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rapamycin aging

Kenneth Maiese
As a result of the advancing age of the global population and the progressive increase in lifespan, neurodegenerative disorders continue to increase in incidence throughout the world. New strategies for neurodegenerative disorders involve the novel pathways of the mechanistic target of rapamycin (mTOR) and the silent mating-type information regulation 2 homolog 1 ( Saccharomyces cerevisiae ) (SIRT1) that can modulate pathways of apoptosis and autophagy. The pathways of mTOR and SIRT1 are closely integrated...
March 9, 2018: Biochemical Society Transactions
Johann Schottler, Niklas Randoll, Ralph Lucius, Amke Caliebe, Johann Roider, Alexa Klettner
Anti-Vascular Endothelial Growth Factor (VEGF) therapy is given repeatedly for an extended period of time to patients when treated for age-related macular degeneration. While short-term effects of anti-VEGF agents on retinal pigment epithelial (RPE) cells have been investigated, the effects of long-term and repeated treatment on these cells are scarce. In this study, we have investigated the effects of anti-VEGF treatment after long-term, repeated treatment on cell aging and morphology. The experiments were conducted in primary porcine RPE cells passage one and two...
March 6, 2018: Experimental Eye Research
Yujie Li, Sandra Finkbeiner, Athina Ganner, Julia Gerber, Marinella Klein, Manuel Grafe, Jakob Kandzia, Antje Thien, Kathrin Thedieck, Gerhard Breves, Thomas Jank, Ralf Baumeister, Gerd Walz, Elke Neumann-Haefelin
The mechanistic target of rapamycin (mTOR) kinase is central to metabolism and growth, and has a conserved role in aging. mTOR functions in two complexes, mTORC1 and mTORC2. In diverse eukaryotes, inhibition of mTORC1 signaling increases lifespan. mTORC1 transduces anabolic signals to stimulate protein synthesis and inhibits autophagy. In this study, we demonstrate that CGEF-1, the C. elegans homolog of the human guanine nucleotide exchange factor Dbl, is a novel binding partner of RHEB-1 and activator of mTORC1 signaling in C...
February 9, 2018: Oncotarget
Sadakatsu Ikeda, Igor F Tsigelny, Åge A Skjevik, Yuko Kono, Michel Mendler, Alexander Kuo, Jason K Sicklick, Gregory Heestand, Kimberly C Banks, AmirAli Talasaz, Richard B Lanman, Scott Lippman, Razelle Kurzrock
BACKGROUND: Because imaging has a high sensitivity to diagnose hepatocellular carcinoma (HCC) and tissue biopsies carry risks such as bleeding, the latter are often not performed in HCC. Blood-derived circulating tumor DNA (ctDNA) analysis can identify somatic alterations, but its utility has not been characterized in HCC. MATERIALS AND METHODS: We evaluated 14 patients with advanced HCC (digital ctDNA sequencing [68 genes]). Mutant relative to wild-type allele fraction was calculated...
February 27, 2018: Oncologist
Jason Bielas, Allen Herbst, Kevin Widjaja, Jessica Hui, Judd M Aiken, Debbie McKenzie, Richard A Miller, Susan Brooks, Jonathan Wanagat
Age-induced mitochondrial DNA deletion mutations may underlie cell loss and tissue aging. Rapamycin extends mouse lifespan and modulates mitochondrial quality control. We hypothesized that reduced deletion mutation abundance may contribute to rapamycin's life extension effects. To test this hypothesis, genetically heterogeneous male and female mice were treated with rapamycin, compounded in chow at 14 or 42 ppm, from 9 months to 22 months of age. Mice under a 40% dietary restriction were included as a control known to protect mtDNA quality...
February 24, 2018: Experimental Gerontology
Maryam Yousefi, Angela Nakauka-Ddamba, Corbett T Berry, Ning Li, Jenna Schoenberger, Kamen P Simeonov, Ryan J Cedeno, Zhengquan Yu, Christopher J Lengner
Aging is a complex process associated with a decline in functionality of adult stem cells affecting tissue homeostasis and regeneration. Calorie restriction (CR) is the only experimental manipulation known to extend lifespan and reduce the incidence of age-related disorders across numerous species. These benefits are likely mediated, at least in part, through the preservation of stem cell function. Here, we show that CR enhances the regenerative capacity of the intestinal epithelium through preservation of an injury-resistant reserve intestinal stem cell (ISC) pool...
February 15, 2018: Stem Cell Reports
Shohreh Majd, John H T Power
BACKGROUND: Emerging evidence supports the hypothesis that metabolism dysfunction is involved in pathogenesis of Alzheimer's disease (AD). One aspect of metabolic dysfunction includes dysregulation of adenosine monophosphate kinase protein kinase (AMPK) and mammalian target of rapamycin (mTOR) metabolic axis, which is extensively present in some of the leading causes of AD such as cerebrovascular diseases, type 2 diabetes and brain ischaemic events. While the molecular basis underlying this metabolic dysregulation remains a significant challenge, mitochondrial dysfunction due to aging appears to be an essential factor to activate AMPK/mTOR signaling pathway, leading to abnormal neuronal energy metabolism and AD pathology...
