significant PCa (Gleason score > 6).

METHODS: As part of a larger prospective longitudinal study of patients with suspicion of PCa undergoing prostate biopsy according to clinical practice, a subgroup of patients (n = 401) with PSA 3-10 ng/ml and no prior biopsies was used to evaluate the contribution of TAV to discern non-significant PCa from significant PCa. The cohort was randomly split for training (2/3) and validation (1/3) of the models. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate TAV in peripheral blood mononucleated cells. Models were generated following principal component analysis and random forest and their utility as risk predictors was evaluated by analyzing their predictive capacity and accuracy, summarized by ROC curves, and their clinical benefit with decision curves analysis.

RESULTS: The median age of the patients was 63 years, with a median PSA of 5 ng/ml and a percentage of PCa diagnosis of 40.6% and significant PCa of 19.2%. Two TAV-based risk models were selected (TAV models 1 and 2) with an AUC ≥ 0.83 in the full study cohort, and AUC > 0.76 in the internal validation cohort. Both models showed an improvement in decision capacity when compared to the application of the PCPT-RC in the low-risk probabilities range. In the validation cohort, with TAV models 1 and 2, 33% /48% of biopsies would have been avoided losing 0/10.3% of significant PCa, respectively. The models were also tested and validated on an independent, retrospective, non contemporary cohort.

CONCLUSIONS: Telomere analysis through TAV should be considered as a new risk-score biomarker with potential to increase the prediction capacity of significant PCa in patients with PSA between 3-10 ng/ml.

RevDate: 2020-05-05

Laroche-Clary A, Chaire V, Verbeke S, et al (2020)

ATR Inhibition Broadly Sensitizes Soft-Tissue Sarcoma Cells to Chemotherapy Independent of Alternative Lengthening Telomere (ALT) Status.

Scientific reports, 10(1):7488 pii:10.1038/s41598-020-63294-z.

Only few drugs have shown activity in patients with advanced soft-tissue and the median overall survival is only 18 months. Alterations of genes involved in the DNA damage repair pathway have been associated with sarcoma risk and prognosis. ATR plays a crucial role in maintaining genomic integrity by responding to a large spectrum of DNA damage, including double strand breaks (DSBs) that interfere with replication. The objective of this study is to evaluate the pre-clinical activity of ATR inhibition in soft tissue sarcomas (STS). We explored the ability of the ATR inhibitor, VE-822, to prevent chemotherapy-induced intra-S-phase checkpoint activation and evaluated the antitumor potential of this combination in vitro and in vivo in STS cell lines and in a patient-derived xenograft model. The combination of VE-822 and gemcitabine in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the S phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. These effects were unrelated to the alternative lengthening of telomeres pathway. In vivo, the combination of VE-822 and gemcitabine significantly enhanced tumor growth inhibition and progression-free survival in an aggressive model of undifferentiated pleomorphic sarcoma. The combination of ATR inhibitor and chemotherapy is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.

RevDate: 2020-05-04

Martens DS, Janssen BG, Bijnens EM, et al (2020)

Association of Parental Socioeconomic Status and Newborn Telomere Length.

JAMA network open, 3(5):e204057 pii:2765374.

Importance: Low socioeconomic status is associated with higher all-cause mortality and risks for aging-related diseases. Biological aging is a potential process underlying health conditions related to social disadvantages, which may be present from birth onward.

Objective: To evaluate the association of parental socioeconomic status with telomere length (TL) at birth, a marker of biological aging.

This prospective birth cohort study was conducted among 1504 mother-newborn pairs in Belgium recruited between February 1, 2010, and July 1, 2017.

Exposures: Parental socioeconomic measures, including maternal educational level, occupation, paternal educational level, and neighborhood income based on median annual household income.

Main Outcomes and Measures: Mean relative TL was measured in cord blood and placental tissue. By constructing a principal component, an integrative socioeconomic measure was derived that integrates parental socioeconomic status and neighborhood income. Multivariable adjusted regression analyses were performed to associate the integrative socioeconomic measure and TL at birth.

Results: In 1026 newborns (517 boys; mean [SD] gestational age, 39.2 [1.4] weeks), a higher socioeconomic status was associated with longer cord blood TL and placental TL. Each unit increment in the integrative socioeconomic status measure was associated with 2.1% (95% CI, 0.9%-3.4%; P < .001) longer cord blood TL in boys, while no association was observed for girls (0.5% longer cord blood TL; 95% CI, -0.9% to 1.8%; P = .50). The sex-specific socioeconomic status interaction revealed a stronger association in boys compared with newborn girls (1.6%; 95% CI, 0.02%-3.3%; P = .047 for interaction). In placental tissue, higher socioeconomic status was associated with 1.8% (95% CI, 0.3%-3.3%; P = .02) longer TL in newborn boys but not in girls (0.4% longer TL; 95% CI, -1.2% to 2.0%; P = .63). For placental tissue, no sex and socioeconomic status interaction on TL was observed (1.4%; 95% CI, -0.5% to 3.4%; P = .16 for interaction).

Conclusions and Relevance: This study suggests that parental socioeconomic status is associated with newborn TL, especially in boys. The results indicate that familial social economic factors are associated with the potential cellular longevity of the next generation, with a potential higher transgenerational vulnerability for newborn boys.

RevDate: 2020-05-02

Aoulad Fares D, Schalekamp-Timmermans S, Nawrot TS, et al (2020)

Preconception telomere length as a novel maternal biomarker to assess the risk of spina bifida in the offspring.

Birth defects research [Epub ahead of print].

BACKGROUND: Periconception interactions between maternal conditions and environmental and genetic factors are involved in the pathogenesis and prevention of neural tube defects (NTD), such as spina bifida. These factors have in common that they can impair the oxidative pathway, resulting in excessive (chronic) oxidative stress and inflammation.

METHODS: Review of the literature concerning underlying mechanisms and biomarkers of aging particularly during reproduction. A number of molecular markers for biological aging have been identified, including telomere length (TL). Excessive telomere shortening is an index of senescence, causes genomic instability and is associated with a higher risk of age-related diseases. Furthermore, TL shortening is associated with the similar environmental and lifestyle exposures associated with NTD risk.

RESULTS: Embryonic mice deficient in the telomerase gene show shorter TL and failure of closure of the neural tube as the main defect, suggesting that this developmental process is among the most sensitive to telomere loss and chromosomal instability.

CONCLUSIONS: From this background, we hypothesize that preconceptional long term exposure to harmful environmental and lifestyle risk factors accelerates a woman's aging process, which can be measured by TL, and thereby her underlying risk of NTD offspring. Alternatively, it might be that women with an increased NTD risk already exhibit a more advanced biological age before the onset of pregnancy compared to women of identical calendar age.

RevDate: 2020-05-01

Cao H, Zhai Y, Ji X, et al (2020)

Non-coding TERRA inhibits the progression of hepatocellular carcinoma via regulating telomerase-mediated telomere length.

Cancer science [Epub ahead of print].

Telomeric repeat-containing RNA (TERRA) is closely involved in the regulation of telomere length, which plays critical role in tumorigenesis. However, the biological significance of TERRA in hepatocellular carcinoma (HCC) remained largely unknown. In this study, we found that HCC cells exhibited a frequent downregulation of TERRA and its positive regulator TTAGGG repeat binding factor-1 (TRF1), whereas the negative regulator TTAGGG repeat binding factor-1 (TRF2) was upregulated. TERRA, TRF1 and TRF2 contributed to poor prognosis of HCC patients. Importantly, we found that the downregulation of TERRA significantly promoted HCC cell growth and metastasis in vitro and in vivo. While, the upregulation of TERRA exhibited an opposite effect. Mechanistically, downregulation of TERRA significantly increased the telomerase activity and promoted the telomere elongation. Moreover, the inhibitory effects of TERRA overexpression on the growth and metastasis of HCC cells were reversed by treatment with TA-65 that activates telomerase activity. In contrast, the pro-tumor effect of TERRA downregulation was reversed by treatment with TMPyP4 that inhibits telomerase activity. Our findings demonstrate that TERRA plays a critical role in HCC cell growth and metastasis, indicating that TERRA is a potential therapeutic target for HCC.

