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ATF3 represses PINK1 gene transcription in lung epithelial cells to control mitochondrial homeostasis
Summary PINK1 (PTEN‐induced putative kinase 1) is a key regulator of mitochondrial homeostasis that is relatively depleted in aging lungs and in lung epithelial cells from patients with idiopathic pulmonary fibrosis (IPF), a disease linked with aging. Impaired PINK1 expression and accumulation of damaged mitochondria in lung epithelial cells from fibrotic lungs were associated with the presence of ER stress. Here, we show that ATF3 (activating transcription factor 3), a member of the integrated stress response (ISR), negatively regulates transcription of the PINK1 gene. An ATF3 binding site within the human PINK1 promote...
Source: Aging Cell - January 24, 2018 Category: Cytology Authors: Marta Bueno, Judith Brands, Lauren Voltz, Kaitlin Fiedler, Brenton Mays, Claudette St. Croix, John Sembrat, Rama K. Mallampalli, Mauricio Rojas, Ana L. Mora Tags: ORIGINAL ARTICLE Source Type: research

Skeletal muscle ex  vivo mitochondrial respiration parallels decline in vivo oxidative capacity, cardiorespiratory fitness, and muscle strength: The Baltimore Longitudinal Study of Aging
Summary Mitochondrial function in human skeletal muscle declines with age. Most evidence for this decline comes from studies that assessed mitochondrial function indirectly, and the impact of such deterioration with respect to physical function has not been clearly delineated. We hypothesized that mitochondrial respiration in permeabilized human muscle fibers declines with age and correlates with phosphocreatine postexercise recovery rate (kPCr), muscle performance, and aerobic fitness. Mitochondrial respiration was assessed by high‐resolution respirometry in saponin‐permeabilized fibers from vastus lateralis muscle bi...
Source: Aging Cell - January 22, 2018 Category: Cytology Authors: Marta Gonzalez ‐Freire, Paul Scalzo, Jarod D'Agostino, Zenobia A. Moore, Alberto Diaz‐Ruiz, Elisa Fabbri, Ariel Zane, Brian Chen, Kevin G. Becker, Elin Lehrmann, Linda Zukley, Chee W. Chia, Toshiko Tanaka, Paul M. Coen, Michel Bernier, Rafael Cabo, Lu Tags: ORIGINAL ARTICLE Source Type: research

T ‐cell Immunoglobulin and ITIM Domain Contributes to CD8+ T‐cell Immunosenescence
In this study, we showed that T‐cell immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif (ITIM) domain (TIGIT), a novel co‐inhibitory receptor, was upregulated in CD8+ T cells of elderly adults. Aged TIGIT+ CD8+ T cells expressed high levels of other inhibitory receptors including PD‐1 and exhibited features of exhaustion such as downregulation of the key costimulatory receptor CD28, representative intrinsic transcriptional regulation, low production of cytokines, and high susceptibility to apoptosis. Importantly, their functional defects associated with aging were reversed by TIGIT knockdown. CD226 d...
Source: Aging Cell - January 19, 2018 Category: Cytology Authors: Yangzi Song, Beibei Wang, Rui Song, Yu Hao, Di Wang, Yuxin Li, Yu Jiang, Ling Xu, Yaluan Ma, Hong Zheng, Yaxian Kong, Hui Zeng Tags: ORIGINAL ARTICLE Source Type: research

(Source: Aging Cell)
Source: Aging Cell - January 17, 2018 Category: Cytology Tags: CORRIGENDUM Source Type: research

Issue Information
(Source: Aging Cell)
Source: Aging Cell - January 17, 2018 Category: Cytology Tags: ISSUE INFORMATION Source Type: research

Senescence chips for ultrahigh ‐throughput isolation and removal of senescent cells
Summary Cellular senescence plays an important role in organismal aging and age‐related diseases. However, it is challenging to isolate low numbers of senescent cells from small volumes of biofluids for downstream analysis. Furthermore, there is no technology that could selectively remove senescent cells in a high‐throughput manner. In this work, we developed a novel microfluidic chip platform, termed senescence chip, for ultrahigh‐throughput isolation and removal of senescent cells. The core component of our senescence chip is a slanted and tunable 3D micropillar array with a variety of shutters in the vertical dire...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Yuchao Chen, Pan Mao, Antoine M. Snijders, Daojing Wang Tags: ORIGINAL ARTICLE Source Type: research

Endothelium ‐specific CYP2J2 overexpression attenuates age‐related insulin resistance
In this study, we investigated the effects of endothelium‐specific CYP2J2 overexpression on age‐related insulin resistance and metabolic dysfunction. Endothelium‐specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2‐CYP2J2‐Tr mice) was utilized. The effects of endothelium‐specific CYP2J2 overexpression on aging‐associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2‐CYP2J2‐Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in ...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Yan Yang, Ruolan Dong, Zhihui Chen, Danli Hu, Menglu Fu, Ying Tang, Dao Wen Wang, Xizhen Xu, Ling Tu Tags: ORIGINAL ARTICLE Source Type: research

