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rapamycin aging

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https://www.readbyqxmd.com/read/28315697/the-role-of-the-tor-pathway-in-mediating-the-link-between-nutrition-and-longevity
#1
REVIEW
Oleh Lushchak, Olha Strilbytska, Veronika Piskovatska, Kenneth B Storey, Alexander Koliada, Alexander Vaiserman
The target of rapamycin (TOR) pathway integrates signals from extracellular and intracellular agents, such as growth factors, nutrients, mediators of energy balance, oxygen availability and other environmental cues. It allows the regulation of multiple cellular processes including protein and lipid synthesis, ribosome biogenesis, autophagy and metabolic processes. Being conserved across different phyla, TOR regulates longevity of various organisms in response to dietary conditions. In this review we described the main components of the TOR pathway and its upstream effectors and downstream processes in relation to aging...
March 15, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28302901/treatment-of-renal-angiomyolipoma-and-other-hamartomas-in-patients-with-tuberous-sclerosis-complex
#2
REVIEW
Joshua A Samuels
Tuberous sclerosis complex is an autosomal dominant genetic disease characterized by growth of benign tumors (hamartomas) in multiple organs, especially the kidneys, brain, heart, lungs, and skin. Tuberous sclerosis complex is usually caused by a mutation in either the tuberous sclerosis complex 1 or tuberous sclerosis complex 2 gene, resulting in constitutive activation of mammalian target of rapamycin signaling. Currently, mammalian target of rapamycin inhibitors are recommended in adult patients with tuberous sclerosis complex for the treatment of asymptomatic, growing renal angiomyolipoma that are >3 cm in diameter and pediatric or adult patients with brain lesions (subependymal giant cell astrocytoma) that either are growing or are not amenable to surgical resection...
March 16, 2017: Clinical Journal of the American Society of Nephrology: CJASN
https://www.readbyqxmd.com/read/28302666/mtorc1-signalling-mediates-pi3k-dependent-large-lipid-droplet-accumulation-in-drosophila-ovarian-nurse-cells
#3
Lawrence B Mensah, Deborah C I Goberdhan, Clive Wilson
Insulin and insulin-like growth factor signalling (IIS), which is primarily mediated by the PI3-kinase (PI3K)/PTEN/Akt kinase signalling cassette, is a highly evolutionary conserved pathway involved in co-ordinating growth, development, ageing and nutrient homeostasis with dietary intake. It controls transcriptional regulators, in addition to promoting signalling by mechanistic Target of Rapamycin (mTOR) Complex 1 (mTORC1), which stimulates biosynthesis of proteins and other macromolecules, and drives organismal growth...
March 16, 2017: Biology Open
https://www.readbyqxmd.com/read/28283069/mtor-signaling-in-growth-metabolism-and-disease
#4
REVIEW
Robert A Saxton, David M Sabatini
The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology...
March 9, 2017: Cell
https://www.readbyqxmd.com/read/28282611/phase-ib-dose-finding-study-of-abiraterone-acetate-plus-buparlisib-bkm120-or-dactolisib-bez235-in-patients-with-castration-resistant-prostate-cancer
#5
Christophe Massard, Kim Nguyen Chi, Daniel Castellano, Johann de Bono, Gwenaelle Gravis, Luc Dirix, Jean-Pascal Machiels, Alain Mita, Begona Mellado Gonzalez, Sabine Turri, Joan Maier, Denes Csonka, Arunava Chakravartty, Karim Fizazi
BACKGROUND: The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signalling axis and androgen receptor (AR) pathways exhibit reciprocal feedback regulation in phosphatase and tensin homologue (PTEN)-deficient metastatic castration-resistant prostate cancer (CRPC) in preclinical models. This phase Ib study evaluated the pan-PI3K inhibitor buparlisib (BKM120) and the dual pan-PI3K/ mammalian target of rapamycin (mTOR) inhibitor dactolisib (BEZ235) in combination with abiraterone acetate (AA) in patients with CRPC...
