当前期刊: Aging Cell Go to current issue    加入关注   
显示样式:        排序: 导出
我的关注
我的收藏
您暂时未登录!
登录
  • Metformin mediates cardioprotection against aging‐induced ischemic necroptosis
    Aging Cell (IF 7.346) Pub Date : 2020-01-14
    Chen Li; Nan Mu; Chunhu Gu; Manling Liu; Zheng Yang; Yue Yin; Mai Chen; Yishi Wang; Yuehu Han; Lu Yu; Heng Ma
    更新日期:2020-01-15
  • The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina
    Aging Cell (IF 7.346) Pub Date : 2020-01-14
    Daniel Chen; Daniel L. Chao; Lorena Rocha; Matthew Kolar; Viet Anh Nguyen Huu; Michal Krawczyk; Manish Dasyani; Tina Wang; Maryam Jafari; Mary Jabari; Kevin D. Ross; Alan Saghatelian; Bruce A. Hamilton; Kang Zhang; Dorota Skowronska‐Krawczyk
    更新日期:2020-01-14
  • Acarbose improved survival for Apc+/Min mice
    Aging Cell (IF 7.346) Pub Date : 2020-01-06
    Sherry G. Dodds; Manish Parihar; Martin Javors; Jia Nie; Nicolas Musi; Zelton Dave Sharp; Paul Hasty
    更新日期:2020-01-06
  • Intrinsically altered lung‐resident γδT cells control lung melanoma by producing interleukin‐17A in the elderly
    Aging Cell (IF 7.346) Pub Date : 2020-01-05
    Min Cheng; Yongyan Chen; Dake Huang; Wen Chen; Weiping Xu; Yin Chen; Guodong Shen; Tingjuan Xu; Gan Shen; Zhigang Tian; Shilian Hu
    更新日期:2020-01-06
  • 1,25‐Dihydroxyvitamin D protects against age‐related osteoporosis by a novel VDR‐Ezh2‐p16 signal axis
    Aging Cell (IF 7.346) Pub Date : 2019-12-26
    Renlei Yang; Jie Chen; Jiao Zhang; Ran Qin; Rong Wang; Yue Qiu; Zhiyuan Mao; David Goltzman; Dengshun Miao
    更新日期:2019-12-27
  • Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension
    Aging Cell (IF 7.346) Pub Date : 2019-12-22
    Lorena Raquel Rocha; Viet Anh Nguyen Huu; Claudia Palomino La Torre; Qianlan Xu; Mary Jabari; Michal Krawczyk; Robert N. Weinreb; Dorota Skowronska‐Krawczyk
    更新日期:2019-12-23
  • A small molecule transcription factor EB activator ameliorates beta‐amyloid precursor protein and Tau pathology in Alzheimer's disease models
    Aging Cell (IF 7.346) Pub Date : 2019-12-19
    Ju‐Xian Song; Sandeep Malampati; Yu Zeng; Siva Sundara Kumar Durairajan; Chuan‐Bin Yang; Benjamin Chun‐Kit Tong; Ashok Iyaswamy; Wen‐Bin Shang; Sravan Gopalkrishnashetty Sreenivasmurthy; Zhou Zhu; King‐Ho Cheung; Jia‐Hong Lu; Chunzhi Tang; Nenggui Xu; Min Li
    更新日期:2019-12-20
  • Hdac3, Setdb1, and Kap1 mark H3K9me3/H3K14ac bivalent regions in young and aged liver
    Aging Cell (IF 7.346) Pub Date : 2019-12-19
    Andrew J. Price; Mohan C. Manjegowda; Jessica Kain; Swetha Anandh; Irina M. Bochkis
    更新日期:2019-12-20
  • A genome‐wide screen identifies genes that suppress the accumulation of spontaneous mutations in young and aged yeast cells
    Aging Cell (IF 7.346) Pub Date : 2019-12-18
    Daniele Novarina; Georges E. Janssens; Koen Bokern; Tim Schut; Noor C. van Oerle; Hinke G. Kazemier; Liesbeth M. Veenhoff; Michael Chang
    更新日期:2019-12-19
  • Prolonged quiescence delays somatic stem cell‐like divisions in Caenorhabditis elegans and is controlled by insulin signaling
    Aging Cell (IF 7.346) Pub Date : 2019-12-18
    María Olmedo; Alejandro Mata‐Cabana; María Jesús Rodríguez‐Palero; Sabas García‐Sánchez; Antonio Fernández‐Yañez; Martha Merrow; Marta Artal‐Sanz
    更新日期:2019-12-19
  • Compromised steady‐state germinal center activity with age in nonhuman primates
    Aging Cell (IF 7.346) Pub Date : 2019-12-15
    Kimberly Shankwitz; Suresh Pallikkuth; Tirupataiah Sirupangi; Daniel Kirk Kvistad; Kyle Blaine Russel; Rajendra Pahwa; Lucio Gama; Richard A. Koup; Li Pan; Francois Villinger; Savita Pahwa; Constantinos Petrovas
    更新日期:2019-12-17
  • Measuring biological aging in humans: A quest
    Aging Cell (IF 7.346) Pub Date : 2019-12-12
    Luigi Ferrucci; Marta Gonzalez‐Freire; Elisa Fabbri; Eleanor Simonsick; Toshiko Tanaka; Zenobia Moore; Shabnam Salimi; Felipe Sierra; Rafael de Cabo
    更新日期:2019-12-13
  • Maf1‐dependent transcriptional regulation of tRNAs prevents genomic instability and is associated with extended lifespan
    Aging Cell (IF 7.346) Pub Date : 2019-12-12
    Mihir Shetty; Chiaki Noguchi; Sydney Wilson; Esteban Martinez; Kazuhiro Shiozaki; Christian Sell; Joshua Chang Mell; Eishi Noguchi
    更新日期:2019-12-13
  • Progerin in muscle leads to thermogenic and metabolic defects via impaired calcium homeostasis
    Aging Cell (IF 7.346) Pub Date : 2019-12-12
    Wan‐Ping Wang; Jing‐Ya Wang; Wen‐Hsin Lin; Cheng‐Heng Kao; Ming‐Chun Hung; Yuan‐Chi Teng; Ting‐Fen Tsai; Ya‐Hui Chi
    更新日期:2019-12-13
  • Rapamycin persistently improves cardiac function in aged, male and female mice, even following cessation of treatment
    Aging Cell (IF 7.346) Pub Date : 2019-12-10
    Ellen Quarles, Nathan Basisty, Ying Ann Chiao, Gennifer Merrihew, Haiwei Gu, Mariya T. Sweetwyne, Jeanne Fredrickson, Ngoc‐Han Nguyen, Maria Razumova, Kristina Kooiker, Farid Moussavi‐Harami, Michael Regnier, Christopher Quarles, Michael MacCoss, Peter S. Rabinovitch
    更新日期:2019-12-11
  • Cellular senescence and chronological age in various human tissues: A systematic review and meta‐analysis
    Aging Cell (IF 7.346) Pub Date : 2019-12-05
    Camilla S. L. Tuttle, Mariette E. C. Waaijer, Monique S. Slee‐Valentijn, Theo Stijnen, Rudi Westendorp, Andrea B. Maier
    更新日期:2019-12-06
  • Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease
    Aging Cell (IF 7.346) Pub Date : 2019-12-04
    Jiyeon Lee, Do‐Eun Kim, Percy Griffin, Patrick W. Sheehan, Dong‐Hou Kim, Erik S Musiek, Seung‐Yong Yoon
    更新日期:2019-12-04
  • Base excision repair but not DNA double‐strand break repair is impaired in aged human adipose‐derived stem cells
    Aging Cell (IF 7.346) Pub Date : 2019-11-29
    Haiping Zhang, Bailian Cai, Anke Geng, Huanyin Tang, Wenjun Zhang, Sheng Li, Ying Jiang, Rong Tan, Xiaoping Wan, Zhiyong Mao
    更新日期:2019-11-30
  • CHIP modulates APP‐induced autophagy‐dependent pathological symptoms in Drosophila
    Aging Cell (IF 7.346) Pub Date : 2019-11-28
    Luming Zhuang, Fei Peng, Yuanyuan Huang, Wenzhe Li, Jiuhong Huang, Yunqiang Chu, Pu Ren, Ying Sun, Yan Zhang, Elleen Xue, Xiaowei Guo, Xiafeng Shen, Lei Xue
    更新日期:2019-11-29
  • Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression
    Aging Cell (IF 7.346) Pub Date : 2019-11-26
    Yao Dang, Yongpan An, Jinzhao He, Boyue Huang, Jie Zhu, Miaomiao Gao, Shun Zhang, Xin Wang, Baoxue Yang, Zhengwei Xie
    更新日期:2019-11-28
  • Osmolyte transporter expression is reduced in photoaged human skin: Implications for skin hydration in aging
    Aging Cell (IF 7.346) Pub Date : 2019-11-26
    April R. Foster, Cecile El Chami, Catherine A. O'Neill, Rachel E. B. Watson
    更新日期:2019-11-27
  • Proteostasis failure and cellular senescence in long‐term cultured postmitotic rat neurons
    Aging Cell (IF 7.346) Pub Date : 2019-11-25
    Shoma Ishikawa, Fuyuki Ishikawa

