A5004870117- DNA Repair Mechanisms
- Mitochondrial Function and Pathology
- Genetics, Aging, and Longevity in Model Organisms
- Telomeres, Telomerase, and Senescence
- Immune Response and Inflammation
- Genetics and Neurodevelopmental Disorders
- Nitric Oxide and Endothelin Effects
- Gut microbiota and health
- Circadian rhythm and melatonin
- Dietary Effects on Health
- Species Distribution and Climate Change
- Immune Cell Function and Interaction
- Phosphodiesterase function and regulation
- Insect and Arachnid Ecology and Behavior
- Amphibian and Reptile Biology
- Muscle Physiology and Disorders
- Diet and metabolism studies
- Helicobacter pylori-related gastroenterology studies
- Carcinogens and Genotoxicity Assessment
- Neuroinflammation and Neurodegeneration Mechanisms
- Epigenetics and DNA Methylation
- Retinoids in leukemia and cellular processes
- Radiation Effects in Electronics
- Antioxidant Activity and Oxidative Stress
- Bone Metabolism and Diseases
Erasmus MC
2015-2025
Erasmus MC Cancer Institute
2022-2024
Erasmus University Rotterdam
2006-2023
Intra Cellular Therapies (United States)
2021
Cancer Genomics Centre
2016
Goethe University Frankfurt
2012
Institute on Aging
2012
National Institute on Aging
2012
National Institutes of Health
2012
Norwood Hospital
2012
The use of Akkermansia muciniphila as potential therapeutic intervention is receiving increasing attention. Health benefits attributed to this bacterium include an improvement metabolic disorders and exerting anti-inflammatory effects. abundance A. associated with a healthy gut in early mid- later life. However, the effects on decline intestinal health during aging process are not investigated yet. We supplemented accelerated Ercc1−/Δ7 mice for 10 weeks histological, transcriptional...
Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and polymerase II chromatin immunoprecipitation followed by to elucidate the underlying mechanisms triggering gene wild-type aged mice. We found that 2-year-old liver, 40% of elongating polymerases are stalled, lowering productive transcription skewing transcriptional output a gene-length-dependent fashion. demonstrate this...
Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that caused by defect in the transcription-coupled subpathway of nucleotide excision (NER). Here, complete inactivation NER Csb(m/m)/Xpa(-/-) mutants causes phenotype reliably mimics human progeroid CS syndrome. Newborn mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis several...
Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed the aging population of developed societies, is associated with vascular DNA damage cell senescence. We hypothesized that cumulative during contributes to dysfunction.In mice genomic instability resulting from defective nucleotide excision repair genes ERCC1 XPD (Ercc1(d/-) Xpd(TTD) mice), we explored age-dependent function compared wild-type mice. Ercc1(d/-) showed increased senescence, accelerated development...
Aging is associated with reduced function, degenerative changes, and increased neuroinflammation of the central nervous system (CNS). Increasing evidence suggests that changes in microglia cells contribute to age-related deterioration CNS. The most prominent change enhanced sensitivity inflammatory stimuli, referred as priming. It unclear if priming due intrinsic ageing or induced by neural environment. We have studied this Ercc1 mutant mice, a DNA repair-deficient mouse model displays...
DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused defective repair. Thyroid state changes during but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator metabolism, in TH signaling have widespread effects. Here, we reveal significant common transcriptomic signature livers from hypothyroid mice, repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A...
Abstract Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging culminates profound metabolic alterations. Our understanding the mechanisms governing redesign upon genomic instability, however, highly rudimentary. Using Ercc1 -defective mice Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled repair (TCR) nucleotide excision (NER) directly affect bioenergetics due to declined transcription, leading increased ATP...
Abstract Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart remain elusive, but evidence indicates that DNA damage is enhanced failing hearts. Here, we tested the hypothesis endogenous repair cardiomyocytes critical for maintaining normal cardiac function, so perturbed of spontaneous drives early onset failure. To increase burden damage, knocked out endonucleases xeroderma pigmentosum complementation group G (XPG)...
Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how damage causes neuronal and whether defects in different systems affect the brain differently largely unknown. Here, we performed systematic detailed analysis neurodegenerative changes mouse models deficient nucleotide excision (NER) transcription-coupled (TCR), two partially overlapping that remove helix-distorting transcription-blocking lesions, respectively, are associated with UV-sensitive syndromes xeroderma...
