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Aging rapamycin

Renee King, Jessica L Hill, Bibek Saha, Yuzhen Tong, Brenda J Strutt, Mark A Russell, Noel G Morgan, Sarah J Richardson, David J Hill
Low birth weight is a risk factor for gestational and type 2 diabetes (T2D). Since mammalian target of rapamycin (mTOR) controls pancreatic β-cell mass and hormone release, we hypothesized that nutritional insult in utero might permanently alter mTOR signaling. Mice were fed a low-protein (LP, 8%) or control (C, 20%) diet throughout pregnancy, and offspring examined until 130 days age. Mice receiving LP were born 12% smaller and β-cell mass was significantly reduced throughout life. Islet mTOR levels were lower in LP-exposed mice and localized predominantly to α-rather than β-cells...
March 12, 2019: Nutrients
Justin J Reid, Melissa A Linden, Frederick F Peelor, Richard A Miller, Karyn L Hamilton, Benjamin F Miller
Treatment with the mTOR inhibitor, rapamycin (RAP), alone and in combination with the antidiabetic drug, metformin (RAP+MET), extends lifespan in mice. The mechanisms underlying lifespan extension are unclear. One possibility is improved capacity for proteostatic maintenance. We have previously characterized peripheral protein synthesis rates following treatment with RAP. However, it is unknown if RAP+MET elicits similar changes, or if either treatment affects protein synthesis in the brain. We hypothesized that 8 weeks of treatment with RAP and RAP+MET would alter brain protein synthesis rates to reflect proteostatic processes...
March 13, 2019: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Alice Barros Câmara, Igor Augusto Brandãob
BACKGROUND: Vitamin D (VD) deficiency affects individuals of different ages in many countries. VD deficiency may be related to several diseases, including cancer. OBJECTIVE: This study aimed to review the relationship between VD deficiency and cancer. METHOD: We describe the proteins involved in cancer pathogenesis and how those proteins can be influenced by VD deficiency. We also investigated a relationship between cancer death rate and solar radiation...
March 12, 2019: Anti-cancer Agents in Medicinal Chemistry
M Bugliani, S Mossuto, F Grano, M Suleiman, L Marselli, U Boggi, P De Simone, D L Eizirik, M Cnop, P Marchetti, V De Tata
Autophagy is the major mechanism involved in degradation and recycling of intracellular components, and its alterations have been proposed to cause beta cell dysfunction. In this study, we explored the effects of autophagy modulation in human islets under conditions associated to endoplasmic reticulum (ER) stress. Human pancreatic islets were isolated by enzymatic digestion and density gradient purification from pancreatic samples of non-diabetic (ND; n = 17; age 65 ± 21 years; gender: 5 M/12 F; BMI 23.4 ± 3...
2019: Frontiers in Endocrinology
Peter J Barnes, Jonathan Baker, Louise E Donnelly
Cellular senescence is now considered an important driving mechanism for chronic lung diseases, particularly COPD and idiopathic pulmonary fibrosis. Cellular senescence is due to replicative and stress-related senescence with activation of p53 and p16INK4a respectively, leading to activation of p21CIP1 and cell cycle arrest. Senescent cells secrete multiple inflammatory proteins known as the senescence-associated secretory phenotype (SASP), leading to low grade chronic inflammation, which further drives senescence...
March 12, 2019: American Journal of Respiratory and Critical Care Medicine
Shomit Sengupta, Emilie Giaime, Sridhar Narayan, Seung Hahm, Jessica Howell, David O'Neill, George P Vlasuk, Eddine Saiah
The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo...
March 11, 2019: Scientific Reports
Xiao-Lin Dong, Zhi-Wen Liu
OBJECTIVE: This study aimed to investigate the expression patterns and relationship of microtubule-associated protein 1 light chain 3 (LC3B) and mammalian target of rapamycin (mTOR) in oral leukoplakia (OLK) in smokers and never-smokers. This work also analyzed the relationship between smoking and the carcinogenic potential of OLK. METHODS: Immunohistochemistry was used to detect the expression of LC3B and mTOR in 120 patients with OLK. Clinical data from 120 smokers and never-smokers with OLK were analyzed...
