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Aging rapamycin

Jun-Kun Zhan, Yan-Jiao Wang, Shuang Li, Yi Wang, Pan Tan, Je-Yu He, Yi-Yin Chen, Hui-Qian Deng, Wu Huang, Xiao Lin, You-Shuo Liu
Age-associated diseases, including vascular diseases, are on the rise with the increase in the aging population. However, the mechanisms of aging and age-associated vascular dysfunction remain to be fully elucidated. Replicative senescence of vascular smooth muscle cells (VSMCs) contributes to aging as well as age-associated vascular diseases. Rapamycin may delay aging-associated diseases via inhibition of the mammalian target of rapamycin (mTOR), but its role in VSMC aging has remained elusive. The present study investigated the involvement of mTOR signaling in replicative senescence of VSMCs...
December 2018: Experimental and Therapeutic Medicine
Sara Hurvitz, Rashi Singh, Brad Adams, Julie A Taguchi, David Chan, Robert A Dichmann, Aurelio Castrellon, Eddie Hu, Jonathan Berkowitz, Aruna Mani, Brian DiCarlo, Rena Callahan, Ira Smalberg, Xiaoyan Wang, Ivana Meglar, Diego Martinez, Evthokia Hobbs, Dennis J Slamon
Background: Improving outcomes for patients with human epidermal growth factor 2-positive (HER2+) central nervous system (CNS) metastases remains an unmet clinical need. This trial evaluated a novel combination of everolimus, lapatinib and capecitabine for this disease. Methods: Patients with trastuzumab-pretreated, HER2+ breast cancer brain metastasis without prior therapy with a mammalian target of rapamycin (mTOR) inhibitor were eligible. Patients received lapatinib and everolimus daily (continuously) and capecitabine twice daily (d1-14) in 21-d cycles...
2018: Therapeutic Advances in Medical Oncology
Andrzej Bartke, Nana Quainoo
Mutations of a single gene can lead to a major increase in longevity in organisms ranging from yeast and worms to insects and mammals. Discovering these mutations (sometimes referred to as "longevity genes") led to identification of evolutionarily conserved molecular, cellular, and organismal mechanisms of aging. Studies in mice provided evidence for the important role of growth hormone (GH) signaling in mammalian aging. Mice with mutations or gene deletions leading to GH deficiency or GH resistance have reduced body size and delayed maturation, but are healthier and more resistant to stress, age slower, and live longer than their normal (wild type) siblings...
2018: Frontiers in Genetics
Mikhail V Blagosklonny
Rapamycin inhibits cell proliferation, yet preserves (re)-proliferative potential (RPP). RPP is a potential of quiescent cells that is lost in senescent cells. mTOR drives conversion from quiescence to senescence (geroconversion). By suppressing geroconversion, rapamycin preserves RPP. Geroconversion is characterized by proliferation-like levels of phospho-S6K/S6/4E-BP1 in nonproliferating cells arrested by p16 and/or p21. mTOR-driven geroconversion is associated with cellular hyperfunction, which in turn leads to organismal aging manifested by age-related diseases...
December 12, 2018: Cell Cycle
Rita M Graze, Ruei-Ying Tzeng, Tiffany S Howard, Michelle N Arbeitman
BACKGROUND: The core functions of the insulin/insulin-like signaling and target of rapamycin (IIS/TOR) pathway are nutrient sensing, energy homeostasis, growth, and regulation of stress responses. This pathway is also known to interact directly and indirectly with the sex determination regulatory hierarchy. The IIS/TOR pathway plays a role in directing sexually dimorphic traits, including dimorphism of growth, metabolism, stress and behavior. Previous studies of sexually dimorphic gene expression in the adult head, which includes both nervous system and endocrine tissues, have revealed variation in sex-differential expression, depending in part on genotype and environment...
December 10, 2018: BMC Genomics
Andre L Silva, Daniéliso R Fusco, Hong S Nga, Henrique M Takase, Ariane M Bravin, Mariana M Contti, Mariana F Valiatti, Luis Gustavo M de Andrade
Background: In animal models, the mammalian target of rapamycin inhibitors (mTORIs) may prevent atherogenesis by the regulation of homeostasis of cholesterol and by a reduced inflammatory response. The aim of this study is to compare the carotid intima-media thickness (cIMT) between de novo tacrolimus/mycophenolate and tacrolimus/sirolimus at low doses. The cIMT is considered a surrogate marker of atherosclerosis. Methods: We evaluated cIMT at baseline and at 6 and 12 months after kidney transplantation in a database derived from a previously published trial...
