DNage BV

Leiden, Netherlands
Leiden, Netherlands
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Borgesius N.Z.,Erasmus University Rotterdam | de Waard M.C.,Cancer Genomics Center | van der Pluijm I.,DNage B.V | Omrani A.,Erasmus University Rotterdam | And 6 more authors.
Journal of Neuroscience | Year: 2011

Age-related cognitive decline and neurodegenerative diseases are a growing challenge for our societies with their aging populations. Accumulation of DNA damage has been proposed to contribute to these impairments, but direct proof that DNA damage results in impaired neuronal plasticity and memory is lacking. Here we take advantage of Ercc1 Δ/- mutant mice, which are impaired in DNA nucleotide excision repair, interstrand crosslink repair, and double-strand break repair. We show that these mice exhibit an agedependent decrease in neuronal plasticity and progressive neuronal pathology, suggestive of neurodegenerative processes. A similar phenotype is observed in mice where the mutation is restricted to excitatory forebrain neurons. Moreover, these neuron-specific mutants develop a learning impairment. Together, these results suggest a causal relationship between unrepaired, accumulating DNA damage, and age-dependent cognitive decline and neurodegeneration. Hence, accumulated DNA damage could therefore be an important factor in the onset and progression of age-related cognitive decline and neurodegenerative diseases. © 2011 the authors.

Burkle A.,University of Konstanz | Moreno-Villanueva M.,University of Konstanz | Bernhard J.,BioTeSys | Blasco M.,Spanish National Cancer Research Center | And 26 more authors.
Mechanisms of Ageing and Development | Year: 2015

Many candidate biomarkers of human ageing have been proposed in the scientific literature but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has proven to serve a useful marker to determine, on its own, biological age. A plausible reason for this is the intrinsic multi-causal and multi-system nature of the ageing process. The recently completed MARK-AGE study was a large-scale integrated project supported by the European Commission. The major aim of this project was to conduct a population study comprising about 3200 subjects in order to identify a set of biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. © 2015 The Authors.

Agency: European Commission | Branch: FP7 | Program: CP-IP | Phase: HEALTH-2007-2.2.2-3 | Award Amount: 15.91M | Year: 2008

The rate of ageing in humans is not uniform, due to genetic heterogeneity and the influence of environmental factors. Age-related changes in body function or composition that could serve as a measure of biological age and predict the onset of age-related diseases and/or residual lifetime are termed biomarkers of ageing. Many candidate biomarkers have been proposed but in all cases their variability in cross-sectional studies is considerable, and therefore no single measurement has so far proven to yield a useful biomarker of ageing on its own, probably due to the multi-causal and multi-system nature of ageing. We propose to conduct a population study (3,300 probands) to identify a set biomarkers of ageing which, as a combination of parameters with appropriate weighting, would measure biological age better than any marker in isolation. Two large groups of subjects will be recruited, i.e. (1) randomly recruited age-stratified individuals from the general population covering the age range 35-74 years and (2) subjects born from a long-living parent belonging to a family with long living sibling(s) already recruited in the framework of the GEHA project. For genetic reasons such individuals (GEHA offspring) are expected to age at a slower rate. They will be recruited together with their spouses as controls, thus allowing initial validation of the biomarkers identified. (3) A small number of patients with progeroid syndromes will also be included in the study. A wide range of candidate biomarkers will be tested, including (a) classical ones for which data from several smaller studies have been published; (b) new ones, based on recent preliminary data, as well as (c) novel ones, based on recent research on mechanistic aspects of ageing, conducted by project participants. Bioinformatics will be used in order to extract a robust set of biomarkers of human ageing from the large amounts of data to be generated and to derive a model for healthy ageing.

Vroegrijk I.O.C.M.,Leiden University | van Diepen J.A.,Leiden University | van den Berg S.,Leiden University | Westbroek I.,DNage B.V. | And 9 more authors.
Food and Chemical Toxicology | Year: 2011

Background: Pomegranate seed oil has been shown to protect against diet induced obesity and insulin resistance. Objective: To characterize the metabolic effects of punicic acid on high fat diet induced obesity and insulin resistance. Design: High-fat diet or high-fat diet with 1% Pomegranate seed oil (PUA) was fed for 12. weeks to induce obesity and insulin resistance. We assessed body weight and composition (pSABRE DEXA-scan), energy expenditure (Columbus Instruments) and insulin sensitivity at the end of the 12. weeks. Results: PSO intake resulted in a lower body weight, 30.5 ± 2.9 vs 33.8 ± 3.2. g PSO vs HFD respectively, p=0.02, without affecting food intake or energy expenditure. The lower body weight was fully explained by a decreased body fat mass, 3.3 ± 2.3 vs 6.7 ± 2.7. g for PSO and HFD fed mice, respectively, p=0.02. Insulin clamps showed that PSO did not affect liver insulin sensitivity but clearly improved peripheral insulin sensitivity, 164 ± 52% vs 92 ± 24% for PSO and HFD fed mice respectively, p=0.01. Conclusions: We conclude that dietary PSO ameliorates high-fat diet induced obesity and insulin resistance in mice, independent of changes in food intake or energy expenditure. © 2011 Elsevier Ltd.