February 1, 2019: Hua Xi Kou Qiang Yi Xue za Zhi, Huaxi Kouqiang Yixue Zazhi, West China Journal of Stomatology
Archana Unnikrishnan, Kavitha Kurup, Adam B Salmon, Arlan Richardson
Since the initial suggestion that rapamycin, an inhibitor of TOR nutrient signaling, increased lifespan comparable to dietary restriction, investigators have viewed rapamycin as a potential dietary restriction mimetic. Both dietary restriction and rapamycin increase lifespan across a wide range of evolutionarily diverse species (including yeast, C. elegans,Drosophila, and mice) as well as reducing pathology and improving physiological functions that decline with age in mice. The purpose of this article is to review the research comparing the effect of dietary restriction and rapamycin in mice...
March 11, 2019: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Jianjian Shi, Michelle Surma, Yang Yang, Lei Wei
In this study, we investigated the pathophysiological impact of Rho-associated coiled-coil-containing protein kinase (ROCK)1 and ROCK2 double deletion vs. single deletion on cardiac remodeling. Utilizing a cardiomyocyte-specific and tamoxifen-inducible MerCreMer recombinase (MCM), 3 mouse lines (MCM/ROCK1fl/fl /ROCK2fl/fl , MCM/ROCK1fl/fl , and MCM/ROCK2fl/fl ) were generated. As early as 5 d after inducible deletion, the double ROCK knockout hearts exhibited reduced phosphorylation of myosin light chain (MLC) and focal adhesion kinase (FAK), supporting a role for ROCK activity in regulating the nonsarcomeric cytoskeleton...
March 8, 2019: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Xiao-Yan Peng, Yong Wang, Haibo Hu, Xian-Jin Zhang, Qi Li
Coronary artery disease (CAD) is the most common type of cardiovascular disease and becomes a leading cause of death worldwide. Aiming to uncover the underlying molecular features for different types of CAD, we classified 352 CAD cases into three subgroups based on gene expression profiles, which were retrieved from the Gene Expression Omnibus database. Also, these subgroups present different expression patterns and clinical characteristics. To uncover the transcriptomic differences between the subgroups, weighted gene co-expression analysis (WGCNA) was used and identified six subgroup-specific WGCNA modules...
February 25, 2019: Journal of Cellular Physiology
Ricarda Blöte, Nima Memaran, Bianca Borchert-Mörlins, Daniela Thurn-Valsassina, Imeke Goldschmidt, Rita Beier, Martin Sauer, Carsten Müller, Giselle Sarganas, Jun Oh, Rainer Büscher, Markus J Kemper, Rizky I Sugianto, Jelena Epping, Bernhard M W Schmidt, Anette Melk
BACKGROUND: Cardiovascular (CV) comorbidity is of increasing importance after transplantation (Tx). Metabolic syndrome (MS) contributes to the risk for CV sequelae. Our aim was to assess the risk for MS in pediatric solid organ and stem cell transplant recipients by comparing them to matched untransplanted peers in a multicenter study. METHODS: We prospectively assessed MS in 295 pediatric transplant recipients and compared them to 1.475 age- and sex-matched controls...
February 19, 2019: Transplantation
Olena Kucheryavenko, Glyn Nelson, Thomas von Zglinicki, Viktor I Korolchuk, Bernadette Carroll
Cellular senescence has recently been established as a key driver of organismal ageing. The state of senescence is controlled by extensive rewiring of signalling pathways, at the heart of which lies the mammalian Target of Rapamycin Complex I (mTORC1). Here we discuss recent publications aiming to establish the mechanisms by which mTORC1 drives the senescence program. In particular, we highlight our data indicating that mTORC1 can be used as a target for senescence cell elimination in vitro. Suppression of mTORC1 is known to extend lifespan of yeast, worms, flies and some mouse models and our proof-of-concept experiments suggest that it can also act by reducing senescent cell load in vivo...
February 23, 2019: Biogerontology
Sabrina N Dumas, Dudley W Lamming
Inhibition of mTORC1 (mechanistic Target Of Rapamycin Complex 1) with the pharmaceutical rapamycin prolongs the lifespan and healthspan of model organisms including rodents, with evidence now emerging that rapamycin and its analogs may also have rejuvenative effects in dogs and humans. However, the side effects associated with long-term rapamycin treatment, many of which are due to inhibition of a second mTOR complex, mTORC2, have seemed to preclude the routine use of rapamycin as a therapy for age-related diseases...
February 22, 2019: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Francesca Chiarini, Camilla Evangelisti, Vittoria Cenni, Antonietta Fazio, Francesca Paganelli, Alberto M Martelli, Giovanna Lattanzi
The mechanistic target of rapamycin (mTOR) is a ubiquitous serine/threonine kinase that regulates anabolic and catabolic processes, in response to environmental inputs. The existence of mTOR in numerous cell compartments explains its specific ability to sense stress, execute growth signals, and regulate autophagy. mTOR signaling deregulation is closely related to aging and age-related disorders, among which progeroid laminopathies represent genetically characterized clinical entities with well-defined phenotypes...
