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https://www.readbyqxmd.com/read/28916781/6-bromo-indirubin-3-oxime-6bio-a-glycogen-synthase-kinase-3%C3%AE-inhibitor-activates-cytoprotective-cellular-modules-and-suppresses-cellular-senescence-mediated-biomolecular-damage-in-human-fibroblasts
#1
Aimilia D Sklirou, Nicolas Gaboriaud-Kolar, Issidora Papassideri, Alexios-Leandros Skaltsounis, Ioannis P Trougakos
As genetic interventions or extended caloric restriction cannot be applied in humans, many studies have been devoted to the identification of natural products that can prolong healthspan. 6-bromoindirubin-3'-oxime (6BIO), a hemi-synthetic derivative of indirubins found in edible mollusks and plants, is a potent inhibitor of Glycogen synthase kinase 3β (Gsk-3β). This pleiotropic kinase has been implicated in various age-related diseases including tumorigenesis, neurodegeneration and diabetes. Accordingly, 6BIO has shown anti-tumor and anti-neurodegenerative activities; nevertheless, the potential role of 6BIO in normal human cells senescence remains largely unknown...
September 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28879423/transcriptional-effects-of-apoe4-relevance-to-alzheimer-s-disease
#2
REVIEW
Veena Theendakara, Clare A Peters-Libeu, Dale E Bredesen, Rammohan V Rao
The major genetic risk factor for sporadic Alzheimer's disease (AD) is the lipid binding and transporting carrier protein apolipoprotein E, epsilon 4 allele (ApoE4). One of the unsolved mysteries of AD is how the presence of ApoE4 elicits this age-associated, currently incurable neurodegenerative disease. Recently, we showed that ApoE4 acts as a transcription factor and binds to the promoters of genes involved in a range of processes linked to aging and AD disease pathogenesis. These findings point to novel therapeutic strategies for AD and aging, resulting in an extension of human healthspan, the disease-free and functional period of life...
September 6, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28878259/promoting-drp1-mediated-mitochondrial-fission-in-midlife-prolongs-healthy-lifespan-of-drosophila-melanogaster
#3
Anil Rana, Matheus P Oliveira, Andy V Khamoui, Ricardo Aparicio, Michael Rera, Harry B Rossiter, David W Walker
The accumulation of dysfunctional mitochondria has been implicated in aging, but a deeper understanding of mitochondrial dynamics and mitophagy during aging is missing. Here, we show that upregulating Drp1-a Dynamin-related protein that promotes mitochondrial fission-in midlife, prolongs Drosophila lifespan and healthspan. We find that short-term induction of Drp1, in midlife, is sufficient to improve organismal health and prolong lifespan, and observe a midlife shift toward a more elongated mitochondrial morphology, which is linked to the accumulation of dysfunctional mitochondria in aged flight muscle...
September 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/28877458/ketogenic-diet-reduces-midlife-mortality-and-improves-memory-in-aging-mice
#4
John C Newman, Anthony J Covarrubias, Minghao Zhao, Xinxing Yu, Philip Gut, Che-Ping Ng, Yu Huang, Saptarsi Haldar, Eric Verdin
Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28877457/a-ketogenic-diet-extends-longevity-and-healthspan-in-adult-mice
#5
Megan N Roberts, Marita A Wallace, Alexey A Tomilov, Zeyu Zhou, George R Marcotte, Dianna Tran, Gabriella Perez, Elena Gutierrez-Casado, Shinichiro Koike, Trina A Knotts, Denise M Imai, Stephen M Griffey, Kyoungmi Kim, Kevork Hagopian, Fawaz G Haj, Keith Baar, Gino A Cortopassi, Jon J Ramsey, Jose Alberto Lopez-Dominguez
Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28874954/aging-molecular-pathways-and-implications-on-the-cardiovascular-system
#6
REVIEW
Arthur José Pontes Oliveira de Almeida, Thaís Porto Ribeiro, Isac Almeida de Medeiros
The world's population over 60 years is growing rapidly, reaching 22% of the global population in the next decades. Despite the increase in global longevity, individual healthspan needs to follow this growth. Several diseases have their prevalence increased by age, such as cardiovascular diseases, the leading cause of morbidity and mortality worldwide. Understanding the aging biology mechanisms is fundamental to the pursuit of cardiovascular health. In this way, aging is characterized by a gradual decline in physiological functions, involving the increased number in senescent cells into the body...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28871086/identification-of-hsp90-inhibitors-as-a-novel-class-of-senolytics
#7
Heike Fuhrmann-Stroissnigg, Yuan Yuan Ling, Jing Zhao, Sara J McGowan, Yi Zhu, Robert W Brooks, Diego Grassi, Siobhan Q Gregg, Jennifer L Stripay, Akaitz Dorronsoro, Lana Corbo, Priscilla Tang, Christina Bukata, Nadja Ring, Mauro Giacca, Xuesen Li, Tamara Tchkonia, James L Kirkland, Laura J Niedernhofer, Paul D Robbins
Aging is the main risk factor for many chronic degenerative diseases and cancer. Increased senescent cell burden in various tissues is a major contributor to aging and age-related diseases. Recently, a new class of drugs termed senolytics were demonstrated to extending healthspan, reducing frailty and improving stem cell function in multiple murine models of aging. To identify novel and more optimal senotherapeutic drugs and combinations, we established a senescence associated β-galactosidase assay as a screening platform to rapidly identify drugs that specifically affect senescent cells...
