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https://www.readbyqxmd.com/read/29330421/premature-recruitment-of-oocyte-pool-and-increased-mtor-activity-in-fmr1-knockout-mice-and-reversal-of-phenotype-with-rapamycin
#1
E Mok-Lin, M Ascano, A Serganov, Z Rosenwaks, T Tuschl, Z Williams
While mutations in the fragile X mental retardation-1 (FMR1) gene are associated with varying reproductive outcomes in females, the effects of a complete lack of FMR1 expression are not known. Here, we studied the ovarian and reproductive phenotypes in an Fmr1 knockout (KO) mouse model and the role of mammalian target of rapamycin (mTOR) signaling. Breeding, histologic and mTOR signaling data were obtained at multiple time points in KO and wild type (WT) mice fed a control or rapamycin (mTOR inhibitor) diet...
January 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29329496/positive-feedback-regulation-of-subchondral-h-type-vessel-formation-by-chondrocyte-promotes-osteoarthritis-development-in-mice
#2
Jiansen Lu, Haiyan Zhang, Daozhang Cai, Chun Zeng, Pinglin Lai, Yan Shao, Hang Fang, Delong Li, Jiayao Ouyang, Chang Zhao, Denghui Xie, Bin Huang, Jian Yang, Yu Jiang, Xiaochun Bai
Vascular-invasion-mediated interactions between activated articular chondrocytes and subchondral bone are essential for osteoarthritis (OA) development. Here, we determined the role of nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) signaling in the crosstalk across the bone cartilage interface and its regulatory mechanisms. Then mice with chondrocyte-specific mTORC1 activation (Tsc1 CKO and Tsc1 CKOER ) or inhibition (Raptor CKOER ) and their littermate controls were subjected to OA induced by destabilization of the medial meniscus (DMM) or not...
January 12, 2018: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
https://www.readbyqxmd.com/read/29329306/lifespan-extension-without-fertility-reduction-following-dietary-addition-of-the-autophagy-activator-torin1-in-drosophila-melanogaster
#3
Janet S Mason, Tom Wileman, Tracey Chapman
Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan...
2018: PloS One
https://www.readbyqxmd.com/read/29320772/a-perfect-storm-the-role-of-the-mammalian-target-of-rapamycin-mtor-in-cerebrovascular-dysfunction-of-alzheimer-s-disease-a-mini-review
#4
Candice E Van Skike, Veronica Galvan
Cerebrovascular dysfunction is detected prior to the onset of cognitive and histopathological changes in Alzheimer's disease (AD). Increasing evidence indicates a critical role of cerebrovascular dysfunction in the initiation and progression of AD. Recent studies identified the mechanistic/mammalian target of rapamycin (mTOR) as a critical effector of cerebrovascular dysfunction in AD. mTOR has a key role in the regulation of metabolism, but some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function...
January 11, 2018: Gerontology
https://www.readbyqxmd.com/read/29312653/while-reinforcing-cell-cycle-arrest-rapamycin-and-torins-suppress-senescence-in-uva-irradiated-fibroblasts
#5
Olga V Leontieva, Mikhail V Blagosklonny
Sunlight predisposes to skin cancer and melanomas. Ultraviolet A (UVA), a long wave component of sunlight, can reach dermal fibroblasts. Here we studied UVA-induced senescence in human fibroblasts in vitro. It is known that senescence occurs, when cell cycle is arrested, but mTOR is still active, thus converting arrest to senescence (geroconversion). We showed that, while arresting cell cycle, UVA did not inhibit mTOR, enabling geroconversion. In UVA-treated cells, mTOR remained fully active. Rapamycin and Torins 1/ 2 prevented UVA-induced senescent phenotype, although they further re-enforced cell cycle arrest...
December 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/29311260/mtor-signaling-in-stem-and-progenitor-cells
#6
REVIEW
Delong Meng, Anderson R Frank, Jenna L Jewell
The mammalian target of rapamycin (mTOR) senses nutrients and growth factors to coordinate cell growth, metabolism and autophagy. Extensive research has mapped the signaling pathways regulated by mTOR that are involved in human diseases, such as cancer, and in diabetes and ageing. Recently, however, new studies have demonstrated important roles for mTOR in promoting the differentiation of adult stem cells, driving the growth and proliferation of stem and progenitor cells, and dictating the differentiation program of multipotent stem cell populations...
January 8, 2018: Development
https://www.readbyqxmd.com/read/29304191/short-term-low-dose-mtorc1-inhibition-in-aged-rats-counter-regulates-age-related-gene-changes-and-blocks-age-related-kidney-pathology
#7
Tea Shavlakadze, Jiang Zhu, Sharon Wang, Weihua Zhou, Bret Morin, Marc A Egerman, Lin Fan, Yanqun Wang, Oleg Iartchouk, Angelika Meyer, Reginald Valdez, Joan B Mannick, Lloyd B Klickstein, David J Glass
Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase lifespan and delay age-related phenotypes in many species. However the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6 and 24-month old rats in the kidney, liver and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle...
