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https://www.readbyqxmd.com/read/29165314/towards-natural-mimetics-of-metformin-and-rapamycin
#1
Alexander Aliper, Leslie Jellen, Franco Cortese, Artem Artemov, Darla Karpinsky-Semper, Alexey Moskalev, Andrew G Swick, Alex Zhavoronkov
Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects...
November 15, 2017: Aging
https://www.readbyqxmd.com/read/29141215/octopamine-drives-endurance-exercise-adaptations-in-drosophila
#2
Alyson Sujkowski, Divya Ramesh, Axel Brockmann, Robert Wessells
Endurance exercise is an effective therapeutic intervention with substantial pro-healthspan effects. Male Drosophila respond to a ramped daily program of exercise by inducing conserved physiological responses similar to those seen in mice and humans. Female flies respond to an exercise stimulus but do not experience the adaptive training response seen in males. Here, we use female flies as a model to demonstrate that differences in exercise response are mediated by differences in neuronal activity. The activity of octopaminergic neurons is specifically required to induce the conserved cellular and physiological changes seen following endurance training...
November 14, 2017: Cell Reports
https://www.readbyqxmd.com/read/29135455/transcriptome-wide-association-study-of-inflammatory-biologic-age
#3
Honghuang Lin, Kathryn L Lunetta, Qiang Zhao, Jian Rong, Emelia J Benjamin, Michael M Mendelson, Roby Joehanes, Daniel Levy, Martin G Larson, Joanne M Murabito
Chronic low grade inflammation is a fundamental mechanism of aging. We estimated biologic age using nine biomarkers from diverse inflammatory pathways and we hypothesized that genes associated with inflammatory biological age would provide insights into human aging. In Framingham Offspring Study participants at examination 8 (2005 to 2008), we used the Klemera-Doubal method to estimate inflammatory biologic age and we computed the difference (∆Age) between biologic age and chronologic age. Gene expression in whole blood was measured using the Affymetrix Human Exon 1...
November 11, 2017: Aging
https://www.readbyqxmd.com/read/29133780/o-glcnacylation-of-sirt1-enhances-its-deacetylase-activity-and-promotes-cytoprotection-under-stress
#4
Cuifang Han, Yuchao Gu, Hui Shan, Wenyi Mi, Jiahui Sun, Minghui Shi, Xinling Zhang, Xinzhi Lu, Feng Han, Qianhong Gong, Wengong Yu
SIRT1 is the most evolutionarily conserved mammalian sirtuin, and it plays a vital role in the regulation of metabolism, stress responses, genome stability, and ageing. As a stress sensor, SIRT1 deacetylase activity is significantly increased during stresses, but the molecular mechanisms are not yet fully clear. Here, we show that SIRT1 is dynamically modified with O-GlcNAc at Ser 549 in its carboxy-terminal region, which directly increases its deacetylase activity both in vitro and in vivo. The O-GlcNAcylation of SIRT1 is elevated during genotoxic, oxidative, and metabolic stress stimuli in cellular and mouse models, thereby increasing SIRT1 deacetylase activity and protecting cells from stress-induced apoptosis...
November 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29125735/resveratrol-exerts-antioxidant-effects-by-activating-sirt2-to-deacetylate-prx1
#5
Yanchao Pan, Hua Zhang, Yueting Zheng, Juanzuo Zhou, Jing Yuan, Yang Yu, Jiangyun Wang
Resveratrol is a promising chemical agent that treats multiple aging-related diseases and improves healthspan. While reactive oxygen species (ROS) undoubtedly play ubiquitous roles in the aging process and resveratrol has been shown to be an effective antioxidant, the mechanism through which resveratrol acts against oxidative stress remains unknown. Here we show that resveratrol activates Sirt2 to deacetylate Prx1, leading to increased H2O2 reduction activity and decreased cellular H2O2 concentration. Knockdown of Sirt2 or Prx1 by RNA interference abrogates resveratrol's ability to reduce H2O2 level in HepG2 cells...
