NPJ Aging and Mechanisms of Disease最新文献_第6页

Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy 延长寿命的药物去甲二氢愈创木酸抑制p300并激活自噬

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-07-30 DOI: 10.1038/s41514-019-0037-7

T. Tezil, Manish Chamoli, Che-Ping Ng, Roman P. Simon, Victoria J. Butler, M. Jung, J. Andersen, A. Kao, E. Verdin

引用次数: 22

Tissue-specific alteration of gene expression and function by RU486 and the GeneSwitch system. RU486和GeneSwitch系统对基因表达和功能的组织特异性改变。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-05-21 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-019-0036-8

Maricela Robles-Murguia, Liam C Hunt, David Finkelstein, Yiping Fan, Fabio Demontis

引用次数: 16

Erratum: Publisher Correction: Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging. 在衰老过程中，Lgr5的表观遗传沉默诱导肠上皮类器官衰老。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-03-07 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-019-0035-9

Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito

引用次数: 8

Caveolin-1 as a pathophysiological factor and target in psoriasis. 小窝蛋白-1在银屑病中的病理生理因子和靶点研究。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-02-05 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-019-0034-x

Ilja L Kruglikov, Philipp E Scherer

引用次数: 25

Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease. 在阿尔茨海默病大鼠模型中，职业性有机磷暴露会破坏小胶质细胞并加速缺陷。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-01-22 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-018-0033-3

Jaymie R Voorhees, Matthew T Remy, Claire M Erickson, Laura M Dutca, Daniel J Brat, Andrew A Pieper

{"title":"Occupational-like organophosphate exposure disrupts microglia and accelerates deficits in a rat model of Alzheimer's disease.","authors":"Jaymie R Voorhees, Matthew T Remy, Claire M Erickson, Laura M Dutca, Daniel J Brat, Andrew A Pieper","doi":"10.1038/s41514-018-0033-3","DOIUrl":"https://doi.org/10.1038/s41514-018-0033-3","url":null,"abstract":"Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females. The effect on neurodegeneration was more severe in males, and was also associated with accelerated cognitive impairment. Females did not exhibit accelerated cognitive impairment after CPF exposure, and amyloid deposition and tauopathy were unchanged in both males and females. Microglial dysregulation may mediate the increased risk of AD associated with occupational organophosphate exposure, and future therapies to preserve or restore normal microglia might help prevent AD in genetically vulnerable individuals exposed to CPF or other disease-accelerating environmental agents.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"3"},"PeriodicalIF":5.0,"publicationDate":"2019-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0033-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36912992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 32

New drugs for pharmacological extension of replicative life span in normal and progeroid cells. 延长正常细胞和类早衰细胞复制寿命的新药。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2019-01-16 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-018-0032-4

Sergei Vatolin, Tomas Radivoyevitch, Jaroslaw P Maciejewski

引用次数: 9

Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging. 表观遗传沉默Lgr5可诱导肠上皮类器官在衰老过程中衰老。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2018-12-01 eCollection Date: 2019-01-01 DOI: 10.1038/s41514-018-0031-5

Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito

{"title":"Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging.","authors":"Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito","doi":"10.1038/s41514-018-0031-5","DOIUrl":"https://doi.org/10.1038/s41514-018-0031-5","url":null,"abstract":"To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a (p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice. We further treated intestinal epithelial organoids from aged mice with nicotinamide mononucleotide (NMN), a key NAD+ intermediate. As a result, the organoids showed a higher NAD+ level, increased cell proliferative ability, activation of Lgr5 and suppression of senescence-associated genes, indicating that treatment with NMN could ameliorate senescence-related changes in intestinal epithelia. These findings suggest that organoids derived from aged animals could be a powerful research tool for investigating the molecular mechanisms underlying stem cell aging and for development of some form of anti-aging intervention, thus contributing to prolongation of healthy life expectancy.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"5 ","pages":"1"},"PeriodicalIF":5.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0031-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36813363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells. 磷酸化降低的ISGF3与衰老细胞中干扰素诱导基因的组成性表达有关。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2018-11-15 eCollection Date: 2018-01-01 DOI: 10.1038/s41514-018-0030-6

