MedWorm.com provides a medical RSS filtering service. Over 6000 RSS medical sources are combined and output via different filters. This feed contains the latest items from the 'Aging Cell' source. Tue, 07 Feb 2012 08:48:49 +0100 http://www.medworm.com/index.php?rid=5657933&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00803.x SummaryRECQL4 is associated with Rothmund‐Thomson Syndrome (RTS), a rare autosomal recessive disorder characterized by premature aging, genomic instability and cancer predisposition. RECQL4 is a member of the RecQ‐ helicase family, and has many similarities to WRN protein, which is also implicated in premature aging. There is no information about whether any of the RecQ helicases play roles in mitochondrial biogenesis, which is strongly implicated in the aging process. Here, we used microscopy to visualize RECQL4 in mitochondria. Fractionation of human and mouse cells also showed that RECQL4 was present in mitochondria. Q‐PCR amplification of mitochondrial DNA demonstrated that mtDNA damage accumulated in RECQL4‐deficient cells. Microarray analysis suggested that mitochondrial bioe... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5657933 Wed, 01 Feb 2012 05:00:00 +0100 5657933 http://www.medworm.com/index.php?rid=5645118&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00790.x In conclusion, the results presented herein highlight for the first time an interesting link between skewing of XCI and healthy aging and longevity. We speculate that the allelic imbalance produced by XCI skewing may compromise the cooperative and compensatory organization occurring between the two cell populations that make up the female mosaic. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5645118 Wed, 01 Feb 2012 05:00:00 +0100 5645118 http://www.medworm.com/index.php?rid=5636805&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00802.x Previous studies have shown that telomere dysfunction induces alteration in the systemic (circulatory) environment impairing the differentiation of hematopoietic stem cells (HSCs) but these defects can be reverted by re‐exposing HSCs to an environment with functional telomeres. In contrast, HSC intrinsic telomere dysfunction induces permanent and irreversible limitations in the repopulation capacity partially depending on the induction checkpoints such as cell cycle arrest or apoptosis. It is currently unknown whether telomere dysfunctional environment can induce irreversible, cell intrinsic defects impairing the function of HSCs. Here we analyzed the functional reserves of murine, wildtype HSCs with intact telomeres that were transiently exposed to a telomere dysfunctional environment (... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5636805 Sat, 28 Jan 2012 18:10:22 +0100 5636805 http://www.medworm.com/index.php?rid=5626236&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00800.x SummarySleep:wake cycles break down with age, but the causes of this degeneration are not clear. Using a Drosophila model we addressed the contribution of circadian mechanisms to this aged‐induced deterioration. We found that in old flies free‐running circadian rhythms (behavioral rhythms assayed in constant darkness) have a longer period and an unstable phase before they eventually degenerate. Surprisingly, rhythms are weaker in light:dark cycles and the circadian‐regulated morning peak of activity is diminished under these conditions. On a molecular level, aging results in reduced amplitude of circadian clock gene expression in peripheral tissues. However, oscillations of the clock protein PERIOD (PER) are robust and synchronized among different clock neurons, even in very old, arr... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5626236 Wed, 25 Jan 2012 15:37:46 +0100 5626236 http://www.medworm.com/index.php?rid=5626238&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00798.x SummaryDietary restriction (DR) extends the lifespan of a wide range of species, although the universality of this effect has never been quantitatively examined. Here we report the first comprehensive comparative meta‐analysis of DR across studies and species. Overall, DR significantly increased lifespan but this effect is modulated by several factors. In general, DR has less effect in extending lifespan in males and also in non‐model organisms. Surprisingly, the proportion of protein intake was more important for life‐extension via DR than the degree of caloric restriction. Furthermore, we show that reduction in both age‐dependent and age‐independent mortality rates drive life‐extension by DR among the well‐studied laboratory model species (yeast, nematode worms, fruit flies... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5626238 Mon, 23 Jan 2012 05:00:00 +0100 5626238 http://www.medworm.com/index.php?rid=5626237&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00799.x SummarySynaptic dysfunction is considered the primary substrate for the functional declines observed within the nervous system during age‐related neurodegenerative disease. Dietary restriction (DR), which extends lifespan in numerous species, has been shown to have beneficial effects on many neurodegenerative disease models. Existing data sets suggest that the effects of DR during disease include the amelioration of synaptic dysfunction but evidence of the beneficial effects of diet on the synapse is lacking. Dynactin mutant flies have significant increases in mortality rates and exhibit progressive loss of motor function. Using a novel fly motor disease model, we demonstrate that mutant flies raised on a low calorie diet have enhanced motor function and improved survival compared to fli... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5626237 Mon, 23 Jan 2012 05:00:00 +0100 5626237 http://www.medworm.com/index.php?rid=5618250&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00797.x In this study, we decipher the molecular mechanism of MMP‐2 activation in WT‐Aβ1‐40‐treated VSMC and provide evidence that matrix metalloprotease (MMP) activity, although playing a critical role in cell detachment disrupting ECM components, is not involved in the wild‐type Aβ1‐40‐induced degeneration of VSMCs. Indeed, whereas this peptide clearly induced VSMC apoptosis, neither preventing MMP‐2 activity, nor hampering the expression of membrane‐type1 MMP, or preventing tissue inhibitors of MMPs‐2 (TIMP‐2) recruitment (two proteins evidenced here as involved in MMP‐2 activation), reduced the number of dead cells. Even the use of broad‐range MMP inhibitors (GM6001 and Batimastat) did not affect WT‐Aβ1‐40‐induced cell apoptosis. Our results, contrast those o... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5618250 Sun, 22 Jan 2012 14:32:04 +0100 5618250 http://www.medworm.com/index.php?rid=5605685&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00794.x This article is a U.S. Government work and is in the public domain in the USA (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5605685 Thu, 19 Jan 2012 13:50:52 +0100 5605685 http://www.medworm.com/index.php?rid=5618251&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00796.x Conclusions:  The present finding revealed a previously unidentified role of klotho in regulating Nox2 protein expression in RASM cells. Klotho not only downregulated Nox2 protein expression and intracellular superoxide production but also attenuated AngII‐induced superoxide production, oxidative damage, and apoptosis. The klotho‐induced suppression of Nox2 protein expression may be mediated by the cAMP–PKA pathway.© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5618251 Thu, 19 Jan 2012 05:00:00 +0100 5618251 http://www.medworm.com/index.php?rid=5595083&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00793.x AbstractWe analyzed MBL2 gene variants in two cohorts of centenarians, octo‐ and nonagenarians and in the general population, one from Sardinia island (Italy), recruited in the frame of the AKea study, and another from Campania (southern Italy), to search for haplotypes related to longevity. We also assessed in vitro the effect of mannose‐binding lectin (MBL) on various human cells at different stage of senescence. The frequency of high and null activity haplotypes was significantly lower and the frequency of intermediate activity haplotype significantly higher in centenarians and in subjects between 80 and 99 years from both the cohorts as compared each to the general population from the same geographic area. Furthermore, serum MBL concentration (also after normalization to serum albu... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5595083 Mon, 16 Jan 2012 16:40:28 +0100 5595083 http://www.medworm.com/index.php?rid=5579191&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00792.x In this study, we investigated the age‐related effects of the reducing agent N‐acetyl‐L‐cysteine (L‐NAC) on the activation of the N‐methyl‐ d‐aspartate receptor (NMDA‐R) by its co‐agonist d‐serine, since alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long‐term dietary supplementation with L‐NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA‐R‐mediated synaptic potentials and theta‐burst‐induced long‐term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous d‐serine. Chronic treatment with L‐NAC, but not acute application of the reducing agent, restored potent d�... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5579191 Thu, 12 Jan 2012 12:40:22 +0100 5579191 http://www.medworm.com/index.php?rid=5645116&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00792.x In this study, we investigated the age‐related effects of the reducing agent N‐acetyl‐L‐cysteine (L‐NAC) on the activation of the N‐methyl‐ d‐aspartate receptor (NMDA‐R) by its co‐agonist d‐serine, because alterations in this mechanism contribute greatly to synaptic plasticity deficits in aged animals. Long‐term dietary supplementation with L‐NAC prevented oxidative damage in the hippocampus of aged rats. Electrophysiological recordings in the CA1 of hippocampal slices indicated that NMDA‐R‐mediated synaptic potentials and theta‐burst‐induced long‐term potentiation (LTP) were depressed in aged animals, deficits that could be reversed by exogenous d‐serine. Chronic treatment with L‐NAC, but not acute application of the reducing agent, restored potent ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5645116 Mon, 09 Jan 2012 05:00:00 +0100 5645116 http://www.medworm.com/index.php?rid=5645117&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00791.x In this study, we show that 18‐month‐old mice treated with rapamycin starting at 2 months of age perform significantly better on a task measuring spatial learning and memory compared to age‐matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15‐month‐old mice with pre‐existing, age‐dependent learning and memory deficits. We further show that the rapamycin‐mediated improvement in learning and memory is associated with a decrease in IL‐1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age‐dependent learning and memory deficits. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5645117 Sat, 31 Dec 2011 05:00:00 +0100 5645117 http://www.medworm.com/index.php?rid=5557453&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00790.x In conclusion, the results presented herein highlight for the first time an interesting link between skewing of XCI and healthy aging and longevity. We speculate that the allelic imbalance produced by XCI skewing may compromise the cooperative and compensatory organisation occurring between the two cell populations that make up the female mosaic.© 2011 The Authors Aging Cell © 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5557453 Sat, 31 Dec 2011 05:00:00 +0100 5557453 http://www.medworm.com/index.php?rid=5557454&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00787.x SummaryThe phosphatidylinositol 3‐kinase (PI3K)/Akt pathway is important for tissue proliferation. Previously, we found that tissue regeneration after partial pancreatic resection was markedly attenuated in aged mice as compared to young mice and that this attenuation was due to an age‐dependent reduction of PI3K/Akt signaling in the pancreatic acini; however, the mechanisms for the age‐associated decline of pancreatic PI3K/Akt signaling remained unknown. To better delineate the mechanisms for the decreased PI3K/Akt activation with aging, age‐associated changes in cell proliferation and PI3K/Akt signaling were investigated in the present study using in vitro primary pancreatic acinar cell cultures derived from young and aged mice. In response to treatment with insulin‐like growth... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5557454 Fri, 30 Dec 2011 05:00:00 +0100 5557454 http://www.medworm.com/index.php?rid=5605697&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00785.x SummaryChanges in epigenetic status and chromatin structure have been shown to associate with aging in many organisms. Here, we report an RNAi screen of putative histone methyltransferases and demethylases in wild‐type Caenorhabditis elegans using reproduction inhibitor. We identified six genes that when inactivated by RNAi, consistently extend lifespan. Five of these genes do not require germline proliferation to affect lifespan. We further characterized two of these genes, the highly homologous SET domain containing genes, set‐9 and set‐26. They share redundant functions in maintaining normal lifespan, while exhibiting differential tissue expression patterns. Furthermore, we found that set‐9 and set‐26 partially act through the Forkhead box O (FOXO) transcription factor, DAF‐... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5605697 Thu, 29 Dec 2011 05:00:00 +0100 5605697 http://www.medworm.com/index.php?rid=5550782&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00786.x In this study, we have evaluated the role of PTP1B in the development of aging‐associated obesity, inflammation and peripheral insulin resistance by assessing metabolic parameters at 3 and 16 months in PTP1B‐/‐ mice maintained on mixed genetic background (C57Bl/6J x 129Sv/J). Whereas fat mass and adipocyte size were increased in wild‐type control mice at 16 months, these parameters did not change with aging in PTP1B‐/‐ mice. Increased levels of pro‐inflammatory cytokines, crown‐like structures and hypoxia‐inducible factor (HIF)‐1α were observed only in adipose tissue from 16‐month old wild‐type mice. Similarly, islet hyperplasia and hyperinsulinemia were observed in wild‐type mice with aging‐associated obesity, but not in PTP1B‐/‐ animals. Leanness in 16‐... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550782 Thu, 29 Dec 2011 05:00:00 +0100 5550782 http://www.medworm.com/index.php?rid=5645119&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00788.x In this study, we used immunoprecipitation assays to show that Nrf2 bound to the active antioxidant response element (ARE) of the catalytic subunit of glutamate cysteine ligase (GCLC) is significantly lower in hepatic chromatin from aged vs. young rats. Moreover, the activity at this ARE locus is diminished during aging because of the presence of Bach1 and the absence of CREB‐binding protein (CBP), a transcriptional repressor and co‐activator, respectively. Further analysis reveals that Nrf2 occupies an alternate ARE site located −2.2 kb downstream from the normally active ARE binding site in livers of old rats, indicating an age‐specific adaptation to maintain gene expression. Our results, thus, show that the conversion of Nrf2 binding from an active ARE to an alternative ARE el... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5645119 Wed, 28 Dec 2011 05:00:00 +0100 5645119 http://www.medworm.com/index.php?rid=5550783&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00788.x SummaryNFE2‐related factor 2 (Nrf2) transcriptionally governs the cellular response to harmful electrophiles, xenobiotics, and reactive oxygen species. Its nuclear levels decline with age (Suh et al., 2004), which in part explains the age‐related loss of phase II detoxification. However, little work has yet characterized how age affects Nrf2 DNA binding, or the role that alterations to the Nrf2 transcriptional apparatus plays in modulating Nrf2‐mediated gene expression. In the present study we used immunoprecipitation assays to show that Nrf2 bound to the active antioxidant response element (ARE) of the catalytic subunit of glutamate cysteine ligase (GCLC) is significantly lower in hepatic chromatin from aged versus young rats. Moreover, the activity at this ARE locus is diminished d... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550783 Wed, 28 Dec 2011 05:00:00 +0100 5550783 http://www.medworm.com/index.php?rid=5513619&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00780.x SummaryThe African annual fish Nothobranchius furzeri emerged as new model for age research over recent years. N. furzeri show an exceptionally short lifespan, age‐dependent cognitive/ behavioral decline, expression of age‐related biomarkers and susceptibility to lifespan manipulation. In addition, laboratory strains differ largely in lifespan.Here, we set out to study the genetics of lifespan determination. We crossed a short‐ to a long‐lived strain, recorded lifespan and established polymorphic markers. Based on genotypes of 411 marker loci in 404 F2 progeny we built a genetic map comprising 355 markers at an average spacing of 5.5 cM, 22 linkage groups (LGs) and 1,965 cM. By combining marker data with lifespan values we identified one genome‐wide highly significant quantit... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5513619 Fri, 16 Dec 2011 05:00:00 +0100 5513619 http://www.medworm.com/index.php?rid=5513620&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00781.x AbstractWe studied adult neurogenesis in the short‐lived annual fish Nothobranchius furzeri and quantified the effects of aging on the mitotic activity of the neuronal progenitors and the expression of glial fibrillary acid protein (GFAP) in the radial glia.The distribution of neurogenic niches is substantially similar to that of zebrafish and adult stem cells generate neurons which persist in the adult brain. As opposed to zebrafish, however, the N.furzeri genome contains a doublecortin (DCX) gene. DCX is transiently expressed by newly generated neurons in the telencephalon and optic tectum. We also analyzed expression of the microRNA miR‐9 and miR‐124 and found that they have complementary expression domains: miR‐9 is expressed in the neurogenic niches of the telencephalon and th... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5513620 Thu, 15 Dec 2011 05:00:00 +0100 5513620 http://www.medworm.com/index.php?rid=5605698&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00783.x SummaryTo test the hypothesis that the antioxidant enzyme superoxide dismutase (SOD) mimetic TEMPOL improves arterial aging, young (Y, 4–6 months) and old (O, 26–28 months) male C57BL6 mice received regular or TEMPOL‐supplemented (1mM) drinking water for 3 weeks (n = 8 per group). Aortic superoxide was 65% greater in O (P < 0.05 vs. Y), which was normalized by TEMPOL. O had large elastic artery stiffening, as indicated by greater aortic pulse wave velocity (aPWV, 508 ± 22 vs. 418 ± 22 AU), which was associated with increased adventitial collagen I expression (P < 0.05 vs. Y). TEMPOL reversed the age‐associated increases in aPWV (434 ± 21 AU) and collagen in vivo, and SOD reversed the increases in collagen I in adventitial fibroblasts from ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5605698 Tue, 13 Dec 2011 05:00:00 +0100 5605698 http://www.medworm.com/index.php?rid=5595085&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00779.x SummaryHutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder because of a LMNA gene mutation that produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here, we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ∼ 75 kDa, which appears to be defective in loading proliferating cell nuclear antigen (PCNA) and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Because of the crucial role of RFC in DNA replication, our findings provide a mechanist... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5595085 Tue, 13 Dec 2011 05:00:00 +0100 5595085 http://www.medworm.com/index.php?rid=5502612&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00779.x Hutchinson‐Gilford progeria syndrome (HGPS) is a rare genetic disorder due to a LMNA gene mutation which produces a mutant lamin A protein (progerin). Progerin also has been correlated to physiological aging and related diseases. However, how progerin causes the progeria remains unknown. Here we report that the large subunit (RFC1) of replication factor C is cleaved in HGPS cells, leading to the production of a truncated RFC1 of ∼75 kDa which appears to be defective in loading PCNA and pol δ onto DNA for replication. Interestingly, the cleavage can be inhibited by a serine protease inhibitor, suggesting that RFC1 is cleaved by a serine protease. Due to the crucial role of RFC in DNA replication our findings provide a mechanistic interpretation for the observed replicative arrest and p... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5502612 Tue, 13 Dec 2011 05:00:00 +0100 5502612 http://www.medworm.com/index.php?rid=5595084&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00782.x We report here a novel finding that raised CEBPB expression in circulating leukocyte‐derived RNA samples in vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB‐triggered muscle repair: if this mechanism is confirmed, it may provide a target for intervention to protect and enhance aging muscle. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5595084 Thu, 08 Dec 2011 05:00:00 +0100 5595084 http://www.medworm.com/index.php?rid=5550785&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00775.x In this study, we investigated the two TERC and four TERT SNPs in middle‐aged, old, and oldest‐old Danes (58–100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest‐old and 736 middle‐aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross‐sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, P = 0.014). No TERT variatio... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550785 Fri, 02 Dec 2011 05:00:00 +0100 5550785 http://www.medworm.com/index.php?rid=5570495&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2012.00789.x SummaryOver the last ten years, various screens of small molecules have been conducted to find long‐sought interventions in aging. Most of these studies were performed in invertebrates but the demonstration of pharmacological lifespan extension in the mouse has created considerable excitement. Since aging is a common risk factor for several chronic diseases, there is a reasonable expectation that some compounds capable of extending lifespan will be useful for preventing a range of age‐related diseases. One of the potential targets is protein aggregation which is associated with several age‐related diseases. Genetic studies have long indicated that protein homeostasis is a critical component of longevity but recently a series of chemicals have been identified in the nematode Caenorhab... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5570495 Thu, 01 Dec 2011 05:00:00 +0100 5570495 http://www.medworm.com/index.php?rid=5557452&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00791.x In this study, we show that 18‐month‐old mice treated with rapamycin starting at two months of age perform significantly better on a task measuring spatial learning and memory compared to age‐matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15‐month‐old mice with pre‐existing, age‐dependent learning and memory deficits. We further show that the rapamycin‐mediated improvement in learning and memory is associated with a decrease in IL‐1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age‐dependent learning and memory deficits.© 2011 The Authors Aging Cell© 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and I... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5557452 Thu, 01 Dec 2011 05:00:00 +0100 5557452 http://www.medworm.com/index.php?rid=5550781&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00785.x SummaryChanges of epigenetic status and chromatin structure have been shown to associate with aging in many organisms. Here, we report an RNAi screen of putative histone methyltransferases and demethylases in wild type C. elegans using reproduction inhibitor. We identified six genes that, when inactivated by RNAi, consistently extend lifespan. Five of these genes do not require germline proliferation to affect lifespan. We further characterized two of these genes, the highly homologous SET‐domain containing genes, set‐9 and set‐26. They share redundant functions in maintaining normal lifespan, while exhibiting differential tissue expression patterns. Furthermore, we found that set‐9 and set‐26 partially act through the FOXO transcription factor, DAF‐16, to modulate lifespan. In... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550781 Thu, 01 Dec 2011 05:00:00 +0100 5550781 http://www.medworm.com/index.php?rid=5521968&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00778.x SummaryATM and p53, effectors of the DNA damage checkpoint, are generally considered pro‐apoptotic in neurons. We show that DNA damage and checkpoint activation occurs in postmitotic neurons in animal models of tauopathy, neurodegenerative disorders that include Alzheimer’s disease. Surprisingly, checkpoint attenuation potently increases neurodegeneration through aberrant cell cycle re‐entry of postmitotic neurons. These data suggest an unexpected neuroprotective role for the DNA damage checkpoint in tauopathies.© 2011 The Authors Aging Cell© 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5521968 Thu, 01 Dec 2011 05:00:00 +0100 5521968 http://www.medworm.com/index.php?rid=5513618&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00784.x AbstractReplicative senescence has fundamental implications on cell morphology, proliferation and differentiation potential. Here we describe a simple method to track long‐term culture based on continuous DNA‐methylation changes at six specific CpG sites. This epigenetic senescence signature can be used as biomarker for various cell types to predict the state of cellular senescence with regard to the number of passages, population doublings or days of in vitro culture.© 2011 The Authors Aging Cell© 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5513618 Thu, 01 Dec 2011 05:00:00 +0100 5513618 http://www.medworm.com/index.php?rid=5502611&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00783.x AbstractTo test the hypothesis that the antioxidant enzyme superoxide dismutase (SOD) mimetic TEMPOL improves arterial aging, young (Y, 4‐6 mo) and old (O, 26‐28 mo) male C57BL6 mice received regular or TEMPOL‐supplemented (1mM) drinking water for 3 weeks (n=8/group). Aortic superoxide was 65% greater in O (p<0.05 vs. Y), which was normalized by TEMPOL. O had large elastic artery stiffening, as indicated by greater aortic pulse wave velocity (aPWV, 508 ± 22 vs. 418 ± 22 AU), which was associated with increased adventitial collagen I expression (p<0.05 vs. Y). TEMPOL reversed the age‐associated increases in aPWV (434 ± 21 AU) and collagen in vivo, and SOD reversed increases in collagen I in adventitial fibroblasts from older rats in vitro. Isolated carotid arteries of O had... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5502611 Thu, 01 Dec 2011 05:00:00 +0100 5502611 http://www.medworm.com/index.php?rid=5484786&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00782.x Conclusions:  We report here a novel finding that raised CEBPB expression in circulating leukocyte derived RNA samples in‐vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB triggered muscle repair: if this mechanism is confirmed it may provide a target for intervention to protect and enhance aging muscle.© 2011 The Authors Aging Cell© 2011 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5484786 Thu, 01 Dec 2011 05:00:00 +0100 5484786 http://www.medworm.com/index.php?rid=5466765&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00775.x In this study we investigated the two TERC and four TERT SNPs in middle‐aged, old, and oldest‐old Danes (58‐100 years) and their association with LTL (n=864) and longevity (n=1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest‐old and 736 middle‐aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross‐sectional and a longitudinal approach.Applying an additive model we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = ‐0.08, p = 0.011) and in male rs12696304 G carriers (regression coefficient = ‐0.13, p = 0.014). No TERT variations showed association. Moreover, th... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5466765 Thu, 01 Dec 2011 05:00:00 +0100 5466765 http://www.medworm.com/index.php?rid=5455244&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00776.x SummaryThe human cornea is a tri‐laminar structure composed of several cell types with substantial mitotic potential. Age‐related changes in the cornea are associated with declining visual acuity and the onset of overt age‐related corneal diseases. Corneal transplantation is commonly used to restore vision in patients with damaged or diseased corneas. However, the supply of donor tissue is limited, and thus there is considerable interest in the development of tissue‐engineered alternatives. A major obstacle to these approaches is the short replicative lifespan of primary human corneal endothelial cells (HCEC). Accordingly, a comprehensive investigation of the signalling pathways and mechanisms underpinning proliferative lifespan and senescence in HCEC was undertaken. The effects of... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5455244 Wed, 30 Nov 2011 02:06:56 +0100 5455244 http://www.medworm.com/index.php?rid=5550784&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00776.x SummaryThe human cornea is a tri‐laminar structure composed of several cell types with substantial mitotic potential. Age‐related changes in the cornea are associated with declining visual acuity and the onset of overt age‐related corneal diseases. Corneal transplantation is commonly used to restore vision in patients with damaged or diseased corneas. However, the supply of donor tissue is limited, and thus there is considerable interest in the development of tissue‐engineered alternatives. A major obstacle to these approaches is the short replicative lifespan of primary human corneal endothelial cells (HCEC). Accordingly, a comprehensive investigation of the signalling pathways and mechanisms underpinning proliferative lifespan and senescence in HCEC was undertaken. The effects of... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550784 Tue, 29 Nov 2011 05:00:00 +0100 5550784 http://www.medworm.com/index.php?rid=5455245&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00777.x SummaryThe cholesteryl ester transfer protein (CETP) gene plays an essential role in regulating cholesterol homeostasis and is a candidate susceptibility gene for late onset Alzheimer’s disease (AD). Recent finding suggests that the CETP I405V polymorphism (rs5882) is associated with a slower rate of memory decline and a lower risk of incident dementia. Using data from two ongoing epidemiologic clinical‐pathologic cohort studies of aging and dementia in the United States, the Religious Order Study and the Memory and Aging Project, we evaluated the association of the CETP I405V polymorphism (rs5882) with cognitive decline and risk of incident AD in more than 1,300 participants of European ancestry. Our results suggest that the CETP I405V polymorphism was associated with a faster rather ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5455245 Mon, 28 Nov 2011 05:00:00 +0100 5455245 http://www.medworm.com/index.php?rid=5438889&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00771.x SummaryAge‐related changes in immunity are well documented in humans and laboratory mammals. Using blood samples collected from wild Soay sheep, we show that pronounced differences in T cell subsets and inflammatory markers among age classes are also evident under natural conditions. These shifts parallel those observed in mammals experiencing protected environments. We found progressive declines in the proportion of naïve CD4 T cells with age, a precipitous drop in γδ T cells after the second year of life, and an increase in acute phase protein levels amongst geriatric sheep. Our findings suggest immune aging patterns observed in laboratory and domestic mammals may generalise to more complex, challenging environments and could have fitness costs under natural conditions. (Source: Agi... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5438889 Thu, 24 Nov 2011 01:33:51 +0100 5438889 http://www.medworm.com/index.php?rid=5438893&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00765.x SummaryWhile it is generally recognized that misfolding of specific proteins can cause late‐onset disease, the contribution of protein aggregation to the normal aging process is less well understood. To address this issue, a mass spectrometry‐based proteomic analysis was performed to identify proteins that adopt sodium dodecyl sulfate (SDS)‐insoluble conformations during aging in C. elegans. SDS Insoluble proteins extracted from young and aged C. elegans were chemically labelled by isobaric tagging for relative and absolute quantification (iTRAQ) and identified by liquid chromatography and mass spectrometry. Two hundred and three proteins were identified as being significantly enriched in an SDS‐insoluble fraction in aged nematodes and were largely absent from a similar protein fra... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5438893 Mon, 21 Nov 2011 05:00:00 +0100 5438893 http://www.medworm.com/index.php?rid=5438892&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00772.x SummaryNaked mole‐rats (Heterocephalus glaber), the longest‐lived rodents, live 7‐10 times longer than similarly–sized mice and exhibit normal activities for ∼75% of their lives. Little is known about the mechanisms that allow them to delay the aging process and live so long. Neuregulin‐1 (NRG‐1) signaling is critical for normal brain function during both development and adulthood. We hypothesized that long‐lived species will maintain higher levels of NRG‐1 and that this contributes to their sustained brain function and concomitant maintenance of normal activity. We monitored the levels of NRG‐1 and its receptor ErbB4 in H. glaber at different ages ranging from 1 day to 26 years and found that levels for NRG‐1 and ErbB4 were sustained throughout development and adulth... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5438892 Mon, 21 Nov 2011 05:00:00 +0100 5438892 http://www.medworm.com/index.php?rid=5438891&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00773.x SummaryThe thymus is the most rapidly aging tissue in the body, with progressive atrophy beginning as early as birth and not later than adolescence. Latent regenerative potential exists in the atrophic thymus, since certain stimuli can induce quantitative regrowth, but qualitative function of T lymphocytes produced by the regenerated organ has not been fully assessed. Using a genome‐wide computational approach, we show that accelerated thymic aging is primarily a function of stromal cells, and that while overall cellularity of the thymus can be restored, many other aspects of thymic function cannot. Medullary islet complexity and tissue‐restricted antigen expression decrease with age, representing potential mechanisms for age‐related increases in autoimmune disease, but neither of th... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5438891 Mon, 21 Nov 2011 05:00:00 +0100 5438891 http://www.medworm.com/index.php?rid=5438890&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00774.x SummaryAging is characterized by a progressive loss of muscle mass and impaired contractility (e.g., decline in force, velocity and power). Although the slowing of contraction speed in aging muscle is well described, the underlying molecular mechanisms responsible for the decrement in speed are unknown. Myosin heavy chain (MHC) isoforms are the primary molecules determining contractile velocity; however the contraction speed of single fibers within a given MHC isoform type is variable. Recent evidence propose that the decline in shortening velocity (Vo) with aging is associated with a decrease in the relative content of essential myosin light chain 3f (MLC3f) isoform. In the current study, we first evaluated the relative content of MLC3f isoform and Vo in adult and old rats. We then used r... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5438890 Mon, 21 Nov 2011 05:00:00 +0100 5438890 http://www.medworm.com/index.php?rid=5419777&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00770.x SummaryDeletion of the p66Shc gene results in lean and healthy mice, retards aging and protects from aging‐associated diseases, raising the question of why p66Shc has been selected, and what is its physiological role. We have investigated survival and reproduction of p66Shc‐/‐ mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions deletion of p66Shc was strongly counterselected. Laboratory studies revealed that p66Shc‐/‐ mice have defects in fat accumulation, thermoregulation and reproduction, suggesting that p66Shc has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the s... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5419777 Fri, 18 Nov 2011 15:59:00 +0100 5419777 http://www.medworm.com/index.php?rid=5550786&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00768.x SummaryIn Caenorhabditis elegans and Drosophila, removing germline stem cells increases lifespan. In C. elegans, this lifespan extension requires DAF‐16, a FOXO transcription factor, and DAF‐12, a nuclear hormone receptor. To better understand the regulatory relationships between DAF‐16 and DAF‐12, we used microarray analysis to identify downstream genes. We found that these two transcription factors influence the expression of distinct but overlapping sets of genes in response to loss of the germline. In addition, we identified several new genes that are required for loss of the germline to increase lifespan. One, phi‐62, encodes a conserved, predicted RNA‐binding protein. PHI‐62 influences DAF‐16‐dependent transcription, possibly by collaborating with TCER‐1, a putat... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5550786 Tue, 15 Nov 2011 05:00:00 +0100 5550786 http://www.medworm.com/index.php?rid=5419779&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00768.x SummaryIn C. elegans and Drosophila, removing germline stem cells increases lifespan. In C. elegans, this lifespan extension requires DAF‐16, a FOXO transcription factor and DAF‐12, a nuclear hormone receptor. To better understand the regulatory relationships between DAF‐16 and DAF‐12, we used microarray analysis to identify downstream genes. We found that these two transcription factors influence the expression of distinct but overlapping sets of genes in response to loss of the germline. In addition, we identified several new genes that are required for loss of the germline to increase lifespan. One, phi‐62, encodes a conserved, predicted RNA binding protein. PHI‐62 influences DAF‐16‐dependent transcription, possibly by collaborating with TCER‐1, a putative transcriptio... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5419779 Tue, 15 Nov 2011 05:00:00 +0100 5419779 http://www.medworm.com/index.php?rid=5419778&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00769.x In conclusion, CR maintained mitochondrial protein synthesis while decreasing cellular proliferation during a time of energetic stress, which is consistent with the concept that CR increases somatic maintenance. Alternative mechanisms to global translation initiation may be responsible for selective translation of mitochondrial proteins. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5419778 Tue, 15 Nov 2011 05:00:00 +0100 5419778 http://www.medworm.com/index.php?rid=5405208&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00761.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5405208 Tue, 15 Nov 2011 00:38:43 +0100 5405208 http://www.medworm.com/index.php?rid=5405207&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00751.x SummaryLong‐lived mutant mice, both Ames dwarf and growth hormone receptor gene–disrupted or knockout strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here, we report, in both these long‐lived mice, that three up‐regulated lead microRNAs, miR‐470, miR‐669b, and miR‐681, are involved in posttranscriptional regulation of genes pertinent to growth hormone/IGF1 signaling. All three are most prominently localized in the hippocampus and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase. The decline in these genes’ expression translates into decreased phosphorylation of downstream molecules AKT and FoxO3a. Cultures transfected with either miR‐470, miR‐669b, or miR‐681 show repressed endogenous e... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5405207 Tue, 15 Nov 2011 00:38:40 +0100 5405207 http://www.medworm.com/index.php?rid=5405206&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00749.x SummaryWe recently reported that N‐glycosylation changes during human aging. To further investigate the molecular basis determining these alterations, the aging process in mice was studied. N‐glycan profiling of mouse serum glycoproteins in different age groups of healthy C57BL/6 mice showed substantial age‐related changes in three major N‐glycan structures: under‐galactosylated biantennary (NGA2F), biantennary (NA2), and core α‐1,6‐fucosylated ‐β‐galactosylated biantennary structures (NA2F). Mice defective in klotho gene expression (kl/kl), which have a shortened lifespan, displayed a similar but accelerated trend. Interestingly, the opposite trend was observed in slow‐aging Snell Dwarf mice (dw/dw) and in mice fed a calorically restricted diet. We also discovered th... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5405206 Tue, 15 Nov 2011 00:38:37 +0100 5405206 http://www.medworm.com/index.php?rid=5378272&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00766.x AbstractOxidative stress contributes to the pathogenesis of aging‐associated heart failure. Among various signaling pathways mediating oxidative stress, the NAD+‐dependent protein deacetylase SirT1 has been implicated in the protection of heart muscle. Expression of a locally acting IGF‐1 propeptide (mIGF‐1) helps the heart to recover from infarct and enhances SirT1 expression in cardiomyocytes in vitro, exerting protection from hypertrophic and oxidative stresses. To study the role of mIGF‐1/SirT1 signaling in vivo, we generated cardiac‐specific mIGF‐1 transgenic mice in which SirT1 was depleted from adult cardiomyocytes in a tamoxifen‐inducible and conditional fashion. Analysis of these mice confirmed that mIGF‐1‐induced SirT1 activity is necessary to protect the hear... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5378272 Thu, 03 Nov 2011 04:00:00 +0100 5378272 http://www.medworm.com/index.php?rid=5378273&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00764.x SummaryBecause most cancer patients are aged and because immunological functions are altered during aging, it is important to account for aging‐associated immunological alterations in the design of new cancer immunotherapies. We thus compared immune populations in young and aged mice and found that B7‐DC+ (PD‐L2/CD273) B cells, a minor population in young mice, were significantly increased in aged mice. Induction of both Th1 and Th17 cells was significantly augmented by B7‐DC+ B cells from aged mice and this effect was blocked with anti‐B7‐DC antibodies in vitro and in vivo. Moreover, retardation of tumor growth in aged mice was largely B7‐DC‐dependent. Tumor growth in young mice was significantly inhibited by immunization with B7‐DC+ B cells from aged mice due to increas... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5378273 Tue, 01 Nov 2011 04:00:00 +0100 5378273 http://www.medworm.com/index.php?rid=5378275&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00763.x SummaryMice with targeted deletion of the growth hormone receptor (GHRKO mice) are GH resistant, small, obese, hypoinsulinemic, highly insulin sensitive and remarkably long‐lived. To elucidate the unexpected coexistence of adiposity with improved insulin sensitivity and extended longevity, we examined effects of surgical removal of visceral (epididymal and perinephric) fat on metabolic traits related to insulin signaling and longevity. Comparison of results obtained in GHRKO mice and in normal animals from the same strain revealed disparate effects of visceral fat removal (VFR) on insulin and glucose tolerance, adiponectin levels, accumulation of ectopic fat, phosphorylation of insulin signaling intermediates, body temperature and respiratory quotient (RQ). Overall, VFR produced the expe... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5378275 Mon, 31 Oct 2011 04:00:00 +0100 5378275 http://www.medworm.com/index.php?rid=5378274&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00762.x SummaryAging and age‐related diseases can be viewed as the result of the lifelong accumulation of stress insults. The identification of mutant strains and genes which are responsive to stress and can alter longevity profiles provides new therapeutic targets for age‐related diseases. Here we reported that a Drosophila strain with reduced expression of ribose‐5‐phosphate isomerase (rpi), EP2456, exhibits increased resistance to oxidative stress and enhanced lifespan. In addition, the strain also displays higher levels of NADPH. The knockdown of rpi in neurons by double‐stranded RNA interference recapitulated the lifespan extension and oxidative stress resistance in Drosophila. This manipulation was also found to ameliorate the effects of genetic manipulations aimed at creating a mo... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5378274 Mon, 31 Oct 2011 04:00:00 +0100 5378274 http://www.medworm.com/index.php?rid=5344936&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00758.x SummaryEndothelial progenitor cells (EPCs) play an important role in repairing endothelial injury. Aging is associated with EPC dysfunction. Physical exercise has a beneficial impact on EPC activity. However, whether physical exercise can enhance the endothelial repair capacity of EPCs in healthy men with aging is not clear. Here, we investigated the effects of physical exercise on reendothelialization capacity and CXC chemokine receptor four (CXCR4) signaling in human EPCs. Before and after 12 weeks exercise, EPCs were isolated from elderly and young men. In vitro function and in vivo reendothelialization capacity of EPCs in a mouse model of carotid artery injury were measured. The expression of CXCR4 and its downstream signaling target Janus kinase‐2 (JAK‐2) were determined. Before e... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5344936 Mon, 24 Oct 2011 04:00:00 +0100 5344936 http://www.medworm.com/index.php?rid=5344935&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00759.x SummaryAging is accompanied by a progressive decline in immune function. Studies have shown age‐related decreases in expression and signaling efficiency of Toll‐like receptors (TLRs) in monocytes and dendritic cells and dysregulation of macrophage TLR3. Using a multivariable mixed effect model, we report a highly significant increase in TLR5 induced production of IL‐8 from monocytes of older individuals (p<0.0001). Elevated IL‐8 is accompanied by increased expression of TLR5, both protein and mRNA, and by increased levels of TLR5 mediated phosphorylation of MAPK p38 and ERK. We noted incomplete activation of NF‐κB in response to TLR5 signaling in monocytes of elderly donors, as reflected by the absence of an associated increase in the production of TNF‐α. Elevated TLR5 may... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5344935 Mon, 24 Oct 2011 04:00:00 +0100 5344935 http://www.medworm.com/index.php?rid=5419780&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00756.x SummaryOxidative stress is considered to promote aging and age‐related disorders such as tauopathy. Although recent reports suggest that oxidative stress under certain conditions possesses anti‐aging properties, no such conditions have been reported to ameliorate protein‐misfolding diseases. Here, we used neuronal and murine models that overexpress human tau to demonstrate that mild oxidative stress generated by alloxan suppresses several phenotypes of tauopathy. Alloxan treatment reduced HSP90 levels and promoted proteasomal degradation of tau, c‐Jun N‐amino terminal kinase, and histone deacetylase (HDAC) 6. Moreover, reduced soluble tau (phosphorylated tau) levels suppressed the formation of insoluble tau in tau transgenic mice, while reduced HDAC6 levels contributed to microtu... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5419780 Sat, 08 Oct 2011 04:00:00 +0100 5419780 http://www.medworm.com/index.php?rid=5302616&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00756.x SummaryOxidative stress is considered to promote aging and age‐related disorders like tauopathy. Although recent reports suggest that oxidative stress under certain conditions possesses anti‐aging properties, no such conditions have been reported to ameliorate protein‐misfolding diseases. Here we used neuronal and murine models that overexpress human tau to demonstrate that mild oxidative stress generated by alloxan suppresses several phenotypes of tauopathy. Alloxan treatment reduced HSP90 levels and promoted proteasomal degradation of tau, JNK, and histone deacetylase (HDAC) 6. Moreover, reduced soluble tau (phosphorylated tau) levels suppressed the formation of insoluble tau in tau transgenic mice, while reduced HDAC6 levels contributed to microtubule stability by increasing tubul... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5302616 Sat, 08 Oct 2011 04:00:00 +0100 5302616 http://www.medworm.com/index.php?rid=5302615&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00755.x This study suggests an interaction between TL, and both subtelomeric and LINE‐1 methylation which may be altered based on mutation status of telomere biology genes.Published 2011. This article is a U.S. Government work and is in the public domain in the USA. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5302615 Sat, 08 Oct 2011 04:00:00 +0100 5302615 http://www.medworm.com/index.php?rid=5302614&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00757.x SummaryAge‐associated immune dysfunction, characterized by increased systemic levels of cytokines, manifests as an increased susceptibility to infections. Thus, understanding these negative regulators of the immune response has paved the way to delineating signaling pathways that impact immune senescence. In the present study, we found that miR‐146a, which negatively regulated the expression of IL‐1β and IL‐6, was highly expressed in aged mice. However, there was a lack of response to stimulation of LPS and pro‐inflammatory cytokines in macrophages of aged mice. As a result, the negative feedback regulation loop with miR‐146a involving down‐regulation of inflammation factors was interrupted in aged mice. Aberrant NF‐κB binding to the miR‐146a promoter was demonstrated a... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5302614 Sat, 08 Oct 2011 04:00:00 +0100 5302614 http://www.medworm.com/index.php?rid=5419781&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00752.x SummaryEpidemiologic studies indicate that the risks for major age‐related debilities including coronary heart disease, diabetes, and age‐related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets, but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age‐related retinal lesions that precede AMD (hereafter called AMD‐like lesions). We found that consuming a higher GI diet promotes these AMD‐like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (P < 0.02) and severity (P < 0.05) of hallmark age‐rela... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5419781 Mon, 03 Oct 2011 04:00:00 +0100 5419781 http://www.medworm.com/index.php?rid=5282876&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00751.x SummaryLong‐lived mutant mice, both Ames dwarf and growth hormone receptor gene disrupted or knockout (GHRKO) strains, exhibit heightened cognitive robustness and altered IGF1 signaling in the brain. Here we report, in both these long‐lived mice, that three up‐regulated lead microRNAs, miR‐470, ‐669b, and ‐681, are involved in post‐transcriptional regulation of genes pertinent to growth hormone (GH)/IGF1 signaling. All three are most prominently localized in the hippocampus, and correspond to reduced expression of key IGF1 signaling genes: IGF1, IGF1R, and PI3 kinase. The decline in these genes’ expression translates into decreased phosphorylation of downstream molecules AKT and FoxO3a. Cultures transfected with either miR‐470, ‐669b, or ‐681 show repressed endogenous... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5282876 Mon, 03 Oct 2011 04:00:00 +0100 5282876 http://www.medworm.com/index.php?rid=5282875&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00752.x SummaryEpidemiologic studies indicate that the risks for major age‐related debilities including CHD, diabetes, and age‐related macular degeneration (AMD) are diminished in people who consume lower glycemic index (GI) diets but lack of a unifying physiobiochemical mechanism that explains the salutary effect is a barrier to implementing dietary practices that capture the benefits of consuming lower GI diets. We established a simple murine model of age‐related retinal lesions that precede AMD (hereafter called AMD‐like lesions). We found that consuming a higher GI diet promotes these AMD‐like lesions. However, mice that consumed the lower vs. higher GI diet had significantly reduced frequency (p<0.02) and severity (p<0.05) of hallmark age‐related retinal lesions such as basa... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5282875 Mon, 03 Oct 2011 04:00:00 +0100 5282875 http://www.medworm.com/index.php?rid=5378271&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00767.x SummaryProtein misfolding is a common theme in aging and several age‐related diseases such as Alzheimer’s and Parkinson’s disease. The processes involved in the development of these diseases are many and complex. Here, we show that components of the basement membrane, particularly laminin, affect protein integrity of the muscle cells they support. We knocked down gene expression of epi‐1, a laminin α‐chain, and found that this resulted in increased proteotoxicity in different Caenorhabditis elegans transgenic models expressing aggregating proteins in the body wall muscle. The effect could partially be rescued by decreased insulin‐like signaling, known to slow the aging process and the onset of various age‐related diseases. Our data points to an underlying molecular mechanism... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5378271 Sat, 01 Oct 2011 04:00:00 +0100 5378271 http://www.medworm.com/index.php?rid=5344934&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00760.x Several studies suggest that the generation of Aβ is highly dependent on the levels of cholesterol within membranes’ detergent resistant microdomains (DRM). Indeed, the APP cleaving machinery, namely β‐ and γ‐secretase, has been shown to be present in DRM and their activity depends on membrane cholesterol levels. Counterintuitive to the localization of the cleavage machinery, the substrate, APP, localizes to membrane detergent soluble microdomains enriched in phospholipids (PL), indicating that Aβ generation is highly dependent on the capacity of enzyme and substrate to diffuse along the lateral plane of the membrane and, therefore, on the internal equilibrium of the different lipids of DRM and non‐DRM domains. Here, we studied to which extent changes in the content of a main n... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5344934 Sat, 01 Oct 2011 04:00:00 +0100 5344934 http://www.medworm.com/index.php?rid=5302613&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00754.x SummaryEmbryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent a promising therapeutic tool for many diseases, including aged tissues and organs at high risk of failure. However, the intrinsic self‐renewal and pluripotency of ES and iPS cells makes them tumorigenic and hence the risk of tumor development hinders their clinical application. Here we present a novel approach to limit their tumorigenicity and increase their safety through increased copy number of tumor suppressors. iPS containing an extra copy of the p53 or Ink4a/ARF locus show normal pluripotency, as determined by in vitro and in vivo differentiation assays*. Yet, while retaining full pluripotency, they also possess an improved engagement of the p53 pathway during teratocarcinoma formation, which leads ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5302613 Sat, 01 Oct 2011 04:00:00 +0100 5302613 http://www.medworm.com/index.php?rid=5282874&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00753.x SummaryAged epidermal cells have the capacity to dedifferentiate into stem cell‐like cells. However, the signals that regulate the dedifferentiation of aged epidermal cells remain unclear. Here, we provide evidence that Wnt/β‐catenin is critical for aged epidermal cell dedifferentiation in vivo and in vitro. Some aged epidermal cells in human ultrathin epidermal sheets lacking basal stem cells transplanted onto wounds dedifferentiated into stem cell‐like cells which were positive for CK19 and β1 integrin but negative for CK10. In addition, Wnt/β‐catenin pathway was activated during this process. There was increased expression of Wnt‐1, Wnt‐4, Wnt‐7a, β‐catenin, cyclin D1, and c‐myc. Secreted frizzled‐related protein 1, a Wnt/β‐catenin pathway inhibitor, blocked d... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5282874 Sat, 01 Oct 2011 04:00:00 +0100 5282874 http://www.medworm.com/index.php?rid=5258306&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00750.x SummaryPre‐lamin A and progerin have been implicated in normal ageing and the pathogenesis of age‐related degenerative diseases termed laminopathies. Here, we show that mature lamin A has an essential role in cellular fitness and that oxidative damage to lamin A is involved in cellular senescence. Primary human dermal fibroblasts (HDFs) aged replicatively or by pro‐oxidants acquire a range of dysmorphic nuclear shapes. We observed that conserved cysteine residues in the lamin A tail domain become hyper‐oxidized in senescent fibroblasts, which inhibits the formation of lamin A inter‐ and intra‐molecular disulfide bonds. Both in the absence of lamin A or in the presence of a lamin A cysteine‐to‐alanine mutant which eliminates these cysteine residues 522, 588 and 591, mild oxi... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5258306 Tue, 27 Sep 2011 19:45:54 +0100 5258306 http://www.medworm.com/index.php?rid=5247742&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00748.x SummaryWe tested the hypothesis that older men who perform habitual aerobic exercise do not demonstrate age‐associated vascular endothelial oxidative stress compared with their sedentary peers. Older exercising men (n=13, 62±2 y) had higher (P<0.05) physical activity (79±7 vs. 30±6 MET h/wk) and maximal exercise oxygen consumption (42±1 vs. 29±1 ml/kg/min) vs. sedentary men (n=28, 63±1 y). Brachial artery flow‐mediated dilation, a measure of vascular endothelial function, was greater (P<0.05) in the exercising vs. sedentary older men (6.3±0.5 vs. 4.9±0.4%Δ) and not different than young controls (n=20, 25±1 y, 7.1 ± 0.5%Δ). In vascular endothelial cells sampled from the brachial artery, nitrotyrosine, a marker of oxidative stress, was 51% lower in the exercising vs. se... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5247742 Sat, 24 Sep 2011 02:00:57 +0100 5247742 http://www.medworm.com/index.php?rid=5258307&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00749.x AbstractWe recently reported that N‐glycosylation changes during human aging. To further investigate the molecular basis determining these alterations, the aging process in mice was studied. N‐glycan profiling of mouse serum glycoproteins in different age groups of healthy C57BL/6 mice showed substantial age‐related changes in three major N‐glycan structures: under‐galactosylated biantennary (NGA2F), biantennary (NA2), and core α‐1,6‐fucosylated ‐β‐galactosylated biantennary structures (NA2F). Mice defective in klotho gene expression (kl/kl), which have a shortened lifespan, displayed a similar but accelerated trend. Interestingly, the opposite trend was observed in slow‐aging Snell Dwarf mice (dw/dw) and in mice fed a calorically restricted diet. We also discovered t... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5258307 Fri, 23 Sep 2011 04:00:00 +0100 5258307 http://www.medworm.com/index.php?rid=5247745&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00745.x SummaryTo determine whether mitochondrial dysfunction is causally related to muscle atrophy with aging, we examined respiratory capacity, H2O2 emission, and function of the mitochondrial permeability transition pore (mPTP) in permeabilized myofibers prepared from four rat muscles that span a range of fiber type, and degree of age‐related atrophy. Muscle atrophy with aging was greatest in fast twitch gastrocnemius (Gas) muscle (‐38%), intermediate in both the fast twitch extensor digitorum longus (EDL) and slow twitch soleus (Sol) muscles (‐21%), and non‐existent in adductor longus (AL) muscle (+47%). In contrast, indices of mitochondrial dysfunction did not correspond to this differential degree of atrophy. Specifically, despite higher protein expression for oxidative phosphorylati... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5247745 Tue, 20 Sep 2011 04:00:00 +0100 5247745 http://www.medworm.com/index.php?rid=5247744&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00746.x SummaryThe Id (inhibitor of differentiation or DNA binding) family of transcription regulators plays an important role in cell proliferation, differentiation and senescence. However, regulation of Id expression during these processes is poorly understood. Id proteins are known to undergo rapid turnover mediated by the ubiquitin‐proteasome pathway. Anaphase‐promoting complex has been shown to ubiquitinate Id2, but E3 ubiquitin ligase(s) that ubiquitinate other Id family members are not known. Here we report for the first time the identification of Smurf2 as the E3 ligase that ubiquitinates Id1 and Id3. Smurf2‐mediated ubiquitination and consequent degradation of Id1 or Id3 plays an important role in the regulation of Id expression in senescent cells. Furthermore, we found that Id1 is ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5247744 Tue, 20 Sep 2011 04:00:00 +0100 5247744 http://www.medworm.com/index.php?rid=5247743&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00747.x SummaryIn Caenorhabditis elegans, the insulin/IGF pathway participates in the decision to initiate dauer development. Dauer is a diapause stage that is triggered by environmental stresses, such as a lack of nutrients. Insulin/IGF receptor mutants arrest constitutively in dauer, an effect that can be suppressed by mutations in other elements of the insulin/IGF pathway or by a reduction in the activity of the nuclear hormone receptor daf‐12. We have isolated a pkc‐1 mutant which acts as a novel suppressor of the dauer phenotypes caused by insulin/IGF receptor mutations. Interactions between insulin/IGF mutants and the pkc‐1 suppressor mutant are similar to those described for daf‐12 or the DAF‐12 co‐regulator din‐1. Moreover, we show that the expression of the DAF‐12 target d... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5247743 Tue, 20 Sep 2011 04:00:00 +0100 5247743 http://www.medworm.com/index.php?rid=5220805&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00739.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5220805 Thu, 15 Sep 2011 16:25:28 +0100 5220805 http://www.medworm.com/index.php?rid=5220804&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00744.x SummaryRecent studies have found associations of leukocyte telomere length (TL) with diseases of aging and with longevity. However, it is unknown whether birth leukocyte TL or its age‐dependent attrition― the two factors that determine leukocyte TL dynamics― explains these associations, since acquiring this information entails monitoring individuals over their entire life course. We tested in dogs a model of leukocyte TL dynamics, based on the following premises: (i) TL is synchronized among somatic tissues; (ii) TL in skeletal muscle, which is largely post‐mitotic, is a measure of TL in early development; (iii) the difference between TL in leukocytes and muscle (ΔLMTL) is the extent of leukocyte TL shortening since early development. Using this model, we observed in 83 dogs (ages... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5220804 Thu, 15 Sep 2011 16:24:45 +0100 5220804 http://www.medworm.com/index.php?rid=5312248&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00743.x SummaryHutchinson–Gilford progeria syndrome (HGPS or progeria) is a very rare genetic disorder with clinical features suggestive of premature aging. Here, we show that induced expression of the most common HGPS mutation (LMNA c.1824C>T, p.G608G) results in a decreased epidermal population of adult stem cells and impaired wound healing in mice. Isolation and growth of primary keratinocytes from these mice demonstrated a reduced proliferative potential and ability to form colonies. Downregulation of the epidermal stem cell maintenance protein p63 with accompanying activation of DNA repair and premature senescence was the probable cause of this loss of adult stem cells. Additionally, upregulation of multiple genes in major inflammatory pathways indicated an activated inflammatory respons... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5312248 Thu, 08 Sep 2011 04:00:00 +0100 5312248 http://www.medworm.com/index.php?rid=5205516&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00741.x SummaryMales and females often age at different rates resulting in longevity ‘gender gaps’, where one sex outlives the other. Why the sexes have different lifespans is an age old question, still fiercely debated today. One cellular process related to lifespan, that is known to differ according to sex, is the rate at which the protective telomere chromosome caps are lost. In humans, males have shorter lifespans and greater telomere shortening. This has led to speculation in the medical literature that sex‐specific telomere shortening is one cause of sex‐specific mortality. However, telomere shortening may be a cause and/or a consequence of the processes that govern survival, and to infer general principles from studies of single taxa may be misleading. Here we review recent work on ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5205516 Thu, 08 Sep 2011 04:00:00 +0100 5205516 http://www.medworm.com/index.php?rid=5205515&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00742.x SummaryActivation of Sir2‐orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan‐extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short‐lived sir2Δ yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2Δ lifespan defect is a rare phenotype among longevity interventions and suggest that sir2Δ cells senesce rapidly by a mechanism distinct from that of wild‐type cells. They also demonstrate that failure to observe... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5205515 Thu, 08 Sep 2011 04:00:00 +0100 5205515 http://www.medworm.com/index.php?rid=5205517&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00740.x SummaryAging is associated with increased adiposity in white adipose tissues and impaired thermogenesis in brown adipose tissues; both contribute to increased incidences of obesity and type 2 diabetes. Ghrelin is the only known circulating orexigenic hormone that promotes adiposity. In this paper, we show that ablation of the ghrelin receptor (growth hormone secretagogue receptor, GHS‐R) improves insulin sensitivity during aging. Compared to wild‐type (WT) mice, old Ghsr‐/‐ mice have reduced fat and preserve a healthier lipid profile. Old Ghsr‐/‐ mice also exhibit elevated energy expenditure and resting metabolic rate, yet have similar food intake and locomotor activity. While GHS‐R expression in white and brown adipose tissues was below detection in the young mice, GHS‐R e... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5205517 Mon, 05 Sep 2011 04:00:00 +0100 5205517 http://www.medworm.com/index.php?rid=5235461&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00738.x SummaryAging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in Caenorhabditis elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here, we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX‐1, RBR‐2, LSD‐1, and T26A5.5. Interestingly, UTX‐1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx‐1 knockdown and heterozygous mutation... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5235461 Thu, 11 Aug 2011 04:00:00 +0100 5235461 http://www.medworm.com/index.php?rid=5125592&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00737.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5125592 Wed, 10 Aug 2011 23:00:00 +0100 5125592 http://www.medworm.com/index.php?rid=5158204&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00735.x In this study, we tested the hypotheses (i) that age affects responsiveness to 25OHD3 and expression/activity of CYP27B1 in hMSCs and (ii) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age‐related declines in osteoblastogenesis (n = 8, P = 0.0286) and in CYP27B1 gene expression (n = 27, r = −0.498; P = 0.008) in hMSCs. Unlike hMSCs from young subjects (≤50 years), hMSCs from older subjects (≥55 years) were resistant to 25OHD3 stimulation of osteoblastogenesis. PTH1‐34 (100 nm) provided hMSCs with responsiveness to 25OHD3 (P = 0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)2D3 synthesis, of cAMP response element binding protein (CREB) activation, and of CYP27B1 upreg... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5158204 Sun, 07 Aug 2011 23:00:00 +0100 5158204 http://www.medworm.com/index.php?rid=5107206&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00735.x In this study, we tested the hypotheses 1) that age affects responsiveness to 25OHD3 and expression/activity of CYP27B1 in hMSCs, and 2) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age‐related declines in osteoblastogenesis (n=8, p=0.0286) and in CYP27B1 gene expression (n=27, r=‐0.498; p=0.008) in hMSCs. Unlike hMSCs from young subjects (≤ 50‐years), hMSCs from older subjects (≥ 55‐years) were resistant to 25OHD3 stimulation of osteoblastogenesis. PTH1‐34 (100 nM) provided hMSCs with responsiveness to 25OHD3 (p=0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)2D3 synthesis, of CREB activation, and of CYP27B1 upregulation. Both increases in CYP27B1 expression by PTH were obliterated by CREB�... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5107206 Sun, 07 Aug 2011 23:00:00 +0100 5107206 http://www.medworm.com/index.php?rid=5205514&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00743.x SummaryHutchinson‐Gilford progeria syndrome (HGPS or progeria) is a very rare genetic disorder with clinical features suggestive of premature aging. Here, we show that induced expression of the most common HGPS mutation (LMNA c.1824C>T, p.G608G) results in a decreased epidermal population of adult stem cells and impaired wound healing in mice. Isolation and growth of primary keratinocytes from these mice demonstrated a reduced proliferative potential and ability to form colonies. Downregulation of the epidermal stem cell maintenance protein p63 with accompanying activation of DNA repair and premature senescence was the probable cause of this loss of adult stem cells. Additionally, upregulation of multiple genes in major inflammatory pathways indicated an activated inflammatory respons... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5205514 Mon, 01 Aug 2011 04:00:00 +0100 5205514 http://www.medworm.com/index.php?rid=5125591&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00738.x SummaryAging is accompanied by alterations in epigenetic marks that control chromatin states, including histone acetylation and methylation. Enzymes that reversibly affect histone marks associated with active chromatin have recently been found to regulate aging in C. elegans. However, relatively little is known about the importance for aging of histone marks associated with repressed chromatin. Here we use a targeted RNAi screen in C. elegans to identify four histone demethylases that significantly regulate worm lifespan, UTX‐1, RBR‐2, LSD‐1, and T26A5.5. Interestingly, UTX‐1 belongs to a conserved family of histone demethylases specific for lysine 27 of histone H3 (H3K27me3), a mark associated with repressed chromatin. Both utx‐1 knock‐down and heterozygous mutation of utx‐1... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5125591 Sun, 31 Jul 2011 23:00:00 +0100 5125591 http://www.medworm.com/index.php?rid=5107205&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00736.x AbstractActivation of the Her2 (ErbB2) oncogene is implicated in development of breast, ovary and other cancers. Here we show that expression of NeuT, a mutant activated rodent isoform of Her2, in immortalized breast epithelial cells, while promoting senescence‐associated morphological changes, up‐regulation of senescence‐associated β‐galactosidase activity, and accumulation of the cyclin dependent kinase inhibitor p21, failed to trigger the major senescence end‐point, i.e. permanent growth arrest. Similar senescence‐associated phenotype with incomplete growth arrest, which we dubbed SWING, could also be triggered by expression of the Ras oncogene. SWING phenotype was stable, and persisted in tumor xenografts established from NeuT‐transduced cells. Furthermore, a significant... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5107205 Sun, 31 Jul 2011 23:00:00 +0100 5107205 http://www.medworm.com/index.php?rid=5050021&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00734.x SummaryAbnormal levels of Reactive oxygen species (ROS) and inflammatory cytokines have been observed in the skeletal muscle during muscle wasting including sarcopenia. However the mechanisms that signal ROS production and prolonged maintenance of ROS levels during muscle wasting are not fully understood. Here we show that Myostatin (Mstn) is a pro‐oxidant and signals the generation of ROS in muscle cells. Mstn, a Transforming Growth Factor‐β (TGF‐β) family member, has been shown to play an important role in skeletal muscle wasting by increasing protein degradation. Our results here show that Mstn induces oxidative stress by producing ROS in skeletal muscle cells through Tumor Necrosis Factor‐α (TNF‐α) signaling via NF‐κB and NADPH oxidase. Aged Mstn null (Mstn‐/‐) mus... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5050021 Fri, 22 Jul 2011 13:56:03 +0100 5050021 http://www.medworm.com/index.php?rid=5027566&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00729.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5027566 Fri, 15 Jul 2011 01:26:40 +0100 5027566 http://www.medworm.com/index.php?rid=5027565&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00728.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5027565 Fri, 15 Jul 2011 01:26:39 +0100 5027565 http://www.medworm.com/index.php?rid=5118313&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00732.x In conclusion, IgA and IgM responses are significantly impaired in the elderly pneumococcal response and are likely key mediators of protection. Hydrophilicity and/or small size of the IGH CDR3 appear to be important in these responses. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5118313 Mon, 04 Jul 2011 23:00:00 +0100 5118313 http://www.medworm.com/index.php?rid=5107207&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00731.x SummaryFluorescence loss in photobleaching experiments and analysis of mitochondrial function using superoxide and redox potential biosensors revealed that mitochondria within individual yeast cells are physically and functionally distinct. Mitochondria that are retained in mother cells during yeast cell division have a significantly more oxidizing redox potential and higher superoxide levels compared to mitochondria in buds. Retention of mitochondria with more oxidizing redox potential in mother cells occurs to the same extent in young and older cells and can account for the age‐associated decline in total cellular mitochondrial redox potential in yeast as they age from 0 to 5 generations. Deletion of Mmr1p, a member of the DSL1 family of tethering proteins that localizes to mitochondri... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5107207 Mon, 04 Jul 2011 23:00:00 +0100 5107207 http://www.medworm.com/index.php?rid=5007702&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00731.x SummaryFluorescence loss in photobleaching experiments and analysis of mitochondrial function using superoxide and redox potential biosensors revealed that mitochondria within individual yeast cells are physically and functionally distinct. Mitochondria that are retained in mother cells during yeast cell division have significantly lower redox potential and higher superoxide levels compared to mitochondria in buds. Retention of mitochondria with lower redox potential in mother cells occurs to the same extent in young and older cells, and can account for the age‐associated decline in total cellular mitochondrial redox potential in yeast as they age from 0‐5 generations. Deletion of Mmr1p, a member of the DSL1 family of tethering proteins that localizes to mitochondria at the bud tip and... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5007702 Mon, 04 Jul 2011 23:00:00 +0100 5007702 http://www.medworm.com/index.php?rid=5107208&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00730.x SummaryIt is well established that immune responses are diminished in the old. However, we still do not have a clear understanding of what dictates the dysfunction of old T cells at the molecular level. Although microarray analysis has been used to compare young and old T cells, identifying hundreds of genes that are differentially expressed among these populations, it has been difficult to utilize this information to pinpoint which biological pathways truly affect the function of aged T cells. To better define differences between young and old naïve CD4+ and CD8+ T cells, microarray analysis was performed pre‐ and post‐TCR stimulation for 4, 12, 24 and 72 h. Our data indicate that many genes are differentially expressed in the old compared to the young at all five time points. Thes... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5107208 Mon, 27 Jun 2011 23:00:00 +0100 5107208 http://www.medworm.com/index.php?rid=5050023&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00727.x SummaryAlternative splicing involving intron retention plays a key role in the regulation of gene expression. We previously reported that the alternatively spliced short isoform of endoglin (S‐endoglin) is induced during the aging or senescence of endothelial cells by a mechanism of intron retention. In this work, we demonstrate that the alternative splicing factor or splicing factor‐2 (ASF/SF2) is involved in the synthesis of endoglin. Overexpression of ASF/SF2 in endothelial cells switched the balance between the two endoglin isoforms, favoring the synthesis of S‐endoglin. Using a minigene reporter vector and RNA immunoprecipitation experiments, it was shown that ASF/SF2 interacts with the nucleotide sequence of the endoglin minigene, suggesting the direct involvement of ASF/SF2. A... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5050023 Mon, 13 Jun 2011 23:00:00 +0100 5050023 http://www.medworm.com/index.php?rid=5050022&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00726.x We examined human peripheral blood leukocyte in‐vivo RNA in a large‐scale transcriptomic microarray study (subjects aged 30–104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following‐up findings in a replication set (n = 240). We confirmed expression of key results by real‐time PCR. Of 16 571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (area under the curve in replication set; 95%). The focused nature of age‐related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metaboli... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5050022 Sun, 12 Jun 2011 23:00:00 +0100 5050022 http://www.medworm.com/index.php?rid=4933546&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00726.x We examined human peripheral blood leucocyte in‐vivo RNA in a large‐scale transcriptomic microarray study (subjects aged 30 to 104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following‐up findings in a replication set (n=240). We confirmed expression of key results by real‐time PCR. Of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (Area Under the Curve in replication set; 95%). The focussed nature of age‐related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways w... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4933546 Sun, 12 Jun 2011 23:00:00 +0100 4933546 http://www.medworm.com/index.php?rid=5019015&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00733.x SummaryBile acids are cholesterol‐derived signaling molecules that regulate mammalian metabolism through sterol‐sensing nuclear receptor transcription factors. In C. elegans, bile acid‐like steroids called dafachronic acids (DAs) control developmental timing and longevity by activating the nuclear receptor DAF‐12. However, little is known about the biosynthesis of these molecules. Here we show that the DAF‐36/Rieske oxygenase works at the first committed step, converting cholesterol to 7‐dehydrocholesterol. Its elucidation as a cholesterol 7‐desaturase provides crucial biochemical evidence that such oxygenases are key steroidogenic enzymes. By controlling DA production, DAF‐36 regulates DAF‐12 activities for reproductive development and longevity, and may illuminate relat... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5019015 Tue, 31 May 2011 23:00:00 +0100 5019015 http://www.medworm.com/index.php?rid=5007701&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00732.x In conclusion, IgA and IgM responses are significantly impaired in the elderly pneumococcal response and are likely key mediators of protection. Hydrophilicity and/or small size of the IGH CDR3 appear to be important in these responses. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=5007701 Tue, 31 May 2011 23:00:00 +0100 5007701 http://www.medworm.com/index.php?rid=4975522&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00730.x SummaryIt is well established that immune responses are diminished in the old. However, we still do not have a clear understanding of what dictates the dysfunction of old T cells at the molecular level. Although microarray analysis has been used to compare young and old T cells, identifying hundreds of genes that are differentially expressed among these populations, it has been difficult to utilize this information to pinpoint which biological pathways truly affect the function of aged T cells. To better define differences between young and old naïve CD4+ and CD8+ T cells, microarray analysis was performed pre‐ and post‐TCR stimulation for 4, 12, 24 and 72 hours. Our data indicate that many genes are differentially expressed in the old compared to the young at all five time points. Th... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4975522 Tue, 31 May 2011 23:00:00 +0100 4975522 http://www.medworm.com/index.php?rid=4933545&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00727.x SUMMARYAlternative splicing involving intron retention plays a key role in the regulation of gene expression. We previously reported that the alternatively spliced short isoform of endoglin (S‐endoglin) is induced during the aging or senescence of endothelial cells by a mechanism of intron retention. In this work, we demonstrate that the splicing factor ASF/SF2 is involved in the synthesis of endoglin. Overexpression of ASF/SF2 in endothelial cells switched the balance between the two endoglin isoforms, favoring the synthesis of S‐endoglin. Using a minigene reporter vector and RNA immunoprecipitation experiments, it was shown that ASF/SF2 interacts with the nucleotide sequence of the endoglin minigene, suggesting the direct involvement of ASF/SF2. Accordingly, the sequence recognized b... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4933545 Tue, 31 May 2011 23:00:00 +0100 4933545 http://www.medworm.com/index.php?rid=4892317&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00725.x AbstractOne of the most prominent changes during T‐cell aging in humans is the accumulation of CD28null T cells, mainly CD8+ but also CD4+ T cells. Enhancing the functional properties of these cells may be important since they provide an antigen‐specific defense against chronic infections. Recent studies have shown that IL‐15 does in fact play an appreciable role in CD4 memory T cell under physiological conditions. We found that treatment with IL‐15 increased the frequency of elderly CD4+CD28null T cells by a preferential proliferation of these cells compared to CD4+CD28+ T cells. IL‐15 induced an activated phenotype in CD4+CD28null T cells. Although the surface expression of IL‐15R α‐chain was not increased, the transcription factor STAT‐5 was preferentially activated. IL... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4892317 Tue, 31 May 2011 23:00:00 +0100 4892317 http://www.medworm.com/index.php?rid=4883261&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00724.x SummaryIncreasing evidence indicates that Alzheimer’s disease (AD), one of the most diffused aging pathologies, and diabetes may be related. Here we demonstrate that insulin signaling protects LAN5 cells by amyloid‐β42 (Aβ) induced toxicity. Aβ affects both activation of insulin receptors (IRs) and the levels of phospho‐Akt, a critical signaling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro‐apoptotic transcription factor activated by ROS generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show that the recovery of the organelle integrity recruits active Akt translocation to the mitochon... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4883261 Tue, 31 May 2011 23:00:00 +0100 4883261 http://www.medworm.com/index.php?rid=5007703&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00724.x SummaryIncreasing evidence indicates that Alzheimer’s disease, one of the most diffused aging pathologies, and diabetes may be related. Here, we demonstrate that insulin signalling protects LAN5 cells by amyloid‐β42 (Aβ)‐induced toxicity. Aβ affects both activation of insulin receptors and the levels of phospho‐Akt, a critical signalling molecule in this pathway. In contrast, oxidative stress induced by Aβ can be antagonized by active Akt that, in turn, inhibits Foxo3a, a pro‐apoptotic transcription factor activated by reactive oxygen species generation. Insulin cascade protects against mitochondrial damage caused by Aβ treatment, restoring the mitochondrial membrane potential. Moreover, we show that the recovery of the organelle integrity recruits active Akt translocation t... Aging Cell journals http://www.medworm.com/rss/comments.php?id=5007703 Sun, 29 May 2011 23:00:00 +0100 5007703 http://www.medworm.com/index.php?rid=4883262&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00723.x SummaryAmong vertebrates that can be kept in captivity the annual fish Nothobranchius furzeri possesses the shortest known lifespan. It also shows typical signs of ageing and is therefore an ideal model to assess the role of different physiological and environmental parameters on ageing and lifespan determination. Here we used Nothobranchius furzeri to study whether ageing is associated with mitochondrial DNA (mtDNA) alterations and changes of mitochondrial function. We sequenced the complete mitochondrial genome of N. furzeri and found an extended control region. Large‐scale mtDNA deletions have been frequently described to accumulate in other organisms with age, but there was no evidence for the presence of detectable age‐related mtDNA deletions in N. furzeri. However, mtDNA copy num... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4883262 Sun, 29 May 2011 23:00:00 +0100 4883262 http://www.medworm.com/index.php?rid=4862228&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00722.x SummaryReprogramming of somatic cells to a pluripotent state was first accomplished using retroviral vectors for transient expression of pluripotency‐associated transcription factors. This seminal work was followed by numerous studies reporting alternative (non‐insertional) reprogramming methods, and various conditions to improve the efficiency of reprogramming. These studies have contributed little to an understanding of global mechanisms underlying reprogramming efficiency. Here we report that inhibition of the mTOR (mammalian target of rapamycin) pathway by rapamycin or PP242 enhances the efficiency of reprogramming to induced pluripotent stem cells (iPSCs). Inhibition of the insulin/IGF‐1 signaling pathway, which like mTOR is involved in control of longevity, also enhance... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4862228 Thu, 26 May 2011 02:38:05 +0100 4862228 http://www.medworm.com/index.php?rid=4862230&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00720.x This study is the first to suggest a second negative consequence for the senescence‐associated secretory phenotype. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4862230 Tue, 24 May 2011 23:00:00 +0100 4862230 http://www.medworm.com/index.php?rid=4862229&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00721.x SummarySelective degeneration of nigrostriatal dopaminergic neurons in Parkinson disease (PD) can be modeled by the administration of the neurotoxin 1‐methyl‐4‐phenylpyridinium (MPP+). Since abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this study, we investigated the effect of MPP+ on mitochondrial dynamics and assessed temporal and causal relationship with other toxic effects induced by MPP+ in neuronal cells. In SH‐SY5Y cells, MPP+ causes a rapid increase in mitochondrial fragmentation followed by a second wave of increase in mitochondrial fragmentation, along with increased DLP1 expression and mitochondrial translocation. Genetic inactivation of DLP1 completely blocks MPP+‐induced mitochondrial fragmentation. Notably, such rescue pa... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4862229 Tue, 24 May 2011 23:00:00 +0100 4862229 http://www.medworm.com/index.php?rid=4812952&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00715.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4812952 Thu, 12 May 2011 10:40:33 +0100 4812952 http://www.medworm.com/index.php?rid=4812951&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00710.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4812951 Thu, 12 May 2011 10:40:21 +0100 4812951 http://www.medworm.com/index.php?rid=4883263&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00719.x We report that depletion of lamin A/C expression in normal human cells leads to a dramatic downregulation of the Rb family of tumor suppressors and a defect in cell proliferation. Lamin A/C‐depleted cells exhibited a flat morphology and accumulated markers of cellular senescence. This senescent phenotype was accompanied by engagement of the p53 tumor suppressor and induction of the p53 target gene p21 and was prevented by small hairpin RNAs against p53, p21, or by the oncoprotein Mdm2. The expression of E2F target genes, normally required for cell cycle progression, was downregulated after lamin A/C depletion but restored after the inactivation of p53. A similar senescence response was observed in myoblasts from a patient with a lamin A mutation causing muscular dystrophy. We thus reveal... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4883263 Sun, 01 May 2011 23:00:00 +0100 4883263 http://www.medworm.com/index.php?rid=4767794&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00716.x SummaryAlthough extensively studied in C. elegans, no work has yet demonstrated for Drosophila melanogaster whether reduced insulin/IGF signaling (IIS) requires the FOXO transcription factor (foxo) to extend lifespan. Here we conduct genetic epistasis analysis to determine if foxo is required for chico mutants (insulin receptor substrate) to reduce age‐specific mortality and thus extend lifespan. The mutant chico1 allele strongly extends lifespan relative to wildtype sibs. A mutant of foxo eliminates most of this chico survival benefit. In addition, we used a factorial proportional hazard analysis to formally study the main effects of chico and of foxo, and to determine how these genes interact to influence mortality. We document that foxo indeed contributes to how chico increases lifesp... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4767794 Sun, 24 Apr 2011 23:00:00 +0100 4767794 http://www.medworm.com/index.php?rid=4747409&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00716.x SummaryAlthough extensively studied in C. elegans, no work has yet demonstrated for Drosophila melanogaster whether reduced insulin/IGF signaling (IIS) requires the FOXO transcription factor (foxo) to extend lifespan. Here we conduct genetic epistasis analysis to determine if foxo is required for chico mutants (insulin receptor substrate) to reduce age‐specific mortality and thus extend lifespan. The mutant chico1 allele strongly extends lifespan relative to wildtype sibs. A null mutant of foxo eliminates most of this chico survival benefit. This result suggests that the FOXO transcription factor is indeed downstream of the insulin receptor substrate in the control of longevity, however the conclusion overlooks that survival is somewhat repressed by foxo mutants alone. We therefore used ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4747409 Sun, 24 Apr 2011 23:00:00 +0100 4747409 http://www.medworm.com/index.php?rid=4747408&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00717.x In conclusion, age‐related intrinsic alterations in signaling responses to osteoanabolic agents like PTH may contribute to cellular and tissue aging of the human skeleton. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4747408 Sun, 24 Apr 2011 23:00:00 +0100 4747408 http://www.medworm.com/index.php?rid=4862232&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00713.x We report here a number of novel approaches to study the pathobiology of aging C. elegans. We combined histological staining of serial‐sectioned tissues, transmission electron microscopy, and confocal microscopy with 3D volumetric reconstructions and characterized age‐related morphological changes in multiple wild‐type individuals at different ages. This enabled us to identify several novel pathologies with age in the C. elegans intestine, including the loss of critical nuclei, the degradation of intestinal microvilli, changes in the size, shape, and cytoplasmic contents of the intestine, and altered morphologies caused by ingested bacteria. The three‐dimensional models we have created of tissues and cellular components from multiple individuals of different ages represent a uniq... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4862232 Sun, 17 Apr 2011 23:00:00 +0100 4862232 http://www.medworm.com/index.php?rid=4862231&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00714.x In this study, we investigated the aging‐associated microRNA cluster 17–92, which targets the ECM proteins connective tissue growth factor (CTGF) and thrombospondin‐1 (TSP‐1). We employed aged mice with a failure‐resistant (C57Bl6) and failure‐prone (C57Bl6 × 129Sv) genetic background and extrapolated our findings to human age‐associated heart failure. In aging‐associated heart failure, we linked an aging‐induced increase in the ECM proteins CTGF and TSP‐1 to a decreased expression of their targeting microRNAs 18a, 19a, and 19b, all members of the miR‐17–92 cluster. Failure‐resistant mice showed an opposite expression pattern for both the ECM proteins and the microRNAs. We showed that these expression changes are specific for cardiomyocytes and are absent in ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4862231 Sun, 17 Apr 2011 23:00:00 +0100 4862231 http://www.medworm.com/index.php?rid=4723497&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00713.x We report here a number of novel approaches to study the pathobiology of aging C. elegans. We combined histological staining of serial‐sectioned tissues, transmission electron microscopy, and confocal microscopy with 3‐D volumetric reconstructions, and characterized age‐related morphological changes of multiple wild‐type individuals at different ages. This enabled us to identify several novel pathologies with age in the C. elegans intestine, including loss of critical nuclei, degradation of intestinal microvilli, changes in the size, shape, and cytoplasmic contents of the intestine, and altered morphologies due to ingested bacteria. The three‐dimensional models we have created of tissues and cellular components from multiple individuals of different ages, represent a unique resou... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4723497 Sun, 17 Apr 2011 23:00:00 +0100 4723497 http://www.medworm.com/index.php?rid=4676485&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00703.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4676485 Mon, 04 Apr 2011 23:00:00 +0100 4676485 http://www.medworm.com/index.php?rid=4753464&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00711.x SummaryHere, we report that inactivation of the Caenorhabditis elegans dynamin‐related protein DRP‐1, a key component responsible for mitochondrial fission and conserved from yeast to humans, dramatically enhanced the effect of reduced insulin signaling (IIS) to extend lifespan. This represents the first report of a beneficial impact of manipulating mitochondrial dynamics on animal lifespan and suggests that mitochondrial morphology and IIS cooperate to modulate aging. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4753464 Sun, 03 Apr 2011 23:00:00 +0100 4753464 http://www.medworm.com/index.php?rid=4676484&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00712.x SummaryOxidative damage affects protein structure and function. Progressive accumulation of oxidized proteins is considered a putative mechanism of aging; however, empirical evidence supporting their role in aging is inconsistent. This inconsistency may reflect a failure to distinguish damage to particular cellular compartments. We found significant reduction of protein carbonyl in the insoluble, but not the soluble, fraction of liver tissues of long‐lived compared to short‐lived animals. Of cellular components analyzed, only nuclear protein carbonyl level was uniformly reduced in long‐lived compared with short‐lived animals. This observation suggests that attenuated accumulation of protein carbonyls in the nucleus, where they can affect multiple aspects of gene expression and DNA ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4676484 Sun, 03 Apr 2011 23:00:00 +0100 4676484 http://www.medworm.com/index.php?rid=4775155&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00719.x We report that depletion of lamin A/C expression in normal human cells leads to a dramatic downregulation of the Rb family of tumor suppressors and a defect in cell proliferation. Lamin A/C depleted cells exhibited a flat morphology and accumulated markers of cellular senescence. This senescent phenotype was accompanied by engagement of the p53 tumor suppressor and induction of the p53 target gene p21 and was prevented by small hairpin RNAs against p53, p21 or by the oncoprotein Mdm2. The expression of E2F target genes, normally required for cell cycle progression, was downregulated after lamin A/C depletion but restored after inactivation of p53. A similar senescence response was observed in myoblasts from a patient with a lamin A mutation causing muscular dystrophy. We thus reveal a prev... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4775155 Thu, 31 Mar 2011 23:00:00 +0100 4775155 http://www.medworm.com/index.php?rid=4747407&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00718.x We examined telomeres/telomerase in cultured cells from >60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (<20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co‐evolved with body size. Multiple independent times smaller, shorter‐lived species changed to having longer telomeres and expressing telomerase. Tra... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4747407 Thu, 31 Mar 2011 23:00:00 +0100 4747407 http://www.medworm.com/index.php?rid=4723496&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00714.x SummaryTo understand the process of cardiac aging, it is of crucial importance to gain insight in the age‐related changes in gene expression in the senescent failing heart. Age‐related cardiac remodeling is known to be accompanied by changes in extracellular matrix (ECM) gene and protein levels. Small non‐coding microRNAs regulate gene expression in cardiac development and disease, and have been implicated in the aging process and in the regulation of ECM proteins. However, their role in age‐related cardiac remodeling and heart failure is unknown. In the present study, we investigated the aging‐associated microRNA cluster 17∼92, which targets the ECM proteins connective tissue growth factor (CTGF) and thrombospondin‐1 (TSP‐1). We employed aged mice with a failure resistant ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4723496 Thu, 31 Mar 2011 23:00:00 +0100 4723496 http://www.medworm.com/index.php?rid=4676483&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00711.x SummaryHere we report that inactivation of the C. elegans dynamin‐related protein DRP‐1, a key component responsible for mitochondrial fission and conserved from yeast to humans, dramatically enhanced the effect of reduced insulin signaling (IIS) to extend lifespan. This represents the first report of a beneficial impact of manipulating mitochondrial dynamics on animal lifespan and suggests that mitochondrial morphology and IIS cooperate to modulate aging. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4676483 Thu, 31 Mar 2011 23:00:00 +0100 4676483 http://www.medworm.com/index.php?rid=4642357&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00709.x AbstractMice lacking Cu,Zn superoxide dismutase (SOD1) show accelerated, age‐related loss of muscle mass. Lack of SOD1 may lead to increased superoxide, reduced nitric oxide (NO) and increased peroxynitrite, each of which could initiate muscle fiber loss. Single muscle fibers from flexor digitorum brevis of wild type and Sod1‐/‐ mice were loaded with NO‐sensitive (4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein diacetate, DAF‐FM) and superoxide‐sensitive (dihydroethidium, DHE) probes. Gastrocnemius muscles were analysed for SOD enzymes, nitric oxide synthases (NOS) and 3‐nitrotyrosine (3‐NT) content. A lack of SOD1 did not increase superoxide availability at rest since no increase in ethidium or 2‐hydroxyethidium (2‐HE) formation from DHE was seen in fiber... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4642357 Mon, 28 Mar 2011 20:40:50 +0100 4642357 http://www.medworm.com/index.php?rid=4788870&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00709.x SummaryMice lacking Cu,Zn superoxide dismutase (SOD1) show accelerated, age‐related loss of muscle mass. Lack of SOD1 may lead to increased superoxide, reduced nitric oxide (NO), and increased peroxynitrite, each of which could initiate muscle fiber loss. Single muscle fibers from flexor digitorum brevis of wild‐type (WT) and Sod1−/− mice were loaded with NO‐sensitive (4‐amino‐5‐methylamino‐2′,7′‐difluorofluorescein diacetate, DAF‐FM) and superoxide‐sensitive (dihydroethidium, DHE) probes. Gastrocnemius muscles were analyzed for SOD enzymes, nitric oxide synthases (NOS), and 3‐nitrotyrosine (3‐NT) content. A lack of SOD1 did not increase superoxide availability at rest because no increase in ethidium or 2‐hydroxyethidium (2‐HE) formation from DHE was see... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4788870 Sun, 27 Mar 2011 23:00:00 +0100 4788870 http://www.medworm.com/index.php?rid=4775156&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00708.x SummaryWe previously described an association between Alzheimer’s disease (AD) and a single‐nucleotide polymorphism −980C/G (rs3754048) in the promoter of the anterior pharynx‐defective‐1a (APH‐1A) gene. Here, we examine the potential of this −980C/G polymorphism to affect APH‐1A transcription and confer a risk of AD. We validated the presence of APH‐1A promoter polymorphism −980C/G in other two Chinese cohort sets (450 AD and 450 controls). Subsequently, we measured APH‐1A mRNA and protein levels and γ‐secretase activity in C or G allele carriers. Finally, we examined the polymorphism’s transcriptional function using a dual‐luciferase reporter assay and also tracked transcription factor binding to the variant promoter sequence with electrophoretic mobility shi... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4775156 Sun, 27 Mar 2011 23:00:00 +0100 4775156 http://www.medworm.com/index.php?rid=4642359&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00707.x SummaryThe insulin/IGF‐like signaling (IIS) pathway in metazoans has evolutionarily conserved roles in growth control, metabolic homeostasis, stress responses, reproduction and lifespan. Genetic manipulations that reduce IIS in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse have been shown not only to produce substantial increases in lifespan but also to ameliorate several age‐related diseases. In C. elegans, the multitude of phenotypes produced by reduction of IIS are all suppressed in the absence of the worm FOXO transcription factor, DAF‐16, suggesting that they are all under common regulation. It is not yet clear in other animal models whether the activity of FOXOs mediate all of the physiological effects of reduced IIS, especially i... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4642359 Sun, 27 Mar 2011 23:00:00 +0100 4642359 http://www.medworm.com/index.php?rid=4642358&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00708.x SUMMARYWe previously described an association between Alzheimer’s disease (AD) and a single nucleotide polymorphism −980C/G (rs3754048) in the promoter of the anterior pharynx‐defective‐1a (APH‐1A) gene. Here we examine the potential of this −980C/G polymorphism to affect APH‐1A transcription and confer a risk for AD. We validated the presence of APH‐1A promoter polymorphism −980C/G in other two Chinese cohort sets (450 AD and 450 controls). Subsequently, we measured APH‐1A mRNA and protein levels and γ‐secretase activity in C or G allele carriers. Finally, we examined the polymorphism’s transcriptional function using a dual‐luciferase reporter assay and also tracked transcription factor binding to the variant promoter sequence with electrophoretic mobility shift... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4642358 Sun, 27 Mar 2011 23:00:00 +0100 4642358 http://www.medworm.com/index.php?rid=4622106&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00700.x AbstractHere, we show that a small‐molecule activator of telomerase (TA‐65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsuficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc+/‐ MEFs). Importantly, TA‐65 does not cause telomere elongation or rescues DNA damage in similarly treated telomerase‐deficient G3 Terc‐/‐ littermate MEFs. These results indicate that TA‐65 treatment results in telomerase‐dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA‐65 mechanism of action is through the telomerase... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4622106 Wed, 23 Mar 2011 04:54:57 +0100 4622106 http://www.medworm.com/index.php?rid=4614983&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00706.x SummaryStore‐operated Ca2+ entry (SOCE) is a robust mechanism in skeletal muscle, supported by abundant STIM1 and Orai1 in the junctional membranes. The precise role of SOCE in skeletal muscle Ca2+ homeostasis and excitation‐contraction coupling remains to be defined. Regardless, it remains important to determine whether the function and capacity of SOCE changes in aged skeletal muscle. We identified an approximate 40% decline in the expression of the integral SOCE protein, stromal interacting molecule 1 (STIM1), but no such decline in its coupling partner, Orai1, in muscle fibers from aged mice. To determine whether this changed aspects of SOCE functionality in skeletal muscle in aged mice, Ca2+ in the cytoplasm and t‐system were continuously and simultaneously imaged on a confocal ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4614983 Mon, 21 Mar 2011 19:04:36 +0100 4614983 http://www.medworm.com/index.php?rid=4788871&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00705.x In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4788871 Mon, 21 Mar 2011 00:00:00 +0100 4788871 http://www.medworm.com/index.php?rid=4614985&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00704.x SummarySkin‐derived precursors (SKPs) are embryonic neural crest‐derived multipotent progenitor cells with properties of dermal stem cells. Although a large number of studies deal with their differentiation ability and potential applications in tissue damage repair, few studies have concentrated on the regulation of SKP self‐renewal. Here, we found that after separation from their physiological microenvironment, human foreskin‐derived SKPs (hSKPs) quickly senesced and lost their self‐renewal ability. We observed a sharp decrease in Akt activity during this process, suggesting a possible role of the PI3K‐Akt pathway in hSKP maintenance in vitro. Blocking this pathway with several inhibitors inhibited hSKP proliferation and sphere formation, and increased hSKP senescence. In cont... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4614985 Mon, 21 Mar 2011 00:00:00 +0100 4614985 http://www.medworm.com/index.php?rid=4614984&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00705.x In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE ε4 allele. No other major longevity locus was found. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4614984 Mon, 21 Mar 2011 00:00:00 +0100 4614984 http://www.medworm.com/index.php?rid=4580845&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00684.x (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4580845 Mon, 14 Mar 2011 09:53:49 +0100 4580845 http://www.medworm.com/index.php?rid=4580844&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00670.x SummaryArgonaute 2 (Ago2) has a leading function in miRNA‐induced RNA silencing, a conserved gene regulatory mechanism in cells and organisms. miRNAs are critical for stem cell self‐renewal, development, and other functions. Here, we report that nuclear Ago2, by binding to a specific region of functional genes, directly controls adipose tissue–derived stem cell (ATSC) survival in response to a critical dose of reactive oxygen species (ROS)‐mediated oxidative cell damage or senescence. The role of nuclear Ago2 has not been previously reported. Here, we show that human ATSCs in which Ago2 was downregulated underwent apoptosis. Silencing of Ago2 in ATSCs significantly induces upregulation of miR10b and miR23b expression. These miRNAs directly interfere with ROS‐scavenging gene expre... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4580844 Mon, 14 Mar 2011 09:53:44 +0100 4580844 http://www.medworm.com/index.php?rid=4704387&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00698.x SummaryIn mammals, the forkhead box class O (FOXO) family of transcription factors consists of the four members FOXO1, FOXO3A, FOXO4, and FOXO6. The FOXO genes are homologues of daf‐16, a key regulator of the insulin‐IGF1 signaling pathway and a modulator of lifespan in Caenorhabditis elegans. Recently, variants in FOXO3A have consistently been associated with human longevity in various populations worldwide. Given this confirmed finding, it is conceivable that polymorphisms in the other FOXO genes might have a similar effect on human longevity. To evaluate whether allelic variation in FOXO1, FOXO4, and FOXO6 influences the ability to become long‐lived, we performed a comprehensive haplotype‐tagging analysis of the three genes in a group of 1447 centenarians/nonagenarians and 1029 ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4704387 Wed, 09 Mar 2011 00:00:00 +0100 4704387 http://www.medworm.com/index.php?rid=4704386&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00699.x We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c‐fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age‐related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4704386 Wed, 09 Mar 2011 00:00:00 +0100 4704386 http://www.medworm.com/index.php?rid=4565735&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00696.x SummaryHuman chromosome ends associate with shelterin, a six‐protein complex that protects telomeric DNA from being recognized as sites of DNA damage. The shelterin subunit TRF2 has been implicated in the protection of chromosome ends by facilitating their organization into the protective capping structure and by associating with several accessory proteins involved in various DNA transactions. Here we describe the characterization of DDX39 DEAD‐box RNA helicase as a novel TRF2‐interacting protein. DDX39 directly interacts with the telomeric repeat binding factor homology (TRFH) domain of TRF2 via the FXLXP motif (where X is any amino acid). DDX39 is also found in association with catalytically competent telomerase in cell lysates through an interaction with hTERT but has no effect on... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4565735 Wed, 09 Mar 2011 00:00:00 +0100 4565735 http://www.medworm.com/index.php?rid=4565734&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00698.x SUMMARYIn mammals, the forkhead box class O (FOXO) family of transcription factors consists of the four members FOXO1, FOXO3A, FOXO4 and FOXO6. The FOXO genes are homologues of daf‐16, a key regulator of the insulin‐IGF1 signalling pathway and a modulator of lifespan in C. elegans. Recently, variants in FOXO3A have consistently been associated with human longevity in various populations worldwide. Given this confirmed finding, it is conceivable that polymorphisms in the other FOXO genes might have a similar effect on human longevity. To evaluate whether allelic variation in FOXO1, FOXO4 and FOXO6 influences the ability to become long‐lived, we performed a comprehensive haplotype‐tagging analysis of the three genes in a group of 1447 centenarians/nonagenarians and 1029 younger contr... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4565734 Wed, 09 Mar 2011 00:00:00 +0100 4565734 http://www.medworm.com/index.php?rid=4565733&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00697.x SummaryDampening of insulin/insulin like growth factor‐1 (IGF1) signaling results in extension of lifespan in invertebrate as well as murine models. The impact of this evolutionarily conserved pathway on modulation of human lifespan remains unclear. We previously identified two IGF1R mutations (Ala‐37‐Thr and Arg‐407‐His) that are enriched in Ashkenazi Jewish centenarians as compared to younger controls and are associated with reduced activity of the IGF1 receptor as measured in immortalized lymphocytes. To determine whether these human longevity‐associated IGF1R mutations affect IGF1 signaling, we engineered mouse embryonic fibroblasts (MEFs) expressing the different human IGF1R variants in a mouse Igf1r null background. The results indicate that MEFs expressing the human long... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4565733 Wed, 09 Mar 2011 00:00:00 +0100 4565733 http://www.medworm.com/index.php?rid=4565732&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00699.x We report that old mice show greater sleep/wake transitions in the active period with markedly shortened wake periods, shortened latencies to sleep, and less wake time in the subjective day in response to a novel social encounter. Consistent with sleep/wake instability and reduced social encounter wakefulness, orexinergic and noradrenergic wake neurons in aged mice show reduced c‐fos response to wakefulness and endoplasmic reticulum dyshomeostasis with increased nuclear translocation of CHOP and GADD34. We have identified an age‐related unfolded protein response injury to and dysfunction of wake neurons. It is anticipated that these changes contribute to sleep/wake fragmentation and cognitive impairment in aging. (Source: Aging Cell) Aging Cell journals http://www.medworm.com/rss/comments.php?id=4565732 Wed, 09 Mar 2011 00:00:00 +0100 4565732 http://www.medworm.com/index.php?rid=4565731&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00701.x SummaryAging is associated with gradual decline of skeletal muscle strength and mass often leading to diminished muscle quality. This phenomenon is known as sarcopenia and affects about 30% of the over 60‐year old population. Androgens act as anabolic agents regulating muscle mass and improving muscle performance. The role of female sex steroids as well as the ability of skeletal muscle tissue to locally produce sex steroids has been less extensively studied. We show that despite the extensive systemic deficit of sex steroid hormones in postmenopausal compared to premenopausal women, the hormone content of skeletal muscle does not follow the same trend. In contrast to the systemic levels, muscle tissue of post‐ and premenopausal women had similar concentrations of dehydroepiandrosteron... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4565731 Wed, 09 Mar 2011 00:00:00 +0100 4565731 http://www.medworm.com/index.php?rid=4676487&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00692.x SummaryHematopoietic stem cells (HSCs) are the source for the life‐long supply of functional cells in peripheral blood while they simultaneously maintain their own reserve pool. However, there is accumulating evidence that HSCs are themselves subject to quantitative and qualitative exhaustion. Although several processes linked to mitotic activity can potentially account for the observed aging phenomena (e.g., DNA damage, telomere shortening, epigenetic modification), a precise understanding of HSC exhaustion is still missing. It is particularly unclear how individual aging processes on the single‐cell level translate on the phenotypic level of the overall tissue and whether there is a functional implication of an age‐structured HSC population. We address these issues by applying a no... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4676487 Tue, 08 Mar 2011 00:00:00 +0100 4676487 http://www.medworm.com/index.php?rid=4676486&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00693.x SummaryCalorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR’s antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate‐injected mice. While CR was protective in control mice challenged with a two‐stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the monosodium glutamate‐treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite‐suppressed mice. We propose that some of CR’s beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the a... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4676486 Tue, 08 Mar 2011 00:00:00 +0100 4676486 http://www.medworm.com/index.php?rid=4559976&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00691.x SummaryThe female cardioprotective advantage, present in mammals of a reproductively‐competent age, is lost during the transition to a postreproductive state. The role of reproductive hormones in this transition is most evident in women with premature ovarian failure, where reduced estrogen production has been associated with an increased incidence of early death from cardiovascular disease. Previously, we reported that postreproductive‐aged mice that received young ovaries displayed an increased life span. Subsequent histopathological analysis suggested the presence of a cardioprotective effect associated with the restoration of ovarian influence. This restoration in postreproductive‐aged mice produced a sharp decrease in evidence of significant cardiomyopathy at death, compared wit... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4559976 Tue, 08 Mar 2011 00:00:00 +0100 4559976 http://www.medworm.com/index.php?rid=4559975&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00692.x SummaryHematopoietic stem cells (HSC) are the source for the life‐long supply of functional cells in peripheral blood while they simultaneously maintain their own reserve pool. However, there is accumulating evidence that HSCs are themselves subject to quantitative and qualitative exhaustion. Although several processes linked to mitotic activity can potentially account for the observed aging phenomena (e.g. DNA damage, telomere shortening, epigenetic modification) a precise understanding of HSC exhaustion is still missing. It is particularly unclear how individual aging processes on the single‐cell level translate on the phenotypic level of the overall tissue and whether there is a functional implication of an age‐structured HSC population.We address these issues by applying a novel ... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4559975 Tue, 08 Mar 2011 00:00:00 +0100 4559975 http://www.medworm.com/index.php?rid=4559974&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00694.x SummaryAstrocytes secrete growth factors that are both neuroprotective and supportive for the local environment. Identified by glial fibrillary acidic protein (GFAP) expression, astrocytes exhibit heterogeneity in morphology and in expression of phenotypic markers and growth factors throughout different adult brain regions. In adult neurogenic niches, astrocytes secrete vascular endothelial growth factor (VEGF) and fibroblast growth factor‐2 (FGF‐2) within the neurogenic niche, and are also a source of special GFAP‐positive multipotent neural stem cells (NSCs). Normal aging is accompanied by a decline in CNS function and reduced neurogenesis. We asked if a decreased availability of astrocyte‐derived factors may contribute to the age‐related decline in neurogenesis. Determining al... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4559974 Tue, 08 Mar 2011 00:00:00 +0100 4559974 http://www.medworm.com/index.php?rid=4559973&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00693.x SummaryCalorie restriction (CR) is known to have profound effects on tumor incidence. A typical consequence of CR is hunger, and we hypothesized that the neuroendocrine response to CR might in part mediate CR’s antitumor effects. We tested CR under appetite suppression using two models: neuropeptide Y (NPY) knockout mice and monosodium glutamate (MSG)‐injected mice. While CR was protective in control mice challenged with a two‐stage skin carcinogenesis model, papilloma development was neither delayed nor reduced by CR in the MSG‐treated and NPY knockout mice. Adiponectin levels were also not increased by CR in the appetite‐suppressed mice. We propose that some of CR’s beneficial effects cannot be separated from those imposed on appetite, and that NPY neurons in the arcuate nucl... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4559973 Tue, 08 Mar 2011 00:00:00 +0100 4559973 http://www.medworm.com/index.php?rid=4693091&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00688.x SummaryOne goal of aging research is to develop interventions that combat age‐related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here, we report that celecoxib, a nonsteroidal anti‐inflammatory drug widely used to treat pain and inflammation, extends Caenorhabditis elegans lifespan and delays the age‐associated physiological changes, such as motor activity decline. Celecoxib also delays the progression of age‐related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent cyclooxygenase‐2 (COX‐2) inhibitor. However, the result from a structural–activity analysis demonstrated that the antiaging effec... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4693091 Wed, 23 Feb 2011 00:00:00 +0100 4693091 http://www.medworm.com/index.php?rid=4696487&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00685.x SummaryBeta amyloid (βA) plays a central role in the pathogenesis of the most common and devastating neurodegenerative disorder, Alzheimer’s disease (AD). The mechanisms of βA neurotoxicity remain controversial, but include dysregulation of calcium homeostasis and oxidative stress. A large body of data suggest that cholesterol plays a significant role in AD. In mixed cultures containing hippocampal neurons and astrocytes, we have shown that neurotoxic βA peptides (1–42 and 25–35) cause sporadic cytosolic calcium ([Ca2+]c) signals in astrocytes but not in neurons, initiating a cascade that ends in neuronal death. We now show, using the cholesterol‐sensitive fluorescent probe, Filipin, that membrane cholesterol is significantly higher in astrocytes than in neurons and mediates the... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4696487 Fri, 18 Feb 2011 00:00:00 +0100 4696487 http://www.medworm.com/index.php?rid=4693092&cid=s_32037_171_f&fid=32037&url=http%3A%2F%2Fdx.doi.org%2F10.1111%252Fj.1474-9726.2011.00687.x SummarySeveral age‐related traits are associated with shorter telomeres, the structures that cap the end of linear chromosomes. A common polymorphism near the telomere maintenance gene TERT has been associated with several cancers, but relationships with other aging traits such as physical capability have not been reported. As part of the Healthy Ageing across the Life Course (HALCyon) collaborative research programme, men and women aged between 44 and 90 years from nine UK cohorts were genotyped for the single‐nucleotide polymorphism (SNP) rs401681. We then investigated relationships between the SNP and 30 age‐related phenotypes, including cognitive and physical capability, blood lipid levels and lung function, pooling within‐study genotypic effects in meta‐analyses. No signif... Aging Cell journals http://www.medworm.com/rss/comments.php?id=4693092 Fri, 18 Feb 2011 00:00:00 +0100 4693092