RevDate: 2020-05-01

Lu Y, Jiang H, Li B, et al (2020)

Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism.

Annals of translational medicine, 8(6):357.

Background: Small vessel vasculitis (SVV) is a group of systemic autoimmune diseases that are mediated by neutrophil extracellular traps (NETs) in response to cathelicidin LL37, an aging molecular marker, which could be induced by telomere dysfunction. Therefore, in this study, we evaluated the hypothesis that telomere dysfunction in neutrophils may promote SVV via an LL37-NETs-dependent mechanism.

Methods: We contrasted the release of neutrophil NETs from mice with telomere dysfunction, mice with DNA damage and wide-type mice. Neutrophil telomere length, the expression of LL37, and the formation of NETs were measured in SVV patients and healthy controls (HCs). The co-expression of γH2AX, LL37, and NETs were detected in SVV patients to evaluate the association of the immune aging of neutrophils and pro-inflammatory conditions. LL37 inhibitor was used to verify its key role in NETs release in SVV patients and DNA damage mice.

Results: We found that NETs were over-induced by telomere dysfunction and DNA damage in mice, which may be associated with a marked increase in LL37. For patients with SVV, telomeres in neutrophils were significantly shortened, which was also associated with higher levels of LL37 and NETs. Inhibition of LL37 reduced the NETs released from neutrophils.

Conclusions: Taken together, the results of these studies suggest that dysfunction of telomeres may promote SVV through the mechanism of LL37-dependent NETs. Thus, targeting the LL37-NETs may be a novel therapy for SVV.

RevDate: 2020-05-01

Dong K, Zhang Y, Huang JJ, et al (2020)

Shorter leucocyte telomere length as a potential biomarker for nonalcoholic fatty liver disease-related advanced fibrosis in T2DM patients.

Annals of translational medicine, 8(6):308.

Background: Telomere length has been linked to hepatic fibrosis. Type 2 diabetes mellitus (T2DM) is considered as a particular risk for the development of hepatic fibrosis. This study is to explore the association of leucocyte telomere length (LTL) and nonalcoholic fatty liver disease (NAFLD)-related advanced fibrosis in T2DM patients.

Methods: A total of 442 patients with T2DM were enrolled from Tongji Hospital, Wuhan, China. Clinical features were collected and LTL was measured by Southern blot-based terminal restriction fragment length. Hepatic advanced fibrosis was determined by both the NAFLD fibrosis score (NFS) and fibrosis-4 score (FIB-4). Explanatory factors for advanced fibrosis in T2DM patients were identified using multiple logistic regressions.

Results: T2DM patients with advanced fibrosis had significant shorter LTL than the no-advanced group. Additionally, LTL, age, male and aminotransferase (ALT) were significantly associated with advanced fibrosis status in T2DM patients. Longer diabetes duration was found to have a strong association with advanced fibrosis in elder T2DM patients.

Conclusions: Shorter LTL was significantly associated with advanced fibrosis in T2DM patients. Longer diabetes duration was an independent risk factor for advanced fibrosis in old T2DM patients. Shorter LTL may be used as a biomarker for advanced fibrosis in T2DM patients.

RevDate: 2020-05-01

Choudhury AR, Ju Z, Djojosubroto MW, et al (2020)

Author Correction: Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

RevDate: 2020-05-01

Ingles ED, JE Deakin (2020)

Comparative Cytogenetic Mapping and Telomere Analysis Provide Evolutionary Predictions for Devil Facial Tumour 2.

Genes, 11(5): pii:genes11050480.

The emergence of a second transmissible tumour in the Tasmanian devil population, devil facial tumour 2 (DFT2), has prompted questions on the origin and evolution of these transmissible tumours. We used a combination of cytogenetic mapping and telomere length measurements to predict the evolutionary trajectory of chromosome rearrangements in DFT2. Gene mapping by fluorescence in situ hybridization (FISH) provided insight into the chromosome rearrangements in DFT2 and identified the evolution of two distinct DFT2 lineages. A comparison of devil facial tumour 1 (DFT1) and DFT2 chromosome rearrangements indicated that both started with the fusion of a chromosome, with potentially critically short telomeres, to chromosome 1 to form dicentric chromosomes. In DFT1, the dicentric chromosome resulted in breakage-fusion-bridge cycles leading to highly rearranged chromosomes. In contrast, the silencing of a centromere on the dicentric chromosome in DFT2 stabilized the chromosome, resulting in a less rearranged karyotype than DFT1. DFT2 retains a bimodal distribution of telomere length dimorphism observed on Tasmanian devil chromosomes, a feature lost in DFT1. Using long term cell culture, we observed homogenization of telomere length over time. We predict a similar homogenization of telomere lengths occurred in DFT1, and that DFT2 is unlikely to undergo further substantial rearrangements due to maintained telomere length.

RevDate: 2020-04-30

De Vusser K, Winckelmans E, Martens D, et al (2020)

Intrarenal arteriosclerosis and telomere attrition associate with dysregulation of the cholesterol pathway.

Aging, 12: pii:103098 [Epub ahead of print].

BACKGROUND: Recently, we demonstrated that arteriosclerosis in the smaller intrarenal arteries is associated with shorter telomere length, independently of history of cardiovascular events and calendar age. This suggests that intrarenal arteriosclerosis reflects replicative senescence, although the underlying molecular alterations remain unclear.

RESULTS: Shorter intrarenal telomere length associated significantly with the presence of renal arteriosclerosis (T/S ratio 0.91±0.15 vs. 1.20±0.23 with vs. without arteriosclerosis, p=0.007, test cohort; T/S ratio 0.98 ±0.26 vs. 1.03 ±0.18 with vs. without arteriosclerosis, p=0.02, validation cohort). The presence versus absence of intrarenal arteriosclerosis was associated with differential expression of 1472 transcripts. Pathway analysis revealed enrichment of molecules involved in the superpathway of cholesterol biosynthesis as the most significant. The differential expression of these genes was confirmed in the independent validation cohort. Furthermore, the specific mRNA expression of the molecules in the superpathway of cholesterol biosynthesis associated significantly with intrarenal telomere length, and with history of cardiovascular events.

INTERPRETATION: Our study illustrates that the superpathway of cholesterol biosynthesis interacts with the previously published association between shorter telomere length and arteriosclerosis.

METHODS: This study included a test cohort of 40 consecutive kidney donors (calendar age 48.0 ± 15), with biopsies obtained prior to transplantation. Intrarenal leucocyte telomere length content was assessed using quantitative RT-PCR. Whole genome microarray mRNA expression analysis was performed using Affymetrix Gene 2.0 ST arrays. We investigated the associations between mRNA gene expression, telomere length as marker of replicative senescence, and intrarenal arteriosclerosis (Banff "cv" score = vascular fibrous intimal thickening = intimal hyperplasia) using adjusted multiple regression models. For biological interpretation and pathway overrepresentation analysis, we used Ingenuity Pathway Analysis. The significant pathways and genes were validated in an independent validation cohort of 173 kidney biopsies obtained prior to transplantation.

RevDate: 2020-04-30

M'kacher R, Colicchio B, Borie C, et al (2020)

Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility.

Genes, 11(5): pii:genes11050475.

Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10-4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.

RevDate: 2020-04-28

Hsu RYC, Lin YC, Redon C, et al (2020)

ORCA/LRWD1 Regulates Homologous Recombination at ALT-Telomeres by Modulating Heterochromatin Organization.

iScience, 23(5):101038 pii:S2589-0042(20)30222-4 [Epub ahead of print].