January 3, 2018: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
https://www.readbyqxmd.com/read/29246926/combined-active-humoral-and-cellular-immunization-approaches-for-the-treatment-of-synucleinopathies
#8
Edward Rockenstein, Gary Ostroff, Fusun Dikengil, Florentina Rus, Michael Mante, Jazmin Florio, Anthony Adame, Ivy Trinh, Changyoun Kim, Cassia Overk, Eliezer Masliah, Robert A Rissman
Dementia with Lewy bodies (DLB), Parkinson's disease (PD) and Multiple System Atrophy (MSA) are age-related neurodegenerative disorders characterized by progressive accumulation of α-synuclein (α-syn) and jointly termed synucleinopathies. Currently, no disease-modifying treatments are available for these disorders. Previous preclinical studies showed that active and passive immunizations targeting α-syn partially ameliorates behavioral deficits and α-syn accumulation; however, it is unknown if combining humoral and cellular immunization might act synergistically to reduce inflammation and improve microglial-mediated α-syn clearance...
December 15, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29228105/metformin-attenuates-susceptibility-to-inflammation-induced-preterm-birth-in-mice-with-higher-endocannabinoid-levels
#9
Xiaofei Sun, Alexandra Tavenier, Wenbo Deng, Emma Leishman, Heather B Bradshaw, Sudhansu K Dey
Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with MAPK p38 activation. Previous studies have shown that mammalian target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In the present study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways...
December 5, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29220665/mtorc1-activation-during-repeated-regeneration-impairs-somatic-stem-cell-maintenance
#10
Samantha Haller, Subir Kapuria, Rebeccah R Riley, Monique N O'Leary, Katherine H Schreiber, Julie K Andersen, Simon Melov, Jianwen Que, Thomas A Rando, Jason Rock, Brian K Kennedy, Joseph T Rodgers, Heinrich Jasper
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling...
December 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29212667/lung-tissue-gene-expression-signature-for-the-ageing-lung-in-copd
#11
Maaike de Vries, Alen Faiz, Roy R Woldhuis, Dirkje S Postma, Tristan V de Jong, Don D Sin, Yohan Bossé, David C Nickle, Victor Guryev, Wim Timens, Maarten van den Berge, Corry-Anke Brandsma
INTRODUCTION: COPD is a chronic, progressive, inflammatory disease of the lungs and the third leading cause of death worldwide. The current knowledge of the pathophysiology of COPD is limited and novel insights in underlying disease mechanisms are urgently needed. Since there are clear parallels between ageing and COPD, we investigated genes underlying lung ageing in general and abnormal lung ageing in COPD. METHODS: Whole genome mRNA profiling was performed on lung tissue samples (n=1197) and differential gene expression with increasing age was analysed using an adjusted linear regression model...
December 6, 2017: Thorax
https://www.readbyqxmd.com/read/29210174/autophagy-controls-mesenchymal-stem-cell-properties-and-senescence-during-bone-aging
#12
Yang Ma, Meng Qi, Ying An, Liqiang Zhang, Rui Yang, Daniel H Doro, Wenjia Liu, Yan Jin
Bone marrow-derived mesenchymal stem cells (BMMSCs) exhibit degenerative changes, including imbalanced differentiation and reduced proliferation during aging, that contribute to age-related bone loss. We demonstrate here that autophagy is significantly reduced in aged BMMSCs compared with young BMMSCs. The autophagy inhibitor 3-methyladenine (3-MA) could turn young BMMSCs into a relatively aged state by reducing their osteogenic differentiation and proliferation capacity and enhancing their adipogenic differentiation capacity...
December 6, 2017: Aging Cell
https://www.readbyqxmd.com/read/29208258/durability-of-sirolimus-for-lymphangioleiomyomatosis
#13
Alexandra Martirossian, Shiwan Shah, Lola Carrete, Jose Valle, Vincent Valentine
Lymphangioleiomyomatosis (LAM), a rare, multisystem disorder primarily affecting women of reproductive age, is characterized by cystic-appearing lung lesions, progressive loss of lung function, chylous effusions and renal angiomyolipomas. Sirolimus, an mammalian target of rapamycin inhibitor, has been shown to stabilize lung function, reduce symptoms and resolve chylous effusions in the short term for patients with LAM. Herein, we report a premenopausal female with LAM who experienced complete and durable resolution of her chylothoraces with significant and sustained improvement in lung function on sirolimus...
December 2017: American Journal of the Medical Sciences
https://www.readbyqxmd.com/read/29199229/mammalian-target-of-rapamycin-mtor-as-a-potential-therapeutic-target-in-pathological-ocular-angiogenesis
#14
Tsutomu Nakahara, Akane Morita, Rina Yagasaki, Asami Mori, Kenji Sakamoto
Pathological ocular angiogenesis is a causative factor of retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. Vascular endothelial growth factor (VEGF) plays an important role in pathological angiogenesis, and anti-VEGF agents have been used to treat the ocular diseases that are driven by pathological angiogenesis. However, adverse effects associated with the blockade of VEGF signaling, including impairments of normal retinal vascular growth and retinal function, were suggested...