March 3, 2017: European Journal of Cancer
https://www.readbyqxmd.com/read/28281664/genetic-interactions-and-functional-analyses-of-the-fission-yeast-gsk3-and-amk2-single-and-double-mutants-defective-in-torc1-dependent-processes
#6
Charalampos Rallis, StJohn Townsend, Jürg Bähler
The Target of Rapamycin (TOR) signalling network plays important roles in aging and disease. The AMP-activated protein kinase (AMPK) and the Gsk3 kinase inhibit TOR during stress. We performed genetic interaction screens using synthetic genetic arrays (SGA) with gsk3 and amk2 as query mutants, the latter encoding the regulatory subunit of AMPK. We identified 69 negative and 82 positive common genetic interactors, with functions related to cellular growth and stress. The 120 gsk3-specific negative interactors included genes functioning in translation and ribosomes...
March 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28265573/autophagy-protects-advanced-glycation-end-product-induced-apoptosis-and-expression-of-mmp-3-and-mmp-13-in-rat-chondrocytes
#7
Wenzhou Huang, Peng Ao, Jian Li, Tianlong Wu, Libiao Xu, Zhongbo Deng, Wenjie Chen, Changchang Yin, Xigao Cheng
Aging is one of the most prominent risk factors for the pathological progression of osteoarthritis (OA). One feature of age-related changes in OA is advanced glycation end products (AGEs) accumulation in articular cartilage. Autophagy plays a cellular housekeeping role by removing dysfunctional cellular organelles and proteins. However, the relationship between autophagy and AGE-associated OA is unknown. The aim of this study is to determine whether autophagy participates in the pathology of AGE-treated chondrocytes and to investigate the exact role of autophagy in AGE-induced cell apoptosis and expression of matrix metalloproteinase- (MMP-) 3 and MMP-13...
2017: BioMed Research International
https://www.readbyqxmd.com/read/28264931/key-proteins-and-pathways-that-regulate-lifespan
#8
Haihui Pan, Toren Finkel
Here, we review three sets of key proteins and their corresponding downstream pathways that have been linked to extending lifespan and promoting health span in a wide range of organisms. In particular, we review the biology of the sirtuin family of proteins, the Insulin/Insulin-like Growth Factor (IGF) signaling (IIS) pathway, and the mechanistic Target of Rapamycin (mTOR). Using insights derived from simple model organisms, mice and humans we discuss how these proteins and pathways may potentially alter the rate of aging...
March 6, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28260047/induced-pluripotent-stem-cells-from-patients-with-focal-cortical-dysplasia-and-refractory-epilepsy
#9
Daniel Rodrigo Marinowic, Fernanda Majolo, Alessandra Deise Sebben, Vinicius Duval da Silva, Tiago Giuliani Lopes, Eliseu Paglioli, André Palmini, Denise Cantarelli Machado, Jaderson Costa da Costa
Focal cortical dysplasia (FCD) is caused by numerous alterations, which can be divided into abnormalities of the cortical architecture and cytological variations; however, the exact etiology of FCD remains unknown. The generation of induced pluripotent stem cells (iPSCs) from the cells of patients with neurological diseases, and their subsequent tissue‑specific differentiation, serves as an invaluable source for testing and studying the initial development and subsequent progression of diseases associated with the central nervous system...
March 1, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28257663/molecular-pathways-related-to-the-longevity-promotion-and-cognitive-improvement-of-cistanche-tubulosa-in-drosophila
#10
Wei-Yong Lin, Chun Yao, Jack Cheng, Shung-Te Kao, Fuu-Jen Tsai, Hsin-Ping Liu
BACKGROUND: The aging process, including physical dysfunction and age-related memory impairment (AMI), are considered to be correlated with cumulative oxidative damages and insulin/IGF-1 signaling pathway. PURPOSE: The present study was to elucidate the in vivo effects on delaying aging and ameliorating AMI and underlying molecular mechanisms of Cistanche tubulosa (CT), a herb used in traditional Chinese medicine to improve sexual function and treat kidney dysfunction...