February 15, 2019: International Journal of Molecular Sciences
Jie Li, Brandon A Kemp, Nancy L Howell, James Massey, Krzysztof Mińczuk, Qiao Huang, Mahendra D Chordia, R Jack Roy, James T Patrie, Giovanni E Davogustto, Christopher M Kramer, Frederick H Epstein, Robert M Carey, Heinrich Taegtmeyer, Susanna R Keller, Bijoy K Kundu
Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2-[18 F] fluoro-2-deoxy-D-glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts...
February 19, 2019: Journal of the American Heart Association
Wenda Wang, Hao Guo, Bing Shi, Hao Sun, Hanzhong Li, Yushi Zhang, Yi Cai
OBJECTIVE: To investigate factors influencing the volume response of everolimus and sirolimus in tuberous sclerosis complex (TSC) associated-angiomyolipomas (AML). METHODS: A retrospective analysis of 30 cases of TSC-AML treated by mTOR inhibitors (everolimus 18 cases, and sirolimus 12 cases) between April 2014 and November 2017 at our center was carried out. Epidemiological data, therapeutic response and influence factors were reviewed and analyzed. Age, sex, associated with SEGA and/or LAM or not, plasma rapamycin concentration, AML volume at baseline, and mean CT value of AML in the maximum cross-section at baseline were analyzed as potential influencing factors...
February 11, 2019: International Urology and Nephrology
Pan Tan, Haiqin Wang, Junkun Zhan, Xinyu Ma, Xingjun Cui, Yanjiao Wang, Yi Wang, Jiayu Zhong, Youshuo Liu
Vascular senescence is considered to be an independent risk factor for cardiovascular diseases. The present study aimed to investigate the effects of rapamycin on miR‑30a and its relationship with autophagy and senescence in vascular smooth muscle cells (VSMCs). Young and aging VSMCs were treated with rapamycin or transfected with miR‑30a mimics. Measurement of cellular senescence was conducted using senescence‑associated (SA)‑β‑Galactosidase (gal) staining. Dual luciferase reporter assay was used to confirm binding for miR‑30a and Beclin1...
January 23, 2019: International Journal of Molecular Medicine
Harris Bell-Temin, Matthew J Yousefzadeh, Andrey Bondarenko, Ellen Quarles, Jacqueline Jones-Laughner, Paul D Robbins, Warren Ladiges, Laura J Niedernhofer, Nathan A Yates
Aging is an ill-defined process that increases the risk of morbidity and mortality. Aging is also heterogeneous meaning that biological and chronological age can differ. Here, we used unbiased differential mass spectrometry to quantify thousands of proteins in mouse liver and select those that that consistently change in expression as mice age. A panel of 14 proteins from inbred C57BL/6 mice was used to equate chronological and biological age in this reference population, against which other mice could be compared...
February 11, 2019: Aging
Dong Liu, Liqun Xu, Xiaoyan Zhang, Changhong Shi, Shubin Qiao, Zhiqiang Ma, Jiansong Yuan
Aging may aggravate the damage and dysfunction of different components of multiorgan and thus increasing multiorgan ischemia/reperfusion (IR) injury. IR injury occurs in many organs and tissues, which is a major cause of morbidity and mortality worldwide. The kinase mammalian target of rapamycin (mTOR), an atypical serine/threonine protein kinase, involves in the pathophysiological process of IR injury. In this review, we first briefly introduce the molecular features of mTOR, the association between mTOR and aging, and especially its role on autophagy...
February 2019: Aging and Disease
Tyler A Churchward-Venne, Philippe J M Pinckaers, Joey S J Smeets, Wouter M Peeters, Antoine H Zorenc, Henk Schierbeek, Ian Rollo, Lex B Verdijk, Luc J C van Loon
Background: Protein ingestion during recovery from resistance-type exercise increases postexercise muscle protein synthesis rates. Whey protein has been reported to have greater anabolic properties than soy protein, an effect which may be attributed to the higher leucine content of whey. Objective: The objective of this study was to compare postprandial myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis rates after ingestion of carbohydrate with whey, soy, or soy protein enriched with free leucine (to match the leucine content of whey) during recovery from a single bout of concurrent resistance- and endurance-type exercise in young healthy men...
January 29, 2019: Journal of Nutrition
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