Telomeres are maintained by telomerase or in a subset of cancer cells by a homologous recombination (HR)-based mechanism, Alternative Lengthening of Telomeres (ALT). The mechanisms regulating telomere-homeostasis in ALT cells remain unclear. We report that a replication initiator protein, Origin Recognition Complex-Associated (ORCA/LRWD1), by localizing at the ALT-telomeres, modulates HR activity. ORCA's localization to the ALT-telomeres is facilitated by its interaction to SUMOylated shelterin components. The loss of ORCA in ALT-positive cells elevates the levels of two mediators of HR, RPA and RAD51, and consistent with this, we observe increased ALT-associated promyelocytic leukemia body formation and telomere sister chromatid exchange. ORCA binds to RPA and modulates the association of RPA to telomeres. Finally, the loss of ORCA causes global chromatin decondensation, including at the telomeres. Our results demonstrate that ORCA acts as an inhibitor of HR by modulating RPA binding to ssDNA and inducing chromatin compaction.

RevDate: 2020-04-28

Ashrafi A, Cosentino S, Kang MS, et al (2020)

Leukocyte Telomere Length Is Unrelated to Cognitive Performance Among Non-Demented and Demented Persons: An Examination of Long Life Family Study Participants.

Journal of the International Neuropsychological Society : JINS pii:S1355617720000363 [Epub ahead of print].

OBJECTIVE: Leukocyte telomere length (LTL) is a widely hypothesized biomarker of biological aging. Persons with shorter LTL may have a greater likelihood of developing dementia. We investigate whether LTL is associated with cognitive function, differently for individuals without cognitive impairment versus individuals with dementia or incipient dementia.

METHOD: Enrolled subjects belong to the Long Life Family Study (LLFS), a multi-generational cohort study, where enrollment was predicated upon exceptional family longevity. Included subjects had valid cognitive and telomere data at baseline. Exclusion criteria were age ≤ 60 years, outlying LTL, and missing sociodemographic/clinical information. Analyses were performed using linear regression with generalized estimating equations, adjusting for sex, age, education, country, generation, and lymphocyte percentage.

RESULTS: Older age and male gender were associated with shorter LTL, and LTL was significantly longer in family members than spouse controls (p < 0.005). LTL was not associated with working or episodic memory, semantic processing, and information processing speed for 1613 cognitively unimpaired individuals as well as 597 individuals with dementia or incipient dementia (p < 0.005), who scored significantly lower on all cognitive domains (p < 0.005).

CONCLUSIONS: Within this unique LLFS cohort, a group of families assembled on the basis of exceptional survival, LTL is unrelated to cognitive ability for individuals with and without cognitive impairment. LTL does not change in the context of degenerative disease for these individuals who are biologically younger than the general population.

RevDate: 2020-04-28

Ley B, Liu S, Elicker BM, et al (2020)

Telomere length in patients with unclassifiable interstitial lung disease: a cohort study.

RevDate: 2020-04-27

Liao TC, Ma TZ, Chen SB, et al (2020)

Human telomere double G-quadruplex recognition by berberine-bisquinolinium imaging conjugates in vitro and cells.

International journal of biological macromolecules pii:S0141-8130(20)33034-8 [Epub ahead of print].

Molecular tools of double or multimeric G-quadruplexes have been given higher requirements on detection sensitivity, thermal stabilization and cell imaging to establish functions of these G-quadruplex aggregates and biological mechanisms as anticancer reagents. Here, two smart berberine-bisquinolinium conjugates (Ber-360A and Ber-PDS) by linking the berberine fluorophore ligand and an established G-quadruplex binder (i.e. bisquinolinium scaffold), have been designed and evaluated their activities and mechanisms for G-quadruplex aggregation. Two conjugates, especially Ber-PDS, are two highly selective, sensitive and fluorescent sensors which can distinguish human telomere double G-quadruplexes from other type G-quadruplexes and ds DNA. These two ligands could be the first example to stack two adjacent G-quadruplex units and fluorescently recognize human telomere double G-quadruplexes. Furthermore, conjugate Ber-PDS could enter the nucleoli and target G-quadruplex DNA through microscopy experiments, and also display strong telomerase inhibition and antitumor activities.

RevDate: 2020-04-27

Kordowitzki P, Hamdi M, Derevyanko A, et al (2020)

The effect of rapamycin on bovine oocyte maturation success and metaphase telomere length maintenance.

Aging, 12: pii:103126 [Epub ahead of print].

Maternal aging-associated reduction of oocyte viability is a common feature in mammals, but more research is needed to counteract this process. In women, the first aging phenotype appears with a decline in reproductive function, and the follicle number gradually decreases from menarche to menopause. Cows can be used as a model of early human embryonic development and reproductive aging because both species share a very high degree of similarity during follicle selection, cleavage, and blastocyst formation. Recently, it has been proposed that the main driver of aging is the mammalian target of rapamycin (mTOR) signaling rather than reactive oxygen species. Based on these observations, the study aimed to investigate for the first time the possible role of rapamycin on oocyte maturation, embryonic development, and telomere length in the bovine species, as a target for future strategies for female infertility caused by advanced maternal age. The 1nm rapamycin in vitro treatment showed the best results for maturation rates (95.21±4.18%) of oocytes and was considered for further experiments. In conclusion, rapamycin influenced maturation rates of oocytes in a concentration-dependent manner. Our results also suggest a possible link between mTOR, telomere maintenance, and bovine blastocyst formation.

RevDate: 2020-04-27

Mason-Osann E, Terranova K, Lupo N, et al (2020)

RAD54 promotes alternative lengthening of telomeres by mediating branch migration.

EMBO reports [Epub ahead of print].

Cancer cells can activate the alternative lengthening of telomeres (ALT) pathway to promote replicative immortality. The ALT pathway promotes telomere elongation through a homologous recombination pathway known as break-induced replication (BIR), which is often engaged to repair single-ended double-stranded breaks (DSBs). Single-ended DSBs are resected to promote strand invasion and facilitate the formation of a local displacement loop (D-loop), which can trigger DNA synthesis, and ultimately promote telomere elongation. However, the exact proteins involved in the maturation, migration, and resolution of D-loops at ALT telomeres are unclear. In vitro, the DNA translocase RAD54 both binds D-loops and promotes branch migration suggesting that RAD54 may function to promote ALT activity. Here, we demonstrate that RAD54 is enriched at ALT telomeres and promotes telomeric DNA synthesis through its ATPase-dependent branch migration activity. Loss of RAD54 leads to the formation of unresolved recombination intermediates at telomeres that form ultra-fine anaphase bridges in mitosis. These data demonstrate an important role for RAD54 in promoting ALT-mediated telomere synthesis.

RevDate: 2020-04-25

Zencir S, Hsieh MH, Hsu JS, et al (2020)

Selected ellipticine derivatives, known to target topoisomerase II, suppress the alternative lengthening of telomere (ALT) pathway in telomerase-negative cells.

Journal of cancer research and clinical oncology pii:10.1007/s00432-020-03213-x [Epub ahead of print].

BACKGROUND: DNA topoisomerase and telomerase enzymes are popular targets of several anti-tumor drugs. Smooth proceeding of telomeric recombination requires Topoisomerase II (Top2), which is involved in telomere-telomere recombination through functioning in relaxation of positive supercoils among the cells adopting telomerase-independent Alternative lengthening of telomere (ALT) pathway. Most of the inhibitors reported so far have been designed to targetsolely telomerase-positive cells, which can potentially lead to therapeutic failure because tumor cells treated with telomerase inhibitors can activate the ALT pathway for telomere maintenance. Knowing that ALT cells are more sensitive against a Top2 inhibitor, ICRF-93 agent, compared to telomerase-positive cells, we analyzed two selected ellipticine derivatives that we recently reported as TopII-targeting compounds, to assess their effects on the formation of DNA breaks and suppression of ALT pathway.