    Cellular senescence, a stress‐induced irreversible cell cycle arrest, has been defined for mitotic cells and is implicated in aging of replicative tissues. Age‐related functional decline in the brain is often attributed to a failure of protein homeostasis (proteostasis), largely in postmitotic neurons, which accordingly is a process distinct by definition from senescence. It is nevertheless possible that proteostasis failure and cellular senescence have overlapping molecular mechanisms. Here, we identify postmitotic cellular senescence as an adaptive stress response to proteostasis failure. Primary rat hippocampal neurons in long‐term cultures show molecular changes indicative of both senescence (senescence‐associated β‐galactosidase, p16, and loss of lamin B1) and proteostasis failure relevant to Alzheimer's disease. In addition, we demonstrate that the senescent neurons exhibit resistance to stress. Importantly, treatment of the cultures with an mTOR antagonist, protein synthesis inhibitor, or chemical compound that reduces the amount of protein aggregates relieved the proteotoxic stresses as well as the appearance of senescence markers. Our data propose mechanistic insights into the pathophysiological brain aging by establishing senescence as a primary cell‐autonomous neuroprotective response.

    更新日期:2019-11-26
  • MicroRNA‐188 regulates aging‐associated metabolic phenotype
    Aging Cell (IF 7.346) Pub Date : 2019-11-25
    Yan Huang, Ye Xiao, Ya Liu, Min Guo, Qi Guo, Fangliang Zhou, Ting Liu, Tian Su, Yuzhong Xiao, Xiang‐Hang Luo

    With the increasing aging population, aging‐associated diseases are becoming epidemic worldwide, including aging‐associated metabolic dysfunction. However, the underlying mechanisms are poorly understood. In the present study, we aimed to investigate the role of microRNA miR‐188 in the aging‐associated metabolic phenotype. The results showed that the expression of miR‐188 increased gradually in brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) of mice during aging. MiR‐188 knockout mice were resistant to the aging‐associated metabolic phenotype and had higher energy expenditure. Meanwhile, adipose tissue‐specific miR‐188 transgenic mice displayed the opposite phenotype. Mechanistically, we identified the thermogenic‐related gene Prdm16 (encoding PR domain containing 16) as the direct target of miR‐188. Notably, inhibition of miR‐188 expression in BAT and iWAT of aged mice by tail vein injection of antagomiR‐188 ameliorated aging‐associated metabolic dysfunction significantly. Taken together, our findings suggested that miR‐188 plays an important role in the regulation of the aging‐associated metabolic phenotype, and targeting miR‐188 could be an effective strategy to prevent aging‐associated metabolic dysfunction.

