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Aging Cell

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https://www.readbyqxmd.com/read/28436203/endoplasmic-reticulum-proteostasis-impairment-in-aging
#1
REVIEW
Gabriela Martínez, Claudia Duran-Aniotz, Felipe Cabral-Miranda, Juan P Vivar, Claudio Hetz
Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function...
April 23, 2017: Aging Cell
https://www.readbyqxmd.com/read/28421666/genetic-interplay-between-human-longevity-and-metabolic-pathways-a-large-scale-eqtl-study
#2
Robert Häsler, Geetha Venkatesh, Qihua Tan, Friederike Flachsbart, Anupam Sinha, Philip Rosenstiel, Wolfgang Lieb, Stefan Schreiber, Kaare Christensen, Lene Christiansen, Almut Nebel
Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study (eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years...
April 19, 2017: Aging Cell
https://www.readbyqxmd.com/read/28401731/impact-of-early-personal-history-characteristics-on-the-pace-of-aging-implications-for-clinical-trials-of-therapies-to-slow-aging-and-extend-healthspan
#3
Daniel W Belsky, Avshalom Caspi, Harvey J Cohen, William E Kraus, Sandhya Ramrakha, Richie Poulton, Terrie E Moffitt
Therapies to extend healthspan are poised to move from laboratory animal models to human clinical trials. Translation from mouse to human will entail challenges, among them the multifactorial heterogeneity of human aging. To inform clinical trials about this heterogeneity, we report how humans' pace of biological aging relates to personal-history characteristics. Because geroprotective therapies must be delivered by midlife to prevent age-related disease onset, we studied young-adult members of the Dunedin Study 1972-73 birth cohort (n = 954)...
April 12, 2017: Aging Cell
https://www.readbyqxmd.com/read/28401730/dna-damage-and-senescence-in-osteoprogenitors-expressing-osx1-may-cause-their-decrease-with-age
#4
Ha-Neui Kim, Jianhui Chang, Lijian Shao, Li Han, Srividhya Iyer, Stavros C Manolagas, Charles A O'Brien, Robert L Jilka, Daohong Zhou, Maria Almeida
Age-related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age-dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown...
April 12, 2017: Aging Cell
https://www.readbyqxmd.com/read/28401650/caenorhabditis-elegans-orthologs-of-human-genes-differentially-expressed-with-age-are-enriched-for-determinants-of-longevity
#5
George L Sutphin, Grant Backer, Susan Sheehan, Shannon Bean, Caroline Corban, Teresa Liu, Marjolein J Peters, Joyce B J van Meurs, Joanne M Murabito, Andrew D Johnson, Ron Korstanje
We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported...
April 12, 2017: Aging Cell
https://www.readbyqxmd.com/read/28383136/age-related-decline-in-bubr1-impairs-adult-hippocampal-neurogenesis
#6
Zhongxi Yang, Heechul Jun, Chan-Ii Choi, Ki Hyun Yoo, Chang Hoon Cho, Syed Mohammed Qasim Hussaini, Ambrosia J Simmons, Seonhee Kim, Jan M van Deursen, Darren J Baker, Mi-Hyeon Jang
Aging causes significant declines in adult hippocampal neurogenesis and leads to cognitive disability. Emerging evidence demonstrates that decline in the mitotic checkpoint kinase BubR1 level occurs with natural aging and induces progeroid features in both mice and children with mosaic variegated aneuploidy syndrome. Whether BubR1 contributes to age-related deficits in hippocampal neurogenesis is yet to be determined. Here we report that BubR1 expression is significantly reduced with natural aging in the mouse brain...