Mari Yamagami, Motoyuki Otsuka, Takahiro Kishikawa, Kazuma Sekiba, Takahiro Seimiya, Eri Tanaka, Tatsunori Suzuki, Rei Ishibashi, Motoko Ohno, Kazuhiko Koike

{"title":"ISGF3 with reduced phosphorylation is associated with constitutive expression of interferon-induced genes in aging cells.","authors":"Mari Yamagami, Motoyuki Otsuka, Takahiro Kishikawa, Kazuma Sekiba, Takahiro Seimiya, Eri Tanaka, Tatsunori Suzuki, Rei Ishibashi, Motoko Ohno, Kazuhiko Koike","doi":"10.1038/s41514-018-0030-6","DOIUrl":"https://doi.org/10.1038/s41514-018-0030-6","url":null,"abstract":"During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE)-mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"11"},"PeriodicalIF":5.0,"publicationDate":"2018-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0030-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36700152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 8

CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves. CA1 Nampt敲除重现了烟酰胺单核苷酸改善的老年小鼠海马认知表型。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2018-11-08 eCollection Date: 2018-01-01 DOI: 10.1038/s41514-018-0029-z

Sean Johnson, David F Wozniak, S Imai

{"title":"CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves.","authors":"Sean Johnson, David F Wozniak, S Imai","doi":"10.1038/s41514-018-0029-z","DOIUrl":"https://doi.org/10.1038/s41514-018-0029-z","url":null,"abstract":"Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase (Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase (Cask) as a potential downstream effector in response to age-associated NAD+ reduction in the hippocampus. Cask expression is responsive to NAD+ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD+ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD+ availability through supplementation of NAD+ intermediates, such as NMN.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"10"},"PeriodicalIF":5.0,"publicationDate":"2018-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0029-z","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36665165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 38

Clampdown of inflammation in aging and anticancer therapies by limiting upregulation and activation of GPCR, CXCR4. 通过限制GPCR、CXCR4的上调和激活来抑制衰老和抗癌治疗中的炎症。

IF 5

NPJ Aging and Mechanisms of Disease Pub Date : 2018-08-30 eCollection Date: 2018-01-01 DOI: 10.1038/s41514-018-0028-0

Raji R Nair, Shreyas V Madiwale, Deepak Kumar Saini

{"title":"Clampdown of inflammation in aging and anticancer therapies by limiting upregulation and activation of GPCR, CXCR4.","authors":"Raji R Nair, Shreyas V Madiwale, Deepak Kumar Saini","doi":"10.1038/s41514-018-0028-0","DOIUrl":"https://doi.org/10.1038/s41514-018-0028-0","url":null,"abstract":"One of the major pathological outcomes of DNA damage during aging or anticancer therapy is enhanced inflammation. However, the underlying signaling mechanism that drives this is not well understood. Here, we show that in response to DNA damage, ubiquitously expressed GPCR, CXCR4 is upregulated through the ATM kinase-HIF1α dependent DNA damage response (DDR) signaling, and enhances inflammatory response when activated by its ligand, chemokine CXCL12. A pharmacologically active compound screen revealed that this increased inflammation is dependent on reduction in cAMP levels achieved through activation of Gαi through CXCR4 receptor and PDE4A. Through in vivo analysis in mice where DNA damage was induced by irradiation, we validated that CXCR4 is induced systemically after DNA damage and inhibition of its activity or its induction blocked inflammation as well as tissue injury. We thus report a unique DNA damage-linked inflammatory cascade, which is mediated by expression level changes in a GPCR and can be targeted to counteract inflammation during anticancer therapies as well as aging.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":"9"},"PeriodicalIF":5.0,"publicationDate":"2018-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-018-0028-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36457804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 9