    更新日期:2019-11-26
  • Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models
    Aging Cell (IF 7.346) Pub Date : 2019-11-25
    Heesun Choi, Haeng Jun Kim, Jinhee Yang, Sehyun Chae, Wonik Lee, Sunwoo Chung, Jisoo Kim, Hyunjung Choi, Hyeseung Song, Chang Kon Lee, Jae Hyun Jun, Yong Jae Lee, Kyunghyeon Lee, Semi Kim, Hye‐ri Sim, Young Il Choi, Keun Ho Ryu, Jong‐Chan Park, Dongjoon Lee, Sun‐Ho Han, Daehee Hwang, Jangbeen Kyung, Inhee Mook‐Jung

    Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLPAPT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLPAPT mice.

    更新日期:2019-11-26
  • Extra virgin olive oil improves synaptic activity, short‐term plasticity, memory, and neuropathology in a tauopathy model
    Aging Cell (IF 7.346) Pub Date : 2019-11-24
    Elisabetta Lauretti, Miroslav Nenov, Ozlem Dincer, Luigi Iuliano, Domenico Praticò

    In recent years, increasing evidence has accumulated supporting the health benefits of extra virgin olive oil (EVOO). Previous studies showed that EVOO supplementation improves Alzheimer's disease (AD)‐like amyloidotic phenotype of transgenic mice. However, while much attention has been focused on EVOO‐mediated modulation of Aβ processing, its direct influence on tau metabolism in vivo and synaptic function is still poorly characterized. In this study, we investigated the effect of chronic supplementation of EVOO on the phenotype of a relevant mouse model of tauopathy, human transgenic tau mice (hTau). Starting at 6 months of age, hTau mice were fed chow diet supplemented with EVOO or vehicle for additional 6 months, and then the effect on their phenotype was assessed. At the end of the treatment, compared with control mice receiving EVOO displayed improved memory and cognition which was associated with increased basal synaptic activity and short‐term plasticity. This effect was accompanied by an upregulation of complexin 1, a key presynaptic protein. Moreover, EVOO treatment resulted in a significant reduction of tau oligomers and phosphorylated tau at specific epitopes. Our findings demonstrate that EVOO directly improves synaptic activity, short‐term plasticity, and memory while decreasing tau neuropathology in the hTau mice. These results strengthen the healthy benefits of EVOO and further support the therapeutic potential of this natural product not only for AD but also for primary tauopathies.

    更新日期:2019-11-26
  • Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging‐associated tumorigenesis induced by ultraviolet B
    Aging Cell (IF 7.346) Pub Date : 2019-11-21
    Wen‐Li Hsu, Ming‐Hsien Tsai, Ching‐Ying Wu, Jui‐Lin Liang, Jian‐He Lu, Jennifer S. Kahle, Hsin‐Su Yu, Chia‐Jung Yen, Chen‐Tung Yen, Yi‐Chun Hsieh, Yung‐Yun Huang, Li‐Ching Lin, Tsung‐Fu Tsai, Chu‐Huang Chen, Tohru Yoshioka
    更新日期:2019-11-22
  • Short‐term interleukin‐37 treatment improves vascular endothelial function, endurance exercise capacity, and whole‐body glucose metabolism in old mice
    Aging Cell (IF 7.346) Pub Date : 2019-11-21
    Dov B. Ballak, Vienna E. Brunt, Zachary J. Sapinsley, Brian P. Ziemba, James J. Richey, Melanie C. Zigler, Lawrence C. Johnson, Rachel A. Gioscia‐Ryan, Rachel Culp‐Hill, Elan Z. Eisenmesser, Angelo D'Alessandro, Charles A. Dinarello, Douglas R. Seals
    更新日期:2019-11-22
  • Decreased pericellular matrix production and selection for enhanced cell membrane repair may impair osteocyte responses to mechanical loading in the aging skeleton
    Aging Cell (IF 7.346) Pub Date : 2019-11-19
    Mackenzie L. Hagan, Kanglun Yu, Jiali Zhu, Brooke N. Vinson, Rachel L. Roberts, Marlian Montesinos Cartagena, Maribeth H. Johnson, Liyun Wang, Carlos M. Isales, Mark W. Hamrick, Paul L. McNeil, Meghan E. McGee‐Lawrence
    更新日期:2019-11-20
  • Rap1‐mediated nucleosome displacement can regulate gene expression in senescent cells without impacting the pace of senescence
    Aging Cell (IF 7.346) Pub Date : 2019-11-19
    Shufei Song, Javier V. Perez, William Svitko, M. Daniel Ricketts, Elliot Dean, David Schultz, Ronen Marmorstein, F. Brad Johnson
    更新日期:2019-11-20
  • Global metabolic profiling to model biological processes of aging in twins
    Aging Cell (IF 7.346) Pub Date : 2019-11-19
    Bryan J. Bunning, Kévin Contrepois, Brittany Lee‐McMullen, Gopal Krishna R. Dhondalay, Wenming Zhang, Dana Tupa, Olivia Raeber, Manisha Desai, Kari C. Nadeau, Michael P. Snyder, Sandra Andorf
    更新日期:2019-11-20
  • Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin
    Aging Cell (IF 7.346) Pub Date : 2019-11-18
    Dong Eun Kim, Martijn E. T. Dollé, Wilbert P. Vermeij, Akos Gyenis, Katharina Vogel, Jan H. J. Hoeijmakers, Christopher D. Wiley, Albert R. Davalos, Paul Hasty, Pierre‐Yves Desprez, Judith Campisi
    更新日期:2019-11-18
  • Amelioration of age‐related brain function decline by Bruton's tyrosine kinase inhibition
    Aging Cell (IF 7.346) Pub Date : 2019-11-17
    Akang E. Ekpenyong‐Akiba, Marta Poblocka, Mohammad Althubiti, Miran Rada, Diana Jurk, Sandra Germano, Gabriella Kocsis‐Fodor, Yu Shi, Juan J. Canales, Salvador Macip
    更新日期:2019-11-18
  • Age‐dependent DNA methylation patterns on the Y chromosome in elderly males
    Aging Cell (IF 7.346) Pub Date : 2019-02-21
    Jesper B. Lund, Shuxia Li, Kaare Christensen, Jonas Mengel‐From, Mette Soerensen, Riccardo E. Marioni, John Starr, Alison Pattie, Ian J. Deary, Jan Baumbach, Qihua Tan

