Sperka T.,Leibniz Institute for Age Research |
Sperka T.,University of Ulm |
Wang J.,Leibniz Institute for Age Research |
Wang J.,University of Ulm |
And 2 more authors.
Nature Reviews Molecular Cell Biology | Year: 2012
DNA damage induces cell-intrinsic checkpoints, including p53 and retinoblastoma (RB), as well as upstream regulators (exonuclease 1 (EXO1), ataxia telangiectasia mutated (ATM), ATR, p16 INK4a and p19 ARF) and downstream targets (p21, PUMA (p53 upregulated modulator of apoptosis) and sestrins). Clearance of damaged cells by cell-intrinsic checkpoints suppresses carcinogenesis but as a downside may impair stem cell and tissue maintenance during ageing. Modulating the activity of DNA damage checkpoints can either accelerate or decelerate tissue ageing and age-related carcinogenesis. The outcome depends on cell-intrinsic and cell-extrinsic mechanisms that regulate the clearance of damaged cells and on the molecular context in ageing tissues, including the level of DNA damage accumulation itself. © 2012 Macmillan Publishers Limited. All rights reserved.
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.
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.
Horn S.,Leibniz Institute for Age Research |
Heuer H.,Leibniz Institute for Age Research
Molecular and Cellular Endocrinology | Year: 2010
Thyroid hormone is essential for proper brain development since it acts on processes such as neuronal migration and differentiation, myelination and synaptogenesis. In this review, we summarize the consequences of thyroid hormone deficiency for brain development with special focus on the cerebellum, an important target of thyroid action. In addition, we discuss the role of iodothyronine deiodinases and thyroid hormone transporters in regulating local thyroid hormone concentrations as well as current knowledge about the function of thyroid hormone receptors and their target genes during brain maturation. Despite considerable progress in recent years in deciphering thyroid hormone signaling pathways we still know very little on the molecular level by which mode of action thyroid hormone exerts its cell-specific effects. Hence, we will particularly address the open questions that remain to be addressed in order to better understand the role of thyroid hormone in brain development. © 2009 Elsevier Ireland Ltd. All rights reserved.
Koch P.,Leibniz Institute for Age Research |
Platzer M.,Leibniz Institute for Age Research |
Downie B.R.,Leibniz Institute for Age Research
Nucleic Acids Research | Year: 2014
Generation of repeat libraries is a critical step for analysis of complex genomes. In the era of next-generation sequencing (NGS), such libraries are usually produced using a whole-genome shotgun (WGS) derived reference sequence whose completeness greatly influences the quality of derived repeat libraries. We describe here a de novo repeat assembly method - RepARK (Repetitive motif detection by Assembly of Repetitive K-mers) - which avoids potential biases by using abundant k-mers of NGS WGS reads without requiring a reference genome. For validation, repeat consensuses derived from simulated and real Drosophila melanogaster NGS WGS reads were compared to repeat libraries generated by four established methods. RepARK is orders of magnitude faster than the other methods and generates libraries that are: (i) composed almost entirely of repetitive motifs, (ii) more comprehensive and (iii) almost completely annotated by TEclass. Additionally, we show that the RepARK method is applicable to complex genomes like human and can even serve as a diagnostic tool to identify repetitive sequences contaminating NGS datasets. © 2014 The Author(s) 2014.
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.
Leibniz Institute for Age Research | Date: 2012-08-30
Members of the Amyloid Precursor Protein family (APP molecules) and their neurotoxic cleavage product A are key players in the development of Alzheimers disease (AD). Proteolytic processing of APP molecules is influenced by metal ions, protein ligands and its oligomerization state. X-ray structures of the metal bound molecule at 2.6-2.0 resolution are presented, providing structural and functional bases for the regulation of APP molecules using conformational information. A metal-dependent molecular switch located within the E2 domain of APP coinciding with a high affinity copper and zinc binding site within the monomeric E2 domain was evaluated. The metal specific coordination spheres of this E2 domain comprise four evolutionary conserved histidine residues. Metal binding induces large conformational changes relative to the metal free protein. This conformational change provides a basis for influencing APP molecule processing and thus trafficking and the production of A.
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.
Hartmann M.,Leibniz Institute for Age Research |
Herrlich A.,Harvard University |
Herrlich P.,Leibniz Institute for Age Research
Trends in Biochemical Sciences | Year: 2013
Many life-essential molecules such as growth factors, cytokines, ectoenzymes, and decoy receptors are produced by ectodomain cleavage of transmembrane precursor molecules. Not surprisingly, misregulation of such essential functions is linked to numerous diseases. Ectodomain cleavage is the function of transmembrane ADAMs (a disintegrin and metalloprotease) and other membrane-bound metalloproteases, which have an extracellular catalytic domain. Almost all work on ectodomain cleavage regulation has focused on the control of enzyme activity determined by substrate cleavage as surrogate. However, the number of substrates far exceeds the number of enzymes. Specificity can therefore not be achieved by solely modulating enzyme activity. Here, we argue that specific regulatory pathways must exist to control the availability and susceptibility of substrates. © 2013 Elsevier Ltd.
Gunes C.,Leibniz Institute for Age Research |
Rudolph K.L.,Leibniz Institute for Age Research
Cell | Year: 2013
Telomere shortening impairs proliferation of transformed cells but also leads to cancer initiation by inducing chromosomal instability. Here, we discuss recent developments in our understanding of the role of telomeres in replication stress and how telomerase expression in somatic stem cells may affect genome integrity control and carcinogenesis. © 2013 Elsevier Inc.