METHODS: Cell viability, Comet, C-Circle assays, dot blot, immunofluorescence staining, and telomere fluorescence in situ hybridization (FISH) staining were used for determining the effect of the compounds on ALT status of tumor cells.

RESULTS AND CONCLUSIONS: Treatment of ALT cells with ellipticine derivatives resulted in the formation of DNA breaks and suppression of ALT-associated phenotypes in vitro. Our results will contribute to the development of therapeutic strategies combining telomerase and ALT pathway inhibitors.

RevDate: 2020-04-24

Alonso-Pedrero L, Ojeda-Rodríguez A, Martínez-González MA, et al (2020)

Ultra-processed food consumption and the risk of short telomeres in an elderly population of the Seguimiento Universidad de Navarra (SUN) Project.

The American journal of clinical nutrition pii:5824715 [Epub ahead of print].

BACKGROUND: Telomere length (TL) is a marker of biological age that may be affected by dietary factors through oxidation and inflammation mechanisms. In addition, ultra-processed food (UPF) consumption has increased worldwide and it has been associated with the risk of developing several diseases.

OBJECTIVES: We aimed to evaluate the association between UPF consumption and the risk of having short telomeres in an elderly population of the Seguimiento Universidad de Navarra (SUN) Project.

METHODS: This is a cross-sectional study of 886 participants (645 men and 241 women) aged 57-91 y recruited from the SUN Project (Spain, 1999-2018). TL was measured from saliva samples by real-time qPCR at baseline and UPF consumption was collected using a validated 136-item FFQ and classified according to the NOVA system. We evaluated the association between consumption of energy-adjusted UPF categorized into quartiles (low, medium-low, medium-high, and high consumption) and the risk of having short telomeres (<20th percentile) using logistic regression models.

RESULTS: Those participants with the highest UPF consumption had almost twice the odds of having short telomeres compared with those with the lowest consumption (adjusted OR: 1.82; 95% CI: 1.05, 3.22; P-trend = 0.03).

CONCLUSIONS: A higher consumption of UPF (>3 servings/d) was associated with higher risk of having shorter telomeres in an elderly Spanish population of the SUN Project.This trial was registered at clinicaltrials.gov as NCT02669602.

RevDate: 2020-04-23

Vetter VM, Spira D, Banszerus VL, et al (2020)

Epigenetic Clock and Leukocyte Telomere Length are Associated with Vitamin D Status, but not with Functional Assessments and Frailty in the Berlin Aging Study II.

The journals of gerontology. Series A, Biological sciences and medical sciences pii:5824319 [Epub ahead of print].

DNA methylation (DNAm) age acceleration, a parameter derived via the epigenetic clock, has recently been suggested as a biomarker of aging. We hypothesized that accelerated biological aging, measured by both this new and the established biomarker of aging, relative leukocyte telomere length (rLTL), are associated with vitamin D deficiency. Moreover, we tested for an association between rLTL/DNAm age acceleration and different clinical assessments for functional capacity, including the Fried frailty score. Cross-sectional data of 1,649 participants of the Berlin Aging Study II was available (∼50% female, age: 22-37 and 60-84 years). A seven cytosine-phosphate-guanine clock was estimated to calculate the DNAm age acceleration. rLTL was measured by quantitative real-time PCR. 25-hydroxyvitamin D (25(OH)D) serum levels <25 nmol/L was defined as vitamin D deficiency and <50 nmol/L as vitamin Dinsufficiency. Vitamin D-sufficient individuals had a 1.4 years lower mean DNAm age acceleration (p<0.05, ANOVA) and a 0.11 longer rLTL (p<0.001, ANOVA) than vitamin D-deficient participants. Likewise, vitamin D sufficient participants had lower DNAm age acceleration (β=1.060, p=0.001) and longer rLTL (β=-0.070; p<0.001) than vitamin D non-sufficient subjects in covariate adjusted analysis. Neither DNAm age acceleration nor rLTL were significantly associated with the Fried frailty score or the functional assessments. Only the clock drawing test was associated with DNAm age acceleration (subgroup of older men: β=1.898, p=0.002). Whether the analyzed biomarkers of aging can be used to predict an individual's functional capacity or will be associated with frailty in the advanced course of aging, will be clarified by future longitudinal analyses.

RevDate: 2020-04-23

Lewis CR, Taguinod F, Jepsen WM, et al (2020)

Telomere Length and Autism Spectrum Disorder Within the Family: Relationships With Cognition and Sensory Symptoms.

Autism research : official journal of the International Society for Autism Research [Epub ahead of print].

Telomeres are repetitive noncoding deoxynucleotide sequences that cap chromosomes to protect DNA. Telomere length (TL) is affected by both genetic and environmental factors, and shortening of telomeres is associated with multiple neuropsychiatric disorders, early life stress, and age-related cognitive dysfunction. Two previous studies associated shorter TL with autism spectrum disorder (ASD). We aimed to replicate this finding, describe TL in unaffected siblings, and explore novel relationships with symptoms and cognitive function in families with ASD. Participants were 212 male children and adolescents ages 1-17 years (86 with ASD, 57 unaffected siblings, and 69 typically developing [TD]) and 64 parents. TL was measured from blood leukocytes with quantitative real-time polymerase chain reaction and results are expressed by relative ratios with a single copy gene. We replicated that children and adolescents with ASD have shorter TL, compared to TD, and show that unaffected siblings have TL in between those of TD and ASD. We present novel associations between TL and sensory symptoms in ASD. Finally, we demonstrate cognitive functions, but not autistic traits, are related to TL in parents of children with ASD. Cognitive function and TL were not related in children and adolescents. As the third replication, our results elicit confidence in the finding that ASD is associated with shorter TL. Our novel sensory investigation suggests that shortened TL may be a biological mechanism of sensory symptoms in ASD. Furthermore, results highlight the need to better understand relationships between cognition, aging, and TL in families with ASD. Autism Res 2020. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Telomeres cap chromosomes to protect DNA. They progressively shorten as people age and are related to health outcomes. We replicated previous findings that children and adolescents with autism spectrum disorder (ASD) have shorter telomeres, compared to typically developing (TD), and show that unaffected siblings have telomere length (TL) in between those of TD and ASD. We find shortened TL is related to more severe sensory symptoms. This may mean families with ASD, especially those with elevated sensory symptoms, are at risk for worse age-related health outcomes.

RevDate: 2020-04-23

Mangge H, Herrmann M, Almer G, et al (2020)

Telomere shortening associates with elevated insulin and nuchal fat accumulation.

Scientific reports, 10(1):6863 pii:10.1038/s41598-020-63916-6.

Obesity and relative leucocyte telomere length (RTL) are both linked to accelerated aging and premature mortality. We examined if nuchal subcutaneous adipose tissue (SAT) thickness, a surrogate marker of central trunk-weighted obesity, is an independent predictor of RTL that provides information beyond BMI, metabolic and inflammatory markers. RTL and nuchal SAT thickness were determined in 362 participants of the STYJOBS/EDECTA study (STYrian Juvenile Obesity Study, Early DEteCTion of atherosclerosis), which included overweight individuals and matched eutrophic controls. Fasting plasma samples were used for the measurement of leptin, resistin, adiponectin, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), liver enzymes, creatinine, cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, oxidized LDL, triglycerides, homocysteine and uric acid. Furthermore, all participants underwent carotid artery ultrasound. Obese individuals had markedly higher body mass index (BMI), nuchal SAT thickness, hip and waist circumferences and carotid intima media thickness (IMT) than eutrophic controls. In addition, they showed typical biochemical abnormalities related to energy metabolism, systemic inflammation and liver function. RTL was inversely correlated with nuchal SAT thickness, IMT, hs-CRP, alkaline phosphatase, insulin, resistin, and leptin. Positive correlations were seen with homocysteine and creatinine. Stepwise linear regression analyses identified nuchal SAT thickness and insulin as the only significant predictors of RTL. In conclusion, nuchal SAT thickness is a robust predictor of RTL that provides information beyond traditional obesity-related metabolic and inflammatory biomarkers. This suggests an important role of fat depots at the neck for accelerated telomere shortening.