    The Y chromosome, a sex chromosome that only exists in males, has been ignored in traditional epigenetic association studies for multiple reasons. However, sex differences in aging‐related phenotypes and mortality could suggest a critical role of the sex chromosomes in the aging process. We obtained blood‐based DNA methylation data on the Y chromosome for 624 men from four cohorts and performed a chromosome‐wide epigenetic association analysis to detect Y‐linked CpGs differentially methylated over age and cross‐validated the significant CpGs in the four cohorts. We identified 40–219 significant CpG sites (false discovery rate <0.05) with >82% of them hypermethylated with increasing age, which is in strong contrast to the patterns reported on the autosomal chromosomes. Comparing the rate of change in the Y‐linked DNA methylation across cohorts that represent different age intervals revealed a trend of acceleration in DNA methylation with increasing age. The age‐dependent DNA methylation patterns on the Y chromosome were further examined for their association with all‐cause mortality with results suggesting that the predominant pattern of age‐related hypermethylation on the Y chromosome is associated with reduced risk of death.

    更新日期:2019-11-18
  • Functional microbiome deficits associated with ageing: Chronological age threshold
    Aging Cell (IF 7.346) Pub Date : 2019-11-15
    Susana Ruiz‐Ruiz, Sergio Sanchez‐Carrillo, Sergio Ciordia, María C. Mena, Celia Méndez‐García, David Rojo, Rafael Bargiela, Elisa Zubeldia‐Varela, Mónica Martínez‐Martínez, Coral Barbas, Manuel Ferrer, Andrés Moya
    更新日期:2019-11-15
  • Longevity in response to lowered insulin signaling requires glycine N‐methyltransferase‐dependent spermidine production
    Aging Cell (IF 7.346) Pub Date : 2019-11-13
    Luke S. Tain, Chirag Jain, Tobias Nespital, Jenny Froehlich, Yvonne Hinze, Sebastian Grönke, Linda Partridge
    更新日期:2019-11-13
  • Lysophosphatidic acid receptor LPA3 prevents oxidative stress and cellular senescence in Hutchinson–Gilford progeria syndrome
    Aging Cell (IF 7.346) Pub Date : 2019-11-12
    Wei‐Min Chen, Jui‐Chung Chiang, Yueh‐Chien Lin, Yu‐Nung Lin, Pei‐Yun Chuang, Ya‐Chi Chang, Chien‐Chin Chen, Kao‐Yi Wu, Jung‐Chien Hsieh, Shih‐Kuo Chen, Wei‐Pang Huang, Benjamin P. C. Chen, Hsinyu Lee
    更新日期:2019-11-13
  • Corrupted ER‐mitochondrial calcium homeostasis promotes the collapse of proteostasis
    Aging Cell (IF 7.346) Pub Date : 2019-11-12
    Zahra Ashkavand, Shaarika Sarasija, Kerry C. Ryan, Jocelyn T. Laboy, Kenneth R. Norman
    更新日期:2019-11-13
  • mTOR drives cerebrovascular, synaptic, and cognitive dysfunction in normative aging
    Aging Cell (IF 7.346) Pub Date : 2019-11-06
    Candice E. Van Skike, Ai‐Ling Lin, Raquel Roberts Burbank, Jonathan J. Halloran, Stephen F. Hernandez, James Cuvillier, Vanessa Y. Soto, Stacy A. Hussong, Jordan B. Jahrling, Martin A. Javors, Matthew J. Hart, Kathleen E. Fischer, Steven N. Austad, Veronica Galvan
    更新日期:2019-11-07
  • Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice
    Aging Cell (IF 7.346) Pub Date : 2019-11-06
    Qiyu Tian, Junxing Zhao, Qiyuan Yang, Bo Wang, Jeanene M. Deavila, Mei-Jun Zhu, Min Du
    更新日期:2019-11-06
  • A tissue‐specific screen of ceramide expression in aged mice identifies ceramide synthase‐1 and ceramide synthase‐5 as potential regulators of fiber size and strength in skeletal muscle
    Aging Cell (IF 7.346) Pub Date : 2019-11-06
    Bettina Tosetti, Susanne Brodesser, Anna Brunn, Martina Deckert, Matthias Blüher, Wolfram Doehner, Stefan D. Anker, Daniela Wenzel, Bernd Fleischmann, Carola Pongratz, Franziska Peters, Olaf Utermöhlen, Martin Krönke
    更新日期:2019-11-06
  • Tau inhibits PKA by nuclear proteasome‐dependent PKAR2α elevation with suppressed CREB/GluA1 phosphorylation
    Aging Cell (IF 7.346) Pub Date : 2019-10-31
    Jinwang Ye, Yaling Yin, Huanhuan Liu, Lin Fang, Xiaoqing Tao, Linyu Wei, Yue Zuo, Ying Yin, Dan Ke, Jian‐Zhi Wang

    Intraneuronal accumulation of wild‐type tau plays a key role in Alzheimer's disease, while the mechanisms underlying tauopathy and memory impairment remain unclear. Here, we report that overexpressing full‐length wild‐type human tau (hTau) in mouse hippocampus induces learning and memory deficits with remarkably reduced levels of multiple synapse‐ and memory‐associated proteins. Overexpressing hTau inhibits the activity of protein kinase A (PKA) and decreases the phosphorylation level of cAMP‐response element binding protein (CREB), GluA1, and TrkB with reduced BDNF mRNA and protein levels both in vitro and in vivo. Simultaneously, overexpressing hTau increased PKAR2α (an inhibitory subunit of PKA) in nuclear fraction and inactivated proteasome activity. With an increased association of PKAR2α with PA28γ (a nuclear proteasome activator), the formation of PA28γ‐20S proteasome complex remarkably decreased in the nuclear fraction, followed by a reduced interaction of PKAR2α with 20S proteasome. Both downregulating PKAR2α by shRNA and upregulating proteasome by expressing PA28γ rescued hTau‐induced PKA inhibition and CREB dephosphorylation, and upregulating PKA improved hTau‐induced cognitive deficits in mice. Together, these data reveal that intracellular tau accumulation induces synapse and memory impairments by inhibiting PKA/CREB/BDNF/TrkB and PKA/GluA1 signaling, and deficit of PA28γ‐20S proteasome complex formation contributes to PKAR2α elevation and PKA inhibition.

