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Haim Y. Cohen - One of the best experts on this subject based on the ideXlab platform.
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characterization of physiological defects in adult SIRT6 mice
PLOS ONE, 2017Co-Authors: Victoria Peshti, Yariv Kanfi, Liat Nahum, Alexey Obolensky, Moran Rathaus, Maytal Avraham, Simon Tinman, Eyal Banin, Haim Y. CohenAbstract:The NAD+-dependent SIRT6 deacetylase was shown to be a major regulator of lifespan and healthspan. Mice deficient for SIRT6 develop a premature aging phenotype and metabolic defects, and die before four weeks of age. Thus, the effect of SIRT6 deficiency in adult mice is unknown. Here we show that SIRT6-/- mice in mixed 129/SvJ/BALB/c background reach adulthood, allowing examination of SIRT6-related metabolic and developmental phenotypes in adult mice. In this mixed background, at 200 days of age, more than 80% of the female knock-out mice were alive whereas only 10% of male knock-out mice survived. In comparison to their wild-type littermates, SIRT6 deficient mice have reduced body weight, increased glucose uptake and exhibit an age-dependent progressive impairment of retinal function accompanied by thinning of retinal layers. Together, these results demonstrate a role for SIRT6 in metabolism and age-related ocular changes in adult mice and suggest a gender specific regulation of lifespan by SIRT6.
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SIRT6, a protein with many faces
Biogerontology, 2013Co-Authors: Asaf A. Gertler, Haim Y. CohenAbstract:Sirtuins are NAD+ dependent deacylases enzymes. There are seven mammalian sirtuins, SIRT1–SIRT7, which are localized to different cellular compartments and are capable of diverse catalytic activities. SIRT6 is a key regulator of healthy ageing. In the past decade our understanding of SIRT6 significantly increased in many different aspects. We know its cellular localization, catalytic activities, substrates and the pathways it is involved in. This review discusses the recent discoveries regarding the SIRT6 enzyme.
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SIRT6 exhibits nucleosome dependent deacetylase activity
Nucleic Acids Research, 2013Co-Authors: Shaul Barth, Yariv Kanfi, Haim Y. CohenAbstract:The SIRT6 deacetylase is a key regulator of mammalian genome stability, metabolism and lifespan. Previous studies indicated that SIRT6 exhibits poor deacetylase activity in vitro. Here, we explored the specific conditions that allow SIRT6 to function as a significant deacetylase. We show that SIRT6 associates with the nucleosome and deacetylates histones H3 and H4 when they are packaged as nucleosomes, but not as free histones. In contrast, SIRT1 shows the opposite characteristics. Thus, our results show that SIRT6 activity is nucleosome dependent, and suggest that its binding to the nucleosome might convert it into an active structure.
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multiple regulatory layers of srebp1 2 by SIRT6
Cell Reports, 2013Co-Authors: Sivan Elhanati, Yariv Kanfi, Shaul Barth, Asael Roichman, Alexander Varvak, Ilana Carmelgross, Gilad Gibor, Haim Y. CohenAbstract:Summary The NAD + -dependent protein deacetylase SIRT6 regulates genome stability, cancer, and lifespan. Mice overexpressing SIRT6 (MOSES) have lower low-density lipoprotein cholesterol levels and are protected against the physiological damage of obesity. Here, we examined the role of SIRT6 in cholesterol regulation via the lipogenic transcription factors SREBP1 and SREBP2, and AMP-activated protein kinase (AMPK). We show that SIRT6 represses SREBP1 and SREBP2 by at least three mechanisms. First, SIRT6 represses the transcription levels of SREBP1/SREBP2 and that of their target genes. Second, SIRT6 inhibits the cleavage of SREBP1/SREBP2 into their active forms. Third, SIRT6 activates AMPK by increasing the AMP/ATP ratio, which promotes phosphorylation and inhibition of SREBP1 by AMPK. Reciprocally, the expression of miR33a and miR33b from the introns of SREBP2 and SREBP1, respectively, represses SIRT6 levels. Together, these findings explain the mechanism underlying the improved cholesterol homeostasis in MOSES mice, revealing a relationship between fat metabolism and longevity.
