Publications by authors named "Renata Brandt"

27 Publications

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Selective PDE1 inhibition ameliorates vascular function, reduces inflammatory response, and lowers blood pressure in ageing animals.

J Pharmacol Exp Ther 2021 Jun 7. Epub 2021 Jun 7.

Erasmus MC, Netherlands

Diminished nitric oxide - cGMP -mediated relaxation plays a crucial role in cardiovascular ageing, leading to decreased vasodilation, vascular hypertrophy and stiffening, and ultimately cardiovascular dysfunction. Ageing is the time-related worsening of physiological function due to complex cellular and molecular interactions, and is at least partly driven by DNA damage. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice provides us an efficient tool to accelerate vascular ageing, explore mechanisms, and test potential treatments. Previously we identified the cGMP-degrading enzyme phosphodiesterase 1 as a potential treatment target in vascular ageing. In the present study, we studied the effect of acute and chronic treatment with ITI-214, a selective phosphodiesterase 1 inhibitor on vascular ageing features in mice. Compared to wild-type mice, mice at the age of 14 weeks showed decreased reactive hyperemia, diminished endothelium-dependent and -independent responses of arteries in organ baths, carotid wall hypertrophy, and elevated circulating levels of inflammatory cytokines. Acute ITI-214 treatment in organ baths restored the arterial endothelium-independent vasodilation in mice. An 8-week treatment with 100 mg/kg/d ITI-214 improved endothelium-independent relaxation in both aorta and coronary arteries, at least partly restored the diminished reactive hyperemia, lowered the systolic and diastolic blood pressure, normalized the carotid hypertrophy, and ameliorated inflammatory responses exclusively in mice. These findings suggest PDE1 inhibition would provide a powerful tool for nitric oxide - cGMP augmentation and have significant therapeutic potential to battle arteriopathy related to ageing. The findings implicate the key role of PDE1 in vascular function and might be of clinical importance for prevention of mortalities and morbidities related to vascular complications during ageing, as well as for progeria patients that show a high risk of cardiovascular disease.
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http://dx.doi.org/10.1124/jpet.121.000628DOI Listing
June 2021

Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice.

Aging Cell 2021 02 23;20(2):e13302. Epub 2021 Jan 23.

Centre for Health Protection, National Institute for Public Health and the Environment (RIVM, Bilthoven, The Netherlands.

Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1 mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.
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http://dx.doi.org/10.1111/acel.13302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884048PMC
February 2021

Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.

Int J Mol Sci 2020 Jun 30;21(13). Epub 2020 Jun 30.

Department of Internal Medicine, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands.

Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme ERCC1 endonuclease in mice, as in the case of mice, can be used as a tool to accelerate aging. mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in mice. mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.
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http://dx.doi.org/10.3390/ijms21134667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369923PMC
June 2020

Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.

Clin Sci (Lond) 2020 04;134(7):727-746

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.

We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of ERCC1 (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.
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http://dx.doi.org/10.1042/CS20190124DOI Listing
April 2020

DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering.

Nat Commun 2019 10 25;10(1):4887. Epub 2019 Oct 25.

Department of Molecular Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.
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http://dx.doi.org/10.1038/s41467-019-12640-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814737PMC
October 2019

Different developmental environments reveal multitrait plastic responses in South American Anostomidae fish.

J Exp Zool B Mol Dev Evol 2019 11 10;332(7):238-244. Epub 2019 Oct 10.

Departamento de Biologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.