December 2018: Clinical Kidney Journal
Qi Xu, Shimrit Uliel-Sibony, Christopher Dunham, Harvey Sarnat, Laura Flores-Sarnat, Ledia Brunga, Scott Davidson, Winnie Lo, Adam Shlien, Mary Connolly, Cyrus Boelman, Anita Datta
Hemimegalencephaly is a hamartomatous malformation of one hemisphere. Functional hemispherectomy, the definitive treatment, is associated with significant morbidity and mortality in early infancy. Dysregulation of the mTOR pathway can result in malformations of cortical development, and mTOR inhibitors can effectively reduce seizures in tuberous sclerosis complex. We report a 6-day-old female with hemimegalencephaly and frequent seizures despite 9 antiseizure medications. At 3 months of age, while awaiting hemispherectomy, an mTOR inhibitor, rapamycin, was initiated by the neurologist...
December 5, 2018: Journal of Child Neurology
Manoël Prouteau, Robbie Loewith
Metabolism is the sum of the life-giving chemical processes that occur within a cell. Proper regulation of these processes is essential for all organisms to thrive and prosper. When external factors are too extreme, or if internal regulation is corrupted through genetic or epigenetic changes, metabolic homeostasis is no longer achievable and diseases such as metabolic syndrome or cancer, aging, and, ultimately, death ensue. Metabolic reactions are catalyzed by proteins, and the in vitro kinetic properties of these enzymes have been studied by biochemists for many decades...
December 3, 2018: Biomolecules
Yongting Luo, Wenyi Xu, Guannan Li, Wei Cui
In all eukaryotes, the mechanistic target of rapamycin (mTOR) signaling emerges as a master regulator of homeostasis, which integrates environmental inputs, including nutrients, energy, and growth factors, to regulate many fundamental cellular processes such as cell growth and metabolism. mTOR signaling functions through two structurally and functionally distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which correspond to two major branches of signal output. While mTORC1 is well characterized for its structure, regulation, and function in the last decade, information of mTORC2 signaling is only rapidly expanding in recent years, from structural biology, signaling network, to functional impact...
2018: Oxidative Medicine and Cellular Longevity
Yi Huang, Yan Chen, Amanda Marie Shaw, Howard Goldfine, Junqiang Tian, Jiyang Cai
Signaling pathways mediated by the mechanistic target of rapamycin (mTOR) play key roles in aging and age-related diseases. As a downstream protein of mTOR, transcription factor EB (TFEB) controls lysosome biogenesis and cellular trafficking, processes that are essential for the functions of phagocytic cells like the retinal pigment epithelium (RPE). In the current study, we show that a naturally occurring polyphenolic compound, quercetin, promoted TFEB nuclear translocation and enhanced its transcriptional activity in cultured RPE cells...
2018: Oxidative Medicine and Cellular Longevity
Sofia D Viana, Flávio Reis, Rui Alves
The mammalian (or mechanistic) target of rapamycin (mTOR) pathway has a key role in the regulation of a variety of biological processes pivotal for cellular life, aging, and death. Impaired activity of mTOR complexes (mTORC1/mTORC2), particularly mTORC1 overactivation, has been implicated in a plethora of age-related disorders, including human renal diseases. Since the discovery of rapamycin (or sirolimus), more than four decades ago, advances in our understanding of how mTOR participates in renal physiological and pathological mechanisms have grown exponentially, due to both preclinical studies in animal models with genetic modification of some mTOR components as well as due to evidence coming from the clinical experience...
2018: Oxidative Medicine and Cellular Longevity
Jacques Hugon, François Mouton-Liger, Emmanuel Cognat, Julien Dumurgier, Claire Paquet
Alzheimer's disease (AD) is marked by memory disturbances followed by aphasia, apraxia and agnosia. Brain lesions include the accumulation of the amyloid peptide in extracellular plaques, neurofibrillary tangles with abnormally phosphorylated tau protein and synaptic and neuronal loss. New findings have suggested that brain lesions could occur one or two decades before the first clinical signs. This asymptomatic preclinical phase could be an opportunity to put in place a secondary prevention but the detection of these brain lesions can only be achieved so far by cerebrospinal fluid (CSF) evaluation or molecular amyloid and tau PET imaging...
2018: Frontiers in Aging Neuroscience
Yajun Wang, Jianxin Tan, Hongmei Du, Xue Liu, Siliang Wang, Simeng Wu, Zhe Yuan, Xike Zhu
Adipocyte deposition is believed to be a primary characteristic of age-related thymic involution. Herein, we cultured primary thymic stromal cells (TSCs), used rosiglitazone, a potent peroxisome proliferator-activated receptor γ (PPARγ) agonist, to induce adipogenic differentiation, and investigated the differentially expressed genes during adipogenic differentiation by using RNA-sequencing analysis. Furthermore, the effects of Notch1 on rosiglitazone-induced adipogenic differentiation of TSCs as well as the underlying mechanisms were also investigated...