    更新日期:2019-11-01
  • Cell senescence contributes to tissue regeneration in zebrafish
    Aging Cell (IF 7.346) Pub Date : 2019-10-31
    Sabela Da Silva‐Álvarez, Jorge Guerra‐Varela, Daniel Sobrido‐Cameán, Ana Quelle, Antón Barreiro‐Iglesias, Laura Sánchez, Manuel Collado

    Cellular senescence is a stress response that limits the proliferation of damaged cells by establishing a permanent cell cycle arrest. Different stimuli can trigger senescence but excessive production or impaired clearance of these cells can lead to their accumulation during aging with deleterious effects. Despite this potential negative side of cell senescence, its physiological role as a pro‐regenerative and morphogenetic force has emerged recently after the identification of programmed cell senescence during embryogenesis and during wound healing and limb regeneration. Here, we explored the conservation of tissue injury‐induced senescence in a model of complex regeneration, the zebrafish. Fin amputation in adult fish led to the appearance of senescent cells at the site of damage, and their removal impaired tissue regeneration. Despite many conceptual similarities, this tissue repair response is different from developmental senescence. Our results lend support to the notion that cell senescence is a positive response promoting tissue repair and homeostasis.

    更新日期:2019-11-01
  • Mitochondrial mass governs the extent of human T cell senescence.
    Aging Cell (IF 7.346) Pub Date : null
    Lauren A Callender,Elizabeth C Carroll,Emilia A Bober,Arne N Akbar,Egle Solito,Sian M Henson

    The susceptibility of human CD4+ and CD8+ T cells to senesce differs, with CD8+ T cells acquiring an immunosenescent phenotype faster than the CD4+ T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human CD4+ T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8+ T cells has knock-on consequences for nutrient usage, metabolism and function. It is scientifically valid to say T cell uptake more lipid and glucose than their CD8+ counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent CD4+ T cells allows for more proliferation and migration than observed in the senescent CD8+ subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human CD4+ T cells, through the addition of low-dose rotenone, causes the generation of a CD4+ T cell with a CD8+ -like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.

    更新日期:2019-11-01
  • Sustained NFκB inhibition improves insulin sensitivity but is detrimental to muscle health.
    Aging Cell (IF 7.346) Pub Date : 2017-05-31
    Ning Zhang,Joseph M Valentine,You Zhou,Mengyao E Li,Yiqiang Zhang,Arunabh Bhattacharya,Michael E Walsh,Katherine E Fischer,Steven N Austad,Pawel Osmulski,Maria Gaczynska,Steven E Shoelson,Holly Van Remmen,Hung I Chen,Yidong Chen,Hanyu Liang,Nicolas Musi

    Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IκBα mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild-type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function.

    更新日期:2019-11-01
  • Valproic acid extends Caenorhabditis elegans lifespan.
    Aging Cell (IF 7.346) Pub Date : 2008-02-06
    Kimberley Evason,James J Collins,Cheng Huang,Stacie Hughes,Kerry Kornfeld

    Aging is an important biological phenomenon and a major contributor to human disease and disability, but no drugs have been demonstrated to delay human aging. Caenorhabditis elegans is a valuable model for studies of animal aging, and the analysis of drugs that extend the lifespan of this animal can elucidate mechanisms of aging and might lead to treatments for age-related disease. By testing drugs that are Food and Drug Administration approved for human use, we discovered that the mood stabilizer and anticonvulsant valproic acid (VA) extended C. elegans lifespan. VA also delayed age-related declines of body movement, indicating that VA delays aging. Valproic acid is a small carboxylic acid that is the most frequently prescribed anticonvulsant drug in humans. A structure-activity analysis demonstrated that the related compound valpromide also extends lifespan. Valproic acid treatment may modulate the insulin/IGF-1 growth factor signaling pathway, because VA promoted dauer larvae formation and DAF-16 nuclear localization. To investigate the mechanism of action of VA in delaying aging, we analyzed the effects of combining VA with other compounds that extend the lifespan of C. elegans. Combined treatment of animals with VA and the heterocyclic anticonvulsant trimethadione caused a lifespan extension that was significantly greater than treatment with either of these drugs alone. These data suggest that the mechanism of action of VA is distinct from that of trimethadione, and demonstrate that lifespan-extending drugs can be combined to produce additive effects.

    更新日期:2019-11-01
  • The relationship between DNA methylation and telomere length in dyskeratosis congenita.
    Aging Cell (IF 7.346) Pub Date : 2011-10-11
    Shahinaz M Gadalla,Hormuzd A Katki,Fatma M Shebl,Neelam Giri,Blanche P Alter,Sharon A Savage

    The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE-1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation-negative relatives. Pearson's correlation coefficient and linear regression models were used to evaluate the relationship between age-standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE-1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase-complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE-1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE-1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE-1 (r = -0.17), subtelomeric (r = -0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE-1 methylation, which may be altered based on mutation status of telomere biology genes.