February 22, 2018: Current Alzheimer Research
Fei-Hu Lin, Wei-Ling Zhang, Hong Li, Xiao-Dan Tian, Jie Zhang, Xiao Li, Chuan-Yong Li, Jing-He Tan
Mechanisms for post-maturation oocyte aging (PMOA) are not fully understood, and whether autophagy plays any role in PMOA is unknown. To explore the role of autophagy in PMOA, expression of autophagosomes and effects of the autophagy (macro-autophagy) activity on PMOA were observed in mouse oocytes. Oocyte activation rates and active caspase-3 levels increased continuously from 0 to 18 h of in vitro aging. While levels of microtubule-associated protein light chain 3 (LC3)-II increased up to 12 h and decreased thereafter, contents of p62 decreased from 0 to 12 h and then elevated to basal level by 18 h...
February 22, 2018: Cell Death & Disease
James W Larrick, Jasmine W Larrick, Andrew R Mendelsohn
Advancing age is the biggest risk factor for development for the major life-threatening diseases in industrialized nations accounting for >90% of deaths. Alzheimer's dementia (AD) is among the most devastating. Currently approved therapies fail to slow progression of the disease, providing only modest improvements in memory. Recently reported work describes mechanistic studies of J147, a promising therapeutic molecule previously shown to rescue the severe cognitive deficits exhibited by aged, transgenic AD mice...
February 2018: Rejuvenation Research
Jiraporn Jirakkakul, Sittiruk Roytrakul, Chettida Srisuksam, Pratchya Swangmaneecharern, Suthathip Kittisenachai, Janthima Jaresitthikunchai, Juntira Punya, Peerada Prommeenate, Jittisak Senachak, Laihong So, Anuwat Tachaleat, Morakot Tanticharoen, Supapon Cheevadhanarak, Songsak Wattanachaisaereekul, Alongkorn Amnuaykanjanasin
The quality of Beauveria bassiana conidia directly affects the virulence against insects. In this study, continuous subculturing of B. bassiana on both rice grains and potato dextrose agar (PDA) resulted in 55 and 49 % conidial yield reduction after 12 passages and 68 and 60 % virulence reduction after 20 and 12 passages at four d post-inoculation, respectively. The passage through Tenebrio molitor and Spodoptera exigua restored the virulence of rice and PDA subcultures, respectively. To explore the molecular mechanisms underlying the conidial quality and the decline of virulence after multiple subculturing, we investigated the conidial proteomic changes...
February 2018: Fungal Biology
Koyo Ohno, Yoshiaki Saito, Akiko Tamasaki-Kondo, Atsushi Kambe, Yasushi Horie, Shinsuke Kato, Yoshihiro Maegaki
We report the case of a 19-year-old female with cerebellar ganglioglioma that was diagnosed at 4 years of age. Despite treatment with partial resection, radiation, and chemotherapy, residual tumor slowly expanded into the brainstem and upper cervical cord, resulting in nocturnal hypopnea, progressive tetraparesis, and feeding difficulty during 8-10 years of age. Initiation of temozolomide and bevacizumab was effective in preventing further expansion of the tumor, and the patient has been treated at home and in school with noninvasive positive pressure ventilation and gastrostomy...
December 2017: Yonago Acta Medica
H Richard Alexander, Claire Yue Li, Timothy J Kennedy
PURPOSE: Diffuse malignant peritoneal mesothelioma (MPM) is a rare and ultimately fatal cancer that was first described just over a century ago. It is a diffuse malignancy arising from the mesothelial lining of the peritoneum; morbidity and mortality from MPM is due to its propensity to progress locoregionally within the abdominal cavity. METHODS: The purpose of this article is to review the current state-of-the-science related to the diagnosis, staging, and treatment of MPM...
February 8, 2018: Annals of Surgical Oncology
Wen Xu, Jian Cao, Yan Zhou, Lina Wang, Guoqi Zhu
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15...
February 5, 2018: Neurobiology of Learning and Memory
Amal Houssaini, Marielle Breau, Kanny Kebe, Shariq Abid, Elisabeth Marcos, Larissa Lipskaia, Dominique Rideau, Aurelien Parpaleix, Jin Huang, Valerie Amsellem, Nora Vienney, Pierre Validire, Bernard Maitre, Aya Attwe, Christina Lukas, David Vindrieux, Jorge Boczkowski, Genevieve Derumeaux, Mario Pende, David Bernard, Silke Meiners, Serge Adnot
Chronic obstructive pulmonary disease (COPD) is a highly prevalent and devastating condition for which no curative treatment is available. Exaggerated lung cell senescence may be a major pathogenic factor. Here, we investigated the potential role for mTOR signaling in lung cell senescence and alterations in COPD using lung tissue and derived cultured cells from patients with COPD and from age- and sex-matched control smokers. Cell senescence in COPD was linked to mTOR activation, and mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the proinflammatory senescence-associated secretory phenotype...
