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Bohm K.J.,Leibniz Institute for Age Research
Archives of Toxicology | Year: 2015

Copper is a trace element required to maintain essential life processes. In healthy organisms, copper metabolism is well balanced. If this balance is destroyed, the cellular level of free copper might increase and cause toxic effects. So far, the molecular mechanisms of copper intoxication are understood only partly. The present study revealed that the kinesin-dependent transport system is strongly affected by copper(II) ions. Both the microtubules, along which kinesin moves, and the kinesin itself were found to be the target structures of copper ions: Microtubule formation was suppressed by copper ions (IC50 26–70 µM) apparently chiefly by inhibition of binding of microtubule-associated proteins to tubulin. This inhibition could be widely compensated by the microtubule-stabilising agent paclitaxel. In addition, copper ions strongly inhibited the ATPase activity of neuron-specific kinesin KIF5A. At final KIF5A concentration of 112 nM, an IC50 of 1.3 µM was determined. Correspondingly, the motility activity of KIF5A, measured as velocity of microtubules gliding across a kinesin-covered surface, was blocked. The effects of copper ions on microtubules and on KIF5A are suggested to contribute to impaired transport processes within brain and other organs in cases of copper ion surplus. © 2014, Springer-Verlag Berlin Heidelberg. Source


Tozzini E.T.,Leibniz Institute for Age Research
BMC evolutionary biology | Year: 2013

Early evolutionary theories of aging predict that populations which experience low extrinsic mortality evolve a retarded onset of senescence. Experimental support for this theory in vertebrates is scarce, in part for the difficulty of quantifying extrinsic mortality and its condition- and density-dependent components that -when considered- can lead to predictions markedly different to those of the "classical" theories. Here, we study annual fish of the genus Nothobranchius whose maximum lifespan is dictated by the duration of the water bodies they inhabit. Different populations of annual fish do not experience different strengths of extrinsic mortality throughout their life span, but are subject to differential timing (and predictability) of a sudden habitat cessation. In this respect, our study allows testing how aging evolves in natural environments when populations vary in the prospect of survival, but condition-dependent survival has a limited effect. We use 10 Nothobranchius populations from seasonal pools that differ in their duration to test how this parameter affects longevity and aging in two independent clades of these annual fishes. We found that replicated populations from a dry region showed markedly shorter captive lifespan than populations from a humid region. Shorter lifespan correlated with accelerated accumulation of lipofuscin (an established age marker) in both clades. Analysis of wild individuals confirmed that fish from drier habitats accumulate lipofuscin faster also under natural conditions. This indicates faster physiological deterioration in shorter-lived populations. Our data provide a strong quantitative example of how extrinsic mortality can shape evolution of senescence in a vertebrate clade. Nothobranchius is emerging as a genomic model species. The characterization of pairs of closely related species with different longevities should provide a powerful paradigm for the identification of genetic variations responsible for evolution of senescence in natural populations. Source


Jung M.J.,Leibniz Institute for Age Research
Nature Medicine | Year: 2016

Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source


Greulich K.O.,Leibniz Institute for Age Research
Journal of Biophotonics | Year: 2011

This contribution reviews recent applications of micromanipulation, by UV photons, in DNA repair and ageing research as well as in the evaluation of the phototoxicity of drugs. In some cases, micromanipulation is combined with the comet assay, a technique, which allows a direct view on DNA damages. It is shown that, in humans, the sensitivity of DNA to UV induced damage and its subsequent repair is surprisingly stable up to high age and that drugs which are usually non-toxic induce DNA damage when irradiated in parallel by UV irradiation. Using the immune fluorescent comet assay, IFCA, a variant of the comet assay, direct comparison of the effects of ionizing 137Cs radiation with those of localized UV radiation is possible. When a laser microbeam is used to damage DNA in a cell nucleus with high temporal and spatial resolution, it can be observed directly how repair molecules accumulate (are recruited) at the site of damage. Comparison of the recruitment speed allows establishing an order of DNA repair events. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source


Heuer H.,Leibniz Institute for Age Research | Visser T.J.,Erasmus Medical Center
Biochimica et Biophysica Acta - General Subjects | Year: 2013

Background: As a prerequisite for thyroid hormone (TH) metabolism and action TH has to be transported into cells where TH deiodinases and receptors are located. The trans-membrane passage of TH is facilitated by TH transporters of which the monocarboxylate transporter MCT8 has been most intensively studied. Inactivating mutations in the gene encoding MCT8 are associated with a severe form of psychomotor retardation and abnormal serum TH levels (Allan-Herndon-Dudley syndrome). In order to define the underlying pathogenic mechanisms, Mct8 knockout mice have been generated and intensively studied. Most surprisingly, Mct8 ko mice do not show any neurological symptoms but fully replicate the abnormal serum thyroid state. Scope of review: We will summarize the findings of these mouse studies that shed light on various aspects of Mct8 deficiency and unambiguously demonstrated the pivotal role of Mct8 in mediating TH transport in various tissues. These studies have also revealed the presence of the complex interplay between different pathogenic mechanisms that contribute to the generation of the abnormal TH serum profile. Major conclusions: Most importantly, studies of Mct8 ko mice indicated the presence of additional TH transporters that act in concert with Mct8. Interesting candidates for such a function are the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting polypeptide Oatp1c1. General significance: Overall, the analysis of Mct8 deficient mice has greatly expanded our knowledge about the (patho-) physiological function of this transporter and established a sound basis for the characterization of additional TH transporter candidates. This article is part of a Special Issue entitled Thyroid hormone signalling. © 2012 Elsevier B.V. All rights reserved. Source

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