Complex phenotypes result from developmental processes integrating genetic, epigenetic, and environmental information. Although changing environments combine several signals that may induce multitrait plastic responses, literature often decodes developmental plasticity into single trait variation as a function of isolated environmental signals. To address the multivariate nature of developmental plasticity, we evaluated how different combinations of environmental signals influence the development of morphological and behavioral traits. We raised Megaleporinus macrocephalus (Anostomidae) in four different developmental environments, and found that foraging position and structural complexity during development induced different morphotypes, which overlapped with behavioral patterns. Foraging position induced distinct patterns of mouth and fin positioning and overall body shape, which were accentuated by structural complexity. Moreover, fish most often chose conditions similar to their developmental environments. Combined signals during development, therefore, revealed environment-specific phenotypic patterns associating morphology and behavior. Such results endorse the ability of developmental processes to influence the variation present in natural populations. Implications of addressing the multivariate essence of developmental plasticity transcend the evolutionary theory and inspire applications in several fields.
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http://dx.doi.org/10.1002/jez.b.22905DOI Listing
November 2019

Compression of morbidity in a progeroid mouse model through the attenuation of myostatin/activin signalling.

J Cachexia Sarcopenia Muscle 2019 06 27;10(3):662-686. Epub 2019 Mar 27.

School of Biological Sciences, University of Reading, Reading, UK.

Background: One of the principles underpinning our understanding of ageing is that DNA damage induces a stress response that shifts cellular resources from growth towards maintenance. A contrasting and seemingly irreconcilable view is that prompting growth of, for example, skeletal muscle confers systemic benefit.

Methods: To investigate the robustness of these axioms, we induced muscle growth in a murine progeroid model through the use of activin receptor IIB ligand trap that dampens myostatin/activin signalling. Progeric mice were then investigated for neurological and muscle function as well as cellular profiling of the muscle, kidney, liver, and bone.

Results: We show that muscle of Ercc1 progeroid mice undergoes severe wasting (decreases in hind limb muscle mass of 40-60% compared with normal mass), which is largely protected by attenuating myostatin/activin signalling using soluble activin receptor type IIB (sActRIIB) (increase of 30-62% compared with untreated progeric). sActRIIB-treated progeroid mice maintained muscle activity (distance travel per hour: 5.6 m in untreated mice vs. 13.7 m in treated) and increased specific force (19.3 mN/mg in untreated vs. 24.0 mN/mg in treated). sActRIIb treatment of progeroid mice also improved satellite cell function especially their ability to proliferate on their native substrate (2.5 cells per fibre in untreated progeroids vs. 5.4 in sActRIIB-treated progeroids after 72 h in culture). Besides direct protective effects on muscle, we show systemic improvements to other organs including the structure and function of the kidneys; there was a major decrease in the protein content in urine (albumin/creatinine of 4.9 sActRIIB treated vs. 15.7 in untreated), which is likely to be a result in the normalization of podocyte foot processes, which constitute the filtration apparatus (glomerular basement membrane thickness reduced from 224 to 177 nm following sActRIIB treatment). Treatment of the progeric mice with the activin ligand trap protected against the development of liver abnormalities including polyploidy (18.3% untreated vs. 8.1% treated) and osteoporosis (trabecular bone volume; 0.30 mm in treated progeroid mice vs. 0.14 mm in untreated mice, cortical bone volume; 0.30 mm in treated progeroid mice vs. 0.22 mm in untreated mice). The onset of neurological abnormalities was delayed (by ~5 weeks) and their severity reduced, overall sustaining health without affecting lifespan.

Conclusions: This study questions the notion that tissue growth and maintaining tissue function during ageing are incompatible mechanisms. It highlights the need for future investigations to assess the potential of therapies based on myostatin/activin blockade to compress morbidity and promote healthy ageing.
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http://dx.doi.org/10.1002/jcsm.12404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596402PMC
June 2019

ameliorates the age-related decline in colonic mucus thickness and attenuates immune activation in accelerated aging mice.

Immun Ageing 2019 8;16. Epub 2019 Mar 8.

4Laboratory of Microbiology, Wageningen University and Research, Wageningen, The Netherlands.