2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29190625/mtor-as-regulator-of-lifespan-aging-and-cellular-senescence-a-mini-review
#15
Thomas Weichhart
The mechanistic target of rapamycin (mTOR) network is an evolutionary conserved signaling hub that senses and integrates environmental and intracellular nutrient and growth factor signals to coordinate basic cellular and organismal responses such as cell growth, proliferation, apoptosis, and inflammation depending on the individual cell and tissue. A growing list of evidence suggests that mTOR signaling influences longevity and aging. Inhibition of the mTOR complex 1 (mTORC1) with rapamycin is currently the only known pharmacological treatment that increases lifespan in all model organisms studied...
December 1, 2017: Gerontology
https://www.readbyqxmd.com/read/29189123/anti-aging-drugs-prospect-of-longer-life
#16
Blanka Klimova, Michal Novotny, Kamil Kuca
BACKGROUND: Aging is a natural part of human life. However, recent discoveries indicate that pharmacological approaches used for the improvement and possibly, for the delay of the aging process, might shed a new light on this topic. This might obviously contribute to the extension of the active life of older people and maintenance of their quality of life, which could consequently reduce both social and economic burden of each country, especially the developed ones. OBJECTIVE: The purpose of this study is to explore pharmacological discoveries which may help to the delay or improvement of the aging process...
November 29, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/29186112/rna-polymerase-iii-limits-longevity-downstream-of-torc1
#17
Danny Filer, Maximillian A Thompson, Vakil Takhaveev, Adam J Dobson, Ilektra Kotronaki, James W M Green, Matthias Heinemann, Jennifer M A Tullet, Nazif Alic
Three distinct RNA polymerases transcribe different classes of genes in the eukaryotic nucleus. RNA polymerase (Pol) III is the essential, evolutionarily conserved enzyme that generates short, non-coding RNAs, including tRNAs and 5S rRNA. The historical focus on transcription of protein-coding genes has left the roles of Pol III in organismal physiology relatively unexplored. Target of rapamycin kinase complex 1 (TORC1) regulates Pol III activity, and is also an important determinant of longevity. This raises the possibility that Pol III is involved in ageing...
November 29, 2017: Nature
https://www.readbyqxmd.com/read/29178390/foxo-protects-against-age-progressive-axonal-degeneration
#18
Inah Hwang, Hwanhee Oh, Evan Santo, Do-Yeon Kim, John W Chen, Roderick T Bronson, Jason W Locasale, Yoonmi Na, Jaclyn Lee, Stewart Reed, Miklos Toth, Wai H Yu, Florian L Muller, Jihye Paik
Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age-progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system-specific deletion of Foxo transcription factors in mice accelerates aging-related axonal tract degeneration, which is followed by motor dysfunction...
November 26, 2017: Aging Cell
https://www.readbyqxmd.com/read/29174969/resveratrol-modulates-response-against-acute-inflammatory-stimuli-in-aged-mouse-brain
#19
V Palomera-Ávalos, C Griñán-Ferré, V Izquierdo, A Camins, C Sanfeliu, A M Canudas, M Pallàs
With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more susceptible to infections and diseases. Here, the objective was to demonstrate the effect of dietary resveratrol in aged mice in potentiating brain defenses against LipoPolySaccharide (LPS). Acute LPS injection induced a strong proinflammatory effect in 24-months-old C57/BL6 mice hippocampi, increasing InterLeukin (Il)-6, Tumor Necrosis Factor-alpha (Tnf-α), Il-1β, and C-X-C motif chemokine (Cxcl10) gene expression levels...
November 23, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/29174818/inhibition-of-advanced-glycation-endproduct-age-rescues-against-streptozotocin-induced-diabetic-cardiomyopathy-role-of-autophagy-and-er-stress
#20
Zhaohui Pei, Qinqin Deng, Sara A Babcock, Emily Y He, Jun Ren, Yingmei Zhang
Diabetes mellitus leads to oxidative stress and contractile dysfunction in the heart. Although several rationales have been speculated, the precise mechanism behind diabetic cardiomyopathy remains elusive. This study was designed to assess the role of inhibition of advanced glycation endproducts (AGE) in streptozotocin (STZ)-induced diabetic cardiac dysfunction. Cardiac contractile function was assessed in normal C57BL/6 and STZ (200mg/kg, single injection and maintained for 2 wks)-induced diabetic mice treated with or without the AGE inhibitor aminoguanidine (50mg/kg/d in drinking water) for 2 weeks using echocardiography and IonOptix MyoCam techniques...
November 22, 2017: Toxicology Letters
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