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The guardian: metabolic and tumour‐suppressive effects of SIRT6
The EMBO Journal, 2012Co-Authors: Batya Lerrer, Haim Y. CohenAbstract:Many cancer cells produce energy by increasing aerobic glycolysis instead of oxidative metabolism. SIRT6, a member of the sirtuins NAD+-dependent deacetylase family, has been shown to be involved in multiple cellular processes including metabolism and ageing. In a recent study, Sebastian et al (2012) demonstrate a role of SIRT6 as a tumour suppressor that modulates aerobic glycolysis and inhibits ribosome biogenesis by repressing MYC transcriptional activity. Cancer cells, in contrast to normal cells, generate the energy needed for their cellular processes by increasing aerobic glycolysis, a phenomenon termed ‘the Warburg effect' (Vander Heiden et al, 2009). Sirtuins, a family of NAD+-dependent deacetylases, have been linked to longevity in a variety of model organisms. These enzymes modulate a large set of biological processes, including cell survival, development, chromatin dynamics, DNA repair, metabolism and other phenomena (Houtkooper et al, 2012). Of particular interest is one member of this family, SIRT6, which is involved in regulation of mammalian ageing and metabolism (Kanfi et al, 2012). SIRT6 regulates many cancer-related pathways, including genome stability, by modulating DNA double-strand break, base excision repair (BER) and inflammation via repression of NFkB and telomere maintenance (Kawahara et al, 2009; Jia et al, 2012). It was thus suggested that SIRT6 may play a major role in tumour development. In their recent study, Sebastian et al (2012) provide the first direct demonstration of SIRT6 function in tumorigenesis. The authors demonstrate that SIRT6 acts as tumour suppressor by modulating the metabolism of cancer cells. An initial indication of the relationship between SIRT6 and glucose metabolism was provided by Mostoslavsky et al (2006), who showed that SIRT6-deficient mice display severe metabolic abnormalities, including loss of subcutaneous fat, lymphopenia and acute hypoglycemia, which leads to death of the mice before they reach 1 month of age. The severe hypoglycemia of SIRT6−/− mice was later explained by Zhong et al (2010), who demonstrated that SIRT6 regulates glucose homoeostasis via inhibiting multiple glycolytic genes, including the glucose transporter Glut1, by promoter binding and -deacetylation. This allows mitochondrial oxidative phosphorylation—but not glycolysis—to generate efficient ATP production. Accordingly, loss of SIRT6 increases glycolysis and diminishes mitochondrial respiration. To demonstrate the involvement of SIRT6 in skewing cancer metabolism, the authors performed several key experiments. Injection of wild-type (WT) MEFs into immunodeficient mice, in the absence of oncogene activation, does not generate tumours. However, Sebastian et al showed that SIRT6-knockout (KO) MEFs formed tumours (even without oncogene activation). Moreover, re-expression of SIRT6 in KO MEFs completely abolished tumour formation. These results suggested that SIRT6 is a bona fide tumour suppressor. However, the mechanism(s) by which SIRT6 mediates its tumour suppressor activity remain elusive. Interestingly, immortalized SIRT6 KO MEFs exhibit increased glucose uptake and lactate production as well as higher levels of glycolytic enzymes. Based on these observations, the authors suggested that SIRT6 blocks the transition towards aerobic glycolysis. They further provide in vivo support for such a model by reporting increased colorectal adenomatosis in Apc−/− mice carrying a specific intestinal deletion of SIRT6. Like other landmark research, this study paves the way for addressing additional interesting questions. First, it is not clear whether the increased Warburg effect due to SIRT6 deficiency precedes or follows the initiation of tumour development. The authors provide intriguing evidence that the SIRT6-deficient cells form tumours regardless of oncogene activation. They also described a reduction in SIRT6 expression in various tumours, mostly in pancreatic and colorectal cancers. However, whether a mutation or deletion in SIRT6 is the primary and direct cause of tumour onset remains unknown. Second, the transcription factor MYC is a key regulator of ribosome biogenesis. Interestingly, Sebastian et al, demonstrate that SIRT6 functions as a regulator of ribosome metabolism by co-repressing MYC transcriptional activity. In line with this observation, a previous study (Kanfi et al, 2008) showed that SIRT6 levels increased upon nutrient deprivation in cultured cells and in rats fed with a calorie-restricted diet. Therefore, it would be highly informative to establish a role for SIRT6 in repressing translation under conditions of limited energy sources. Further, it would be interesting to follow the tumour-suppressive function of SIRT6 in the context of reduced tumorigenesis as described during calorie restriction (Weindruch, 1992). Third, SIRT6 regulates many pathways that can contribute