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rapamycin aging

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https://www.readbyqxmd.com/read/27906092/alterations-to-mtorc1-signaling-in-the-skeletal-muscle-differentially-affect-whole-body-metabolism
#1
Maitea Guridi, Barbara Kupr, Klaas Romanino, Shuo Lin, Denis Falcetta, Lionel Tintignac, Markus A Rüegg
BACKGROUND: The mammalian target of rapamycin complex 1 (mTORC1) is a central node in a network of signaling pathways controlling cell growth and survival. This multiprotein complex integrates external signals and affects different nutrient pathways in various organs. However, it is not clear how alterations of mTORC1 signaling in skeletal muscle affect whole-body metabolism. RESULTS: We characterized the metabolic phenotype of young and old raptor muscle knock-out (RAmKO) and TSC1 muscle knock-out (TSCmKO) mice, where mTORC1 activity in skeletal muscle is inhibited or constitutively activated, respectively...
March 21, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27902456/long-term-caloric-restriction-in-apoe-deficient-mice-results-in-neuroprotection-via-fgf21-induced-ampk-mtor-pathway
#2
Claire Rühlmann, Tjark Wölk, Tobias Blümel, Laura Stahn, Brigitte Vollmar, Angela Kuhla
Caloric restriction (CR) decelerates the aging process, extends lifespan and exerts neuroprotective effects in diverse species by so far unknown mechanisms. Based on known neuroprotective effects of fibroblastic growth factor 21 (Fgf21) we speculate that CR upregulates Fgf21, which phosphorylates neuronal AMP-activated protein kinase (AMPK), leading to a decrease of mammalian target of rapamycin (mTOR) signaling activity and an inhibition of tau-hyperphosphorylation. This in turn reduces the formation of neurofibrillary tangles, a neuropathological hallmark of Alzheimer´s disease...
November 29, 2016: Aging
https://www.readbyqxmd.com/read/27895779/potential-impact-of-mtor-inhibitors-on-cervical-squamous-cell-carcinoma-a-systematic-review
#3
Daniele Xavier Assad, Silvia Taveira Elias, Andréia Cristina Melo, Carlos Gil Ferreira, Graziela De Luca Canto, Eliete Neves Silva Guerra
The aim of the present systematic review was to analyze the potential impact of mammalian target of rapamycin (mTOR) inhibitors on the treatment of cervical squamous cell carcinoma (CSCC). A systematic literature search was conducted in PubMed, PMC, Scopus, Cochrane Library, LILACS, Web of Science, Google Scholar and ScienceDirect on January 19, 2015, without time and language restrictions. Studies that evaluated women of any age with CSCC and who received mTOR inhibitors alone or in association with other treatments were considered...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27893038/targeting-the-pi3k-akt-mtor-pathway-for-the-treatment-of-mesenchymal-triple-negative-breast-cancer-evidence-from-a-phase-1-trial-of-mtor-inhibition-in-combination-with-liposomal-doxorubicin-and-bevacizumab
#4
Reva K Basho, Michael Gilcrease, Rashmi K Murthy, Thorunn Helgason, Daniel D Karp, Funda Meric-Bernstam, Kenneth R Hess, Shelley M Herbrich, Vicente Valero, Constance Albarracin, Jennifer K Litton, Mariana Chavez-MacGregor, Nuhad K Ibrahim, James L Murray, Kimberly B Koenig, David Hong, Vivek Subbiah, Razelle Kurzrock, Filip Janku, Stacy L Moulder
Importance: Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy...
November 23, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27883166/effect-of-low-dose-rapamycin-on-senescence-markers-and-physical-functioning-in-older-adults-with-coronary-artery-disease-results-of-a-pilot-study
#5
M Singh, M D Jensen, A Lerman, S Kushwaha, C S Rihal, B J Gersh, A Behfar, T Tchkonia, R J Thomas, R J Lennon, L R Keenan, A G Moore, J L Kirkland
Rapamycin, an mTOR inhibitor affects senescence through suppression of senescence-associated secretory phenotype (SASP). We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men. Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased...