The mitochondrial ATP synthase is a shared drug target for aging and dementia
Summary Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age‐associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in ...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Joshua Goldberg, Antonio Currais, Marguerite Prior, Wolfgang Fischer, Chandramouli Chiruta, Eric Ratliff, Daniel Daugherty, Richard Dargusch, Kim Finley, Pau B. Esparza ‐Moltó, José M. Cuezva, Pamela Maher, Michael Petrascheck, David Schubert Tags: ORIGINAL ARTICLE Source Type: research

UNC ‐120/SRF independently controls muscle aging and lifespan in Caenorhabditis elegans
Summary Aging is commonly defined as the loss of global homeostasis, which results from progressive alteration of all organs function. This model is currently challenged by recent data showing that interventions that extend lifespan do not always increase the overall fitness of the organism. These data suggest the existence of tissue‐specific factors that regulate the pace of aging in a cell‐autonomous manner. Here, we investigated aging of Caenorhabditis elegans striated muscles at the subcellular and the physiological level. Our data show that muscle aging is characterized by a dramatic decrease in the expression of ...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Adeline Mergoud dit Lamarche, Laurent Molin, Laura Pierson, Marie ‐Christine Mariol, Jean‐Louis Bessereau, Kathrin Gieseler, Florence Solari Tags: ORIGINAL ARTICLE Source Type: research

Circulating levels of monocyte chemoattractant protein ‐1 as a potential measure of biological age in mice and frailty in humans
Summary A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP‐1/CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 (MCP‐1) levels increased in an age‐dependent manner in wild‐type (WT) mice. That age‐dependent increase was accelerat...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Matthew J. Yousefzadeh, Marissa J. Schafer, Nicole Noren Hooten, Elizabeth J. Atkinson, Michele K. Evans, Darren J. Baker, Ellen K. Quarles, Paul D. Robbins, Warren C. Ladiges, Nathan K. LeBrasseur, Laura J. Niedernhofer Tags: ORIGINAL ARTICLE Source Type: research

Senescence promotes in  vivo reprogramming through p16INK4a and IL‐6
We report that Ink4a, but not Arf, is necessary for OSKM‐induced senescence and, thereby, for the paracrine stimulation of reprogramming. However, in the absence of p53, IL6 production and reprogramming become independent of Ink4a, as revealed by the analysis of Ink4a/Arf/p53 deficient mice. In the case of the cell cycle inhibitor p21, its protein levels are highly elevated upon OSKM activation in a p53‐independent manner, and we show that p21‐null tissues present increased levels of senescence, IL6, and reprogramming. We also report that Il6‐mutant tissues are impaired in undergoing reprogramming, thus reinforcing...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Lluc Mosteiro, Cristina Pantoja, Alba Martino, Manuel Serrano Tags: ORIGINAL ARTICLE Source Type: research

Plasticity of lifelong calorie ‐restricted C57BL/6J mice in adapting to a medium‐fat diet intervention at old age
This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine‐week‐old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitumMF feeding (CR‐MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long‐term exposure to the CR regimen, mice in the CR‐MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration ...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Fenni Rusli, Mark V. Boekschoten, Vincenzo Borelli, Chen Sun, Carolien Lute, Aswin L. Menke, Joost Heuvel, Stefano Salvioli, Claudio Franceschi, Michael M üller, Wilma T. Steegenga Tags: ORIGINAL ARTICLE Source Type: research

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin ‐like signaling pathway
In this study, we use Caenorhabditis elegans to further probe the link between lifespan and healthspan. Using movement decline as a measure of health, we assessed healthspan across the entire lifespan in nine IIS pathway mutants. In one series of experiments, we studied healthspan in mass cultures, and in another series, we studied individuals longitudinally. We found that long‐lived mutants display prolonged mid‐life movement and do not prolong the frailty period. Lastly, we observed that early‐adulthood movement was not predictive of late‐life movement or survival, within identical phenotypes. Overall, these obse...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Breanne L. Newell Stamper, James R. Cypser, Katerina Kechris, David Alan Kitzenberg, Patricia M. Tedesco, Thomas E. Johnson Tags: ORIGINAL ARTICLE Source Type: research

Autophagy controls mesenchymal stem cell properties and senescence during bone aging
In conclusion, our results suggest that autophagy plays a pivotal role in the aging of BMMSCs, and activation of autophagy could partially reverse this aging and may represent a potential therapeutic avenue to clinically treat age‐related bone loss. (Source: Aging Cell)
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Yang Ma, Meng Qi, Ying An, Liqiang Zhang, Rui Yang, Daniel H Doro, Wenjia Liu, Yan Jin Tags: ORIGINAL ARTICLE Source Type: research