to its tumour-suppressive effect. Loss of function mutation in SIRT6 is expected to result in increased chromosomal translocations and decreased genome stability; both mechanisms have been linked to tumour formation. In addition, mutation in SIRT6 might contribute to tumorigenesis via its anti-inflammatory role. In addition, a recent study by Bauer et al (2012) indicates that SIRT6 promotes cell migration in pancreatic cancer cells by enhancing Ca+2 responses. Therefore, mutation in SIRT6 might also have antitumour effects. It would thus be interesting to dissect the contribution of each of these mechanisms to the role of SIRT6 as tumour suppressor. Finally, cancer is an age-related disease; therefore, one of the most puzzling questions is the relationship between the tumour-suppressive role of SIRT6 and its promotion of longevity. Male SIRT6-overexpressing mice (MOSES mice) have increased life span and improved metabolic parameters (Kanfi et al, 2012). The findings of Sebastian et al showing the tumour suppressor potential of SIRT6 together with those of Min et al (2012) who showed that increasing the level of SIRT6 markedly impairs cancer development suggest that the increased longevity may be (in part) due to reduced cancer incidence. Although Kanfi et al did not find a significant change in the number of tumours between WT and MOSES mice, it did appear that tumour onset was delayed in MOSES mice and that reduced cancer incidence might contribute to the lifespan extension. Thus, further research is required to establish the contribution of SIRT6 tumour suppressor activity to longevity. The study of Sebastian et al provides solid evidence for the role of SIRT6 as a tumour suppressor. This adds to the other known functions of SIRT6 that might also operate in the regulation of tumorigenesis (Figure 1). However, to date, no known mutation in SIRT6 has been linked to enhanced cancer development. Therefore, as seen in other tumour suppressors like p53, the activity or the protein levels of SIRT6 might be downregulated during the process of tumorigenesis. The identity of such potential regulators of SIRT6 levels and activity seems an interesting road for future exploration. Figure 1 Regulation of multiple pathways by SIRT6.
Yariv Kanfi - One of the best experts on this subject based on the ideXlab platform.
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SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα
Cell Reports, 2019Co-Authors: Shoshana Naiman, Liat Nahum, Frank K. Huynh, Yair Glick, Yael Shahar, Noga Touitou, Matan Y. Avivi, Asael Roichman, Yariv KanfiAbstract:Summary The pro-longevity enzyme SIRT6 regulates various metabolic pathways. Gene expression analyses in SIRT6 heterozygotic mice identify significant decreases in PPARα signaling, known to regulate multiple metabolic pathways. SIRT6 binds PPARα and its response element within promoter regions and activates gene transcription. SIRT6+/− results in significantly reduced PPARα-induced β-oxidation and its metabolites and reduced alanine and lactate levels, while inducing pyruvate oxidation. Reciprocally, starved SIRT6 transgenic mice show increased pyruvate, acetylcarnitine, and glycerol levels and significantly induce β-oxidation genes in a PPARα-dependent manner. Furthermore, SIRT6 mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. Mechanistically, SIRT6 binds PPARα coactivator NCOA2 and decreases liver NCOA2 K780 acetylation, which stimulates its activation of PPARα in a SIRT6-dependent manner. These coordinated SIRT6 activities lead to regulation of whole-body respiratory exchange ratio and liver fat content, revealing the interactions whereby SIRT6 synchronizes various metabolic pathways, and suggest a mechanism by which SIRT6 maintains healthy liver.
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characterization of physiological defects in adult SIRT6 mice
PLOS ONE, 2017Co-Authors: Victoria Peshti, Yariv Kanfi, Liat Nahum, Alexey Obolensky, Moran Rathaus, Maytal Avraham, Simon Tinman, Eyal Banin, Haim Y. CohenAbstract:The NAD+-dependent SIRT6 deacetylase was shown to be a major regulator of lifespan and healthspan. Mice deficient for SIRT6 develop a premature aging phenotype and metabolic defects, and die before four weeks of age. Thus, the effect of SIRT6 deficiency in adult mice is unknown. Here we show that SIRT6-/- mice in mixed 129/SvJ/BALB/c background reach adulthood, allowing examination of SIRT6-related metabolic and developmental phenotypes in adult mice. In this mixed background, at 200 days of age, more than 80% of the female knock-out mice were alive whereas only 10% of male knock-out mice survived. In comparison to their wild-type littermates, SIRT6 deficient mice have reduced body weight, increased glucose uptake and exhibit an age-dependent progressive impairment of retinal function accompanied by thinning of retinal layers. Together, these results demonstrate a role for SIRT6 in metabolism and age-related ocular changes in adult mice and suggest a gender specific regulation of lifespan by SIRT6.