March 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28244683/rapamycin-treatment-dose-dependently-improves-the-cystic-kidney-in-a-new-adpkd-mouse-model-via-the-mtorc1-and-cell-cycle-associated-cdk1-cyclin-axis
#11
Ao Li, Song Fan, Yuchen Xu, Jialin Meng, Xufeng Shen, Jun Mao, Li Zhang, Xiansheng Zhang, Gilbert Moeckel, Dianqing Wu, Guanqing Wu, Chaozhao Liang
Although translational research into autosomal dominant polycystic kidney disease (ADPKD) and its pathogenesis has made considerable progress, there is presently lack of standardized animal model for preclinical trials. In this study, we developed an orthologous mouse model of human ADPKD by cross-mating Pkd2 conditional-knockout mice (Pkd2(f3) ) to Cre transgenic mice in which Cre is driven by a spectrum of kidney-related promoters. By systematically characterizing the mouse model, we found that Pkd2(f3/f3) mice with a Cre transgene driven by the mouse villin-1 promoter (Vil-Cre;Pkd2(f3/f3) ) develop overt cysts in the kidney, liver and pancreas and die of end-stage renal disease (ESRD) at 4-6 months of age...
February 28, 2017: Journal of Cellular and Molecular Medicine
https://www.readbyqxmd.com/read/28244487/everolimus-in-heavily-pretreated-metastatic-breast-cancer-is-real-world-experience-different
#12
J Bajpai, A Ramaswamy, S Gupta, J Ghosh, S Gulia
BACKGROUND: Drugs targeting mammalian target of rapamycin signaling pathway have been recently approved for treatment of hormone receptor (HR) positive metastatic breast cancer (MBC). However, there is lack of real world data from India on the use of this therapeutic strategy. MATERIALS AND METHODS: A retrospective analysis of MBC patients who had recurrence or progression while receiving aromatase inhibitors (AI's) and further treated with everolimus and either tamoxifen/AI/fulvestrant between March 2012 and June 2014, was undertaken...
July 2016: Indian Journal of Cancer
https://www.readbyqxmd.com/read/28241754/dna-methylation-profiles-of-elderly-individuals-subjected-to-indentured-childhood-labor-and-trauma
#13
Zoya Marinova, Andreas Maercker, Andreas Küffer, Mark D Robinson, Tomasz K Wojdacz, Susanne Walitza, Edna Grünblatt, Andrea Burri
BACKGROUND: Childhood trauma is associated with increased vulnerability to mental and somatic disorders later in life. Epigenetic modifications such as DNA methylation are one potential mechanism through which such long-lasting impairments/consequences can be explained. The aim of the present study was to investigate whether childhood trauma is associated with long-term DNA methylation alterations in old age. METHODS: We assessed genome-wide DNA methylation profiles in a cohort of former indentured child laborers ("Verdingkinder") who suffered severe childhood adversities (N = 30; M age = 75...
February 27, 2017: BMC Medical Genetics
https://www.readbyqxmd.com/read/28239780/sesamin-extends-lifespan-through-pathways-related-to-dietary-restriction-in-caenorhabditis-elegans
#14
Yumiko Nakatani, Yukie Yaguchi, Tomomi Komura, Masakazu Nakadai, Kenji Terao, Eriko Kage-Nakadai, Yoshikazu Nishikawa
PURPOSE: Sesamin, a polyphenolic compound found in sesame seeds, has been reported to exert a variety of beneficial health effects. We have previously reported that sesamin increases the lifespan of Caenorhabditis elegans. In this study, we investigated the molecular mechanisms underlying the longevity effect of sesamin in C. elegans. METHODS: Starting from three days of age, Caenorhabditis elegans animals were fed a standard diet alone or supplemented with sesamin...
February 26, 2017: European Journal of Nutrition
https://www.readbyqxmd.com/read/28229367/inhibition-of-mtor-pathway-by-rapamycin-decreases-p-glycoprotein-expression-and-spontaneous-seizures-in-pharmacoresistant-epilepsy
#15
Xiaosa Chi, Cheng Huang, Rui Li, Wei Wang, Mengqian Wu, Jinmei Li, Dong Zhou
The mammalian target of rapamycin (mTOR) has been demonstrated to mediate multidrug resistance in various tumors by inducing P-glycoprotein (P-gp) overexpression. Here, we investigated the correlation between the mTOR pathway and P-gp expression in pharmacoresistant epilepsy. Temporal cortex specimens were obtained from patients with refractory mesial temporal lobe epilepsy (mTLE) and age-matched controls who underwent surgeries at West China Hospital of Sichuan University between June 2014 and May 2015. We established a rat model of epilepsy kindled by coriaria lactone (CL) and screened pharmacoresistant rats (non-responders) using phenytoin...