April 6, 2017: Aging Cell
https://www.readbyqxmd.com/read/28371119/rapamycin-inhibits-the-secretory-phenotype-of-senescent-cells-by-a-nrf2-independent-mechanism
#7
Rong Wang, Zhen Yu, Bharath Sunchu, James Shoaf, Ivana Dang, Stephanie Zhao, Kelsey Caples, Lynda Bradley, Laura M Beaver, Emily Ho, Christiane V Löhr, Viviana I Perez
Senescent cells contribute to age-related pathology and loss of function, and their selective removal improves physiological function and extends longevity. Rapamycin, an inhibitor of mTOR, inhibits cell senescence in vitro and increases longevity in several species. Nrf2 levels have been shown to decrease with aging and silencing Nrf2 gene induces premature senescence. Therefore, we explored whether Nrf2 is involved in the mechanism by which rapamycin delays cell senescence. In wild-type (WT) mouse fibroblasts, rapamycin increased the levels of Nrf2, and this correlates with the activation of autophagy and a reduction in the induction of cell senescence, as measured by SA-β-galactosidase (β-gal) staining, senescence-associated secretory phenotype (SASP), and p16 and p21 molecular markers...
March 31, 2017: Aging Cell
https://www.readbyqxmd.com/read/28371268/aging-of-the-skeletal-muscle-extracellular-matrix-drives-a-stem-cell-fibrogenic-conversion
#8
Kristen M Stearns-Reider, Antonio D'Amore, Kevin Beezhold, Benjamin Rothrauff, Loredana Cavalli, William R Wagner, David A Vorp, Alkiviadis Tsamis, Sunita Shinde, Changqing Zhang, Aaron Barchowsky, Thomas A Rando, Rocky S Tuan, Fabrisia Ambrosio
Age-related declines in skeletal muscle regeneration have been attributed to muscle stem cell (MuSC) dysfunction. Aged MuSCs display a fibrogenic conversion, leading to fibrosis and impaired recovery after injury. Although studies have demonstrated the influence of in vitro substrate characteristics on stem cell fate, whether and how aging of the extracellular matrix (ECM) affects stem cell behavior has not been investigated. Here, we investigated the direct effect of the aged muscle ECM on MuSC lineage specification...
March 30, 2017: Aging Cell
https://www.readbyqxmd.com/read/28371013/aging-associated-dysregulation-of-homeostatic-immune-response-termination-and-not-initiation
#9
Goutham Pattabiraman, Karol Palasiewicz, John P Galvin, David S Ucker
Immunosenescence is a state of unbalanced immune responsiveness, characterized by a diverse repertoire of seemingly discreet and paradoxical alterations in all aspects of immunity arising in an aging-associated manner. We asked whether aging-associated alterations in the ability of apoptotic cells to elicit immunomodulatory responses (innate apoptotic immunity; IAI) or in IAI responses themselves might underlie the confounding aging-associated anomalies of immunosenescence. We explored this question by examining, as a function of animal age, responsiveness of murine macrophages on the single cell level...
March 30, 2017: Aging Cell
https://www.readbyqxmd.com/read/28345297/residual-cdk1-2-activity-after-dna-damage-promotes-senescence
#10
Erik Müllers, Helena Silva Cascales, Kamila Burdova, Libor Macurek, Arne Lindqvist
In response to DNA damage, a cell can be forced to permanently exit the cell cycle and become senescent. Senescence provides an early barrier against tumor development by preventing proliferation of cells with damaged DNA. By studying single cells, we show that Cdk activity persists after DNA damage until terminal cell cycle exit. This low level of Cdk activity not only allows cell cycle progression, but also promotes cell cycle exit at a decision point in G2 phase. We find that residual Cdk1/2 activity is required for efficient p21 production, allowing for nuclear sequestration of Cyclin B1, subsequent APC/C(C)(dh1) -dependent degradation of mitotic inducers and induction of senescence...
March 26, 2017: Aging Cell
https://www.readbyqxmd.com/read/28317242/chemical-screening-identifies-rock-as-a-target-for-recovering-mitochondrial-function-in-hutchinson-gilford-progeria-syndrome
#11
Hyun Tae Kang, Joon Tae Park, Kobong Choi, Hyo Jei Claudia Choi, Chul Won Jung, Gyu Ree Kim, Young-Sam Lee, Sang Chul Park
Hutchinson-Gilford progeria syndrome (HGPS) constitutes a genetic disease wherein an aging phenotype manifests in childhood. Recent studies indicate that reactive oxygen species (ROS) play important roles in HGPS phenotype progression. Thus, pharmacological reduction in ROS levels has been proposed as a potentially effective treatment for patient with this disorder. In this study, we performed high-throughput screening to find compounds that could reduce ROS levels in HGPS fibroblasts and identified rho-associated protein kinase (ROCK) inhibitor (Y-27632) as an effective agent...