November 10, 2017: Biochemistry
https://www.readbyqxmd.com/read/29117555/mitochondrial-stress-restores-the-heat-shock-response-and-prevents-proteostasis-collapse-during-aging
#6
Johnathan Labbadia, Renee M Brielmann, Mario F Neto, Yi-Fan Lin, Cole M Haynes, Richard I Morimoto
In Caenorhabditis elegans, the programmed repression of the heat shock response (HSR) accompanies the transition to reproductive maturity, leaving cells vulnerable to environmental stress and protein aggregation with age. To identify the factors driving this event, we performed an unbiased genetic screen for suppressors of stress resistance and identified the mitochondrial electron transport chain (ETC) as a central regulator of the age-related decline of the HSR and cytosolic proteostasis. Mild downregulation of ETC activity, either by genetic modulation or exposure to mitochondria-targeted xenobiotics, maintained the HSR in adulthood by increasing HSF-1 binding and RNA polymerase II recruitment at HSF-1 target genes...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/29117554/downregulation-of-the-apelinergic-axis-accelerates-aging-whereas-its-systemic-restoration-improves-the-mammalian-healthspan
#7
Rahul Rai, Asish K Ghosh, Mesut Eren, Alexander R Mackie, Daniel C Levine, So-Youn Kim, Jonathan Cedernaes, Veronica Ramirez, Daniele Procissi, Layton H Smith, Teresa K Woodruff, Joseph Bass, Douglas E Vaughan
Aging drives the occurrence of numerous diseases, including cardiovascular disease (CVD). Recent studies indicate that blood from young mice reduces age-associated pathologies. However, the "anti-aging" factors in juvenile circulation remain poorly identified. Here, we characterize the role of the apelinergic axis in mammalian aging and identify apelin as an anti-aging factor. The expression of apelin (apln) and its receptor (aplnr) exhibits an age-dependent decline in multiple organs. Reduced apln signaling perturbs organismal homeostasis; mice harboring genetic deficiency of aplnr or apln exhibit enhanced cardiovascular, renal, and reproductive aging...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/29107505/system-wide-benefits-of-intermeal-fasting-by-autophagy
#8
Nuria Martinez-Lopez, Elena Tarabra, Miriam Toledo, Marina Garcia-Macia, Srabani Sahu, Luisa Coletto, Ana Batista-Gonzalez, Nir Barzilai, Jeffrey E Pessin, Gary J Schwartz, Sander Kersten, Rajat Singh
Autophagy failure is associated with metabolic insufficiency. Although caloric restriction (CR) extends healthspan, its adherence in humans is poor. We established an isocaloric twice-a-day (ITAD) feeding model wherein ITAD-fed mice consume the same food amount as ad libitum controls but at two short windows early and late in the diurnal cycle. We hypothesized that ITAD feeding will provide two intervals of intermeal fasting per circadian period and induce autophagy. We show that ITAD feeding modifies circadian autophagy and glucose/lipid metabolism that correlate with feeding-driven changes in circulating insulin...
October 24, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/29106993/the-role-of-cellular-senescence-in-aging-through-the-prism-of-koch-like-criteria
#9
REVIEW
Hagai Yanai, Vadim E Fraifeld
Since Hayflick's discovery of cellular senescence (CS), a great volume of knowledge in the field has been accumulated and intensively discussed. Here, we attempted to organize the evidence "for" and "against" the hypothesized causal role of CS in aging. For that purpose, we utilized robust Koch-like logical criteria, based on the assumption that some quantitative relationships between the accumulation of senescent cells and aging rate should exist. If so, it could be expected that (i) the "CS load" would be greater in the premature aging phenotype and lesser in longevity phenotype; (ii) CS would promote age-related diseases, and (iii) the interventions that modulate the levels of senescent cells should also modulate health/lifespan...