    更新日期:2019-11-01
  • Caveolae control the anti-inflammatory phenotype of senescent endothelial cells.
    Aging Cell (IF 7.346) Pub Date : 2014-11-20
    Elizabeth E Powter,Paul R Coleman,Mai H Tran,Angelina J Lay,Patrick Bertolino,Robert G Parton,Mathew A Vadas,Jennifer R Gamble

    Senescent endothelial cells (EC) have been identified in cardiovascular disease, in angiogenic tumour associated vessels and in aged individuals. We have previously identified a novel anti-inflammatory senescent phenotype of EC. We show here that caveolae are critical in the induction of this anti-inflammatory senescent state. Senescent EC induced by either the overexpression of ARHGAP18/SENEX or by H₂O₂ showed significantly increased numbers of caveolae and associated proteins Caveolin-1, cavin-1 and cavin-2. Depletion of these proteins by RNA interference decreased senescence induced by ARHGAP18 and by H₂O₂. ARHGAP18 overexpression induced a predominantly anti-inflammatory senescent population and depletion of the caveolae-associated proteins resulted in the preferential reduction in this senescent population as measured by neutrophil adhesion and adhesion protein expression after TNFα treatment. In confirmation, EC isolated from the aortas of CAV-1(-/-) mice failed to induce this anti-inflammatory senescent cell population upon expression of ARHGAP18, whereas EC from wild-type mice showed a significant increase. NF-κB is one of the major transcription factors mediating the induction of E-selectin and VCAM-1 expression, adhesion molecules responsible for leucocyte attachment to EC. TNFα-induced activation of NF-κB was suppressed in ARHGAP18-induced senescent EC, and this inhibition was reversed by Caveolin-1 knock-down. Thus, out results demonstrate that an increase in caveolae and its component proteins in senescent ECs is associated with inhibition of the NF-kB signalling pathway and promotion of the anti-inflammatory senescent pathway.

    更新日期:2019-11-01
  • Corrigendum.
    Aging Cell (IF 7.346) Pub Date : 2019-03-13

    更新日期:2019-11-01
  • MicroRNA-18 and microRNA-19 regulate CTGF and TSP-1 expression in age-related heart failure.
    Aging Cell (IF 7.346) Pub Date : 2011-04-20
    Geert C van Almen,Wouter Verhesen,Rick E W van Leeuwen,Mathijs van de Vrie,Casper Eurlings,Mark W M Schellings,Melissa Swinnen,Jack P M Cleutjens,Marc A M J van Zandvoort,Stephane Heymans,Blanche Schroen

    To understand the process of cardiac aging, it is of crucial importance to gain insight into the age-related changes in gene expression in the senescent failing heart. Age-related cardiac remodeling is known to be accompanied by changes in extracellular matrix (ECM) gene and protein levels. Small noncoding microRNAs regulate gene expression in cardiac development and disease and have been implicated in the aging process and in the regulation of ECM proteins. However, their role in age-related cardiac remodeling and heart failure is unknown. In this study, we investigated the aging-associated microRNA cluster 17-92, which targets the ECM proteins connective tissue growth factor (CTGF) and thrombospondin-1 (TSP-1). We employed aged mice with a failure-resistant (C57Bl6) and failure-prone (C57Bl6 × 129Sv) genetic background and extrapolated our findings to human age-associated heart failure. In aging-associated heart failure, we linked an aging-induced increase in the ECM proteins CTGF and TSP-1 to a decreased expression of their targeting microRNAs 18a, 19a, and 19b, all members of the miR-17-92 cluster. Failure-resistant mice showed an opposite expression pattern for both the ECM proteins and the microRNAs. We showed that these expression changes are specific for cardiomyocytes and are absent in cardiac fibroblasts. In cardiomyocytes, modulation of miR-18/19 changes the levels of ECM proteins CTGF and TSP-1 and collagens type 1 and 3. Together, our data support a role for cardiomyocyte-derived miR-18/19 during cardiac aging, in the fine-tuning of cardiac ECM protein levels. During aging, decreased miR-18/19 and increased CTGF and TSP-1 levels identify the failure-prone heart.

    更新日期:2019-11-01
  • Inbred mouse strains reveal biomarkers that are pro-longevity, antilongevity or role switching.
    Aging Cell (IF 7.346) Pub Date : 2014-05-28
    Mark Moeller,Misa Hirose,Sarah Mueller,Catrin Roolf,Simone Baltrusch,Saleh Ibrahim,Christian Junghanss,Olaf Wolkenhauer,Robert Jaster,Rüdiger Köhling,Manfred Kunz,Markus Tiedge,Paul N Schofield,Georg Fuellen

    Traditionally, biomarkers of aging are classified as either pro-longevity or antilongevity. Using longitudinal data sets from the large-scale inbred mouse strain study at the Jackson Laboratory Nathan Shock Center, we describe a protocol to identify two kinds of biomarkers: those with prognostic implication for lifespan and those with longitudinal evidence. Our protocol also identifies biomarkers for which, at first sight, there is conflicting evidence. Conflict resolution is possible by postulating a role switch. In these cases, high biomarker values are, for example, antilongevity in early life and pro-longevity in later life. Role-switching biomarkers correspond to features that must, for example, be minimized early, but maximized later, for optimal longevity. The clear-cut pro-longevity biomarkers we found reflect anti-inflammatory, anti-immunosenescent or anti-anaemic mechanisms, whereas clear-cut antilongevity biomarkers reflect inflammatory mechanisms. Many highly significant blood biomarkers relate to immune system features, indicating a shift from adaptive to innate processes, whereas most role-switching biomarkers relate to blood serum features and whole-body phenotypes. Our biomarker classification approach is applicable to any combination of longitudinal studies with life expectancy data, and it provides insights beyond a simplified scheme of biomarkers for long or short lifespan.

    更新日期:2019-11-01
  • Regulation of longevity by regulator of G-protein signaling protein, Loco.
    Aging Cell (IF 7.346) Pub Date : 2011-01-25
    Yuh-Ru Lin,Keetae Kim,Yanfei Yang,Andreas Ivessa,Junichi Sadoshima,Yongkyu Park

    Regulator of G-protein signaling (RGS) proteins contribute to G-protein signaling pathways as activators or repressors with GTPase-activating protein (GAP) activity. To characterize whether regulation of RGS proteins influences longevity in several species, we measured stress responses and lifespan of RGS-overexpressing and RGS-lacking mutants. Reduced expression of Loco, a RGS protein of Drosophila melanogaster, resulted in a longer lifespan for both male and female flies, also exhibiting stronger resistance to three different stressors (starvation, oxidation, and heat) and higher manganese-containing superoxide dismutase (MnSOD) activity. In addition, this reduction in Loco expression increased fat content and diminished cAMP levels. In contrast, overexpression of both genomic and cDNA loco gene significantly shortened the lifespan with weaker stress resistance and lower fat content. Deletion analysis of the Loco demonstrated that its RGS domain is required for the regulation of longevity. Consistently, when expression of RGS14, mammalian homologue of Loco, was reduced in rat fibroblast cells, the resistance to oxidative stress increased with higher MnSOD expression. The changes of yeast Rgs2 expression, which shares a conserved RGS domain with the fly Loco protein, also altered lifespan and stress resistance in Saccharomyces cerevisiae. Here, we provide the first evidence that RGS proteins with GAP activity affect both stress resistance and longevity in several species.