Vermeij W.P.,Leiden University | Vermeij W.P.,DNage BV | Alia A.,Leiden University | Backendorf C.,Leiden University
Journal of Investigative Dermatology | Year: 2011

The cornified cell envelope (CE) is a specialized structure assembled beneath the plasma membrane of keratinocytes in the outermost layers of the epidermis. It is essential for the physical and permeability properties of the barrier function of the skin. Our skin is continuously exposed to atmospheric oxygen and threatened by reactive oxygen species (ROS). Here, we identify the CE as a first line of antioxidant defense and show that the small proline-rich (SPRR) family of CE precursor proteins have a major role in ROS detoxification. Cysteine residues within these proteins are responsible for ROS quenching, resulting in inter- and intramolecular S-S bond formation, both in isolated proteins and purified CEs. The related keratinocyte proline-rich protein is also oxidized on several cysteine residues within the CE. Differences in antioxidant potential between various SPRR family members are likely determined by structural differences rather than by the amount of cysteine residues per protein. Loricrin, a major component of the CE with a higher cysteine content than SPRRs, is a weak ROS quencher and oxidized on a single cysteine residue within the CE. It is inferred that SPRR proteins provide the outermost layer of our skin with a highly adaptive and protective antioxidant shield. © 2011 The Society for Investigative Dermatology.

Nevedomskaya E.,Leiden University | Meissner A.,Leiden University | Goraler S.,Leiden University | De Waard M.,Erasmus Medical Center | And 5 more authors.
Journal of Proteome Research | Year: 2010

Aging is a fundamental biological process for which the mechanism is still largely unknown due to its complex and multifactorial nature. Animal models allow us to simplify this complexity and to study individual factors separately. As there are many causative links between DNA repair deficiency and aging, we studied the ERCC1d/- mouse, which has a modified ERCC1 gene, involved in the Nucleotide Excision Repair, and as a result has a premature aging phenotype. Profiling of these mice on different levels can give an insight into the mechanisms underlying the aging phenotype. In the current study, we have performed metabolic profiling of serum and urine of these mice in comparison to wild type and in relation to aging by 1H NMR spectroscopy. Analysis of metabolic trajectories of animals from 8 to 20 weeks suggested that wild type and ERCC1d/- mutants have similar age-related patterns of changes; however, the difference between genotypes becomes more prominent with age. The main differences between these two genetically diverse groups of mice were found to be associated with altered lipid and energy metabolism, transition to ketosis, and attenuated functions of the liver and kidney. © 2010 American Chemical Society.

Nevedomskaya E.,Leiden University | Ramautar R.,Leiden University | Derks R.,Leiden University | Westbroek I.,DNage BV | And 5 more authors.
Journal of Proteome Research | Year: 2010

Metabolic profiling of biological samples is increasingly used to obtain more insight into the pathophysiology of diseases. For translational studies, biological samples from animal models are explored; however, the volume of these samples can be a limiting factor for metabolic profiling studies. For instance, only a few microliters of urine is often available from small animals like mice. Hence, there is a need for a tailor-made analytical method for metabolic profiling of volume-limited samples. In the present study, the feasibility of capillary electrophoresis time-of-flight mass spectrometry (CE-ToF-MS) for metabolic profiling of urine from mice is evaluated. Special attention is paid to the analytical workflow; that is, such aspects as sample preparation, analysis, and data treatment are discussed from the metabolomics viewpoint. We show that metabolites belonging to several chemical families can be analyzed in mouse urine with the CE-ToF-MS method using minimal sample pretreatment and an in-capillary preconcentration procedure. This exemplifies the advantages of CE-ToF-MS for metabolic profiling of volume-limited samples as loss of material is minimized. The feasibility of the CE-ToF-MS-based workflow for metabolic profiling is illustrated by the analysis of urine samples from wild-type as well as from TTD mutant mice, which are a model for the accelerated aging, with osteoporosis being one of the main hallmarks. © 2010 American Chemical Society.

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