As part of the Nucleotide Excision Repair (NER) process, endonuclease XPG is involved in repair helix-distorting DNA lesions, but protein has also been implicated several other systems, complicating genotype-phenotype relationship patients. Defects can cause either cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with severe neurodevelopmental disorder Cockayne Syndrome (CS), infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic...
Abstract Organs age differently, causing wide heterogeneity in multimorbidity, but underlying mechanisms are largely elusive. To investigate the basis of organ‐specific ageing, we utilized progeroid repair‐deficient Ercc1 Δ /− mouse mutants and systematically compared at tissue, stem cell organoid level two organs representing ageing extremes. intestine shows hardly any accelerated ageing. Nevertheless, found apoptosis reduced numbers intestinal cells (ISCs), loss appears compensated by...
Cardiovascular diseases are the number one cause of death globally. The most important determinant cardiovascular health is a person's age. Aging results in structural changes and functional decline system. DNA damage an contributor to aging process, mice with repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, loss vasomotor control. To determine underlying cause, we compared hallmarks aortas both
Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical neurological impairment. functions transcription-coupled subpathway of nucleotide excision repair. This function may explain but hardly clarifies other CS symptoms. Many these, including retinopathy, are associated with premature aging. We studied eye pathology mouse model for CS. Csb(m/m) mice were hypersensitive to light developed epithelial hyperplasia squamous...
Dietary restriction (DR) and rapamycin extend healthspan life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended trippled span. Here, we show rapamycin, while significantly lowering mTOR signaling, failed to improve nor of Ercc1∆/- mice, contrary tested parallel. Rapamycin interventions focusing on dosage, gender, timing all were unable alter Even genetically modifying signaling increase mice. The absence effects by P53...
Abstract With aging, tryptophan metabolism is affected. Tryptophan has a crucial role in the induction of immune tolerance and maintenance gut microbiota. We, therefore, studied effect dietary restriction young wild-type (WT) mice (118-wk life span) DNA-repair deficient, premature-aged (Ercc1−/Δ7) (20-wk span). First, we found that aging on distribution B T cells bone marrow (BM) periphery 16-wk-old Ercc1−/Δ7 was comparable to 18-mo-old WT mice. Dietary caused an arrest cell development BM,...
Abstract We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which aging outcomes are due to local endothelial DNA damage, was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) in mice (EC-knockout (EC-KO) mice). EC-KO showed progressive decrease microvascular dilation skin, increased leakage kidney, decreased lung perfusion, and aortic stiffness compared with wild-type (WT)....
ABSTRACT Aging is a major risk factor for cardiovascular diseases, and the accumulation of DNA damage significantly contributes to aging process. This study aimed identify underlying molecular mechanisms vascular in DNA‐repair‐deficient progeroid Ercc1 Δ/− mice explore therapeutic effect dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression processes, including extracellular matrix remodeling, aorta. Notably, this indicated presence macrophage‐like...
Abstract Background One of the principles underpinning our understanding ageing is that DNA damage induces a stress response shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view prompting of, for example, skeletal muscle confers systemic benefit. Methods To investigate robustness these axioms, we induced in murine progeroid model through use activin receptor IIB ligand trap dampens myostatin/activin signalling. Progeric mice were then...
Dietary composition can significantly influence health and lifespan, however, robust knowledge on which food components, at what concentration exert long-term effects is still incomplete. Here, we explored the of dietary protein intake Ercc1 Δ/- DNA-repair-deficient mice, are an excellent model for accelerated ageing hyperresponsive to anti-ageing effect restriction. Restricting by 50% extended lifespan in male but not females. levels beyond 80% improved various neurological parameters,...
Aging is a highly complex biological process driven by multiple factors. Its progression can partially be influenced nutritional interventions. Vitamin E lipid-soluble anti-oxidant that investigated as supplement for its ability to prevent or delay the onset of specific aging pathologies, including neurodegenerative disorders.We aimed here investigate effect vitamin during in well characterized mouse model premature aging.Xpg-/- animals received diets with low (~2.5 mg/kg feed), medium (75...