Young plasma reverses age ‐dependent alterations in hepatic function through the restoration of autophagy
Summary Recent studies showing the therapeutic effect of young blood on aging‐associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging‐associated organ injuries, this study was designed to determine the effect of young blood on aging‐induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy. Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 w...
Source: Aging Cell - December 1, 2017 Category: Cytology Authors: Anding Liu, Enshuang Guo, Jiankun Yang, Yan Yang, Shenpei Liu, Xiaojing Jiang, Qi Hu, Olaf Dirsch, Uta Dahmen, Cuntai Zhang, David A Gewirtz, Haoshu Fang Tags: ORIGINAL ARTICLE Source Type: research

FOXO protects against age ‐progressive axonal degeneration
Summary Neurodegeneration resulting in cognitive and motor impairment is an inevitable consequence of aging. Little is known about the genetic regulation of this process despite its overriding importance in normal aging. Here, we identify the Forkhead Box O (FOXO) transcription factor 1, 3, and 4 isoforms as a guardian of neuronal integrity by inhibiting age‐progressive axonal degeneration in mammals. FOXO expression progressively increased in aging human and mouse brains. The nervous system‐specific deletion of Foxo transcription factors in mice accelerates aging‐related axonal tract degeneration, which is foll...
Source: Aging Cell - November 27, 2017 Category: Cytology Authors: Inah Hwang, Hwanhee Oh, Evan Santo, Do ‐Yeon Kim, John W. Chen, Roderick T. Bronson, Jason W. Locasale, Yoonmi Na, Jaclyn Lee, Stewart Reed, Miklos Toth, Wai H. Yu, Florian L. Muller, Jihye Paik Tags: ORIGINAL ARTICLE Source Type: research

17 α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior
Summary Weight loss is an effective intervention for diminishing disease burden in obese older adults. Pharmacological interventions that reduce food intake and thereby promote weight loss may offer effective strategies to reduce age‐related disease. We previously reported that 17α‐estradiol (17α‐E2) administration elicits beneficial effects on metabolism and inflammation in old male mice. These observations were associated with reduced calorie intake. Here, we demonstrate that 17α‐E2 acts through pro‐opiomelanocortin (Pomc) expression in the arcuate nucleus (ARC) to reduce food intake and body ...
Source: Aging Cell - November 23, 2017 Category: Cytology Authors: Frederik J. Steyn, Shyuan T. Ngo, Vicky Ping Chen, Lora C. Bailey ‐Downs, Teresa Y. Xie, Martin Ghadami, Stephen Brimijoin, Willard M. Freeman, Marcelo Rubinstein, Malcolm J. Low, Michael B. Stout Tags: SHORT TAKE Source Type: research

DLP1 ‐dependent mitochondrial fragmentation and redistribution mediate prion‐associated mitochondrial dysfunction and neuronal death
In this study, we investigated the role of DLP1 in mitochondrial fragmentation and dysfunction in neurons using in vitro and in vivo prion disease models. Mitochondria became fragmented and redistributed from axons to soma, correlated with increased mitochondrial DLP1 expression in murine primary neurons (N2a cells) treated with the prion peptide PrP106–126 in vitro as well as in prion strain‐infected hamster brain in vivo. Suppression of DLP1 expression by DPL1 RNAi inhibited prion‐induced mitochondrial fragmentation and dysfunction (measured by ADP/ATP ratio, mitochondrial membrane potential...
Source: Aging Cell - November 23, 2017 Category: Cytology Authors: Chaosi Li, Di Wang, Wei Wu, Wei Yang, Syed Zahid Ali Shah, Ying Zhao, Yuhan Duan, Lu Wang, Xiangmei Zhou, Deming Zhao, Lifeng Yang Tags: Original Article Source Type: research

Comparative proteomic profiling reveals a role for Cisd2 in skeletal muscle aging
Summary Skeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast‐twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlying molecular mechanism is not fully understood. Strikingly, there is a ~70% decrease in Cisd2 protein, a key regulator of lifespan in mice and the disease gene for Wolfram syndrome 2 in humans, within the gastrocnemius after middle age among mice. A proteomics approach w...
Source: Aging Cell - November 23, 2017 Category: Cytology Authors: Yi ‐Long Huang, Zhao‐Qing Shen, Chia‐Yu Wu, Yuan‐Chi Teng, Chen‐Chung Liao, Cheng‐Heng Kao, Liang‐Kung Chen, Chao‐Hsiung Lin, Ting‐Fen Tsai Tags: ORIGINAL ARTICLE Source Type: research

