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Sökning: WFRF:(von Zglinicki Thomas)

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1.
  • Gardner, Michael, et al. (författare)
  • Gender and telomere length : Systematic review and meta-analysis
  • 2014
  • Ingår i: Experimental Gerontology. - : Elsevier. - 0531-5565 .- 1873-6815. ; 51, s. 15-27
  • Forskningsöversikt (refereegranskat)abstract
    • Background: It is widely believed that females have longer telomeres than males, although results from studies have been contradictory. Methods: We carried out a systematic review and meta-analyses to test the hypothesis that in humans, females have longer telomeres than males and that this association becomes stronger with increasing age. Searches were conducted in EMBASE and MEDLINE (by November 2009) and additional datasets were obtained from study investigators. Eligible observational studies measured telomeres for both females and males of any age, had a minimum sample size of 100 and included participants not part of a diseased group. We calculated summary estimates using random-effects meta-analyses. Heterogeneity between studies was investigated using sub-group analysis and meta-regression. Results: Meta-analyses from 36 cohorts (36,230 participants) showed that on average females had longer telomeres than males (standardised difference in telomere length between females and males 0.090, 95% CI 0.015, 0.166; age-adjusted). There was little evidence that these associations varied by age group (p = 1.00) or cell type (p = 0.29). However, the size of this difference did vary by measurement methods, with only Southern blot but neither real-time PCR nor Flow-FISH showing a significant difference. This difference was not associated with random measurement error. Conclusions: Telomere length is longer in females thanmales, although this difference was not universally found in studies that did not use Southern blot methods. Further research on explanations for the methodological differences is required. (C) 2013 Published by Elsevier Inc.
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2.
  • Kurz, Tino, 1974-, et al. (författare)
  • Lysosomal redox-active iron is important for oxidative stress-induced DNA damage
  • 2004
  • Ingår i: Annals of the New York Academy of Sciences. - 0077-8923 .- 1749-6632. ; 1019, s. 285-288
  • Tidskriftsartikel (refereegranskat)abstract
    • Data show that specifically chelating lysosomal redox-active iron can prevent most H2O2-induced DNA damage. Lysosomes seem to contain the major pool of redox-active labile iron within the cell. Under oxidative stress conditions, this iron may then relocate to the nucleus and play an important role for DNA damage by taking part in Fenton reactions.
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3.
  • Kurz, Tino, 1974-, et al. (författare)
  • Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage
  • 2004
  • Ingår i: Biochemical Journal. - 0264-6021 .- 1470-8728. ; 378:3, s. 1039-1045
  • Tidskriftsartikel (refereegranskat)abstract
    • Oxidative damage to nuclear DNA is known to involve site-specific Fenton-type chemistry catalysed by redox-active iron or copper in the immediate vicinity of DNA. However, the presence of transition metals in the nucleus has not been shown convincingly. Recently, it was proposed that a major part of the cellular pool of loose iron is confined within the acidic vacuolar compartment [Yu, Persson, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1243-1252, Persson, Yu, Tirosh, Eaton and Brunk (2003) Free Radical Biol. Med. 34, 1295-1305]. Consequently, rupture of secondary lysosomes, as well as subsequent relocation of labile iron to the nucleus, could be an important intermediary step in the generation of oxidative damage to DNA. To test this concept we employed the potent iron chelator DFO (desferrioxamine) conjugated with starch to form an HMM-DFO (high-molecular-mass DFO complex). The HMM-DFO complex will enter cells only via fluid-phase endocytosis and remain within the acidic vacuolar compartment, thereby chelating redox-active iron exclusively inside the endosomal/lysosomal compartment. Both free DFO and HMM-DFO equally protected lysosomal-membrane integrity against H2O 2-induced oxidative disruption. More importantly, both forms of DFO prevented H2O2-induced strand breaks in nuclear DNA, including telomeres. To exclude the possibility that lysosomal hydrolases, rather than iron, caused the observed DNA damage, limited lysosomal rupture was induced using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride, subsequently, hardly any DNA damage was found. These observations suggest that rapid oxidative damage to cellular DNA is minimal in the absence of redox-active iron and that oxidant-mediated DNA damage, observed in normal cells, is mainly derived from intralysosomal iron translocated to the nucleus after lysosomal rupture.
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5.
  • Martin-Ruiz, Carmen M, et al. (författare)
  • Reproducibility of telomere length assessment : an international collaborative study
  • 2015
  • Ingår i: International Journal of Epidemiology. - : Oxford University Press. - 0300-5771 .- 1464-3685. ; 44:5, s. 1673-1683
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.
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7.