Background: The use of as potential therapeutic intervention is receiving increasing attention. Health benefits attributed to this bacterium include an improvement of metabolic disorders and exerting anti-inflammatory effects. The abundance of is associated with a healthy gut in early mid- and later life. However, the effects of on a decline in intestinal health during the aging process are not investigated yet. We supplemented accelerated aging mice with for 10 weeks and investigated histological, transcriptional and immunological aspects of intestinal health.

Results: The thickness of the colonic mucus layer increased about 3-fold after long-term supplementation and was even significantly thicker compared to mice supplemented with WCFS1. Colonic gene expression profiles pointed towards a decreased expression of genes and pathways related to inflammation and immune function, and suggested a decreased presence of B cells in colon. Total B cell frequencies in spleen and mesenteric lymph nodes were not altered after supplementation. Mature and immature B cell frequencies in bone marrow were increased, whereas B cell precursors were unaffected. These findings implicate that B cell migration rather than production was affected by supplementation. Gene expression profiles in ileum pointed toward a decrease in metabolic- and immune-related processes and antimicrobial peptide production after supplementation. Besides, decreased the frequency of activated CD80CD273 B cells in Peyer's patches. Additionally, the increased numbers of peritoneal resident macrophages and a decrease in Ly6C monocyte frequencies in spleen and mesenteric lymph nodes add evidence for the potentially anti-inflammatory properties of .

Conclusions: Altogether, we show that supplementation with prevented the age-related decline in thickness of the colonic mucus layer and attenuated inflammation and immune-related processes at old age. This study implies that supplementation can contribute to a promotion of healthy aging.
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http://dx.doi.org/10.1186/s12979-019-0145-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408808PMC
March 2019

Phenotypic integration mediated by hormones: associations among digit ratios, body size and testosterone during tadpole development.

BMC Evol Biol 2017 08 2;17(1):175. Epub 2017 Aug 2.

Departamento de Biologia, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, 14040-901, Brazil.

Background: Developmental associations often explain phenotypic integration. The intersected hormonal regulation of ontogenetic processes fosters predictions of steroid-mediated phenotypic integration among sexually dimorphic traits, a statement defied by associations between classical dimorphism predictors (e.g. body size) and traits that apparently lack sex-specific functions (e.g. ratios between the lengths of Digits II and IV - 2D:4D). Developmental bases of female-biased 2D:4D have been identified, but these remain unclear for taxa presenting male-biased 2D:4D (e.g. anura). Here we propose two alternative hypotheses to investigate evolution of male-biased 2D:4D associated with sexually dimorphic body size using Leptodactylus frogs: I)'hypothesis of sex-specific digit responses' - Digit IV would be reactive to testosterone but exhibit responses in the opposite direction of those observed in female-biased 2D:4D lineages, so that Digit IV turns shorter in males; II) 'hypothesis of identity of the dimorphic digit'- Digit II would be the dimorphic digit.

Results: We compiled the following databases using Leptodactylus frogs: 1) adults of two species from natural populations and 2) testosterone-treated L. fuscus at post-metamorphic stage. Studied traits seem monomorphic in L. fuscus; L. podicipinus exhibits male-biased 2D:4D. When present, 2D:4D dimorphism was male-biased and associated with dimorphic body size; sex differences resided on Digit II instead of IV, corroborating our 'hypothesis of identity of the dimorphic digit'. Developmental steroid roles were validated: testosterone-treated L. fuscus frogs were smaller and exhibited masculinized 2D:4D, and Digit II was the digit that responded to testosterone.

Conclusion: We propose a model where evolution of sexual dimorphism in 2D:4D first originates from the advent, in a given digit, of increased tissue sensitivity to steroids. Phenotypic integration with other sexually dimorphic traits would then occur through multi-trait hormonal effects during development. Such process of phenotypic integration seems fitness-independent in its origin and might explain several cases of steroid-mediated integration among sexually dimorphic traits.
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http://dx.doi.org/10.1186/s12862-017-1021-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541650PMC
August 2017

Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging mice.