Cellular aging dynamics after acute malaria infection: A 12 ‐month longitudinal study
Summary Accelerated cellular aging and reduced lifespan have recently been shown in birds chronically infected with malaria parasites. Whether malaria infection also affects cellular aging in humans has not been reported. Here, we assessed the effect of a single acute Plasmodium falciparum malaria infection on cellular aging dynamics in travelers prospectively followed over one year in Sweden. DNA and RNA were extracted from venous blood collected at the time of admission and repeatedly up to one year. Telomere length was measured using real‐time quantitative PCR, while telomerase activity and CDKN2A expression were meas...
Source: Aging Cell - November 16, 2017 Category: Cytology Authors: Muhammad Asghar, Victor Yman, Manijeh Vafa Homann, Klara Sond én, Ulf Hammar, Dennis Hasselquist, Anna Färnert Tags: ORIGINAL ARTICLE Source Type: research

SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer's disease
The objective of this study was to investigate the relationship between SIRT3 and mitochondrial function and neuronal activity in AD. SIRT3 mRNA and protein levels were significantly decreased in AD cerebral cortex, and Ac‐p53 K320 was significantly increased in AD mitochondria. SIRT3 prevented p53‐induced mitochondrial dysfunction and neuronal damage in a deacetylase activity‐dependent manner. Notably, mitochondrially targeted p53 (mito‐p53) directly reduced mitochondria DNA‐encoded ND2 and ND4 gene expression resulting in increased reactive oxygen species (ROS) and reduced mitochondrial oxygen consumption....
Source: Aging Cell - November 11, 2017 Category: Cytology Authors: Junghee Lee, Yunha Kim, Tian Liu, Yu Jin Hwang, Seung Jae Hyeon, Hyeonjoo Im, Kyungeun Lee, Victor E. Alvarez, Ann C. McKee, Soo ‐Jong Um, Manwook Hur, Inhee Mook‐Jung, Neil W. Kowall, Hoon Ryu Tags: Original Article Source Type: research

Running ‐wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post‐transcriptional mechanism
Summary Loss of mitochondrial respiratory flux is a hallmark of skeletal muscle aging, contributing to a progressive decline of muscle strength. Endurance exercise alleviates the decrease in respiratory flux, both in humans and in rodents. Here, we dissect the underlying mechanism of mitochondrial flux decline by integrated analysis of the molecular network. Mice were given a lifelong ad libitum low‐fat or high‐fat sucrose diet and were further divided into sedentary and running‐wheel groups. At 6, 12, 18 and 24 months, muscle weight, triglyceride content and mitochondrial respiratory flux were analysed. Su...
Source: Aging Cell - November 9, 2017 Category: Cytology Authors: Sarah Stolle, Jolita Ciapaite, Aaffien C. Reijne, Alzbeta Talarovicova, Justina C. Wolters, Ra úl Aguirre‐Gamboa, Pieter Vlies, Kim Lange, Pieter B. Neerincx, Gerben Vries, Patrick Deelen, Morris A. Swertz, Yang Li, Rainer Bischoff, Hjalmar P. Permenti Tags: ORIGINAL ARTICLE Source Type: research

Ketone body 3 ‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina
Summary Calorie restriction (CR) being the most robust dietary intervention provides various health benefits. D‐3‐hydroxybutyrate (3HB), a major physiological ketone, has been proposed as an important endogenous molecule for CR. To investigate the role of 3HB in CR, we investigated potential shared mechanisms underlying increased retinal 3HB induced by CR and exogenously applied 3HB without CR to protect against ischemic retinal degeneration. The repeated elevation of retinal 3HB, with or without CR, suppressed retinal degeneration. Metabolomic analysis showed that the antioxidant pentose phosphate pathway and its limi...
Source: Aging Cell - November 9, 2017 Category: Cytology Authors: Yusuke Izuta, Toshihiro Imada, Ryuji Hisamura, Erina Oonishi, Shigeru Nakamura, Emi Inagaki, Masataka Ito, Tomoyoshi Soga, Kazuo Tsubota Tags: ORIGINAL ARTICLE Source Type: research

(Source: Aging Cell)
Source: Aging Cell - November 8, 2017 Category: Cytology Tags: Corrigendum Source Type: research

Issue Information
(Source: Aging Cell)
Source: Aging Cell - November 8, 2017 Category: Cytology Tags: Issue Information Source Type: research

PGC ‐1α affects aging‐related changes in muscle and motor function by modulating specific exercise‐mediated changes in old mice
Summary The age‐related impairment in muscle function results in a drastic decline in motor coordination and mobility in elderly individuals. Regular physical activity is the only efficient intervention to prevent and treat this age‐associated degeneration. However, the mechanisms that underlie the therapeutic effect of exercise in this context remain unclear. We assessed whether endurance exercise training in old age is sufficient to affect muscle and motor function. Moreover, as muscle peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α) is a key regulatory hub in endurance exerc...
Source: Aging Cell - October 25, 2017 Category: Cytology Authors: Jonathan F. Gill, Gesa Santos, Svenia Schnyder, Christoph Handschin Tags: ORIGINAL ARTICLE Source Type: research