September 4, 2017: Nature Communications
https://www.readbyqxmd.com/read/28869295/the-clinical-potential-of-senolytic-drugs
#8
James L Kirkland, Tamara Tchkonia, Yi Zhu, Laura J Niedernhofer, Paul D Robbins
Senolytic drugs are agents that selectively induce apoptosis of senescent cells. These cells accumulate in many tissues with aging and at sites of pathology in multiple chronic diseases. In studies in animals, targeting senescent cells using genetic or pharmacological approaches delays, prevents, or alleviates multiple age-related phenotypes, chronic diseases, geriatric syndromes, and loss of physiological resilience. Among the chronic conditions successfully treated by depleting senescent cells in preclinical studies are frailty, cardiac dysfunction, vascular hyporeactivity and calcification, diabetes mellitus, liver steatosis, osteoporosis, vertebral disk degeneration, pulmonary fibrosis, and radiation-induced damage...
September 4, 2017: Journal of the American Geriatrics Society
https://www.readbyqxmd.com/read/28856337/neurobiological-and-systemic-effects-of-chronic-stress
#9
Bruce S McEwen
The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioral and physiological responses to the stressor, which promote adaptation ("allostasis") but also contribute to pathophysiology ("allostatic load/overload") when overused and dysregulated. The adult as well as developing brain possesses a remarkable ability to show structural and functional plasticity in response to stressful and other experiences, including neuronal replacement, dendritic remodeling and synapse turnover...
January 2017: Chronic stress
https://www.readbyqxmd.com/read/28856219/circulating-markers-of-ageing-and-allostatic-load-a-slow-train-coming
#10
Paul G Shiels, Peter Stenvinkel, Jeroen P Kooman, Dagmara McGuinness
Dealing with the growing burden of age-related morbidities is one of the greatest challenges facing modern society. How we age across the lifecourse and how psychosocial and lifestyle factors interplay with the biology of ageing remains to be fully elucidated. Sensitive and specific biomarkers with which to interrogate the biology of the ageing process are sparse. Recent evidence suggests that non-coding RNAs are key determinants of such processes and that these can be used as potential circulatory bio-markers of ageing...
April 2017: Pract Lab Med
https://www.readbyqxmd.com/read/28855418/analyses-of-selenotranscriptomes-and-selenium-concentrations-in-response-to-dietary-selenium-deficiency-and-age-reveal-common-and-distinct-patterns-by-tissue-and-sex-in-telomere-dysfunctional-mice
#11
Lei Cao, Li Zhang, Huawei Zeng, Ryan Ty Wu, Tung-Lung Wu, Wen-Hsing Cheng
Background: The hierarchies of tissue selenium distribution and selenotranscriptomes are thought to critically affect healthspan and longevity.Objective: We determined selenium status and selenotranscriptomes in response to long-term dietary selenium deficiency and age in tissues of male and female mice.Methods: Weanling telomerase RNA component knockout C57BL/6 mice were fed a selenium-deficient (0.03 mg Se/kg) Torula yeast-based AIN-93G diet or a diet supplemented with sodium selenate (0.15 mg Se/kg) until age 18 or 24 mo...
August 30, 2017: Journal of Nutrition
https://www.readbyqxmd.com/read/28844867/integrated-stress-response-stimulates-fgf21-expression-systemic-enhancer-of-longevity
#12
REVIEW
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
FGF21 is a multifunctional metabolic and stress hormone which is normally expressed in liver but cellular stress, e.g. mitochondrial or endoplasmic reticulum (ER) stress, can induce its expression and subsequent secretion from several mammalian tissues. The stress kinases of the integrated stress response (ISR) pathway stimulate the expression of FGF21 through the activation of ATF4 transcription factor, thus enhancing cellular stress resistance. The metabolic and stress-inducible transactivation mechanisms of FGF21 gene are mostly mediated through separate pathways...