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SIRT6 exhibits nucleosome dependent deacetylase activity
Nucleic Acids Research, 2013Co-Authors: Shaul Barth, Yariv Kanfi, Haim Y. CohenAbstract:The SIRT6 deacetylase is a key regulator of mammalian genome stability, metabolism and lifespan. Previous studies indicated that SIRT6 exhibits poor deacetylase activity in vitro. Here, we explored the specific conditions that allow SIRT6 to function as a significant deacetylase. We show that SIRT6 associates with the nucleosome and deacetylates histones H3 and H4 when they are packaged as nucleosomes, but not as free histones. In contrast, SIRT1 shows the opposite characteristics. Thus, our results show that SIRT6 activity is nucleosome dependent, and suggest that its binding to the nucleosome might convert it into an active structure.
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multiple regulatory layers of srebp1 2 by SIRT6
Cell Reports, 2013Co-Authors: Sivan Elhanati, Yariv Kanfi, Shaul Barth, Asael Roichman, Alexander Varvak, Ilana Carmelgross, Gilad Gibor, Haim Y. CohenAbstract:Summary The NAD + -dependent protein deacetylase SIRT6 regulates genome stability, cancer, and lifespan. Mice overexpressing SIRT6 (MOSES) have lower low-density lipoprotein cholesterol levels and are protected against the physiological damage of obesity. Here, we examined the role of SIRT6 in cholesterol regulation via the lipogenic transcription factors SREBP1 and SREBP2, and AMP-activated protein kinase (AMPK). We show that SIRT6 represses SREBP1 and SREBP2 by at least three mechanisms. First, SIRT6 represses the transcription levels of SREBP1/SREBP2 and that of their target genes. Second, SIRT6 inhibits the cleavage of SREBP1/SREBP2 into their active forms. Third, SIRT6 activates AMPK by increasing the AMP/ATP ratio, which promotes phosphorylation and inhibition of SREBP1 by AMPK. Reciprocally, the expression of miR33a and miR33b from the introns of SREBP2 and SREBP1, respectively, represses SIRT6 levels. Together, these findings explain the mechanism underlying the improved cholesterol homeostasis in MOSES mice, revealing a relationship between fat metabolism and longevity.
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the sirtuin SIRT6 regulates lifespan in male mice
Nature, 2012Co-Authors: Yariv Kanfi, Shoshana Naiman, Gail Amir, Victoria Peshti, Guy Zinman, Liat Nahum, Ziv Barjoseph, Haim Y. CohenAbstract:The role of sirtuins in longevity is controversial, and little is known about mammalian sirtuins; now, male mice that overexpress SIRT6 are shown to have a longer lifespan than wild-type mice, unlike their female counterparts. The role of sirtuin deacetylases in the regulation of lifespan of lower organisms is controversial, and the roles of many of the mammalian sirtuins, SIRT1 to SIRT7, in regulating lifespan are unclear. Here, Haim Cohen and colleagues show that transgenic male — but not female — mice overexpressing exogenous SIRT6 have a significantly longer lifespan than their wild-type littermates. The authors conclude that SIRT6 is an important regulator of mammalian longevity, and they raise the prospect that it might be possible to manipulate SIRT6 levels to treat age-related diseases. The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies1. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial2. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear3. Here we show that male, but not female, transgenic mice overexpressing SIRT6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male SIRT6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan5. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.
Jorge D. Erusalimsky - One of the best experts on this subject based on the ideXlab platform.
