Biomedical subjects

Thomas Von Zglinicki

Publications and source records attributed to Thomas Von Zglinicki.

7 recordsLinked to original sources

PubMed2006

Telomere length predicts poststroke mortality, dementia, and cognitive decline.

OBJECTIVE: Long-term cognitive development is variable among stroke survivors, with a high proportion developing dementia. Early identification of those at risk is highly desirable to target interventions for secondary prevention. Telomere length in peripheral blood mononuclear cells was tested as prognostic risk marker. METHODS: A cohort of 195 nondemented stroke survivors was followed prospectively from 3 months after stroke for 2 years for cognitive assessment and diagnosis of dementia and for 5 years for survival. Telomere lengths in peripheral blood mononuclear cells were measured at 3 months after stroke by in-gel hybridization. Hazard ratios for survival in relation to telomere length and odds ratios for dementia were estimated using multivariate techniques, and changes in Mini-Mental State Examination scores between baseline and 2 years were related to telomere length using multivariate linear regression. RESULTS: Longer telomeres at baseline were associated with reduced risk for death (hazard ratio for linear trend per 1,000 bp = 0.52; 95% confidence interval, 0.28-0.98; p = 0.04, adjusted for age) and dementia (odds ratio for linear trend per 1,000 bp = 0.19; 95% confidence interval, 0.07-0.54; p = 0.002) and less reduction in Mini-Mental State Examination score (p = 0.04, adjusted for baseline score). INTERPRETATION: Telomere length is a prognostic marker for poststroke cognitive decline, dementia, and death.

Aged↗

PubMed2006

Oxygen free radicals in cell senescence: are they signal transducers?

Oxygen free radicals have a major impact on senescence of primary human cells. In replicative senescence, which is induced by uncapping of telomeres, the rate of telomere shortening is largely determined by telomere-specific accumulation of DNA damage induced by reactive oxygen species (ROS). More intense ROS-generating stressors can induce premature senescence via generation of telomere-independent DNA damage. Interestingly, ROS levels were also elevated when premature senescence was triggered by pathways downstream or independent of DNA damage. This has led to the suggestion that ROS generation could be a specific component of the signalling pathways inducing senescence. However, the available data are compatible with the concept that senescence is triggered as a DNA damage response. ROS appear to be involved as inducers of DNA damage rather than as specific signalling molecules. The upregulation of ROS production often seen in premature senescence might be related to retrograde response initiated by mitochondria.

Cellular Senescence↗

PubMed2004

Relocalized redox-active lysosomal iron is an important mediator of oxidative-stress-induced DNA damage.

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 H2O2-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.

DNA Damage↗

PubMed2004

Telomere shortening in human fibroblasts is not dependent on the size of the telomeric-3'-overhang.

Telomeres shorten in human somatic cells with each round of DNA replication, and this shortening is thought to ultimately trigger replicative senescence. Telomere shortening is caused partly by the inability of semiconservative DNA replication to copy a linear strand of DNA to its very end. Post-replicative processing of telomeric ends, producing single-stranded G-rich 3' overhangs, has also been suggested to contribute to telomere shortening. This suggestion implies that a positive correlation should exist between the length of 3' overhangs and the rate of telomere shortening. We confirmed shortening of overhangs as human lung (MRC5) and foreskin (BJ) fibroblasts approach senescence by measuring overhang length using in-gel hybridization. However, a large study of fibroblast strains from 21 donors maintained under conditions which lead to two orders of magnitude of variation in telomere shortening rate failed to show any correlation between telomere overhang length and shortening rate, suggesting that overhang length is neither a cause nor a correlate of telomere shortening.

Electrophoresis, Gel, Pulsed-Field↗

PubMed2003

A DNA damage checkpoint response in telomere-initiated senescence.

Most human somatic cells can undergo only a limited number of population doublings in vitro. This exhaustion of proliferative potential, called senescence, can be triggered when telomeres--the ends of linear chromosomes-cannot fulfil their normal protective functions. Here we show that senescent human fibroblasts display molecular markers characteristic of cells bearing DNA double-strand breaks. These markers include nuclear foci of phosphorylated histone H2AX and their co-localization with DNA repair and DNA damage checkpoint factors such as 53BP1, MDC1 and NBS1. We also show that senescent cells contain activated forms of the DNA damage checkpoint kinases CHK1 and CHK2. Furthermore, by chromatin immunoprecipitation and whole-genome scanning approaches, we show that the chromosome ends of senescent cells directly contribute to the DNA damage response, and that uncapped telomeres directly associate with many, but not all, DNA damage response proteins. Finally, we show that inactivation of DNA damage checkpoint kinases in senescent cells can restore cell-cycle progression into S phase. Thus, we propose that telomere-initiated senescence reflects a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Replicative aging, telomeres, and oxidative stress.

Aging is a very complex phenomenon, both in vivo and in vitro. Free radicals and oxidative stress have been suggested for a long time to be involved in or even to be causal for the aging process. Telomeres are special structures at the end of chromosomes. They shorten during each round of replication and this has been characterized as a mitotic counting mechanism. Our experiments show that the rate of telomere shortening in vitro is modulated by oxidative stress as well as by differences in antioxidative defence capacity between cell strains. In vivo we found a strong correlation between short telomeres in blood lymphocytes and the incidence of vascular dementia. These data suggest that parameters that characterise replicative senescence in vitro offer potential for understanding of, and intervention into, the aging process in vivo.

Aging↗

PubMedDate not supplied

Replicative senescence and the art of counting.

The idea that aging is largely the result of (endogenous) stress appears to be at odds with the concept of biological 'clocks', which seem to programme and terminate cellular aging processes. Here, data are reviewed that show that telomeres, the major clock identified in human cells so far, do in fact measure stress and damage accumulation much more than simple mitotic time. Telomere shortening is significantly stress-dependent due to a telomere-specific damage repair deficiency. This identifies telomere-driven human cell replicative senescence as a stress response with high potential importance for human aging.

Biological Clocks↗