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene ‐induced lung tumors in aged mice
Summary Aging is often accompanied by a dramatic increase in cancer susceptibility. To gain insights into how aging affects tumor susceptibility, we generated a conditional mouse model in which oncogenic KrasG12D was activated specifically in lungs of young (3–5 months) and old (19–24 months) mice. Activation of KrasG12D in old mice resulted in shorter survival and development of higher‐grade lung tumors. Six weeks after KrasG12D activation, old lung tissues contained higher numbers of adenomas than their young tissue counterparts. Lung tumors in old mice displayed higher proliferation rates, as wel...
Source: Aging Cell - October 18, 2017 Category: Cytology Authors: Neha Parikh, Ryan L. Shuck, Mihai Gagea, Lanlan Shen, Lawrence A. Donehower Tags: Original Article Source Type: research

Age ‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits
Summary Recent studies provide evidence of correlations of DNA methylation and expression of protein‐coding genes with human aging. The relations of microRNA expression with age and age‐related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole‐blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P 
Source: Aging Cell - October 17, 2017 Category: Cytology Authors: Tianxiao Huan, George Chen, Chunyu Liu, Anindya Bhattacharya, Jian Rong, Brian H. Chen, Sudha Seshadri, Kahraman Tanriverdi, Jane E. Freedman, Martin G. Larson, Joanne M. Murabito, Daniel Levy Tags: Original Article Source Type: research

Ghrelin deletion protects against age ‐associated hepatic steatosis by downregulating the C/EBPα‐p300/DGAT1 pathway
In conclusion, these studies demonstrate the mechanism by which ghrelin deletion prevents age‐associated hepatic steatosis and suggest that targeting this pathway may offer therapeutic benefit for NAFLD. (Source: Aging Cell)
Source: Aging Cell - October 12, 2017 Category: Cytology Authors: Bobby Guillory, Nicole Jawanmardi, Polina Iakova, Barbara Anderson, Pu Zang, Nikolai A. Timchenko, Jose M. Garcia Tags: Original Article Source Type: research

Interplay of pathogenic forms of human tau with different autophagic pathways
In this study, we analyzed the contribution of three different types of autophagy, macroautophagy, chaperone‐mediated autophagy, and endosomal microautophagy to the degradation of tau protein variants and tau mutations associated with this age‐related disease. We have found that the pathogenic P301L mutation inhibits degradation of tau by any of the three autophagic pathways, whereas the risk‐associated tau mutation A152T reroutes tau for degradation through a different autophagy pathway. We also found defective autophagic degradation of tau when using mutations that mimic common posttranslational modifications in ta...
Source: Aging Cell - October 12, 2017 Category: Cytology Authors: Benjamin Caballero, Yipeng Wang, Antonio Diaz, Inmaculada Tasset, Yves Robert Juste, Eva ‐Maria Mandelkow, Eckhard Mandelkow, Ana Maria Cuervo Tags: Original Article Source Type: research

Age ‐associated dysregulation of protein metabolism in the mammalian oocyte
We examined key nucleolar markers, including upstream binding transcription factor (UBTF), an RNA polymerase I cofactor, and fibrillarin, an rRNA methyltransferase. In oocytes from mice of advanced reproductive age, UBTF was primarily expressed in giant fibrillar centers (GFCs), structures associated with high levels of rDNA transcription, and fibrillarin expression was increased ~2‐fold. At the ultrastructural level, oocyte nucleoli from reproductively old mice had correspondingly more prominent fibrillar centers and dense fibrillar centers relative to young controls and more ribosomes were found in the cytoplasm. Taken...
Source: Aging Cell - October 10, 2017 Category: Cytology Authors: Francesca E. Duncan, Susmita Jasti, Ariel Paulson, John M. Kelsh, Barbara Fegley, Jennifer L. Gerton Tags: Original Article Source Type: research

Brain 5 ‐lipoxygenase over‐expression worsens memory, synaptic integrity, and tau pathology in the P301S mice
Summary Progressive accumulation of highly phosphorylated tau protein isoforms is the main feature of a group of neurodegenerative diseases collectively called tauopathies. Data from human and animal models of these diseases have shown that neuroinflammation often accompanies their pathogenesis. The 5‐lipoxygenase (5LO) is an enzyme widely expressed in the brain and a source of potent pro‐inflammatory mediators, while its pharmacological inhibition modulates the phenotype of a tau transgenic mouse model, the htau mice. By employing an adeno‐associated viral vector system to over‐express 5LO in the brain, we examine...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Alana N. Vagnozzi, Phillip F. Giannopoulos, Domenico Pratic ò Tags: Original Article Source Type: research

Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type ‐1 insulin‐like growth factor receptors in neuronal cells
Summary Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β‐amyloid (Aβ), and neuronal loss. The self‐association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aβ oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain‐derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Stefania Zimbone, Irene Monaco, Fiorenza Gian ì, Giuseppe Pandini, Agata G. Copani, Maria Laura Giuffrida, Enrico Rizzarelli Tags: Original Article Source Type: research

Sirt2 ‐BubR1 acetylation pathway mediates the effects of advanced maternal age on oocyte quality
Summary The level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age‐associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore–microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1‐K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation‐mime...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Danhong Qiu, Xiaojing Hou, Longsen Han, Xiaoyan Li, Juan Ge, Qiang Wang Tags: ORIGINAL ARTICLE Source Type: research

Influence of cell distribution and diabetes status on the association between mitochondrial DNA copy number and aging phenotypes in the InCHIANTI study
Summary Mitochondrial DNA copy number (mtDNA‐CN) estimated in whole blood is a novel marker of mitochondrial mass and function that can be used in large population‐based studies. Analyses that attempt to relate mtDNA‐CN to specific aging phenotypes may be confounded by differences in the distribution of blood cell types across samples. Also, low or high mtDNA‐CN may have a different meaning given the presence of diseases associated with mitochondrial damage. We evaluated the impact of blood cell type distribution and diabetes status on the association between mtDNA‐CN and aging phenotypes, namely chronologic age,...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Ann Zenobia Moore, Jun Ding, Marcus A. Tuke, Andrew R. Wood, Stefania Bandinelli, Timothy M. Frayling, Luigi Ferrucci Tags: Short Take Source Type: research

Anti ‐inflammaging effects of human alpha‐1 antitrypsin
Summary Inflammaging plays an important role in most age‐related diseases. However, the mechanism of inflammaging is largely unknown, and therapeutic control of inflammaging is challenging. Human alpha‐1 antitrypsin (hAAT) has immune‐regulatory, anti‐inflammatory, and cytoprotective properties as demonstrated in several disease models including type 1 diabetes, arthritis, lupus, osteoporosis, and stroke. To test the potential anti‐inflammaging effect of hAAT, we generated transgenic Drosophila lines expressing hAAT. Surprisingly, the lifespan of hAAT‐expressing lines was significantly longer than that of geneti...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Ye Yuan, Benedetto DiCiaccio, Ying Li, Ahmed S. Elshikha, Denis Titov, Brian Brenner, Lee Seifer, Hope Pan, Nurdina Karic, Mohammad A. Akbar, Yuanqing Lu, Sihong Song, Lei Zhou Tags: Original Article Source Type: research

Human CD8+ EMRA T cells display a senescence ‐associated secretory phenotype regulated by p38 MAPK
Summary Cellular senescence is accompanied by a senescence‐associated secretory phenotype (SASP). We show here that primary human senescent CD8+ T cells also display a SASP comprising chemokines, cytokines and extracellular matrix remodelling proteases that are unique to this subset and contribute to age‐associated inflammation. We found the CD8+ CD45RA+CD27− EMRA subset to be the most heterogeneous, with a population aligning with the naïve T cells and another with a closer association to the effector memory subset. However, despite the differing processes that give rise to these senescent CD8+ T cells once...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Lauren A. Callender, Elizabeth C. Carroll, Robert W. J. Beal, Emma S. Chambers, Sussan Nourshargh, Arne N. Akbar, Sian M. Henson Tags: Original Article Source Type: research

In vivo properties of the disaggregase function of J ‐proteins and Hsc70 in Caenorhabditis elegans stress and aging
Summary Protein aggregation is enhanced upon exposure to various stress conditions and aging, which suggests that the quality control machinery regulating protein homeostasis could exhibit varied capacities in different stages of organismal lifespan. Recently, an efficient metazoan disaggregase activity was identified in vitro, which requires the Hsp70 chaperone and Hsp110 nucleotide exchange factor, together with single or cooperating J‐protein co‐chaperones of classes A and B. Here, we describe how the orthologous Hsp70s and J‐protein of Caenorhabditis elegans work together to resolve protein aggregates both i...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Janine Kirstein, Kristin Arnsburg, Annika Scior, Anna Szlachcic, D. Lys Guilbride, Richard I. Morimoto, Bernd Bukau, Nadinath B. Nillegoda Tags: Original Article Source Type: research

Sirtuins at the crossroads of stemness, aging, and cancer
Summary Sirtuins are stress‐responsive proteins that direct various post‐translational modifications (PTMs) and as a result, are considered to be master regulators of several cellular processes. They are known to both extend lifespan and regulate spontaneous tumor development. As both aging and cancer are associated with altered stem cell function, the possibility that the involvement of sirtuins in these events is mediated by their roles in stem cells is worthy of investigation. Research to date suggests that the individual sirtuin family members can differentially regulate embryonic, hematopoietic as well as other ad...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Carol O'Callaghan, Athanassios Vassilopoulos Tags: Review Source Type: research