2016: Journal of Frailty & Aging
https://www.readbyqxmd.com/read/27880763/inhibition-of-mtor-induces-a-paused-pluripotent-state
#6
Aydan Bulut-Karslioglu, Steffen Biechele, Hu Jin, Trisha A Macrae, Miroslav Hejna, Marina Gertsenstein, Jun S Song, Miguel Ramalho-Santos
Cultured pluripotent stem cells are a cornerstone of regenerative medicine owing to their ability to give rise to all cell types of the body. Although pluripotent stem cells can be propagated indefinitely in vitro, pluripotency is paradoxically a transient state in vivo, lasting 2-3 days around the time of blastocyst implantation. The exception to this rule is embryonic diapause, a reversible state of suspended development triggered by unfavourable conditions. Diapause is a physiological reproductive strategy widely employed across the animal kingdom, including in mammals, but its regulation remains poorly understood...
December 1, 2016: Nature
https://www.readbyqxmd.com/read/27878332/accelerated-cardiac-rhabdomyoma-regression-with-everolimus-in-infants-with-tuberous-sclerosis-complex
#7
Fatou Aw, Isabelle Goyer, Marie-Josée Raboisson, Christine Boutin, Philippe Major, Nagib Dahdah
Tuberous sclerosis complex is associated with benign tumors such as cardiac rhabdomyomas (RHM) caused by the disinhibition of the mammalian target of rapamycin (mTOR) protein. Recent reports on everolimus, an mTOR inhibitor, have shown size reduction of RHM. We compared cases recently treated with everolimus to historic controls whose first echocardiography was within first month of life. The largest dimension of the largest RHM was reported as a percentage compared to the earliest echocardiography study. Treatment of the four cases was started at a median age of 6...
November 23, 2016: Pediatric Cardiology
https://www.readbyqxmd.com/read/27874066/cl316-243-a-%C3%AE-3-adrenergic-receptor-agonist-induces-muscle-hypertrophy-and-increased-strength
#8
Daniela Puzzo, Roberto Raiteri, Clotilde Castaldo, Raffaele Capasso, Ester Pagano, Mariateresa Tedesco, Walter Gulisano, Lisaveta Drozd, Pellegrino Lippiello, Agostino Palmeri, Pietro Scotto, Maria Concetta Miniaci
Studies in vitro have demonstrated that β3-adrenergic receptors (β3-ARs) regulate protein metabolism in skeletal muscle by promoting protein synthesis and inhibiting protein degradation. In this study, we evaluated whether activation of β3-ARs by the selective agonist CL316,243 modifies the functional and structural properties of skeletal muscles of healthy mice. Daily injections of CL316,243 for 15 days resulted in a significant improvement in muscle force production, assessed by grip strength and weight tests, and an increased myofiber cross-sectional area, indicative of muscle hypertrophy...
November 22, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27862655/mourning-dr-alfred-g-knudson-the-two-hit-hypothesis-tumor-suppressor-genes-and-the-tuberous-sclerosis-complex
#9
REVIEW
Okio Hino, Toshiyuki Kobayashi
On July 10, 2016, Alfred G. Knudson, Jr., MD, PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two-hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor-predisposing syndromes. To understand the molecular mechanism of two-hit-initiated tumorigenesis, Knudson utilized an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of Tsc2 germline mutations, the Eker rat became a model for tuberous sclerosis complex (TSC), a familial tumor-predisposing syndrome...
November 11, 2016: Cancer Science
https://www.readbyqxmd.com/read/27855118/tethering-telomerase-to-telomeres-increases-genome-instability-and-promotes-chronological-aging-in-yeast
#10
Jun Liu, Ming-Hong He, Jing Peng, Yi-Min Duan, Yi-Si Lu, Zhenfang Wu, Ting Gong, Hong-Tao Li, Jin-Qiu Zhou
Chronological aging of the yeast Saccharomyces cerevisiae is attributed to multi-faceted traits especially those involving genome instability, and has been considered to be an aging model for post-mitotic cells in higher organisms. Telomeres are the physical ends of eukaryotic chromosomes, and are essential for genome integrity and stability. It remains elusive whether dysregulated telomerase activity affects chronological aging. We employed the CDC13-EST2 fusion gene, which tethers telomerase to telomeres, to examine the effect of constitutively active telomerase on chronological lifespan (CLS)...