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SIRT6 protects human endothelial cells from dna damage telomere dysfunction and senescence
Cardiovascular Research, 2013Co-Authors: Anna Cardus, Anna K. Uryga, Gareth Walters, Jorge D. ErusalimskyAbstract:Aims Although endothelial cell senescence is known to play an important role in the development of cardiovascular pathologies, mechanisms that attenuate this process have not been extensively investigated. The aim of this study was to investigate whether SIRT6, a member of the sirtuin family of NAD+-dependent protein deacetylases/ADP-ribosyltransferases, protects endothelial cells from premature senescence and dysfunction, and if so which is its mode of action. Methods and results mRNA expression analysis demonstrated comparable levels of SIRT1 and SIRT6 transcripts in endothelial cells derived from different vascular beds and significantly higher levels of SIRT6 in these cells relative to those in haematopoietic progenitor cells. SIRT6 depletion by RNA interference in human umbilical vein endothelial cells (HUVEC) and aortic endothelial cells reduced cell proliferation, increased the fraction of senescence-associated-β-galactosidase-positive cells, and diminished the ability of the cells to form tubule networks on Matrigel. Further examination of SIRT6-depleted HUVEC demonstrated higher intercellular-adhesion molecule-1 (ICAM-1) and plasminogen-activator inhibitor-1 mRNA, lower levels of endothelial nitric oxide synthase mRNA and protein, higher ICAM-1 surface expression, and up-regulation of p21. Fluorescence microscopy of SIRT6-depleted HUVEC stained with anti-phospho-histone H2A.X and anti-telomere-repeat-binding-factor-1 antibodies showed evidence of increased nuclear DNA damage and the formation of telomere dysfunction-induced foci. Conclusion This work demonstrates that the presence of SIRT6 in endothelial cells confers protection from telomere and genomic DNA damage, thus preventing a decrease in replicative capacity and the onset of premature senescence. These findings suggest that SIRT6 may be important to maintain endothelial homeostatic functions and delay vascular ageing.
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SIRT6 protects human endothelial cells from DNA damage, telomere dysfunction, and senescence
Cardiovascular Research, 2013Co-Authors: Anna Cardus, Anna K. Uryga, Gareth Walters, Jorge D. ErusalimskyAbstract:AIMS: Although endothelial cell senescence is known to play an important role in the development of cardiovascular pathologies, mechanisms that attenuate this process have not been extensively investigated. The aim of this study was to investigate whether SIRT6, a member of the sirtuin family of NAD(+)-dependent protein deacetylases/ADP-ribosyltransferases, protects endothelial cells from premature senescence and dysfunction, and if so which is its mode of action.\n\nMETHODS AND RESULTS: mRNA expression analysis demonstrated comparable levels of SIRT1 and SIRT6 transcripts in endothelial cells derived from different vascular beds and significantly higher levels of SIRT6 in these cells relative to those in haematopoietic progenitor cells. SIRT6 depletion by RNA interference in human umbilical vein endothelial cells (HUVEC) and aortic endothelial cells reduced cell proliferation, increased the fraction of senescence-associated-β-galactosidase-positive cells, and diminished the ability of the cells to form tubule networks on Matrigel. Further examination of SIRT6-depleted HUVEC demonstrated higher intercellular-adhesion molecule-1 (ICAM-1) and plasminogen-activator inhibitor-1 mRNA, lower levels of endothelial nitric oxide synthase mRNA and protein, higher ICAM-1 surface expression, and up-regulation of p21. Fluorescence microscopy of SIRT6-depleted HUVEC stained with anti-phospho-histone H2A.X and anti-telomere-repeat-binding-factor-1 antibodies showed evidence of increased nuclear DNA damage and the formation of telomere dysfunction-induced foci.\n\nCONCLUSION: This work demonstrates that the presence of SIRT6 in endothelial cells confers protection from telomere and genomic DNA damage, thus preventing a decrease in replicative capacity and the onset of premature senescence. These findings suggest that SIRT6 may be important to maintain endothelial homeostatic functions and delay vascular ageing.
Shunsuke Minagawa - One of the best experts on this subject based on the ideXlab platform.
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autophagy induction by SIRT6 through attenuation of insulin like growth factor signaling is involved in the regulation of human bronchial epithelial cell senescence
Journal of Immunology, 2014Co-Authors: Naoki Takasaka, Jun Araya, Hiromichi Hara, Kenji Kobayashi, Yusuke Kurita, Hiroshi Wakui, Yutaka Yoshii, Yoko Yumino, Satoko Fujii, Shunsuke MinagawaAbstract:Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.