RevDate: 2020-04-22

Deo P, Dhillon VS, Lim WM, et al (2020)

Advanced glycation end-products accelerate telomere attrition and increase pro-inflammatory mediators in human WIL2-NS cells.

Mutagenesis pii:5823765 [Epub ahead of print].

This study investigated the effect of dietary sugars and advanced glycation end-products (AGE) on telomere dynamics in WIL2-NS cells. Dietary sugars [glucose (Glu) and fructose (Fru); 0.1 M each] were incubated with bovine serum albumin (BSA) (10 mg/ml) at 60 ± 1°C for 6 weeks to generate AGE-BSA. Liquid chromatography-mass spectrometry (LC-MS/MS) analysis showed total AGE levels as 87.74 ± 4.46 nmol/mg and 84.94 ± 4.28 nmol/mg respectively in Glu-BSA and Fru-BSA model. Cell treatment studies using WIL2-NS cells were based on either glucose, fructose (each 2.5-40 mM) or AGE-BSA (200-600 µg/ml) in a dose-dependent manner for 9 days. Telomere length (TL) was measured using qPCR. Nitric oxide (NO) production and tumour necrosis factor-α (TNF-α) levels were measured in WIL2-NS culture medium. An increasing trend for TNF-α and NO production was observed with higher concentration of glucose (R2 = 0.358; P = 0.019; R2 = 0.307; P = 0.027) and fructose (R2 = 0.669; P = 0.001; R2 = 0.339; P = 0.006). A decreasing trend for TL (R2 = 0.828; P = 0.000), and an increasing trend for NO production (R2 = 0.352; P = 0.031) were observed with increasing Glu-BSA concentrations. Fru-BSA treatment did not show significant trend on TL (R2 = 0.135; P = 0.352) with increasing concentration, however, a significant reduction was observed at 600 µg/ml (P < 0.01) when compared to BSA treatment. No trends for TNF-α levels and a decreasing trend on NO production (R2 = 0.5201; P = 0.019) was observed with increasing Fru-BSA treatment. In conclusion, this study demonstrates a potential relationship between dietary sugars, AGEs and telomere attrition. AGEs may also exert telomere shortening through the production of pro-inflammatory metabolites, which ultimately increase the risk of diabetes complications and age-related disease throughout lifespan.

RevDate: 2020-04-22

Salmina K, Bojko A, Inashkina I, et al (2020)

"Mitotic Slippage" and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.

International journal of molecular sciences, 21(8): pii:ijms21082779.

Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.

RevDate: 2020-04-20

Diala I, Shiohama Y, Fujita T, et al (2020)

Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT.

Nucleosides, nucleotides & nucleic acids, 39(1-3):407-425.

Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.

RevDate: 2020-04-20

Liu Y, Liu Z, Wei Y, et al (2020)

Cloning and preliminary verification of telomere-associated sequences in upland cotton.

Comparative cytogenetics, 14(2):183-195 pii:49391.

Telomeres are structures enriched in repetitive sequences at the end of chromosomes. In this study, using the telomere primer AA(CCCTAAA)3CCC for the single primer PCR, two DNA sequences were obtained from Gossypium hirsutum (Linnaeus, 1753) accession (acc.) TM-1. Sequence analysis showed that the two obtained sequences were all rich in A/T base, which was consistent with the characteristic of the telomere-associated sequence (TAS). They were designated as GhTAS1 and GhTAS2 respectively. GhTAS1 is 489 bp long, with 57.6% of A/T, and GhTAS2 is 539 bp long, with 63.9% of A/T. Fluorescence in situ hybridization results showed that both of the cloned TASs were located at the ends of the partial chromosomes of G. hirsutum, with the strong signals, which further confirmed that GhTAS1 and GhTAS2 were telomere-associated sequences including highly tandemly repetitive sequences. Results of blast against the assembled genome of G. hirsutum showed that GhTAS sequences may be missed on some assembled chromosomes. The results provide important evidence for the evaluation of the integrity of assembled chromosome end sequences, and will also contribute to the further perfection of the draft genomes of cotton.

RevDate: 2020-04-18

Bergstrand S, Böhm S, Malmgren H, et al (2020)

Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome.

Cell death & disease, 11(4):238 pii:10.1038/s41419-020-2421-4.

Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53β (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53β, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53β HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53β-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.

RevDate: 2020-04-17

Natalini JG, George MD, Kawut SM, et al (2020)

Association between antinuclear antibody seropositivity and telomere length: a nationwide population-based study.

Clinical and experimental rheumatology pii:15159 [Epub ahead of print].

OBJECTIVES: Telomere shortening is a well-established marker of biological aging. Whether telomere erosion coincides with age-related increases in antinuclear antibody (ANA) seropositivity remains unknown. Our study aimed to determine the association between ANA seropositivity and shortened telomeres among 1999-2002 National Health and Nutrition Examination Survey (NHANES) subjects.

METHODS: We performed a cross-sectional analysis of 2,188 NHANES study participants with available ANA and telomere length data. ANA testing was performed using indirect immunofluorescence. Telomere lengths were measured via quantitative polymerase chain reaction methods. Applying appropriate sample weighting techniques, we used univariate and multivariate logistic regression methods to assess the association between shortened telomeres (i.e. lowest decile of the cohort) and ANA seropositivity.

RESULTS: ANAs were positive in 322 out of 2,188 (14.7%, 95% CI 13.3-16.3%) individuals. Subjects with shortened telomeres were more likely to be older (p<0.001), male (p=0.005), and have a cancer history (p<0.001). A higher proportion of non-Hispanic white participants (61.6% vs. 49.3%) and a lower proportion of non-Hispanic black participants (7.8% vs. 17.9%) had shortened telomeres (p<0.001). Shortened telomeres were not independently associated with ANA seropositivity (OR 1.48, 95% CI 0.87-2.52, p=0.14). However, female sex (OR 1.91, 95% CI 1.23-2.96, p=0.006), age ≥80 years (OR 2.06, 95% CI 1.08-3.92, p=0.03), and African American race (OR 1.58, 95% CI 1.00-2.51, p=0.05) were independent risk factors for ANA seropositivity. Neither sex nor race modified the relationship between ANA seropositivity and telomere length.

CONCLUSIONS: Telomere erosion does not appear to be responsible for age-related increases in the prevalence of ANA seropositivity.

RevDate: 2020-04-17

Karimi B, Nabizadeh R, M Yunesian (2020)

Association Between Leukocyte Telomere Length and Serum Concentrations of PCBs and Organochlorine Pesticides.

Archives of environmental contamination and toxicology pii:10.1007/s00244-020-00732-z [Epub ahead of print].

Exposure to polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) through food, water, and air occurred during the life, which may change telomere length (TL) in peripheral blood leukocytes. The present study was designed to investigate the association between TL and serum levels of PCBs and OCPs in Tehran male's population. Whole blood samples were randomly taken from 300 adult males, aged between 25 and 40 years. TL was determined by real-time PCR to measure the number of the telomere (T) repeats to the number of a single-copy gene (S). We applied the multivariate linear regression model to compare the effect of each lipid adjusted serum levels of PCBs and OCPs congener on the TL, with adjustment for age, body mass index, education, smoking, and food patterns. Each doubling of the nondioxin-like PCBs, dioxin-like PCBs, and OCPs levels were associated with 1.9% [95% confidence interval (CI) - 0.70 to 5.40%], 2.5% (95% CI 0.30-8.3%), and - 2.4% (95% CI - 0.70 to - 6.2%) variation in the TL, respectively. The percent difference in the TL with exposure to nondioxin-like PCBs, dioxin-like PCBs, and OCPs for participants with older than age 37 years were 6.45% (95% CI 2.81-16.50%), 4.52% (95% CI 1.60-10.54%), and - 7.44% (95% CI - 1.55 to - 15.51%), respectively. Exposures to nondioxin-like PCBs (except for PCB 28 and 52) with high chlorine in structure and dioxin-like PCBs were related to longer TLs. Conversely, serum levels of OCPs can be associated with oxidative stress and systemic inflammation that lead to telomere shortening.