Clin Sci (Lond) 2017 Aug 13;131(15):1941-1953. Epub 2017 Jul 13.

Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus University Medical Center Rotterdam, The Netherlands

DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model ( mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser-eNOS were compromised in DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in mice. mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.
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http://dx.doi.org/10.1042/CS20170026DOI Listing
August 2017

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

Cell 2017 03;169(1):132-147.e16

Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands; The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA. Electronic address:

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
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http://dx.doi.org/10.1016/j.cell.2017.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556182PMC
March 2017

Ecological associations of autopodial osteology in Neotropical geckos.

J Morphol 2017 03 23;278(3):290-299. Epub 2017 Jan 23.

Department of Biology, FFCLRP/USP, Universidade de São Paulo, Ribeirão Preto, SP, 14040-901, Brazil.

Coevolution of form and function inspires investigation of associations between morphological variation and the exploitation of specific ecological settings. Such relationships, based mostly on traits of external morphology, have been extensively described for vertebrates, and especially so for squamates. External features are, however, composed by both soft tissues and bones, and these likely play different biomechanical roles during locomotion, such as in the autopodia. Therefore, ecological trends identified on the basis of external morphological measurements may not be directly correlated with equivalent variation in osteology. Here, we investigate how refined parameters of autopodial osteology relate to ecology, by contrasting climbing and nonclimbing geckos. Our first step consisted of inferring how external and osteological morphometric traits coevolved in the group. Our results corroborate the hypothesis of coevolution between external and osteological elements in the autopodia of geckos, and provides evidence for associations between specific osteological traits and preferred locomotor habit. Specifically, nonclimbers exhibit longer ultimate and penultimate phalanges of Digit V in the manus and pes and also a longer fifth metatarsal in comparison with climbers, a pattern discussed here in the context of the differential demands made upon locomotion in specific ecological contexts. Our study highlights the relevance of osteological information for discussing the evolution of ecological associations of the tetrapod autopodium. J. Morphol. 278:290-299, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jmor.20635DOI Listing
March 2017

Frontline Science: Tryptophan restriction arrests B cell development and enhances microbial diversity in WT and prematurely aging mice.

J Leukoc Biol 2017 04 14;101(4):811-821. Epub 2016 Jul 14.

Cell Biology and Immunology Group, Wageningen University, Wageningen, The Netherlands.

With aging, tryptophan metabolism is affected. Tryptophan has a crucial role in the induction of immune tolerance and the maintenance of gut microbiota. We, therefore, studied the effect of dietary tryptophan restriction in young wild-type (WT) mice (118-wk life span) and in DNA-repair deficient, premature-aged ( ) mice (20-wk life span). First, we found that the effect of aging on the distribution of B and T cells in bone marrow (BM) and in the periphery of 16-wk-old mice was comparable to that in 18-mo-old WT mice. Dietary tryptophan restriction caused an arrest of B cell development in the BM, accompanied by diminished B cell frequencies in the periphery. In general, old mice showed similar responses to tryptophan restriction compared with young WT mice, indicative of age-independent effects. Dietary tryptophan restriction increased microbial diversity and made the gut microbiota composition of old mice more similar to that of young WT mice. The decreased abundances of Alistipes and Akkermansia spp. after dietary tryptophan restriction correlated significantly with decreased B cell precursor numbers. In conclusion, we report that dietary tryptophan restriction arrests B cell development and concomitantly changes gut microbiota composition. Our study suggests a beneficial interplay between dietary tryptophan, B cell development, and gut microbial composition on several aspects of age-induced changes.
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http://dx.doi.org/10.1189/jlb.1HI0216-062RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608003PMC
April 2017

Do Adult Phenotypes Reflect Selection on Juvenile Performance? A Comparative Study on Performance and Morphology in Lizards.

Integr Comp Biol 2016 09 11;56(3):469-78. Epub 2016 Jul 11.

