Telomere Disease

Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
New England Journal of Medicine (Impact Factor: 55.87). 12/2009; 361(24):2353-65. DOI: 10.1056/NEJMra0903373
Source: PubMed
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Available from: Rodrigo T Calado
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    • "The exercise-induced regulation of telomeric genes and miRNAs may provide an important mechanistic link between physical activity, telomeres and improved health. This is an important finding given the extensive evidence linking accelerated telomere shortening to several chronic diseases [39], many of which can be ameliorated by aerobic exercise [40]. Telomere homeostasis underpins the function of several immune cell subsets [41], which in turn play critical roles in chronic pathology such as age-related diseases [42], atherosclerosis [43] and metabolic diseases [44]. "
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    ABSTRACT: Telomeres are specialized nucleoprotein structures that protect chromosomal ends from degradation. These structures progressively shorten during cellular division and can signal replicative senescence below a critical length. Telomere length is predominantly maintained by the enzyme telomerase. Significant decreases in telomere length and telomerase activity are associated with a host of chronic diseases; conversely their maintenance underpins the optimal function of the adaptive immune system. Habitual physical activity is associated with longer leukocyte telomere length; however, the precise mechanisms are unclear. Potential hypotheses include regulation of telomeric gene transcription and/or microRNAs (miRNAs). We investigated the acute exercise-induced response of telomeric genes and miRNAs in twenty-two healthy males (mean age = 24.1±1.55 years). Participants undertook 30 minutes of treadmill running at 80% of peak oxygen uptake. Blood samples were taken before exercise, immediately post-exercise and 60 minutes post-exercise. Total RNA from white blood cells was submitted to miRNA arrays and telomere extension mRNA array. Results were individually validated in white blood cells and sorted T cell lymphocyte subsets using quantitative real-time PCR (qPCR). Telomerase reverse transcriptase (TERT) mRNA (P = 0.001) and sirtuin-6 (SIRT6) (P<0.05) mRNA expression were upregulated in white blood cells after exercise. Fifty-six miRNAs were also differentially regulated post-exercise (FDR <0.05). In silico analysis identified four miRNAs (miR-186, miR-181, miR-15a and miR-96) that potentially targeted telomeric gene mRNA. The four miRNAs exhibited significant upregulation 60 minutes post-exercise (P<0.001). Telomeric repeat binding factor 2, interacting protein (TERF2IP) was identified as a potential binding target for miR-186 and miR-96 and demonstrated concomitant downregulation (P<0.01) at the corresponding time point. Intense cardiorespiratory exercise was sufficient to differentially regulate key telomeric genes and miRNAs in white blood cells. These results may provide a mechanistic insight into telomere homeostasis and improved immune function and physical health.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "conferring resistance to physical and chemical stressors (Sung et al. 2005; Rubio et al. 2004; Calado & Young 2009). Also, lithium that has been widely used as antidepressant in BD (Yatham et al. 2013; Machado-Vieira et al. 2009), recently, its long term use was associated with longer telomeres (Martinsson et al. 2013). "
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    ABSTRACT: Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. Recently, shorten telomeres length has been reported in bipolar disorder (BD) and depression. The enzyme telomerase regulates telomeres length, which has been associated with cellular viability; however it is not clear how telomerase may be involved in the pathophysiology and therapeutics of BD. In the present study, leukocyte telomerase activity was assessed in 28 medication-free BD depressed individuals (DSM-IV-TR criteria) at baseline and after 6 weeks of lithium therapy (n=21) also matched with 23 healthy controls. There was no difference between telomerase activity in subjects with BD depression (before or after lithium) and controls. Improvement of depressive symptoms was negatively associated with telomerase activity after 6 weeks of lithium therapy. This is the first study describing telomerase activity in BD research. Overall, telomerase activity seems not directly involved in the pathophysiology of short-term BD. Lithium's antidepressant effects may involve regulation at telomerase activity. Further studies with larger samples and long-term illness are also warranted.
    Full-text · Article · Apr 2014 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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    • "Extremely shortened telomeres have been reported in severe acquired aplastic anemia (AA) and patients with dyskeratosis congenita (DKC), both of which are associated with progressive bone marrow failure syndromes. Telomere attrition in these patients might result either from increased hematopoietic cell turnover due to autoimmune-mediated depletion of the hematopoietic stem cell pool, or, particularly in DKC, due to direct functional impairment of the telomerase complex by inactivating mutations [49,50]. We analyzed blood from 15 AA and 5 DKC patients, which revealed significantly shorter telomeres than healthy controls (Figure S12b in Additional file 1). "
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    ABSTRACT: Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs - located in the genes ITGA2B, ASPA and PDE4C - were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita - two diseases associated with progressive bone marrow failure and severe telomere attrition - are predicted to be prematurely aged. Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood.
    Full-text · Article · Feb 2014 · Genome biology
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