March 19, 2017: Aging Cell
https://www.readbyqxmd.com/read/28317237/disruption-of-the-cx43-mir21-pathway-leads-to-osteocyte-apoptosis-and-increased-osteoclastogenesis-with-aging
#12
Hannah M Davis, Rafael Pacheco-Costa, Emily G Atkinson, Lucas R Brun, Arancha R Gortazar, Julia Harris, Masahiro Hiasa, Surajudeen A Bolarinwa, Toshiyuki Yoneda, Mircea Ivan, Angela Bruzzaniti, Teresita Bellido, Lilian I Plotkin
Skeletal aging results in apoptosis of osteocytes, cells embedded in bone that control the generation/function of bone forming and resorbing cells. Aging also decreases connexin43 (Cx43) expression in bone; and osteocytic Cx43 deletion partially mimics the skeletal phenotype of old mice. Particularly, aging and Cx43 deletion increase osteocyte apoptosis, and osteoclast number and bone resorption on endocortical bone surfaces. We examined herein the molecular signaling events responsible for osteocyte apoptosis and osteoclast recruitment triggered by aging and Cx43 deficiency...
March 19, 2017: Aging Cell
https://www.readbyqxmd.com/read/28299908/the-drugage-database-of-aging-related-drugs
#13
Diogo Barardo, Daniel Thornton, Harikrishnan Thoppil, Michael Walsh, Samim Sharifi, Susana Ferreira, Andreja Anžič, Maria Fernandes, Patrick Monteiro, Tjaša Grum, Rui Cordeiro, Evandro Araújo De-Souza, Arie Budovsky, Natali Araujo, Jan Gruber, Michael Petrascheck, Vadim E Fraifeld, Alexander Zhavoronkov, Alexey Moskalev, João Pedro de Magalhães
Aging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a curated database of lifespan-extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. Using drug-gene interaction data, we also performed a functional enrichment analysis of targets of lifespan-extending drugs...
March 16, 2017: Aging Cell
https://www.readbyqxmd.com/read/28295976/insulin-like-growth-factor-1-deficiency-exacerbates-hypertension-induced-cerebral-microhemorrhages-in-mice-mimicking-the-aging-phenotype
#14
Stefano Tarantini, Noa M Valcarcel-Ares, Andriy Yabluchanskiy, Zsolt Springo, Gabor A Fulop, Nicole Ashpole, Tripti Gautam, Cory B Giles, Jonathan D Wren, William E Sonntag, Anna Csiszar, Zoltan Ungvari
Clinical and experimental studies show that aging exacerbates hypertension-induced cerebral microhemorrhages (CMHs), which progressively impair neuronal function. There is growing evidence that aging promotes insulin-like growth factor 1 (IGF-1) deficiency, which compromises multiple aspects of cerebromicrovascular and brain health. To determine the role of IGF-1 deficiency in the pathogenesis of CMHs, we induced hypertension in mice with liver-specific knockdown of IGF-1 (Igf1(f/f)  + TBG-Cre-AAV8) and control mice by angiotensin II plus l-NAME treatment...
March 14, 2017: Aging Cell
https://www.readbyqxmd.com/read/28295945/parallel-evolution-of-genes-controlling-mitonuclear-balance-in-short-lived-annual-fishes
#15
Arne Sahm, Martin Bens, Matthias Platzer, Alessandro Cellerino
The current molecular understanding of the aging process derives almost exclusively from the study of random or targeted single-gene mutations in highly inbred laboratory species, mostly invertebrates. Little information is available as to the genetic mechanisms responsible for natural lifespan variation and the evolution of lifespan, especially in vertebrates. Here, we investigated the pattern of positive selection in annual (i.e., short-lived) and nonannual (i.e., longer-lived) African killifishes to identify a genomic substrate for evolution of annual life history (and reduced lifespan)...