Departamento de Biologia - FFCLRP/USP, Laboratório de Evolução de Tetrápodes, Av Bandeirantes, 3900, CEP, Ribeirão Preto - SP 14040-901, Brasil.

When competing for food or other resources, or when confronted with predators, young animals may be at a disadvantage relative to adults because of their smaller size. Additionally, the ongoing differentiation and growth of tissues may constrain performance during early ontogenetic stages. However, juveniles must feed before they can become reproductively active adults and as such the adult phenotype may be the result of an ontogenetic filter imposing selection on juvenile phenotype and performance. Here we present ontogenetic data on head morphology and bite force for different lizard species. We test whether adults reflect selection on juveniles by comparing slopes of growth trajectories before and after sexual maturity in males and females and by examining the variance in head morphology and bite force in juveniles versus adults. Finally, we also present the first results of a selection study where animals were measured, marked and released, and recaptured the subsequent year to test whether head morphology and bite force impact survival.
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http://dx.doi.org/10.1093/icb/icw010DOI Listing
September 2016

Tissue-Specific Suppression of Thyroid Hormone Signaling in Various Mouse Models of Aging.

PLoS One 2016 8;11(3):e0149941. Epub 2016 Mar 8.

Dept of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNA-damaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0149941PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783069PMC
August 2016

Cockayne syndrome group B (Csb) and group a (Csa) deficiencies predispose to hearing loss and cochlear hair cell degeneration in mice.

J Neurosci 2015 Mar;35(10):4280-6

Departments of Regenerative Medicine/Stem Cell Biology, and Otolaryngology, Eli and Edythe Broad Center, University of Southern California, Los Angeles, California 90033

Sensory hair cells in the cochlea, like most neuronal populations that are postmitotic, terminally differentiated, and non-regenerating, depend on robust mechanisms of self-renewal for lifelong survival. We report that hair cell homeostasis requires a specific sub-branch of the DNA damage nucleotide excision repair pathway, termed transcription-coupled repair (TCR). Cockayne syndrome (CS), caused by defects in TCR, is a rare DNA repair disorder with a broad clinical spectrum that includes sensorineural hearing loss. We tested hearing and analyzed the cellular integrity of the organ of Corti in two mouse models of this disease with mutations in the Csb gene (CSB(m/m) mice) and Csa gene (Csa(-/-) mice), respectively. Csb(m/m) and Csa(-/-) mice manifested progressive hearing loss, as measured by an increase in auditory brainstem response thresholds. In contrast to wild-type mice, mutant mice showed reduced or absent otoacoustic emissions, suggesting cochlear outer hair cell impairment. Hearing loss in Csb(m/m) and Csa(-/-) mice correlated with progressive hair cell loss in the base of the organ of Corti, starting between 6 and 13 weeks of age, which increased by 16 weeks of age in a basal-to-apical gradient, with outer hair cells more severely affected than inner hair cells. Our data indicate that the hearing loss observed in CS patients is reproduced in mouse models of this disease. We hypothesize that accumulating DNA damage, secondary to the loss of TCR, contributes to susceptibility to hearing loss.
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http://dx.doi.org/10.1523/JNEUROSCI.5063-14.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4355199PMC
March 2015

Cell-autonomous progeroid changes in conditional mouse models for repair endonuclease XPG deficiency.

PLoS Genet 2014 Oct 9;10(10):e1004686. Epub 2014 Oct 9.

Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg-/- mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4-5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg-/- mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging.
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http://dx.doi.org/10.1371/journal.pgen.1004686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191938PMC
October 2014

Priming of microglia in a DNA-repair deficient model of accelerated aging.

Neurobiol Aging 2014 Sep 28;35(9):2147-60. Epub 2014 Mar 28.