Loss of SIRT2 leads to axonal degeneration and locomotor disability associated with redox and energy imbalance
Summary Sirtuin 2 (SIRT2) is a member of a family of NAD+‐dependent histone deacetylases (HDAC) that play diverse roles in cellular metabolism and especially for aging process. SIRT2 is located in the nucleus, cytoplasm, and mitochondria, is highly expressed in the central nervous system (CNS), and has been reported to regulate a variety of processes including oxidative stress, genome integrity, and myelination. However, little is known about the role of SIRT2 in the nervous system specifically during aging. Here, we show that middle‐aged, 13‐month‐old mice lacking SIRT2 exhibit locomotor dysfunction due to axonal ...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: St éphane Fourcade, Laia Morató, Janani Parameswaran, Montserrat Ruiz, Tatiana Ruiz‐Cortés, Mariona Jové, Alba Naudí, Paloma Martínez‐Redondo, Mara Dierssen, Isidre Ferrer, Francesc Villarroya, Reinald Pamplona, Alejandro Vaquero, Manel Portero Tags: Original Article Source Type: research

Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice
Summary Normal aging is characterized with a decline in hippocampal memory functions that is associated with changes in long‐term potentiation (LTP) of the CA3‐to‐CA1 synapse. Age‐related deficit of the dopaminergic system may contribute to impairment of CA1 LTP. Here we assessed how the modulation of CA1 LTP by dopamine is affected by aging and how it is dependent on the Ca2+ source. In slices from adult mice, the initial slope of the field potential showed strong LTP, but in slices from aged mice LTP was impaired. Dopamine did not affect LTP in adult slices, but enhanced LTP in aged slices. The dopamine D1/D5 rec...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Fangli Guo, Jianhua Zhao, Dandan Zhao, Jiangang Wang, Xiaofang Wang, Zhiwei Feng, Martin Vreugdenhil, Chengbiao Lu Tags: Original Article Source Type: research

TOR ‐mediated regulation of metabolism in aging
Summary Cellular metabolism is regulated by the mTOR kinase, a key component of the molecular nutrient sensor pathway that plays a central role in cellular survival and aging. The mTOR pathway promotes protein and lipid synthesis and inhibits autophagy, a process known for its contribution to longevity in several model organisms. The nutrient‐sensing pathway is regulated at the lysosomal membrane by a number of proteins for which deficiency triggers widespread aging phenotypes in tested animal models. In response to environmental cues, this recently discovered lysosomal nutrient‐sensing complex regulates autophagy tran...
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Henri Antikainen, Monica Driscoll, Gal Haspel, Radek Dobrowolski Tags: Review Source Type: research

miR ‐155 induces ROS generation through downregulation of antioxidation‐related genes in mesenchymal stem cells
In conclusion, our study suggests that miR‐155 is an important mediator connecting aging, inflammation, and ROS generation in stem cells. (Source: Aging Cell)
Source: Aging Cell - October 1, 2017 Category: Cytology Authors: Yuta Onodera, Takeshi Teramura, Toshiyuki Takehara, Kayoko Obora, Tatsufumi Mori, Kanji Fukuda Tags: Original Article Source Type: research

MicroRNAs mir ‐184 and let‐7 alter Drosophila metabolism and longevity
Summary MicroRNAs (miRNAs) are small RNA molecules that regulate gene expression associated with many complex biological processes. By comparing miRNA expression between long‐lived cohorts of Drosophila melanogaster that were fed a low‐nutrient diet with normal‐lived control animals fed a high‐nutrient diet, we identified miR‐184, let‐7, miR‐125, and miR‐100 as candidate miRNAs involved in modulating aging. We found that ubiquitous, adult‐specific overexpression of these individual miRNAs led to significant changes in fat metabolism and/or lifespan. Most impressively, adult‐specific overexpression of le...
Source: Aging Cell - September 30, 2017 Category: Cytology Authors: Christi M. Gendron, Scott D. Pletcher Tags: Short Take Source Type: research

Caloric restriction stabilizes body weight and accelerates behavioral recovery in aged rats after focal ischemia
In conclusion, our study shows that recovery from stroke is enhanced in aged rats by a dietary regimen that reduces body weight prior to infarct. (Source: Aging Cell)
Source: Aging Cell - September 29, 2017 Category: Cytology Authors: Ovidiu Ciobanu, Raluca Elena Sandu, Adrian Tudor Balseanu, Alexandra Zavaleanu, Andrei Gresita, Eugen Bogdan Petcu, Adriana Uzoni, Aurel Popa ‐Wagner Tags: Original Article Source Type: research