March 11, 2017: Aging Cell
https://www.readbyqxmd.com/read/28266167/pathophysiology-of-heart-failure-and-frailty-a-common-inflammatory-origin
#16
REVIEW
Lavanya Bellumkonda, Daniel Tyrrell, Scott L Hummel, Daniel R Goldstein
Frailty, a clinical syndrome that typically occurs in older adults, implies a reduced ability to tolerate biological stressors. Frailty accompanies many age-related diseases but can also occur without overt evidence of end-organ disease. The condition is associated with circulating inflammatory cytokines and sarcopenia, features that are shared with heart failure (HF). However, the biological underpinnings of frailty remain unclear and the interaction with HF is complex. Here, we describe the inflammatory pathophysiology that is associated with frailty and speculate that the inflammation that occurs with frailty shares common origins with HF...
March 7, 2017: Aging Cell
https://www.readbyqxmd.com/read/28256090/sterol-regulatory-element-binding-protein-1c-orchestrates-metabolic-remodeling-of-white-adipose-tissue-by-caloric-restriction
#17
Namiki Fujii, Takumi Narita, Naoyuki Okita, Masaki Kobayashi, Yurika Furuta, Yoshikazu Chujo, Masahiro Sakai, Atsushi Yamada, Kanae Takeda, Tomokazu Konishi, Yuka Sudo, Isao Shimokawa, Yoshikazu Higami
Caloric restriction (CR) can delay onset of several age-related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR-associated metabolic remodeling of WAT remain unclear...
March 3, 2017: Aging Cell
https://www.readbyqxmd.com/read/28247585/aging-yeast-gain-a-competitive-advantage-on-non-optimal-carbon-sources
#18
Stephen Frenk, Grazia Pizza, Rachael V Walker, Jonathan Houseley
Animals, plants and fungi undergo an aging process with remarkable physiological and molecular similarities, suggesting that aging has long been a fact of life for eukaryotes and one to which our unicellular ancestors were subject. Key biochemical pathways that impact longevity evolved prior to multicellularity, and the interactions between these pathways and the aging process therefore emerged in ancient single-celled eukaryotes. Nevertheless, we do not fully understand how aging impacts the fitness of unicellular organisms, and whether such cells gain a benefit from modulating rather than simply suppressing the aging process...
March 1, 2017: Aging Cell
https://www.readbyqxmd.com/read/28229533/expansion-of-myeloid-derived-suppressor-cells-with-aging-in-the-bone-marrow-of-mice-through-a-nf-%C3%AE%C2%BAb-dependent-mechanism
#19
Rafael R Flores, Cheryl L Clauson, Joonseok Cho, Byeong-Chel Lee, Sara J McGowan, Darren J Baker, Laura J Niedernhofer, Paul D Robbins
With aging, there is progressive loss of tissue homeostasis and functional reserve, leading to an impaired response to stress and an increased risk of morbidity and mortality. A key mediator of the cellular response to damage and stress is the transcription factor NF-κB. We demonstrated previously that NF-κB transcriptional activity is upregulated in tissues from both natural aged mice and in a mouse model of a human progeroid syndrome caused by defective repair of DNA damage (ERCC1-deficient mice). We also demonstrated that genetic reduction in the level of the NF-κB subunit p65(RelA) in the Ercc1(-/∆) progeroid mouse model of accelerated aging delayed the onset of age-related pathology including muscle wasting, osteoporosis, and intervertebral disk degeneration...
February 23, 2017: Aging Cell
https://www.readbyqxmd.com/read/28185435/evidence-that-a-mitochondrial-death-spiral-underlies-antagonistic-pleiotropy
#20
REVIEW
Michael Stern
The antagonistic pleiotropy (AP) theory posits that aging occurs because alleles that are detrimental in older organisms are beneficial to growth early in life and thus are maintained in populations. Although genes of the insulin signaling pathway likely participate in AP, the insulin-regulated cellular correlates of AP have not been identified. The mitochondrial quality control process called mitochondrial autophagy (mitophagy), which is inhibited by insulin signaling, might represent a cellular correlate of AP...
February 9, 2017: Aging Cell
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