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accelerated epithelial cell senescence in ipf and the inhibitory role of SIRT6 in tgf β induced senescence of human bronchial epithelial cells
American Journal of Physiology-lung Cellular and Molecular Physiology, 2011Co-Authors: Shunsuke Minagawa, Jun Araya, Hiromichi Hara, Yoko Yumino, Takanori Numata, Satoko Nojiri, Makoto Kawaishi, Makoto Odaka, Toshiaki Morikawa, Stephen L NishimuraAbstract:Reepithelialization of remodeled air spaces with bronchial epithelial cells is a prominent pathological finding in idiopathic pulmonary fibrosis (IPF) and is implicated in IPF pathogenesis. Recent studies suggest that epithelial senescence is a risk factor for development of IPF, indicating such reepithelialization may be influenced by the acceleration of cellular senescence. Among the sirtuin (SIRT) family, SIRT6, a class III histone deacetylase, has been demonstrated to antagonize senescence. We evaluated the senescence of bronchiolization in association with SIRT6 expression in IPF lung. Senescence-associated β-galactosidase staining and immunohistochemical detection of p21 were performed to evaluate cellular senescence. As a model for transforming growth factor (TGF)-β-induced senescence of abnormal reepithelialization, we used primary human bronchial epithelial cells (HBEC). The changes of SIRT6, p21, and interleukin (IL)-1β expression levels in HBEC, as well as type I collagen expression levels in fibroblasts, were evaluated. In IPF lung samples, an increase in markers of senescence and SIRT6 expression was found in the bronchial epithelial cells lining cystically remodeled air spaces. We found that TGF-β induced senescence in primary HBEC by increasing p21 expression, and, whereas TGF-β also induced SIRT6, it was not sufficient to inhibit cellular senescence. However, overexpression of SIRT6 efficiently inhibited TGF-β-induced senescence via proteasomal degradation of p21. TGF-β-induced senescent HBEC secreted increased amounts of IL-1β, which was sufficient to induce myofibroblast differentiation in fibroblasts. These findings suggest that accelerated epithelial senescence plays a role in IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal interactions, which can be antagonized by SIRT6.
Eriko Michishita - One of the best experts on this subject based on the ideXlab platform.
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cell cycle dependent deacetylation of telomeric histone h3 lysine k56 by human SIRT6
Cell Cycle, 2009Co-Authors: Eriko Michishita, Ronald A Mccord, Lisa D Boxer, Matthew F Barber, Tao Hong, Or Gozani, Katrin F ChuaAbstract:SIRT6 is a member of the Sir2 (Silent Information Regulator-2) family of genes, which regulate fundamental processes in aging and lifespan control in multiple organisms.1-3 SIRT6 deficiency in mice results in genomic instability, metabolic defects, and degenerative phenotypes associated with aging.1 Previously, we showed that SIRT6 deacetylates lysine 9 on the N-terminal tail of histone H3 (H3K9Ac) to modulate telomeric chromatin and gene expression.2,3 Here, we identify a second substrate of SIRT6 at chromatin, lysine 56 on the globular core of histone H3 (H3K56Ac). We show that SIRT6 deacetylates H3K56Ac in vitro and in cells, and identify a physiologic role for this activity in maintaining dynamic changes of H3K56 acetylation levels at telomeric chromatin over the cell cycle. Together, these findings provide the first analysis of how H3K56Ac levels are dynamically regulated at human telomeres in response to a mammalian SIRT.
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SIRT6 links histone h3 lysine 9 deacetylation to nf κb dependent gene expression and organismal life span
Cell, 2009Co-Authors: Tiara L A Kawahara, Eriko Michishita, Adam S Adler, Mara Damian, Elisabeth Berber, Ron A MccordAbstract:Summary Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-κB signaling. SIRT6 interacts with the NF-κB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-κB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-κB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-κB-driven gene expression programs in multiple SIRT6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of SIRT6-deficient mice. We propose that SIRT6 attenuates NF-κB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-κB signaling may contribute to premature and normal aging.
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SIRT6 is a histone h3 lysine 9 deacetylase that modulates telomeric chromatin
Nature, 2008Co-Authors: Eriko Michishita, Tiara L A Kawahara, Mara Damian, Elisabeth Berber, Ronald A Mccord, Mitomu Kioi, Hesed Padillanash, Peggie Cheung, Rika Kusumoto, Carl J BarrettAbstract:The Sir2 family member SIRT6 is an NAD-dependent, histone H3 lysine 9 deacetylase enzyme that modulates telomeric chromatin and is required for stable association of WRN, the factor that is mutated in Werner Syndrome. The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae1,2. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype3. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein3, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder4,5. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome4,5. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.