October 26, 2017: Ageing Research Reviews
https://www.readbyqxmd.com/read/29078414/twenty-five-years-of-mtor-uncovering-the-link-from-nutrients-to-growth
#10
David M Sabatini
In my PNAS Inaugural Article, I describe the development of the mTOR field, starting with efforts to understand the mechanism of action of the drug rapamycin, which ∼25 y ago led to the discovery of the mTOR protein kinase. I focus on insights that we have contributed and on work that has been particularly influential to me, as well as provide some personal reflections and stories. We now appreciate that, as part of two distinct complexes, mTORC1 and mTORC2, mTOR is the major regulator of growth (mass accumulation) in animals and is the key link between the availability of nutrients in the environment and the control of most anabolic and catabolic processes...
November 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29055022/the-addition-of-a-developmental-factor-unc-62-to-already-long-lived-worms-increases-lifespan-and-healthspan
#11
Dror Sagi
Aging is a complex trait that is affected by multiple genetic pathways. A relatively unexplored approach is to manipulate multiple independent aging pathways simultaneously in order to observe their cumulative effect on lifespan. Here, we report the phenotypic characterization of a strain with changes in five aging pathways: 1) mitochondrial ROS production, 2) innate immunity, 3) stress response, 4) metabolic control and 5) developmental regulation in old age. The quintuply-modified strain has a lifespan that is 160% longer than the transgenic control strain...
October 20, 2017: Biology Open
https://www.readbyqxmd.com/read/29054535/adipose-tissue-inflammation-in-aging
#12
REVIEW
Theresa Mau, Raymond Yung
Adipose tissue has traditionally been viewed as an organ of interest within studies of obesity and diet-associated metabolic disorders. However, as studies reveal the role white adipose tissue plays as an energy storage, a lipid metabolism site, and an adipokine secretor, it has become recognized as an organ of importance for metabolic health in both the young obese and the old obese. Within the realms of aging research, the pursuit of senolytics has taken the field's spotlight, where the clearance of senescent cells has shown to attenuate aspects of age-related disorders...
October 18, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/29043007/amino-acid-supplements-and-metabolic-health-a-potential-interplay-between-intestinal-microbiota-and-systems-control
#13
REVIEW
Francesco Bifari, Chiara Ruocco, Ilaria Decimo, Guido Fumagalli, Alessandra Valerio, Enzo Nisoli
Dietary supplementation of essential amino acids (EAAs) has been shown to promote healthspan. EAAs regulate, in fact, glucose and lipid metabolism and energy balance, increase mitochondrial biogenesis, and maintain immune homeostasis. Basic science and epidemiological results indicate that dietary macronutrient composition affects healthspan through multiple and integrated mechanisms, and their effects are closely related to the metabolic status to which they act. In particular, EAA supplementation can trigger different and even opposite effects depending on the catabolic and anabolic states of the organisms...
2017: Genes & Nutrition
https://www.readbyqxmd.com/read/29030550/a-conserved-klf-autophagy-pathway-modulates-nematode-lifespan-and-mammalian-age-associated-vascular-dysfunction
#14
Paishiun N Hsieh, Guangjin Zhou, Yiyuan Yuan, Rongli Zhang, Domenick A Prosdocimo, Panjamaporn Sangwung, Anna H Borton, Evgenii Boriushkin, Anne Hamik, Hisashi Fujioka, Ciaran E Fealy, John P Kirwan, Maureen Peters, Yuan Lu, Xudong Liao, Diana Ramírez-Bergeron, Zhaoyang Feng, Mukesh K Jain
Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes. Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models...
October 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29028112/the-role-of-declining-adaptive-homeostasis-in-ageing
#15
Laura C D Pomatto, Kelvin J A Davies
Adaptive homeostasis is, 'the transient expansion or contraction of the homeostatic range for any given physiological parameter in response to exposure to sub-toxic, non-damaging, signalling molecules or events, or the removal or cessation of such molecules or events (Davies, 2016a)." Adaptive homeostasis enables biological systems to make continuous short-term adjustments for optimal functioning despite ever-changing internal and external environments. Initiation of adaptation in response to an appropriate signal allows organisms to successfully cope with much greater, normally toxic, stresses...
