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Premature Aging (premature + aging)
Selected AbstractsPremature aging of the immune system in children with juvenile idiopathic arthritisARTHRITIS & RHEUMATISM, Issue 7 2008Martina Prelog Objective Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence. Methods To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation. Results JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age-matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki-67,positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04). Conclusion Our findings suggest that age-inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies. [source] Lessons learned from DNA repair defective syndromesEXPERIMENTAL DERMATOLOGY, Issue 6 2007Kai-Martin Thoms Abstract:, Genomic instability is the driving force behind cancer development. Human syndromes with DNA repair deficiencies comprise unique opportunities to study the clinical consequences of faulty genome maintenance leading to premature aging and premature cancer development. These syndromes include chromosomal breakage syndromes with defects in DNA damage signal transduction and double-strand break repair, mismatch repair defective syndromes as well as nucleotide excision repair defective syndromes. The same genes that are severely affected in these model diseases may harbour more subtle variations in the ,healthy' normal population leading to genomic instability, cancer development, and accelerated aging at later stages of life. Thus, studying those syndromes and the molecular mechanisms behind can significantly contribute to our understanding of (skin) cancerogenesis as well as to the development of novel individualized preventive and therapeutic anticancer strategies. The establishment of centers of excellence for studying rare genetic model diseases may be helpful in this direction. [source] Characterization of the Drosophila myeloid leukemia factorGENES TO CELLS, Issue 12 2006Séverine Martin-Lannerée In human, the myeloid leukemia factor 1 (hMLF1) has been shown to be involved in acute leukemia, and mlf related genes are present in many animals. Despite their extensive representation and their good conservation, very little is understood about their function. In Drosophila, dMLF physically interacts with both the transcription regulatory factor DREF and an antagonist of the Hedgehog pathway, Suppressor of Fused, whose over-expression in the fly suppresses the toxicity induced by polyglutamine. No connection between these data has, however, been established. Here, we show that dmlf is widely and dynamically expressed during fly development. We isolated and analyzed the first dmlf mutants: embryos lacking maternal dmlf product have a low viability with no specific defect, and dmlf - , adults display weak phenotypes. We monitored dMLF subcellular localization in the fly and cultured cells. We were able to show that, although generally nuclear, dMLF can also be cytoplasmic, depending on the developmental context. Furthermore, two differently spliced variants of dMLF display differential subcellular localization, allowing the identification of regions of dMLF potentially important for its localization. Finally, we demonstrate that dMLF can act developmentally and postdevelopmentally to suppress neurodegeneration and premature aging in a cerebellar ataxia model. [source] Survival responses to oxidative stress and agingGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2010Yuri Miura Oxidative stress is recognized as an important environmental factor in aging; however, because reactive oxygen species (ROS) and related free radicals are normally produced both intra- and extracellularly, air-living organisms cannot avoid the risk of oxidative stress. Consequently, these organisms have evolved various anti-oxidant systems to prevent ROS, scavenge free radicals, repair damaged components and adaptive responses. This review will focus on the repair and adaptive response to oxidative stress, and summarize the changes of these systems as a result aging and their relationship to premature aging. Geriatr Gerontol Int 2010; 10 (Suppl. 1): S1,S9. [source] Acquired localized cutis laxa confined to the face: case report and review of the literatureINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 12 2004Claudia Jimena Perafán Riveros MD Background, Cutis laxa is an uncommon entity characterized by laxity of the skin, which hangs in loose folds, producing the appearance of premature aging. It can be subdivided into congenital and acquired. This latter variant is rare and the skin involvement varies from generalized to localized. We report a case of a localized acquired cutis laxa confined to the face, without preceding inflammatory lesions or systemic compromise. Four similar cases have been reported to date. The etiology remains unknown and there is no definitive treatment. Methods, A 27-year-old White woman came to our hospital with a wrinkled face, pendulous earlobes and drop eyelids. Changes began 5 years prior, and she appeared much older than her age. Results, Histological analysis and ultrastructural examination of skin biopsy revealed reduction and fragmentation of elastic fibers, confirming the diagnosis of cutis laxa. No systemic involvement was diagnosed. The patient was submitted to plastic surgery for repair, with satisfactory results to date. Conclusions, Acquired localized cutis laxa confined to the face without preceding inflammatory lesions is extremely rare. The etiology remains unknown. Clinical features and histopathologic findings confirm the diagnosis. Surgical repair seems to be the only therapeutic choice, but the results are variable and temporary. [source] A role for the Werner syndrome protein in epigenetic inactivation of the pluripotency factor Oct4AGING CELL, Issue 4 2010Johanna A. Smith Summary Werner syndrome (WS) is an autosomal recessive disorder, the hallmarks of which are premature aging and early onset of neoplastic diseases (Orren, 2006; Bohr, 2008). The gene, whose mutation underlies the WS phenotype, is called WRN. The protein encoded by the WRN gene, WRNp, has DNA helicase activity (Gray et al., 1997; Orren, 2006; Bohr, 2008; Opresko, 2008). Extensive evidence suggests that WRNp plays a role in DNA