November 13, 2016: Aging
https://www.readbyqxmd.com/read/27852774/a-drosophila-model-of-neuronopathic-gaucher-disease-demonstrates-lysosomal-autophagic-defects-and-altered-mtor-signalling-and-is-functionally-rescued-by-rapamycin
#11
Kerri J Kinghorn, Sebastian Grönke, Jorge Iván Castillo-Quan, Nathaniel S Woodling, Li Li, Ernestas Sirka, Matthew Gegg, Kevin Mills, John Hardy, Ivana Bjedov, Linda Partridge
Glucocerebrosidase (GBA1) mutations are associated with Gaucher disease (GD), an autosomal recessive disorder caused by functional deficiency of glucocerebrosidase (GBA), a lysosomal enzyme that hydrolyzes glucosylceramide to ceramide and glucose. Neuronopathic forms of GD can be associated with rapid neurological decline (Type II) or manifest as a chronic form (Type III) with a wide spectrum of neurological signs. Furthermore, there is now a well-established link between GBA1 mutations and Parkinson's disease (PD), with heterozygote mutations in GBA1 considered the commonest genetic defect in PD...
November 16, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27837201/efficacy-and-safety-of-topical-sirolimus-therapy-for-facial-angiofibromas-in-the-tuberous-sclerosis-complex-a-randomized-clinical-trial
#12
Mari Wataya-Kaneda, Ayumi Nakamura, Mari Tanaka, Misa Hayashi, Shoji Matsumoto, Koji Yamamoto, Ichiro Katayama
Importance: Inhibitors of mammalian target of rapamycin complex 1, such as sirolimus, effectively target skin lesions in tuberous sclerosis complex (TSC). However, systemic treatment causes adverse effects, and topical sirolimus has shown promise in the treatment of facial angiofibromas. Objective: To evaluate the efficacy, safety, and optimal concentration of a topical sirolimus gel vs placebo for treatment of facial angiofibromas in TSC. Design, Setting, and Participants: A double-blind, placebo-controlled, parallel-group, dose-escalation, phase 2 randomized clinical trial using 3 sirolimus gel concentrations was performed at Osaka University Hospital, Osaka, Japan...
November 12, 2016: JAMA Dermatology
https://www.readbyqxmd.com/read/27830533/analysis-of-the-impact-of-cd200-on-phagocytosis
#13
Anthony Lyons, Aedín M Minogue, Raasay S Jones, Orla Fitzpatrick, Janis Noonan, Veronica A Campbell, Marina A Lynch
One factor that impacts on microglial activation is the interaction between the ubiquitously expressed CD200 and CD200R, which is expressed only on microglia in the brain. Decreased signalling through CD200R, when CD200 expression is reduced, results in microglial activation and may, at least in part, explain the increased cell activity that is observed with age, in models of Alzheimer's and Parkinson's disease as well as in the human diseases. There is evidence of increased microglial activation in CD200-deficient mice, and isolated microglia prepared from these mice are more reactive to inflammatory stimuli like Toll-like receptor 2 and 4 agonists, and interferon-γ...
November 9, 2016: Molecular Neurobiology
https://www.readbyqxmd.com/read/27829998/the-effects-and-mechanism-of-estrogen-on-rats-with-parkinson-s-disease-in-different-age-groups
#14
Xue-Zhong Li, Chen-Yan Sui, Qiang Chen, Yuan-Su Zhuang, Hong Zhang, Xiao-Ping Zhou
OBJECTIVE: In order to investigate the effect and mechanism of estrogen in rotenone-induced Parkinson's disease (PD) rats in different age groups. METHODS: we established rat models of PD by rotenone at different interventions. Then, behavioral tests, immunohistochemistry, western blot, high-performance liquid chromatography-electrochemical detector (HPLC-ECD) and electron microscopy were performed. RESULTS: Results revealed the following: (1) Rotenone significantly reduced rotarod latencies in senile rats, prolonged their climbing pole time, and decreased TH positive cells, DA and its metabolite, DOPAC...
2016: American Journal of Translational Research
https://www.readbyqxmd.com/read/27829242/caloric-restriction-preserves-memory-and-reduces-anxiety-of-aging-mice-with-early-enhancement-of-neurovascular-functions
#15
Ishita Parikh, Janet Guo, Kai-Hsiang Chuang, Yu Zhong, Ralf G Rempe, Jared D Hoffman, Rachel Armstrong, Björn Bauer, Anika M S Hartz, Ai-Ling Lin
Neurovascular integrity plays an important role in protecting cognitive and mental health in aging. Lifestyle interventions that sustain neurovascular integrity may thus be critical on preserving brain functions in aging and reducing the risk for age-related neurodegenerative disorders. Here we show that caloric restriction (CR) had an early effect on neurovascular enhancements, and played a critical role in preserving vascular, cognitive and mental health in aging. In particular, we found that CR significantly enhanced cerebral blood flow (CBF) and blood-brain barrier function in young mice at 5-6 months of age...