Sexually divergent DNA methylation patterns with hippocampal aging
Summary DNA methylation is a central regulator of genome function, and altered methylation patterns are indicative of biological aging and mortality. Age‐related cellular, biochemical, and molecular changes in the hippocampus lead to cognitive impairments and greater vulnerability to neurodegenerative disease that varies between the sexes. The role of hippocampal epigenomic changes with aging in these processes is unknown as no genome‐wide analyses of age‐related methylation changes have considered the factor of sex in a controlled animal model. High‐depth, genome‐wide bisulfite sequencing of young (3 month)...
Source: Aging Cell - September 26, 2017 Category: Cytology Authors: Dustin R. Masser, Niran Hadad, Hunter L. Porter, Colleen A. Mangold, Archana Unnikrishnan, Matthew M. Ford, Cory B. Giles, Constantin Georgescu, Mikhail G. Dozmorov, Jonathan D. Wren, Arlan Richardson, David R. Stanford, Willard M. Freeman Tags: Original Article Source Type: research

Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span
Summary The shelterin complex protects telomeres by preventing them from being degraded and recognized as double‐strand DNA breaks. TRF1 is an essential component of shelterin, with important roles in telomere protection and telomere replication. We previously showed that TRF1 deficiency in the context of different mouse tissues leads to loss of tissue homeostasis owing to impaired stem cell function. Here, we show that TRF1 levels decrease during organismal aging both in mice and in humans. We further show that increasing TRF1 expression in both adult (1‐year‐old) and old (2‐year‐old) mice using gene therapy can...
Source: Aging Cell - September 25, 2017 Category: Cytology Authors: Aksinya Derevyanko, Kurt Whittemore, Ralph P. Schneider, Ver ónica Jiménez, Fàtima Bosch, Maria A. Blasco Tags: Original Article Source Type: research

Transthyretin deposition promotes progression of osteoarthritis
Summary Deposition of amyloid is a common aging‐associated phenomenon in several aging‐related diseases. Osteoarthritis (OA) is the most prevalent joint disease, and aging is its major risk factor. Transthyretin (TTR) is an amyloidogenic protein that is deposited in aging and OA‐affected human cartilage and promotes inflammatory and catabolic responses in cultured chondrocytes. Here, we investigated the role of TTR in vivo using transgenic mice overexpressing wild‐type human TTR (hTTR‐TG). Although TTR protein was detected in cartilage in hTTR‐TG mice, the TTR transgene was highly overexpressed in liver, b...
Source: Aging Cell - September 23, 2017 Category: Cytology Authors: Tokio Matsuzaki, Yukio Akasaki, Merissa Olmer, Oscar Alvarez ‐Garcia, Natalia Reixach, Joel N. Buxbaum, Martin K. Lotz Tags: Original Article Source Type: research

Genetic interaction with temperature is an important determinant of nematode longevity
Summary As in other poikilotherms, longevity in C. elegans varies inversely with temperature; worms are longer‐lived at lower temperatures. While this observation may seem intuitive based on thermodynamics, the molecular and genetic basis for this phenomenon is not well understood. Several recent reports have argued that lifespan changes across temperatures are genetically controlled by temperature‐specific gene regulation. Here, we provide data that both corroborate those studies and suggest that temperature‐specific longevity is more the rule than the exception. By measuring the lifespans of worms with single ...
Source: Aging Cell - September 22, 2017 Category: Cytology Authors: Hillary Miller, Marissa Fletcher, Melissa Primitivo, Alison Leonard, George L. Sutphin, Nicholas Rintala, Matt Kaeberlein, Scott F. Leiser Tags: Short Take Source Type: research

In a randomized trial in prostate cancer patients, dietary protein restriction modifies markers of leptin and insulin signaling in plasma extracellular vesicles
Summary Obesity, metabolic syndrome, and hyperleptinemia are associated with aging and age‐associated diseases including prostate cancer. One experimental approach to inhibit tumor growth is to reduce dietary protein intake and hence levels of circulating amino acids. Dietary protein restriction (PR) increases insulin sensitivity and suppresses prostate cancer cell tumor growth in animal models, providing a rationale for clinical trials. We sought to demonstrate that biomarkers derived from plasma extracellular vesicles (EVs) reflect systemic leptin and insulin signaling and respond to dietary interventions. We studied p...
Source: Aging Cell - September 18, 2017 Category: Cytology Authors: Erez Eitan, Valeria Tosti, Caitlin N. Suire, Edda Cava, Sean Berkowitz, Beatrice Bertozzi, Sophia M. Raefsky, Nicola Veronese, Ryan Spangler, Francesco Spelta, Maja Mustapic, Dimitrios Kapogiannis, Mark P. Mattson, Luigi Fontana Tags: Short Take Source Type: research