  • Nordfjäll, Katarina, 1981- (författare)
  • Telomere length - inheritance pattern and role as a biomarker
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Telomeres are repetitive TTAGGG structures ending each chromosome and thereby protecting its integrity. Due to the end-replication problem, telomeres shorten with each cell division. When reaching a critical telomere length (TL), the cells stop dividing and enter replicative senescence. It has been speculated that telomeres might regulate lifespan at the organism level but this hypothesis is controversial. However, telomeres in human blood cells do shorten with increasing age. Telomerase is an enzyme capable of lengthen telomeres. It consists of a catalytic subunit, hTERT, and a RNA template, hTR. Telomerase is active in germ cells, stem cells, activated lymphocytes and highly proliferating epithelial cells while no activity is found in other somatic cells. One step in order to produce a tumour mass is that cancer cells need to have a limitless replicative potential and this can be achieved by activating telomerase. Most tumour cells express telomerase activity and hence, the enzyme is an interesting target for cancer therapy. Telomere length is in part inherited. Two separate family cohorts were investigated to elucidate the inheritance pattern and a strong paternal inheritance was observed. In the larger, multifamily cohort spanning up to four generations, a weak correlation between the TL of the mother and the child was also found, as well as a significant correlation between grandparent-grandchild pairs. Interestingly, the heritable impact diminished with increasing age, indicating than non-heritable factors might influence TL during life. A functional T to C transition polymorphism in the hTERT promoter was previously reported, showing that the -1327C/C genotype was correlated with shorter TL compared to the alternative genotypes in healthy individuals and in coronary artery disease patients. When investigating 226 myocardial infarction patients and 444 controls separately, no differences were observed regarding mean TL or increased attrition rate between the different genotypes. TL in blood cells is shown to be altered in patients with certain types of solid tumours. In our breast cancer cohort, TL was a strong prognostic marker. Short telomeres were associated with increased survival, especially in young patients and in those with advanced tumours. It has been speculated that cancer patients might have a faster telomere attrition rate than controls but this has not been experimentally proven. Two blood samples from the same individual taken with 9-11 years interval was investigated. Some were diagnosed with a malignancy after the second blood draw. When comparing patients with controls, telomere attrition rate was not correlated to future tumour development. About one third of the individuals elongated their telomeres over a decade and the individual telomere attrition rate was telomere length dependent, showing an inverse correlation to TL at a highly significant level. This strongly suggests that the TL maintenance mechanism shown to provide protection for short telomeres in vitro is important also in human cells in vivo.
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8.
  • Terman, Alexei, 1957- (författare)
  • Mechanisms of lipofuscin/ceroid accumulation and its impact on the function of the lysosomal system
  • 1999
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • The accumulation of lipofuscin - an electron-dense, autofluorescent, polymeric, intralysosomal substance - is a recognized hallmark of aging postmitotic cells. Ceroid- a substance very close, or perhaps even identical, to lipofuscin - is a characteristic of various pathological processes, such as lysosomal storage diseases, malnutrition, atherosclerosis, oxidative stress, ionizing radiation, etc. Although the mechanisms of lipofuscin formation are now rather well understood (Brunk et al., 1992), what causes it to accumulate within aging postmitotic cells (namely, the role of its possibly impaired degradation/exocytosis) is still disputed. Moreover, little is known about whether lipofuscin accumulation interferes with normal cellular functions, perhaps it even promotes cell death and age-associated pathologies. The role, if any, of ceroid accumulation in the pathogenesis of many diseases also is not clear.To gain a better insight into the mechanisms of lipofuscin/ceroid accumulation, and to test whether this accumulation has any negative impact on cellular functions, especially on the autophagocytotic process, we decided to study: (l) the role of oxidative stress (normobaric hyperoxia) and/or lysosomal protease inhibition (leupeptin treatment) in lipofuscin/ceroid accumulation in cultured AG-1518 human fibroblasts and neonatal rat cardiac myocytes; (2) the fate of formed lipofuscin/ceroid after the cessation of oxidative stress and/or protease inhibition; (3) the possible reversal of lipofuscin/ceroid accumulation in vitro with an anti-aging drug centrophenoxine; (4) the survival of lipofuscin/ceroid-loaded fibroblasts under amino acid starvation; (5) the effect of lipofuscin/ceroid accumulation on autophagocytosis and intralysosomal degradation; and (6) the sensitivity of lipofuscin/ceroid-loaded fibroblasts to oxidative stress.We have shown that: (1) both oxidative stress and lysosomal protease inhibition accelerated lipofuscin/ceroid formation, however the effects of these two factors increased dramatically when they acted concurrently; (2) protease-inhibition by itself does not lead to lipofuscin/ceroid formation, but rather allows the prolonged time needed for oxidative modification of autophagocytosed material; (3) lipofuscin/ceroid inclusions formed due to oxidative stress and protease inhibition do not disappear either after returning the cultured cells to normal conditions, during amino acid starvation, or under the influence of centrophenoxine; (4) lipofuscin/ceroid-loaded cells exposed to amino acid starvation show decreased survival time and diminished autophagocytosis; (5) exposure of fibroblasts with various amounts of lipofuscin/ceroid to naphthazarin (a redox cycling quinone producing 0 2 ·-and H20 2) results in selective survival of cells with lower quantities of the pigment; and (6) lipofuscin/ceroid-rich cells have an expanded lysosomal compartment with increased amounts of cathepsin D.The results suggest that: (i) lipofuscin/ceroid forms within secondary lysosomes due to oxidative damage of autophagocytosed material resulting in cross-linking of protein residues by aldehydes formed from decomposed peroxidized unsaturated lipids; (ii) lipofuscin/ceroid is not substantially eliminated from non-dividing cells by degradation or exocytosis, which explains the progressive accumulation of lipofuscin in postmitotic cells with age; and (iii) a heavy lipofuscin/ceroid loading of cells interferes with normal lysosomal functions by making them less able to autophagocytose and more sensitive to oxidative stress, conceivably due to increased amounts of lysosomal enzymes (potential mediators of oxidative damage) and/or due to a possible catalyzing role of lipofuscin/ceroid-associated iron.
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