RevDate: 2020-04-17

Toufektchan E, Lejour V, Durand R, et al (2020)

Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance.

Science advances, 6(15):eaay3511 pii:aay3511.

Dyskeratosis congenita is a cancer-prone inherited bone marrow failure syndrome caused by telomere dysfunction. A mouse model recently suggested that p53 regulates telomere metabolism, but the clinical relevance of this finding remained uncertain. Here, a germline missense mutation of MDM4, a negative regulator of p53, was found in a family with features suggestive of dyskeratosis congenita, e.g., bone marrow hypocellularity, short telomeres, tongue squamous cell carcinoma, and acute myeloid leukemia. Using a mouse model, we show that this mutation (p.T454M) leads to increased p53 activity, decreased telomere length, and bone marrow failure. Variations in p53 activity markedly altered the phenotype of Mdm4 mutant mice, suggesting an explanation for the variable expressivity of disease symptoms in the family. Our data indicate that a germline activation of the p53 pathway may cause telomere dysfunction and point to polymorphisms affecting this pathway as potential genetic modifiers of telomere biology and bone marrow function.

RevDate: 2020-04-16

Criqui M, Qamra A, Chu TW, et al (2020)

Telomere dysfunction cooperates with epigenetic alterations to impair murine embryonic stem cell fate commitment.

eLife, 9: pii:47333 [Epub ahead of print].

The precise relationship between epigenetic perturbations and telomere dysfunction is an extant question. Previously, we showed that telomere dysfunction leads to differentiation instability in murine embryonic stem cells (mESCs) via perturbations in DNA methylation at pluripotency-factor promoters. Here, we uncovered that telomerase reverse transcriptase null (Tert-/-) mESCs exhibit genome-wide perturbations in chromatin accessibility and gene expression during differentiation. These changes were accompanied by an increase of H3K27me3 globally, an altered chromatin landscape at the Pou5f1/Oct4 pluripotency gene promoter, and impaired Tert-/- mESC differentiation. Inhibition of the Polycomb Repressive Complex 2 (PRC2), an H3K27 tri-methyltransferase, exacerbated the impairment in differentiation and pluripotency gene repression in Tert-/- mESCs but not wild-type mESCs, whereas inhibition of H3K27me3 demethylation led to a partial rescue of the Tert-/- phenotype. This data reveals a new interdependent relationship between H3K27me3 and telomere integrity in stem cell lineage commitment that may have implications in aging and cancer.

RevDate: 2020-04-16

Li X, Jiang Y, Qiao S, et al (2020)

Effects of parental HIV on telomere length among children in rural China.

Health psychology : official journal of the Division of Health Psychology, American Psychological Association pii:2020-25433-001 [Epub ahead of print].

OBJECTIVE: Cumulative evidence has shown the adverse effects of HIV-related death and illness on children's psychosocial well-being. However, few studies have examined whether these factors can "get under the skin" to affect children's health. This study, therefore, examined the effects of HIV-related parental death on telomere length, a biomarker of cellular aging. This study further explored whether the results on telomere length were consistent with results based on self-report health outcomes, namely depressive symptoms.

METHOD: A total of 117 children (10-17 years of age) affected by parental HIV (27 children living with HIV-positive parents and 90 AIDS orphans) from Henan China provided blood samples for telomere length assay and completed a survey for depressive symptoms and demographic information.

RESULTS: Results showed that AIDS orphans had a shorter telomere length than children living with HIV-positive parents and that such differences in telomere length were more evident than were differences in depressive symptoms. There were no significant differences in telomere length or depressive symptoms between children who lost one parent and those who lost both.

CONCLUSIONS: The results suggest that HIV-related parental death may contribute to accelerated telomere shortening and highlight that telomere length may be a novel and useful biomarker for health needs assessment in pediatric AIDS care. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

RevDate: 2020-04-16

de Oliveira DM (2020)

Telomere Based Approach for Cancer Therapy.

Current topics in medicinal chemistry, 20(6):409.

RevDate: 2020-04-16

Sethi I, Sharma V, Sharma I, et al (2020)

Telomere Maintenance Genes are associated with Type 2 Diabetes Susceptibility in Northwest Indian Population Group.

Scientific reports, 10(1):6444 pii:10.1038/s41598-020-63510-w.

Telomere length attrition has been implicated in various complex disorders including Type 2 Diabetes (T2D). However, very few candidate gene association studies have been carried out worldwide targeting telomere maintenance genes. In the present study, variants in various critical telomere maintenance pathway genes for T2D susceptibility in Northwest Indian population were explored. With case-control candidate gene association study design, twelve variants from seven telomere maintenance genes were evaluated. Amongst these five variants, rs9419958 (OBFC1), rs4783704 (TERF2), rs16847897 (TERC/LRRC31), rs10936599 (TERC/MYNN), and rs74019828 (CSNK2A2) showed significant association with T2D (at p-value ≤ 0.003, threshold set after Bonferroni correction) in the studied population. In silico analyses of these variants indicated interesting functional roles that warrant experimental validations. Findings showed that variants in telomere maintenance genes are associated with pathogenesis of T2D in Northwest Indian population. We anticipate further, such candidate gene association studies in other Indian populations and worldwide would contribute in understanding the missing heritability of T2D.

RevDate: 2020-04-15

Cleal K, DM Baird (2020)

Catastrophic Endgames: Emerging Mechanisms of Telomere-Driven Genomic Instability.

Trends in genetics : TIG, 36(5):347-359.

When cells progress to malignancy, they must overcome a final telomere-mediated proliferative lifespan barrier called replicative crisis. Crisis is characterized by extensive telomere fusion that drives widespread genomic instability, mitotic arrest, hyperactivation of autophagy, and cell death. Recently, it has become apparent that that the resolution of dicentric chromosomes, which arise from telomere fusions during crisis, can initiate a sequence of events that leads to chromothripsis, a form of extreme genomic catastrophe. Chromothripsis is characterized by localized genomic regions containing tens to thousands of rearrangements and it is becoming increasingly apparent that chromothripsis occurs widely across tumor types and has a clinical impact. Here we discuss how telomere dysfunction can initiate genomic complexity and the emerging mechanisms of chromothripsis.

RevDate: 2020-04-15

Johnson SM, McGinty KA, Hayashi PH, et al (2020)

Large Cell Change in a Small Liver: A Histologic Clue to Short Telomere Syndromes?.

Hepatology (Baltimore, Md.) [Epub ahead of print].

Telomeres are DNA-protein complexes at the ends of chromosomes essential for maintaining genetic stability. Defects in genes coding telomere maintenance proteins rarely occur, resulting in accelerated telomere shortening. Termed short telomere syndromes (STSs), these conditions have diverse clinical manifestations, including premature hair greying, bone marrow failure, pulmonary fibrosis, early-onset malignancy, and cirrhosis. However, liver histopathologic changes have not been thoroughly described in STS patients. Here, we report a case of a patient with clinically-suspected cirrhosis and striking hepatocyte large cell change (LCC) on liver biopsy who was found to have an underlying STS.

RevDate: 2020-04-15

Koneru B, Lopez G, Farooqi A, et al (2020)

Telomere maintenance mechanisms define clinical outcome in high-risk neuroblastoma.