2018: Frontiers in Pharmacology
Rie Yanagisawa, Eiko Koike, Tin-Tin Win-Shwe, Hirohisa Takano
Decabromodiphenyl ether (decaBDE) is a brominated flame retardant used in plastic and textile articles. It has become a ubiquitous environmental contaminant, however; the relationship between decaBDE and obesity remains to be elucidated. We aimed to clarify if oral decaBDE exposure can be a factor in obesity and its related metabolic dysfuctions. Male C57BL/6 J mice were fed a normal (ND, 9.0 kcal% fat) or high-fat (HFD, 62.2 kcal% fat) diet and treated with decaBDE (the equivalent of three doses of 0, 0...
November 20, 2018: Toxicology
J-H Guo, H-Y Wang, Q Zhang, M Feng, L-J Zhang
OBJECTIVE: To explore the effect of low protein diet on nonspecific inflammatory changes in mice during aging and related mechanisms. MATERIALS AND METHODS: Thirty-two 14-month-old female KM mice were randomly divided into 4 groups: control group, low protein group, high protein group, high protein + rapamycin group. Hematoxylin-eosin (HE) staining was performed to observe the pathological changes of the liver. Immunohistochemistry of liver sections was performed to detect the expression of CD68 protein...
November 2018: European Review for Medical and Pharmacological Sciences
Clara Correia-Melo, Jodie Birch, Edward Fielder, Dina Rahmatika, Jennifer Taylor, James Chapman, Anthony Lagnado, Bernadette M Carroll, Satomi Miwa, Gavin Richardson, Diana Jurk, Fiona Oakley, Jelena Mann, Derek A Mann, Viktor I Korolchuk, João F Passos
Increased activation of the major pro-inflammatory NF-κB pathway leads to numerous age-related diseases, including chronic liver disease (CLD). Rapamycin, an inhibitor of mTOR, extends lifespan and healthspan, potentially via suppression of inflammaging, a process which is partially dependent on NF-κB signalling. However, it is unknown if rapamycin has beneficial effects in the context of compromised NF-κB signalling, such as that which occurs in several age-related chronic diseases. In this study, we investigated whether rapamycin could ameliorate age-associated phenotypes in a mouse model of genetically enhanced NF-κB activity (nfκb1-/- ) characterized by low-grade chronic inflammation, accelerated aging and CLD...
November 23, 2018: Aging Cell
Oliver Hahn, Thomas M Stubbs, Wolf Reik, Sebastian Grönke, Andreas Beyer, Linda Partridge
Dietary, pharmacological and genetic interventions can extend health- and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, whole-genome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice)...
November 21, 2018: PLoS Genetics
Qing Zhang, Agnès Duplany, Vincent Moncollin, Sandrine Mouradian, Evelyne Goillot, Laetitia Mazelin, Karine Gauthier, Nathalie Streichenberger, Céline Angleraux, Jie Chen, Shuzhe Ding, Laurent Schaeffer, Yann-Gaël Gangloff
BACKGROUND: The protein kinase mechanistic target of rapamycin (mTOR) controls cellular growth and metabolism. Although balanced mTOR signalling is required for proper muscle homeostasis, partial mTOR inhibition by rapamycin has beneficial effects on various muscle disorders and age-related pathologies. Besides, more potent mTOR inhibitors targeting mTOR catalytic activity have been developed and are in clinical trials. However, the physiological impact of loss of mTOR catalytic activity in skeletal muscle is currently unknown...
November 21, 2018: Journal of Cachexia, Sarcopenia and Muscle
Patrizia A d'Alessio
In this hypothesis paper on paradoxes in preventive medicine, which also deals with the indocility of biological functions, the following issues will be addressed. First, a definition of salutogenesis will be given, providing the origin of this notion of health preservation and disease prevention. Then four paradoxes of the biology of health will be discussed. The first deals with the biomarkers of aging. The second addresses the good and bad of the much praised anti-oxidants. The third details how the mTOR (mammalian transporter of rapamycin) pathway plays a discreet but fundamental role...
November 21, 2018: Dermatologic Therapy
Jun Ren, Yingmei Zhang
Aging, an irreversible biological process, serves as an independent risk factor for chronic disease including cancer, pulmonary, neurodegenerative, and cardiovascular diseases. In particular, high morbidity and mortality have been associated with cardiovascular aging, but effective clinical therapeutic remedies are suboptimal for the ever-rising aging population. Recent evidence suggests a unique role for aberrant aggregate clearance and the protein quality control machinery - the process of autophagy - in shortened lifespan, compromised healthspan, and the onset and development of aging-associated cardiovascular diseases...
December 2018: Trends in Pharmacological Sciences
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