February 8, 2018: JCI Insight
Mitsuhiro Abe, Kenji Tsushima, Jun Ikari, Naoko Kawata, Jiro Terada, Nobuhiro Tanabe, Koichiro Tatsumi
BACKGROUND: Everolimus (ERL), a mammalian target of rapamycin (mTOR) inhibitor, has been used for the management of several advanced cancers. ERL frequently causes lung injury, although the clinical and radiographic features have not been clarified. The aim of this study was to assess the clinical features of ERL-induced lung injury and determine the associated risk factors. METHODS: This single-center, retrospective study included 45 patients (29 men, 16 women; age, 12-78 years) who had received ERL at our hospital between August 2010 and March 2016...
January 2018: Respiratory Medicine
Ellen Kraig, Leslie A Linehan, Hanyu Liang, Terry Q Romo, Qianqian Liu, Yubo Wu, Adriana D Benavides, Tyler J Curiel, Martin A Javors, Nicolas Musi, Laura Chiodo, Wouter Koek, Jonathan A L Gelfond, Dean L Kellogg
Inhibition of the mechanistic target of rapamycin (mTOR) pathway by rapamycin (RAPA), an FDA-approved immunosuppressive drug used as a clinical therapy to prevent solid organ allograft rejection, enhances longevity in mice. Importantly, RAPA was efficacious even when initiated in relatively old animals, suggesting that mTOR inhibition could potentially slow the progression of aging-associated pathologies in older humans (Harrison et al., 2009; Miller et al., 2011). However, the safety and tolerability of RAPA in older human subjects have not yet been demonstrated...
February 3, 2018: Experimental Gerontology
Shanshan Zhang, Xiaoxing Li, Hui-Yun Wang, X F Steven Zheng
MAF1 was discovered as a master repressor of Pol III-dependent transcription in response to diverse extracellular signals, including growth factor, nutrient and stress. It is regulated through posttranslational mechanisms such as phosphorylation. A prominent upstream regulator of MAF1 is the mechanistic target of rapamycin (mTOR) pathway. mTOR kinase directly phosphorylates MAF1, controlling its localization and transcriptional activity. In mammals, MAF1 has also been shown to regulate Pol I- and Pol II-dependent transcription...
January 30, 2018: Biochimica et Biophysica Acta
Liming Huang, Lian Dai, Wenshen Xu, Shu Zhang, Danfang Yan, Xi Shi
Mechanistic target of rapamycin (MTOR) encodes a key modulator of cell growth, proliferation, and apoptosis. Previous studies have demonstrated that the dysregulation of MTOR is involved in the development and progression of several types of cancer, including glioma. In the present study, a comprehensive analysis was conducted to examine whether the expression quantitative trait loci (eQTLs) of MTOR are associated with the progression of glioma. Candidate eQTLs of MTOR were obtained from the Genotype-Tissue Expression eQTL Browser...
January 2018: Oncology Letters
Ashley Azar, Ibiyonu Lawrence, Sebastian Jofre, Joshua Mell, Christian Sell
Both methionine restriction and rapamycin treatment are robust longevity-enhancing regimens for which the mechanisms remain unclear. Cellular senescence is a major contributor to the aging process, and we find that both the methionine and rapamycin regimens delay or prevent activation of the senescence program in human cells. Using a transcriptome-wide analysis, we examined the impact of methionine restriction and rapamycin treatment on senescence-associated gene expression in human cardiac fibroblasts. Our findings have been integrated into gene expression data sets from human lung and skin fibroblasts during senescence...
January 28, 2018: Annals of the New York Academy of Sciences
Peter C Reifsnyder, Sergey Ryzhov, Kevin Flurkey, Rea P Anunciado-Koza, Ian Mills, David E Harrison, Robert A Koza
Rapamycin (RAPA), an inhibitor of mTORC signaling, has been shown to extend life span in mice and other organisms. Recently, animal and human studies have suggested that inhibition of mTORC signaling can alleviate or prevent the development of cardiomyopathy. In view of this, we used a murine model of type 2 diabetes (T2D), BKS-Leprdb , to determine whether RAPA treatment can mitigate the development of T2D-induced cardiomyopathy in adult mice. Female BKS-Leprdb mice fed diet supplemented with RAPA from 11 to 27 weeks of age showed reduced weight gain and significant reductions of fat and lean mass compared with untreated mice...
January 29, 2018: Annals of the New York Academy of Sciences
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