Cancer research pii:0008-5472.CAN-19-3068 [Epub ahead of print].

Neuroblastoma is a childhood cancer with heterogeneous clinical outcomes. To comprehensively assess the impact of telomere maintenance mechanism (TMM) on clinical outcomes in high-risk neuroblastoma, we integrated the C-circle assay (a marker for alternative lengthening of telomeres (ALT)), TERT mRNA expression by RNA sequencing, whole genome/exome sequencing, and clinical co-variates in 134 neuroblastoma patient samples at diagnosis. In addition, we assessed TMM in neuroblastoma cell lines (n=104) and PDX (n=28). ALT was identified in 23.4% of high-risk neuroblastoma tumors and genomic alterations in ATRX were detected in 60% of ALT tumors; 40% of ALT tumors lacked genomic alterations in known ALT-associated genes. High-risk neuroblastoma patients were classified into 3 subgroups (TERT-high, ALT+, and TERT-low/non-ALT) based on presence of C-circles and TERT mRNA expression (above or below median TERT expression). Event-free survival was similar among TERT-high, ALT+, or TERT-low/non-ALT patients. However, overall survival (OS) for TERT-low/non-ALT patients was significantly higher relative to TERT-high or ALT patients (log-rank test; P < 0.01) independent of current clinical and molecular prognostic markers. Consistent with the observed higher OS in patients with TERT-low/non-ALT tumors, continuous shortening of telomeres and decreasing viability occurred in low TERT-expressing, non-ALT patient-derived high-risk neuroblastoma cell lines. These findings demonstrate that assaying TMM with TERT mRNA expression and C-circles provides precise stratification of high-risk neuroblastoma into three subgroups with substantially different OS: a previously undescribed TERT-low/non-ALT cohort with superior overall survival (even after relapse) and two cohorts of patients with poor survival that have distinct molecular therapeutic targets.

RevDate: 2020-04-15

Recagni M, Bidzinska J, Zaffaroni N, et al (2020)

The Role of Alternative Lengthening of Telomeres Mechanism in Cancer: Translational and Therapeutic Implications.

Cancers, 12(4): pii:cancers12040949.

Telomere maintenance mechanisms (i.e., telomerase activity (TA) and the alternative lengthening of telomere (ALT) mechanism) contribute to tumorigenesis by providing unlimited proliferative capacity to cancer cells. Although the role of either telomere maintenance mechanisms seems to be equivalent in providing a limitless proliferative ability to tumor cells, the contribution of TA and ALT to the clinical outcome of patients may differ prominently. In addition, several strategies have been developed to interfere with TA in cancer, including Imetelstat that has been the first telomerase inhibitor tested in clinical trials. Conversely, the limited information available on the molecular underpinnings of ALT has hindered thus far the development of genuine ALT-targeting agents. Moreover, whether anti-telomerase therapies may be hampered or not by possible adaptive responses is still debatable. Nonetheless, it is plausible hypothesizing that treatment with telomerase inhibitors may exert selective pressure for the emergence of cancer cells that become resistant to treatment by activating the ALT mechanism. This notion, together with the evidence that both telomere maintenance mechanisms may coexist within the same tumor and may distinctly impinge on patients' outcomes, suggests that ALT may exert an unexpected role in tumor biology that still needs to be fully elucidated.

RevDate: 2020-04-14

Scarabino D, Peconi M, Broggio E, et al (2020)

Relationship between proinflammatory cytokines (Il-1beta, Il-18) and leukocyte telomere length in mild cognitive impairment and Alzheimer's disease.

Experimental gerontology pii:S0531-5565(20)30293-X [Epub ahead of print].

Inflammation plays a crucial role in Alzheimer's disease (AD). AD neurodegeneration and concurrent involvement of the peripheral immune system may promote leukocyte division and telomere shortening. We examined genotypes and plasma levels of two proinflammatory cytokines, IL-1beta and IL-18, and leukocyte telomere length (LTL) in patients with mild cognitive impairment (MCI) and AD. We wanted to determine whether changes in plasma IL-1beta and IL-18 levels, together with LTL shortening, could be diagnostic for disease progression from MCI to AD. Median plasma IL-1beta levels were in the order MCI patients (2.2 pg/mL) < AD patients (4.0 pg/mL), both of which differed significantly from the controls (0.0 pg/mL). In the AD patients, the lowest IL-1beta levels were associated with the presence of the C allele of IL-1beta rs16944 SNP. Median plasma IL-18 levels were in the order MCI patients (116.3 pg/mL) > AD patients (85.8 pg/mL), both of which were significantly higher than in the controls (17.6 pg/mL). Analysis of LTL showed a progressive reduction in the order controls > MCI > AD patients (p < 0.0001). Overall LTL reduction was correlated with increased plasma IL-1beta levels, substantiating the hypothesis that inflammatory processes secondary to neuroinflammation may trigger telomere attrition. Changes in plasma IL-1beta and Il-18 levels, and LTL seem to reflect shifts in AD stage; they may have potential use as blood biomarkers to monitor disease onset and progression from MCI to AD.

RevDate: 2020-04-14

Langston RE, Palazzola D, Bonnell E, et al (2020)

Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping.

PLoS genetics, 16(4):e1008733 pii:PGENETICS-D-19-01631 [Epub ahead of print].

In budding yeast, Cdc13, Stn1, and Ten1 form the telomere-binding heterotrimer CST complex. Here we investigate the role of Cdc13/CST in maintaining genome stability by using a Chr VII disome system that can generate recombinants, chromosome loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitive CDC13 allele, cdc13F684S, unstable chromosomes frequently arise from problems in or near a telomere. We found that, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes that are then the source for additional chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or chromosome loss). We observed that genome instability arises from a defect in Cdc13's function during DNA replication, not Cdc13's putative post-replication telomere capping function. The molecular nature of the initial unstable chromosomes formed by a Cdc13-defect involves ssDNA and does not involve homologous recombination nor non-homologous end joining; we speculate the original unstable chromosome may be a one-ended double strand break. This system defines a link between Cdc13's function during DNA replication and genome stability in the form of unstable chromosomes, that then progress to form other chromosome changes.

RevDate: 2020-04-14

Viera A, Berenguer I, Ruiz-Torres M, et al (2020)

PDS5 proteins regulate the length of axial elements and telomere integrity during male mouse meiosis.

EMBO reports [Epub ahead of print].

Cohesin cofactors regulate the loading, maintenance, and release of cohesin complexes from chromosomes during mitosis but little is known on their role during vertebrate meiosis. One such cofactor is PDS5, which exists as two paralogs in somatic and germline cells, PDS5A and PDS5B, with unclear functions. Here, we have analyzed their distribution and functions in mouse spermatocytes. We show that simultaneous excision of Pds5A and Pds5B results in severe defects during early prophase I while their individual depletion does not, suggesting their functional redundancy. Shortened axial/lateral elements and a reduction of early recombination nodules are observed after the strong depletion of PDS5A/B proteins. Moreover, telomere integrity and their association to the nuclear envelope are severely compromised. As these defects occur without detectable reduction in chromosome-bound cohesin, we propose that the dynamic behavior of the complex, mediated by PDS5 proteins, is key for successful completion of meiotic prophase I.

RevDate: 2020-04-14

Marques A, Gouveira ÉR, Peralta M, et al (2020)

Cardiorespiratory fitness and telomere length: a systematic review.

Journal of sports sciences [Epub ahead of print].