replication and DNA repair (Chen et al., 2003; Hickson, 2003; Orren, 2006; Turaga et al., 2007; Bohr, 2008). However, WRNp function is not yet fully understood. In this study, we show that WRNp is involved in de novo DNA methylation of the promoter of the Oct4 gene, which encodes a crucial stem cell transcription factor. We demonstrate that WRNp localizes to the Oct4 promoter during retinoic acid-induced differentiation of human pluripotent cells and associates with the de novo methyltransferase Dnmt3b in the chromatin of differentiating pluripotent cells. Depletion of WRNp does not affect demethylation of lysine 4 of the histone H3 at the Oct4 promoter, nor methylation of lysine 9 of H3, but it blocks the recruitment of Dnmt3b to the promoter and results in the reduced methylation of CpG sites within the Oct4 promoter. The lack of DNA methylation was associated with continued, albeit greatly reduced, Oct4 expression in WRN-deficient, retinoic acid-treated cells, which resulted in attenuated differentiation. The presented results reveal a novel function of WRNp and demonstrate that WRNp controls a key step in pluripotent stem cell differentiation. [source] Do mtDNA deletions drive premature aging in mtDNA mutator mice?AGING CELL, Issue 4 2009Yevgenya Kraytsberg Summary Deletions in mitochondrial DNA (mtDNA) have long been suspected to be involved in mammalian aging, but their role remains controversial. Recent research has demonstrated that relatively higher levels of mtDNA deletions correlate with premature aging in mtDNA mutator mice, which led to the conclusion that premature aging in these mice is driven by mtDNA deletions. However, it is reported here that the absolute level of deletions in mutator mice is quite low, especially when compared with the level of point mutations in these mice. It is thus argued that the available data are insufficient to conclude that mtDNA mutations drive premature aging in mtDNA mutator mice. It remains possible that clonal expansion of mtDNA deletions may result in sufficiently high levels to play a role in age-related dysfunction in some cells, but assessing this possibility will require studies of the distribution of these deletions among different cell types and in individual cells. [source] Delayed kinetics of DNA double-strand break processing in normal and pathological agingAGING CELL, Issue 1 2008Olga A. Sedelnikova Summary Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age-dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage-induced foci of phosphorylated histone H2AX (,-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous ,-H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of ,-H2AX foci than those taken from normal donors of comparable age. Further increases in ,-H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to ,-H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of ,-H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of ,-H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging. [source] WRN, the protein deficient in Werner syndrome, plays a critical structural role in optimizing DNA repairAGING CELL, Issue 4 2003Lishan Chen Summary Werner syndrome (WS) predisposes patients to cancer and premature aging, owing to mutations in WRN. The WRN protein is a RECQ-like helicase and is thought to participate in DNA double-strand break (DSB) repair by non-homologous end joining (NHEJ) or homologous recombination (HR). It has been previously shown that non-homologous DNA ends develop extensive deletions during repair in WS cells, and that this WS phenotype was complemented by wild-type (wt) WRN. WRN possesses both 3, , 5, exonuclease and 3, , 5, helicase activities. To determine the relative contributions of each of these distinct enzymatic activities to DSB repair, we examined NHEJ and HR in WS cells (WRN,/,) complemented with either wtWRN, exonuclease-defective WRN (E,), helicase-defective WRN (H,) or exonuclease/helicase-defective WRN (E,H,). The single E, and H, mutants each partially complemented the NHEJ abnormality of WRN,/, cells. Strikingly, the E,H, double mutant complemented the WS deficiency nearly as efficiently as did wtWRN. Similarly, the double mutant complemented the moderate HR deficiency of WS cells nearly as well as did wtWRN, whereas the E, and H, single mutants increased HR to levels higher than those restored by either E,H, or wtWRN. These results suggest that balanced exonuclease and helicase activities of WRN are required for optimal HR. Moreover, WRN appears to play a structural role, independent of its enzymatic activities, in optimizing HR and efficient NHEJ repair. Another human RECQ helicase, BLM, suppressed HR but had little or no effect on NHEJ, suggesting that mammalian RECQ helicases have distinct functions that can finely regulate recombination events. [source] A simple and rapid method to assess lycopene in multiple layers of skin samplesBIOMEDICAL CHROMATOGRAPHY, Issue 2 2010Luciana B. Lopes Abstract Topical application of lycopene is a convenient way to restore antioxidants depleted from the skin by UV radiation and achieve protection against premature aging and cancer. In this study, a simple, rapid and reproducible method to quantify lycopene in different skin layers was developed, validated and employed to assess this compound after skin penetration studies. Lycopene was extracted from the stratum corneum (SC) and viable epidermis and dermis (ED) by vortex homogenization and bath sonication in a mixture of acetonitrile and methanol (52:48, v/v). Lycopene was assayed by HPLC using a C18 column, and acetonitrile:methanol (52:48, v/v) as mobile phase. The quantification limit of lycopene in samples of SC and ED was 35,ng/mL and the assay was linear from 35 to 2000,ng/mL. Within-day and between-days assays coefficients of variation and relative errors (indicative of precision and accuracy) were less than 15% (or 20% for the limit of quantification). Lycopene recovery from SC and ED was dependent on the spiked concentration: for 50,ng/mL, recoveries were 88.3 and 90.5%; for 100,1000,ng/mL, recoveries were 68.6,74.9%. This method has a potential application for lycopene quantification during formulation development and evaluation in the dermatological field. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||