October 13, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/29027899/metformin-extends-c-elegans-lifespan-through-lysosomal-pathway
#16
Jie Chen, Yuhui Ou, Yi Li, Shumei Hu, Li-Wa Shao, Ying Liu
Metformin, a widely used first-line drug for treatment of type 2 diabetes (T2D), has been shown to extend lifespan and delay the onset of age-related diseases. However, its primary locus of action remains unclear. Using a pure in vitro reconstitution system, we demonstrate that metformin acts through the v-ATPase-Ragulator lysosomal pathway to coordinate mTORC1 and AMPK, two hubs governing metabolic programs. We further show in Caenorhabditis elegans that both v-ATPase-mediated TORC1 inhibition and v-ATPase-AXIN/LKB1-mediated AMPK activation contribute to the lifespan extension effect of metformin...
October 13, 2017: ELife
https://www.readbyqxmd.com/read/29020626/uncoupling-of-metabolic-health-from-longevity-through-genetic-alteration-of-adipose-tissue-lipid-binding-proteins
#17
Khanichi N Charles, Min-Dian Li, Feyza Engin, Ana Paula Arruda, Karen Inouye, Gökhan S Hotamisligil
Deterioration of metabolic health is a hallmark of aging and generally assumed to be detrimental to longevity. Exposure to a high-calorie diet impairs metabolism and accelerates aging; conversely, calorie restriction (CR) prevents age-related metabolic diseases and extends lifespan. However, it is unclear whether preservation of metabolic health is sufficient to extend lifespan. We utilized a genetic mouse model lacking Fabp4/5 that confers protection against metabolic diseases and shares molecular and lipidomic features with CR to address this question...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28978421/dietary-carbohydrates-impair-healthspan-and-promote-mortality
#18
Meenakshi Ravichandran, Gerald Grandl, Michael Ristow
The prospective cohort study, named PURE, found that in >135,000 participants from 18 countries, nutritive carbohydrates increase human mortality, whereas dietary fat reduces it, requesting a fundamental change of current nutritional guidelines. Experimental evidence from animal models provides synergizing mechanistic concepts as well as pharmacological options to mimic low-carb or ketogenic diets.
October 3, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28970255/dietary-methionine-restriction-modulates-renal-response-and-attenuates-kidney-injury-in-mice
#19
Diana Cooke, Amadou Ouattara, Gene P Ables
Methionine restriction (MR) extends the lifespan across several species, such as rodents, fruit flies, roundworms, and yeast. MR studies have been conducted on various rodent organs, such as liver, adipose tissue, heart, bones, and skeletal muscle, to elucidate its benefits to the healthspan; however, studies of the direct effect of MR on kidneys are lacking. To investigate the renal effects of MR, we used young and aged unilateral nephrectomized and 5/6 nephrectomized (5/6Nx) mice. Our studies indicated that MR mice experienced polydipsia and polyuria compared with control-fed counterparts...
September 28, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28952131/dynamic-changes-in-p66shc-mrna-expression-in-peripheral-blood-mononuclear-cells-following-resistance-training-intervention-in-old-frail-women-born-to-obese-mothers-a-pilot-study
#20
Alessandra Berry, Marco Bucci, Carla Raggi, Johan G Eriksson, Maria Angela Guzzardi, Pirjo Nuutila, Ville Huovinen, Patricia Iozzo, Francesca Cirulli
The p66Shc gerontogene may affect healthspan by promoting fat accumulation. We assessed changes of p66Shc-mRNA in peripheral tissues in relation to maternal obesity and the moderating effects of resistance-training (RT) exercise in elderly frail women. Thirty-seven women participated in a 4-month RT program. Twenty were offspring of lean/normal weight mothers and 17 were offspring of overweight/obese mothers (OOM). P66Shc was assessed in peripheral blood mononuclear cells (PBMC) and in subcutaneous adipose tissue (SAT) before and after RT...
September 26, 2017: Aging Clinical and Experimental Research
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