This study aimed to systematically review the association between cardiorespiratory fitness and telomere length (TL). Studies were identified from searches in Cochrane Central, PubMed, Scopus, Sportdiscus, and Web of Science databases through July 2019. Eligibility criteria included: cross-sectional, prospective, and experimental study design; outcomes included TL; results expressed the relationship between cardiorespiratory fitness and TL; studies published in English, Portuguese, or Spanish. A total of 20 articles met the inclusion criteria. Sixteen studies (80%) reported a significant relationship between cardiorespiratory fitness, or training load, and TL. Better cardiorespiratory fitness or a large cardiorespiratory training load are associated with an increase in TL. Although, TL was related to regular moderate-to-vigorous aerobic exercise and cardiorespiratory fitness in older healthy humans, it was not related to cardiorespiratory fitness among young subjects. There seems to be a positive and significant relationship between cardiorespiratory fitness and TL, mainly among middle age and older people, which emphasizes the importance of cardiorespiratory fitness for healthy ageing. Therefore, endurance exercise and better cardiorespiratory fitness may regulate the TL in middle age and older adults, slowing the cellular ageing process.

RevDate: 2020-04-11

Rossi M, M Gorospe (2020)

Noncoding RNAs Controlling Telomere Homeostasis in Senescence and Aging.

Trends in molecular medicine, 26(4):422-433.

Aging is a universal and time-dependent biological decline associated with progressive deterioration of cells, tissues, and organs. Age-related decay can eventually lead to pathology such as cardiovascular and neurodegenerative diseases, cancer, and diabetes. A prominent molecular process underlying aging is the progressive shortening of telomeres, the structures that protect the ends of chromosomes, eventually triggering cellular senescence. Noncoding (nc)RNAs are emerging as major regulators of telomere length homeostasis. In this review, we describe the impact of ncRNAs on telomere function and discuss their implications in senescence and age-related diseases. We discuss emerging therapeutic strategies targeting telomere-regulatory ncRNAs in aging pathology.

RevDate: 2020-04-10

Schratz KE, M Armanios (2020)

Cancer and myeloid clonal evolution in the short telomere syndromes.

Current opinion in genetics & development, 60:112-118 pii:S0959-437X(20)30024-1 [Epub ahead of print].

The short telomere syndromes are considered the most common premature aging disorders. Although studies in genetically modified cells and animal models have suggested telomere dysfunction may promote genome instability, only a minority of humans with inherited loss-of-function mutations in telomerase and related genes develop cancer. Solid tumors are overall rare, and the vast majority of cancers are bone marrow-derived with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) comprising three-quarter of cases. In contrast to young short telomere syndrome patients who develop aplastic anemia, MDS and AML are usually diagnosed in adults who have milder short telomere defects. Here, we dissect the mechanisms by which these two bone marrow failure states, aplastic anemia and MDS-AML, evolve in the setting of varying degrees of telomere shortening. We discuss of these observations for patient care as well as for understanding the genetics and biology of age-related myeloid clonal evolution.

RevDate: 2020-04-08

Chalouni M, Rodriguez-Centeno J, Samri A, et al (2020)

Correlation between blood telomere length and CD4+ CD8+ T-cell subsets changes 96 weeks after initiation of antiretroviral therapy in HIV-1-positive individuals.

PloS one, 15(4):e0230772 pii:PONE-D-19-29458.

In 31 participants who started first-line antiretroviral therapy in the NEAT 001/ANRS 143 clinical trial, we found after 96 weeks a statistically significant increase in blood telomere length (TL) of 0.04 (T/S Ratio) (p = 0.03). This increase was positively correlated with both the change in the percentage of CD4+ T-cells and with the decrease of CD38+ molecules on Central Memory CD8+ and negatively correlated with the change in the percentage of CD4+ Effector Memory cells. Increase in TL could be an expression of immune reconstitution and the associated decrease in immune activation. We acknowledge for the low statistical power due to the small sample size and the potential for false positive results due to multiple testing. Hence, further studies are needed to confirm these observations.

RevDate: 2020-04-08

Utyro O, Perła-Kaján J, H Jakubowski (2020)

The Cbs Locus Affects the Expression of Senescence Markers and mtDNA Copy Number, but not Telomere Dynamics in Mice.

International journal of molecular sciences, 21(7): pii:ijms21072520.

Cystathionine β-synthase (CBS) is a housekeeping enzyme that catalyzes the first step of the homocysteine to cysteine transsulfuration pathway. Homozygous deletion of the Cbs gene in mice causes severe hyperhomocysteinemia and reduces life span. Here, we examined a possible involvement of senescence, mitochondrial DNA, and telomeres in the reduced life span of Cbs-/- mice. We found that senescence-related p21, Pai-1, Mcp1, and Il-6 mRNAs were significantly upregulated (2-10-fold) in liver, while p21 was upregulated in the brain of Cbs-/- mice (n = 20) compared with control Cbs+/- siblings (n = 20) in a sex- and age-dependent manner. Telomere length in blood (n = 80), liver (n = 40), and brain (n = 40) was not affected by the Cbs-/- genotype, but varied with sex and/or age. Levels of mitochondrial DNA tended to be reduced in livers, but not brains and blood, of Cbs-/- females (n = 20-40). The Cbs-/- genotype significantly reduced Tert mRNA expression in brain, but not liver, in a sex- and age-dependent manner. Multiple regression analysis showed that the senescence-related liver (but not brain) mRNAs and liver (but not brain or blood) mitochondrial DNA were associated with the Cbs genotype. In contrast, telomere length in blood, brain, and liver was not associated with the Cbs genotype or hyperhomocysteinemia, but was associated with sex (in brain and liver) and age (in brain and blood). Taken together, these findings suggest that the changes in senescence marker expression and mtDNA levels, but not telomere shortening, could account for the reduced life span of Cbs-/- mice.

RevDate: 2020-04-08

Joglekar MV, Satoor SN, Wong WKM, et al (2020)

An Optimised Step-by-Step Protocol for Measuring Relative Telomere Length.

Methods and protocols, 3(2): pii:mps3020027.

Telomeres represent the nucleotide repeat sequences at the ends of chromosomes and are essential for chromosome stability. They can shorten at each round of DNA replication mainly because of incomplete DNA synthesis of the lagging strand. Reduced relative telomere length is associated with aging and a range of disease states. Different methods such as terminal restriction fragment analysis, real-time quantitative PCR (qPCR) and fluorescence in situ hybridization are available to measure telomere length; however, the qPCR-based method is commonly used for large population-based studies. There are multiple variations across qPCR-based methods, including the choice of the single-copy gene, primer sequences, reagents, and data analysis methods in the different reported studies so far. Here, we provide a detailed step-by-step protocol that we have optimized and successfully tested in the hands of other users. This protocol will help researchers interested in measuring relative telomere lengths in cells or across larger clinical cohort/study samples to determine associations of telomere length with health and disease.

RevDate: 2020-04-07

Tan J, L Lan (2020)

The DNA secondary structures at telomeres and genome instability.

Cell & bioscience, 10:47 pii:409.

Telomeric DNA are TTAGGG tandem repeats, which are susceptible for oxidative DNA damage and hotspot regions for formation of DNA secondary structures such as t-loop, D-loop, G-quadruplexes (G4), and R-loop. In the past two decades, unique DNA or RNA secondary structures at telomeres or some specific regions of genome have become promising therapeutic targets. G-quadruplex and R-loops at telomeres or transcribed regions of genome have been considered as the potential targets for cancer therapy. Here we discuss the potentials to target the secondary structures (G4s and R-loops) in genome as therapy approaches.

RevDate: 2020-04-06

Koi Y, Tsutani Y, Nishiyama Y, et al (2020)

Diagnostic performance of peripheral leukocyte telomere G-tail length for detecting breast cancer.

The telomere G-tail (G-tail) plays an essential role in maintaining chromosome stability. In this study, we assessed the leukocyte G-tail length of breast cancer (BC) patients and cancer-free individuals and evaluated the association between the G-tail length and the presence of BC. A significant shortening of the median G-tail length was observed in BC patients compared with cancer-free individuals and was found in the early phase of BC. Our study indicated that the leukocyte G-tail length might be a potential biomarker for BC detection.

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In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

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In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

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In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

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With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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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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