Department of Neuroscience, Section Medical Physiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

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 the age-related deterioration of the CNS. The most prominent age-related change of microglia is enhanced sensitivity to inflammatory stimuli, referred to as priming. It is unclear if priming is due to intrinsic microglia ageing or induced by the ageing neural environment. We have studied this in Ercc1 mutant mice, a DNA repair-deficient mouse model that displays features of accelerated aging in multiple tissues including the CNS. In Ercc1 mutant mice, microglia showed hallmark features of priming such as an exaggerated response to peripheral lipopolysaccharide exposure in terms of cytokine expression and phagocytosis. Specific targeting of the Ercc1 deletion to forebrain neurons resulted in a progressive priming response in microglia exemplified by phenotypic alterations. Summarizing, these data show that neuronal genotoxic stress is sufficient to switch microglia from a resting to a primed state.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.03.025DOI Listing
September 2014

SMC6 is an essential gene in mice, but a hypomorphic mutant in the ATPase domain has a mild phenotype with a range of subtle abnormalities.

DNA Repair (Amst) 2013 May 18;12(5):356-66. Epub 2013 Mar 18.

Genome Damage and Stability Centre, University of Sussex, Falmer, Brighton BN1 9RQ, UK.

Smc5-6 is a highly conserved protein complex related to cohesin and condensin involved in the structural maintenance of chromosomes. In yeasts the Smc5-6 complex is essential for proliferation and is involved in DNA repair and homologous recombination. siRNA depletion of genes involved in the Smc5-6 complex in cultured mammalian cells results in sensitivity to some DNA damaging agents. In order to gain further insight into its role in mammals we have generated mice mutated in the Smc6 gene. A complete knockout resulted in early embryonic lethality, demonstrating that this gene is essential in mammals. However, mutation of the highly conserved serine-994 to alanine in the ATP hydrolysis motif in the SMC6 C-terminal domain, resulted in mice with a surprisingly mild phenotype. With the neo gene selection marker in the intron following the mutation, resulting in reduced expression of the SMC6 gene, the mice were reduced in size, but fertile and had normal lifespans. When the neo gene was removed, the mice had normal size, but detailed phenotypic analysis revealed minor abnormalities in glucose tolerance, haematopoiesis, nociception and global gene expression patterns. Embryonic fibroblasts derived from the ser994 mutant mice were not sensitive to killing by a range of DNA damaging agents, but they were sensitive to the induction of sister chromatid exchanges induced by ultraviolet light or mitomycin C. They also accumulated more oxidative damage than wild-type cells.
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http://dx.doi.org/10.1016/j.dnarep.2013.02.006DOI Listing
May 2013

Evolution of body elongation in gymnophthalmid lizards: relationships with climate.

PLoS One 2012 14;7(11):e49772. Epub 2012 Nov 14.

Department of Biology, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil.

The evolution of elongated body shapes in vertebrates has intrigued biologists for decades and is particularly recurrent among squamates. Several aspects might explain how the environment influences the evolution of body elongation, but climate needs to be incorporated in this scenario to evaluate how it contributes to morphological evolution. Climatic parameters include temperature and precipitation, two variables that likely influence environmental characteristics, including soil texture and substrate coverage, which may define the selective pressures acting during the evolution of morphology. Due to development of geographic information system (GIS) techniques, these variables can now be included in evolutionary biology studies and were used in the present study to test for associations between variation in body shape and climate in the tropical lizard family Gymnophthalmidae. We first investigated how the morphological traits that define body shape are correlated in these lizards and then tested for associations between a descriptor of body elongation and climate. Our analyses revealed that the evolution of body elongation in Gymnophthalmidae involved concomitant changes in different morphological traits: trunk elongation was coupled with limb shortening and a reduction in body diameter, and the gradual variation along this axis was illustrated by less-elongated morphologies exhibiting shorter trunks and longer limbs. The variation identified in Gymnophthalmidae body shape was associated with climate, with the species from more arid environments usually being more elongated. Aridity is associated with high temperatures and low precipitation, which affect additional environmental features, including the habitat structure. This feature may influence the evolution of body shape because contrasting environments likely impose distinct demands for organismal performance in several activities, such as locomotion and thermoregulation. The present study establishes a connection between morphology and a broader natural component, climate, and introduces new questions about the spatial distribution of morphological variation among squamates.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049772PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498171PMC
June 2013

Nucleotide excision DNA repair is associated with age-related vascular dysfunction.