    更新日期:2019-11-01
  • mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts.
    Aging Cell (IF 7.346) Pub Date : 2016-08-28
    Yair Romero,Marta Bueno,Remedios Ramirez,Diana Álvarez,John C Sembrat,Elena A Goncharova,Mauricio Rojas,Moisés Selman,Ana L Mora,Annie Pardo

    Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal disease associated with aging. However, the molecular mechanisms of the aging process that contribute to the pathogenesis of IPF have not been elucidated. IPF is characterized by abundant foci of highly active fibroblasts and myofibroblasts resistant to apoptosis. Remarkably, the role of aging in the autophagy activity of lung fibroblasts and its relationship with apoptosis, as adaptive responses, has not been evaluated previously in this disease. In the present study, we analyzed the dynamics of autophagy in primary lung fibroblasts from IPF compared to young and age-matched normal lung fibroblasts. Our results showed that aging contributes for a lower induction of autophagy on basal conditions and under starvation which is mediated by mTOR pathway activation. Treatment with rapamycin and PP242, that target the PI3K/AKT/mTOR signaling pathway, modified starvation-induced autophagy and apoptosis in IPF fibroblasts. Interestingly, we found a persistent activation of this pathway under starvation that contributes to the apoptosis resistance in IPF fibroblasts. These findings indicate that aging affects adaptive responses to stress decreasing autophagy through activation of mTORC1 in lung fibroblasts. The activation of this pathway also contributes to the resistance to cell death in IPF lung fibroblasts.

    更新日期:2019-11-01
  • Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age.
    Aging Cell (IF 7.346) Pub Date : 2016-08-27
    Allen Herbst,Jonathan Wanagat,Nashwa Cheema,Kevin Widjaja,Debbie McKenzie,Judd M Aiken

    With age, somatically derived mitochondrial DNA (mtDNA) deletion mutations arise in many tissues and species. In skeletal muscle, deletion mutations clonally accumulate along the length of individual fibers. At high intrafiber abundances, these mutations disrupt individual cell respiration and are linked to the activation of apoptosis, intrafiber atrophy, breakage, and necrosis, contributing to fiber loss. This sequence of molecular and cellular events suggests a putative mechanism for the permanent loss of muscle fibers with age. To test whether mtDNA deletion mutation accumulation is a significant contributor to the fiber loss observed in aging muscle, we pharmacologically induced deletion mutation accumulation. We observed a 1200% increase in mtDNA deletion mutation-containing electron transport chain-deficient muscle fibers, an 18% decrease in muscle fiber number and 22% worsening of muscle mass loss. These data affirm the hypothesized role for mtDNA deletion mutation in the etiology of muscle fiber loss at old age.

    更新日期:2019-11-01
  • Alzheimer-related protein APL-1 modulates lifespan through heterochronic gene regulation in Caenorhabditis elegans.
    Aging Cell (IF 7.346) Pub Date : 2016-08-26
    Collin Y Ewald,Vanessa Marfil,Chris Li

    Alzheimer's disease (AD) is an age-associated disease. Mutations in the amyloid precursor protein (APP) may be causative or protective of AD. The presence of two functionally redundant APP-like genes (APLP1/2) has made it difficult to unravel the biological function of APP during aging. The nematode Caenorhabditis elegans contains a single APP family member, apl-1. Here, we assessed the function of APL-1 on C. elegans' lifespan and found tissue-specific effects on lifespan by overexpression of APL-1. Overexpression of APL-1 in neurons causes lifespan reduction, whereas overexpression of APL-1 in the hypodermis causes lifespan extension by repressing the function of the heterochronic transcription factor LIN-14 to preserve youthfulness. APL-1 lifespan extension also requires signaling through the FOXO transcription factor DAF-16, heat-shock factor HSF-1, and vitamin D-like nuclear hormone receptor DAF-12. We propose that reinforcing APL-1 expression in the hypodermis preserves the regulation of heterochronic lin-14 gene network to improve maintenance of somatic tissues via DAF-16/FOXO and HSF-1 to promote healthy aging. Our work reveals a mechanistic link of how a conserved APP-related protein modulates aging.

    更新日期:2019-11-01
  • Reducing translation through eIF4G/IFG-1 improves survival under ER stress that depends on heat shock factor HSF-1 in Caenorhabditis elegans.
    Aging Cell (IF 7.346) Pub Date : 2016-08-20
    Amber C Howard,Jarod Rollins,Santina Snow,Sarah Castor,Aric N Rogers

    Although certain methods of lowering and/or altering mRNA translation are associated with increased lifespan, the mechanisms underlying this effect remain largely unknown. We previously showed that the increased lifespan conferred by reducing expression of eukaryotic translation initiation factor 4G (eIF4G/IFG-1) enhances survival under starvation conditions while shifting protein expression toward factors involved with maintaining ER-dependent protein and lipid balance. In this study, we investigated changes in ER homeostasis and found that lower eIF4G/IFG-1 increased survival under conditions of ER stress. Enhanced survival required the ER stress sensor gene ire-1 and the ER calcium ATPase gene sca-1 and corresponded with increased translation of chaperones that mediate the ER unfolded protein response (UPRER ). Surprisingly, the heat-shock transcription factor gene hsf-1 was also required for enhanced survival, despite having little or no influence on the ability of wild-type animals to survive ER stress. The requirement for hsf-1 led us to re-evaluate the role of eIF4G/IFG-1 on thermotolerance. Results show that lowering expression of this translation factor enhanced thermotolerance, but only after prolonged attenuation, the timing of which corresponded to increased transcription of heat-shock factor transcriptional targets. Results indicate that restricting overall translation through eIF4G/IFG-1 enhances ER and cytoplasmic proteostasis through a mechanism that relies heavily on hsf-1.