November 8, 2016: Aging
https://www.readbyqxmd.com/read/27827806/citrulline-directly-modulates-muscle-protein-synthesis-via-the-pi3k-mapk-4e-bp1-pathways-evidence-from-in-vivo-ex-vivo-and-in-vitro-studies
#16
Servane Le Plénier, Arthur Goron, Athanassia Sotiropoulos, Eliane Archambault, Chantal Guihenneuc, Stéphane Walrand, Jerome Salles, Marion Jourdan, Nathalie Neveux, Luc Cynober, Christophe Moinard
Citrulline (CIT) is an endogenous amino acid produced by the intestine. Recent literature consistently shows CIT to be an activator of muscle protein synthesis (MPS). However, the underlying mechanism is still unknown. Our working hypothesis was that CIT might regulate muscle homeostasis directly through the mTORC1/PI3K/MAPK pathways. Because CIT undergoes both inter-organ and intra-organ trafficking and metabolism, we combined three approaches: in vivo, ex vivo and in vitro. Using a model of malnourished aged rats, CIT supplementation activated the phosphorylation of S6K1 and 4E-BP1 in muscle...
November 8, 2016: American Journal of Physiology. Endocrinology and Metabolism
https://www.readbyqxmd.com/read/27825466/current-therapy-guidelines-for-waldenstrom-s-macroglobulinaemia
#17
REVIEW
Efstathios Kastritis, Meletios A Dimopoulos
Waldenstrom's macroglobulinaemia (WM) is a B-cell neoplasm in which bone marrow is infiltrated by lymphoplasmacytic cells that secrete monoclonal immunoglobulin M (IgM). More than a decade ago, specific criteria were agreed to define diagnosis and symptomatic disease requiring therapy; however, treatment recommendations change as new options emerge. Treatment decisions consider specific disease characteristics (burden of disease, IgM levels, presence of cytopenias) and patient characteristics (age, comorbidities, toxicity)...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27812983/ampk-as-a-pro-longevity-target
#18
Kristopher Burkewitz, Heather J M Weir, William B Mair
Chronic, age-associated diseases are already among the leading causes of morbidity and death in the world, a problem exacerbated by the rapidly rising proportion of elderly in the global population. This emergent epidemic represents the next great challenge for biomedical science and public health. Fortunately, decades of studies into the biology of aging have provided a head start by revealing an evolutionarily conserved network of genes that controls the rate and quality of the aging process itself and which can thereby be targeted for protection against age-onset disease...
2016: EXS
https://www.readbyqxmd.com/read/27811355/clinical-and-immunohistochemical-characteristics-of-type-ii-and-type-i-focal-cortical-dysplasia
#19
Kun Yao, Zejun Duan, Jian Zhou, Lin Li, Feng Zhai, Yanting Dong, Xiaoyan Wang, Zhong Ma, Yu Bian, Xueling Qi, Liang Li
Focal cortical dysplasia (FCD) II and I are major causes for drug-resistant epilepsy. In order to gain insight into the possible correlations between FCD II and FCD I, different clinical characteristics and immunohistochemical expression characteristics in FCD I and II were analyzed. The median age of onset and duration of epilepsy in FCD I and FCD II patients were 2.1 years and 5.3 years vs 2.4 years and 4.5 years. Therefore, the median age of onset and duration of epilepsy were similar in the two groups. Pathological lesions were predominantly located in frontal lobe in FCD II and temporal in FCD I...
November 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27798330/soy-dairy-protein-blend-or-whey-protein-isolate-ingestion-induces-similar-postexercise-muscle-mechanistic-target-of-rapamycin-complex-1-signaling-and-protein-synthesis-responses-in-older-men
#20
Michael S Borack, Paul T Reidy, Syed H Husaini, Melissa M Markofski, Rachel R Deer, Abigail B Richison, Bradley S Lambert, Mark B Cope, Ratna Mukherjea, Kristofer Jennings, Elena Volpi, Blake B Rasmussen
BACKGROUND: Previous work demonstrated that a soy-dairy protein blend (PB) prolongs hyperaminoacidemia and muscle protein synthesis in young adults after resistance exercise. OBJECTIVE: We investigated the effect of PB in older adults. We hypothesized that PB would prolong hyperaminoacidemia, enhancing mechanistic target of rapamycin complex 1 (mTORC1) signaling and muscle protein anabolism compared with a whey protein isolate (WPI). METHODS: This double-blind, randomized controlled trial studied men 55-75 y of age...
October 26, 2016: Journal of Nutrition
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