Circulation 2012 Jul 15;126(4):468-78. Epub 2012 Jun 15.

Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center Rotterdam, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands.

Background: Vascular dysfunction in atherosclerosis and diabetes mellitus, as observed in the aging population of developed societies, is associated with vascular DNA damage and cell senescence. We hypothesized that cumulative DNA damage during aging contributes to vascular dysfunction.

Methods And Results: In mice with genomic instability resulting from the defective nucleotide excision repair genes ERCC1 and XPD (Ercc1(d/-) and Xpd(TTD) mice), we explored age-dependent vascular function compared with that in wild-type mice. Ercc1(d/-) mice showed increased vascular cell senescence, accelerated development of vasodilator dysfunction, increased vascular stiffness, and elevated blood pressure at a very young age. The vasodilator dysfunction was due to decreased endothelial nitric oxide synthase levels and impaired smooth muscle cell function, which involved phosphodiesterase activity. Similar to Ercc1(d/-) mice, age-related endothelium-dependent vasodilator dysfunction in Xpd(TTD) animals was increased. To investigate the implications for human vascular disease, we explored associations between single-nucleotide polymorphisms of selected nucleotide excision repair genes and arterial stiffness within the AortaGen Consortium and found a significant association of a single-nucleotide polymorphism (rs2029298) in the putative promoter region of DDB2 gene with carotid-femoral pulse wave velocity.

Conclusions: Mice with genomic instability recapitulate age-dependent vascular dysfunction as observed in animal models and in humans but with an accelerated progression compared with wild-type mice. In addition, we found associations between variations in human DNA repair genes and markers for vascular stiffness, which is associated with aging. Our study supports the concept that genomic instability contributes importantly to the development of cardiovascular disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.112.104380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430727PMC
July 2012

Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.

PLoS One 2012 10;7(4):e35246. Epub 2012 Apr 10.

Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.

Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323647PMC
October 2012

Age-related neuronal degeneration: complementary roles of nucleotide excision repair and transcription-coupled repair in preventing neuropathology.

PLoS Genet 2011 Dec 8;7(12):e1002405. Epub 2011 Dec 8.

Department of Neuroscience, Erasmus University Medical Center, Rotterdam, The Netherlands.

Neuronal degeneration is a hallmark of many DNA repair syndromes. Yet, how DNA damage causes neuronal degeneration and whether defects in different repair systems affect the brain differently is largely unknown. Here, we performed a systematic detailed analysis of neurodegenerative changes in mouse models deficient in nucleotide excision repair (NER) and transcription-coupled repair (TCR), two partially overlapping DNA repair systems that remove helix-distorting and transcription-blocking lesions, respectively, and that are associated with the UV-sensitive syndromes xeroderma pigmentosum (XP) and Cockayne syndrome (CS). TCR-deficient Csa(-/-) and Csb(-/-) CS mice showed activated microglia cells surrounding oligodendrocytes in regions with myelinated axons throughout the nervous system. This white matter microglia activation was not observed in NER-deficient Xpa(-/-) and Xpc(-/-) XP mice, but also occurred in Xpd(XPCS) mice carrying a point mutation (G602D) in the Xpd gene that is associated with a combined XPCS disorder and causes a partial NER and TCR defect. The white matter abnormalities in TCR-deficient mice are compatible with focal dysmyelination in CS patients. Both TCR-deficient and NER-deficient mice showed no evidence for neuronal degeneration apart from p53 activation in sporadic (Csa(-/-), Csb(-/-)) or highly sporadic (Xpa(-/-), Xpc(-/-)) neurons and astrocytes. To examine to what extent overlap occurs between both repair systems, we generated TCR-deficient mice with selective inactivation of NER in postnatal neurons. These mice develop dramatic age-related cumulative neuronal loss indicating DNA damage substrate overlap and synergism between TCR and NER pathways in neurons, and they uncover the occurrence of spontaneous DNA injury that may trigger neuronal degeneration. We propose that, while Csa(-/-) and Csb(-/-) TCR-deficient mice represent powerful animal models to study the mechanisms underlying myelin abnormalities in CS, neuron-specific inactivation of NER in TCR-deficient mice represents a valuable model for the role of NER in neuronal maintenance and survival.
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http://dx.doi.org/10.1371/journal.pgen.1002405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234220PMC
December 2011

Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice.

Age (Dordr) 2012 Aug 4;34(4):845-61. Epub 2011 Aug 4.

MGC Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus MC, Rotterdam, The Netherlands.

Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism.
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http://dx.doi.org/10.1007/s11357-011-9291-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682057PMC
August 2012

Life-history evolution on tropidurinae lizards: influence of lineage, body size and climate.

PLoS One 2011 13;6(5):e20040. Epub 2011 May 13.

Departamento de Fisiologia, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brazil.

The study of life history variation is central to the evolutionary theory. In many ectothermic lineages, including lizards, life history traits are plastic and relate to several sources of variation including body size, which is both a factor and a life history trait likely to modulate reproductive parameters. Larger species within a lineage, for example tend to be more fecund and have larger clutch size, but clutch size may also be influenced by climate, independently of body size. Thus, the study of climatic effects on lizard fecundity is mandatory on the current scenario of global climatic change. We asked how body and clutch size have responded to climate through time in a group of tropical lizards, the Tropidurinae, and how these two variables relate to each other. We used both traditional and phylogenetic comparative methods. Body and clutch size are variable within Tropidurinae, and both traits are influenced by phylogenetic position. Across the lineage, species which evolved larger size produce more eggs and neither trait is influenced by temperature components. A climatic component of precipitation, however, relates to larger female body size, and therefore seems to exert an indirect relationship on clutch size. This effect of precipitation on body size is likely a correlate of primary production. A decrease in fecundity is expected for Tropidurinae species on continental landmasses, which are predicted to undergo a decrease in summer rainfall.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0020040PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094402PMC
October 2011

Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

PLoS Biol 2007 Jan;5(1):e2

Department of Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.
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http://dx.doi.org/10.1371/journal.pbio.0050002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1698505PMC
January 2007

Retinal degeneration and ionizing radiation hypersensitivity in a mouse model for Cockayne syndrome.

Mol Cell Biol 2007 Feb 4;27(4):1433-41. Epub 2006 Dec 4.

Department of Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.

Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment. CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair. This function may explain the UV sensitivity but hardly clarifies the other CS symptoms. Many of these, including retinopathy, are associated with premature aging. We studied eye pathology in a mouse model for CS. Csb(m/m) mice were hypersensitive to UV light and developed epithelial hyperplasia and squamous cell carcinomas in the cornea, which underscores the importance of transcription-coupled repair of photolesions in the mouse. In addition, we observed a spontaneous loss of retinal photoreceptor cells with age in the Csb(m/m) retina, resulting in a 60% decrease in the number of rods by the age of 18 months. Importantly, when Csb(m/m) mice (as well as Csa(-/-) mice) were exposed to 10 Gy of ionizing radiation, we noticed an increase in apoptotic photoreceptor cells, which was not observed in wild-type animals. This finding, together with our observation that the expression of established oxidative stress marker genes is upregulated in the Csb(m/m) retina, suggests that (endogenous) oxidative DNA lesions play a role in this CS-specific premature-aging feature and supports the oxidative DNA damage theory of aging.
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http://dx.doi.org/10.1128/MCB.01037-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1800713PMC
February 2007