August 24, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28844857/pathways-from-physical-frailty-to-activity-limitation-in-older-people-identifying-moderators-and-mediators-in-the-english-longitudinal-study-of-ageing
#13
Yew Y Ding, Jouni Kuha, Michael Murphy
Physical frailty increases the risk of future activity limitation, which in turn, compromises independent living of older people and limits their healthspan. Thus, we seek to identify moderators and mediators of the effect of physical frailty on activity limitation change in older people, including gender- and age-specific effects. In a longitudinal study using data from waves 2, 4, and 6 of the English Longitudinal Study of Ageing, unique physical frailty factor scores of 4638 respondents aged 65 to 89years are obtained from confirmatory factor analysis of physical frailty, which is specified by three indicators, namely slowness, weakness, and exhaustion...
August 26, 2017: Experimental Gerontology
https://www.readbyqxmd.com/read/28843433/hdac-inhibitors-a-new-promising-drug-class-in-anti-aging-research
#14
REVIEW
Elena G Pasyukova, Alexander M Vaiserman
In the last years, epigenetic regulation of gene expression is regarded as an important factor involved in a broad spectrum of aging-associated processes including loss of physical activity, frailty and genomic instability, and in development of various pathological conditions such as atherosclerosis, type 2 diabetes, cancer, immune deficits and neurodegenerative diseases. Accordingly, inhibitors of the members of superfamilies of histone deacetylases (HDACs) have been proposed, among other drugs targeting epigenetic pathways, as a promising type of therapeutics that is able to combat aging and its manifestations...
August 24, 2017: Mechanisms of Ageing and Development
https://www.readbyqxmd.com/read/28827345/indoles-from-commensal-bacteria-extend-healthspan
#15
Robert Sonowal, Alyson Swimm, Anusmita Sahoo, Liping Luo, Yohei Matsunaga, Ziqi Wu, Jui A Bhingarde, Elizabeth A Ejzak, Ayush Ranawade, Hiroshi Qadota, Domonica N Powell, Christopher T Capaldo, Jonathan M Flacker, Rhienallt M Jones, Guy M Benian, Daniel Kalman
Multiple studies have identified conserved genetic pathways and small molecules associated with extension of lifespan in diverse organisms. However, extending lifespan does not result in concomitant extension in healthspan, defined as the proportion of time that an animal remains healthy and free of age-related infirmities. Rather, mutations that extend lifespan often reduce healthspan and increase frailty. The question arises as to whether factors or mechanisms exist that uncouple these processes and extend healthspan and reduce frailty independent of lifespan...
August 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28826795/regulation-of-stem-cell-aging-by-metabolism-and-epigenetics
#16
REVIEW
Ruotong Ren, Alejandro Ocampo, Guang-Hui Liu, Juan Carlos Izpisua Belmonte
Stem cell aging and exhaustion are considered important drivers of organismal aging. Age-associated declines in stem cell function are characterized by metabolic and epigenetic changes. Understanding the mechanisms underlying these changes will likely reveal novel therapeutic targets for ameliorating age-associated phenotypes and for prolonging human healthspan. Recent studies have shown that metabolism plays an important role in regulating epigenetic modifications and that this regulation dramatically affects the aging process...
September 5, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28815872/a-multimethod-computational-simulation-approach-for-investigating-mitochondrial-dynamics-and-dysfunction-in-degenerative-aging
#17
Timothy E Hoffman, Katherine J Barnett, Lyle Wallis, William H Hanneman
Research in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans...
August 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/28815019/therapeutic-potential-of-systemic-brain-rejuvenation-strategies-for-neurodegenerative-disease
#18
REVIEW
Alana M Horowitz, Saul A Villeda
Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan...
2017: F1000Research
https://www.readbyqxmd.com/read/28814614/role-of-inactivity-in-chronic-diseases-evolutionary-insight-and-pathophysiological-mechanisms
#19
REVIEW
Frank W Booth, Christian K Roberts, John P Thyfault, Gregory N Ruegsegger, Ryan G Toedebusch
This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health...
October 1, 2017: Physiological Reviews
https://www.readbyqxmd.com/read/28802803/metformin-reduces-all-cause-mortality-and-diseases-of-ageing-independent-of-its-effect-on-diabetes-control-a-systematic-review-and-meta-analysis
#20
REVIEW
Jared M Campbell, Susan M Bellman, Matthew D Stephenson, Karolina Lisy
This systematic review investigated whether the insulin sensitiser metformin has a geroprotective effect in humans. Pubmed and Embase were searched along with databases of unpublished studies. Eligible research investigated the effect of metformin on all-cause mortality or diseases of ageing relative to non-diabetic populations or diabetics receiving other therapies with adjustment for disease control achieved. Overall, 260 full-texts were reviewed and 53 met the inclusion criteria. Diabetics taking metformin had significantly lower all-cause mortality than non-diabetics (hazard ratio (HR)=0...
August 10, 2017: Ageing Research Reviews
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