February 22, 2017: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/28212107/rheb-in-neuronal-degeneration-regeneration-and-connectivity
#16
Veena Nambiar Potheraveedu, Miriam Schöpel, Raphael Stoll, Rolf Heumann
The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake...
February 17, 2017: Biological Chemistry
https://www.readbyqxmd.com/read/28211872/rictor-mtorc2-deficiency-enhances-keratinocyte-stress-tolerance-via-mitohormesis
#17
Beatrice Tassone, Stefania Saoncella, Francesco Neri, Ugo Ala, Davide Brusa, Mark A Magnuson, Paolo Provero, Salvatore Oliviero, Chiara Riganti, Enzo Calautti
How metabolic pathways required for epidermal tissue growth and remodeling influence the ability of keratinocytes to survive stressful conditions is still largely unknown. The mechanistic target of rapamycin complex 2 (mTORC2) regulates growth and metabolism of several tissues, but its functions in epidermal cells are poorly defined. Rictor is an adaptor protein essential for mTORC2 activity. To explore the roles of mTORC2 in the epidermis, we have conditionally deleted rictor in mice via K14-Cre-mediated homologous recombination and found that its deficiency causes moderate tissue hypoplasia, reduced keratinocyte proliferation and attenuated hyperplastic response to TPA...
February 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28183786/extracellular-rnas-are-associated-with-insulin-resistance-and-metabolic-phenotypes
#18
Ravi Shah, Venkatesh Murthy, Michael Pacold, Kirsty Danielson, Kahraman Tanriverdi, Martin G Larson, Kristina Hanspers, Alexander Pico, Eric Mick, Jared Reis, Sarah de Ferranti, Elizaveta Freinkman, Daniel Levy, Udo Hoffmann, Stavroula Osganian, Saumya Das, Jane E Freedman
OBJECTIVE: Insulin resistance (IR) is a hallmark of obesity and metabolic disease. Circulating extracellular RNAs (ex-RNAs), stable RNA molecules in plasma, may play a role in IR, though most studies on ex-RNAs in IR are small. We sought to characterize the relationship between ex-RNAs and metabolic phenotypes in a large community-based human cohort. RESEARCH DESIGN AND METHODS: We measured circulating plasma ex-RNAs in 2,317 participants without diabetes in the Framingham Heart Study (FHS) Offspring Cohort at cycle 8 and defined associations between ex-RNAs and IR (measured by circulating insulin level)...
February 9, 2017: Diabetes Care
https://www.readbyqxmd.com/read/28178239/eprs-is-a-critical-mtorc1-s6k1-effector-that-influences-adiposity-in-mice
#19
Abul Arif, Fulvia Terenzi, Alka A Potdar, Jie Jia, Jessica Sacks, Arnab China, Dalia Halawani, Kommireddy Vasu, Xiaoxia Li, J Mark Brown, Jie Chen, Sara C Kozma, George Thomas, Paul L Fox
Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1-S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1-S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS at Ser999 by mTORC1-S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis...
February 16, 2017: Nature
https://www.readbyqxmd.com/read/28177677/mtorc1-inhibitors-rapamycin-and-metformin-affect-cardiovascular-markers-differentially-in-zdf-rats
#20
COMPARATIVE STUDY
Ravi Nistala, Ahmad Raja, Lakshmi Pulakat
Mammalian target for rapamycin complex 1 (mTORC1) is a common target for the action of immunosuppressant macrolide rapamycin and glucose-lowering metformin. Inhibition of mTORC1 can exert both beneficial and detrimental effects in different pathologies. Here, we investigated the differential effects of rapamycin (1.2 mg/kg per day delivered subcutaneously for 6 weeks) and metformin (300 mg/kg per day delivered orally for 11 weeks) treatments on male Zucker diabetic fatty (ZDF) rats that mimic the cardiorenal pathology of type 2 diabetic patients and progress to insulin insufficiency...
March 2017: Canadian Journal of Physiology and Pharmacology
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