    更新日期:2019-11-01
  • Age-associated vascular inflammation promotes monocytosis during atherogenesis.
    Aging Cell (IF 7.346) Pub Date : 2016-05-03
    Wei Du,Christine Wong,Yang Song,Hua Shen,Daniel Mori,Noemi Rotllan,Nathan Price,Anca D Dobrian,Hailong Meng,Steven H Kleinstein,Carlos Fernandez-Hernando,Daniel R Goldstein

    Aging leads to a proinflammatory state within the vasculature without disease, yet whether this inflammatory state occurs during atherogenesis remains unclear. Here, we examined how aging impacts atherosclerosis using Ldlr(-/-) mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr(-/-) mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet (HFD). On a HFD, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.

    更新日期:2019-11-01
  • Age-related changes in miR-143-3p:Igfbp5 interactions affect muscle regeneration.
    Aging Cell (IF 7.346) Pub Date : 2016-01-15
    Ana Soriano-Arroquia,Rachel McCormick,Andrew P Molloy,Anne McArdle,Katarzyna Goljanek-Whysall

    A common characteristic of aging is defective regeneration of skeletal muscle. The molecular pathways underlying age-related decline in muscle regenerative potential remain elusive. microRNAs are novel gene regulators controlling development and homeostasis and the regeneration of most tissues, including skeletal muscle. Here, we use satellite cells and primary myoblasts from mice and humans and an in vitro regeneration model, to show that disrupted expression of microRNA-143-3p and its target gene, Igfbp5, plays an important role in muscle regeneration in vitro. We identified miR-143 as a regulator of the insulin growth factor-binding protein 5 (Igfbp5) in primary myoblasts and show that the expression of miR-143 and its target gene is disrupted in satellite cells from old mice. Moreover, we show that downregulation of miR-143 during aging may act as a compensatory mechanism aiming at improving myogenesis efficiency; however, concomitant upregulation of miR-143 target gene, Igfbp5, is associated with increased cell senescence, thus affecting myogenesis. Our data demonstrate that dysregulation of miR-143-3p:Igfbp5 interactions in satellite cells with age may be responsible for age-related changes in satellite cell function.

    更新日期:2019-11-01
  • Reduced naïve CD8(+) T-cell priming efficacy in elderly adults.
    Aging Cell (IF 7.346) Pub Date : 2015-10-17
    Olivia Briceño,Anna Lissina,Kerstin Wanke,Georgia Afonso,Amrei von Braun,Kristanto Ragon,Tiphaine Miquel,Emma Gostick,Laura Papagno,Karin Stiasny,David A Price,Roberto Mallone,Delphine Sauce,Urs Karrer,Victor Appay

    Aging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8(+) T-cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling naïve CD8(+) T-cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8(+) T-cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8(+) T-cell responses specific for a model antigen. Reduced CD8(+) T-cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the naïve CD8(+) T-cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging.

    更新日期:2019-11-01
  • MicroRNA-125b modulates inflammatory chemokine CCL4 expression in immune cells and its reduction causes CCL4 increase with age.
    Aging Cell (IF 7.346) Pub Date : 2015-01-27
    Nai-Lin Cheng,Xiaochun Chen,Jiewan Kim,Alvin H Shi,Cuong Nguyen,Robert Wersto,Nan-Ping Weng

    Chemokines play a pivotal role in regulating the immune response through a tightly controlled expression. Elevated levels of inflammatory chemokines commonly occur with aging but the mechanism underlying this age-associated change is not fully understood. Here, we report the role of microRNA-125b (miR-125b) in regulating inflammatory CC chemokine 4 (CCL4) expression in human immune cells and its altered expression with aging. We first analyzed the mRNA level of CCL4 in eight different types of immune cells including CD4 and CD8 T-cell subsets (naïve, central and effector memory), B cells and monocytes in blood from both young (≤42 years) and old (≥70 years) adults. We observed that monocytes and naïve CD8 T cells expressed higher levels of CCL4 and exhibited an age-related increase in CCL4. We then found the level of miR-125b was inversely correlated with the level of CCL4 in these cells, and the level of miR-125b was reduced in monocytes and naïve CD8 T cells of the old compared to the young adults. Knock-down of miR-125b by shRNA in monocytes and naïve CD8 T cells led to an increase of CCL4 protein, whereas enhanced miR-125b expression by transfection in naïve CD8 T cells resulted in a reduction of the CCL4 mRNA and protein in response to stimulation. Finally, we demonstrated that miR-125b action requires the 'seed' sequence in 3'UTR of CCL4. Together these findings demonstrated that miR-125b is a negative regulator of CCL4 and its reduction is partially responsible for the age-related increase of CCL4.

    更新日期:2019-11-01
  • SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.
    Aging Cell (IF 7.346) Pub Date : 2014-06-17
    Evi M Mercken,Sarah J Mitchell,Alejandro Martin-Montalvo,Robin K Minor,Maria Almeida,Ana P Gomes,Morten Scheibye-Knudsen,Hector H Palacios,Jordan J Licata,Yongqing Zhang,Kevin G Becker,Husam Khraiwesh,José A González-Reyes,José M Villalba,Joseph A Baur,Peter Elliott,Christoph Westphal,George P Vlasuk,James L Ellis,David A Sinclair,Michel Bernier,Rafael de Cabo

    Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans.

    更新日期:2019-11-01
Contents have been reproduced by permission of the publishers.
导出
全部期刊列表>>
2020新春特辑
限时免费阅读临床医学内容
ACS材料视界
科学报告最新纳米科学与技术研究
清华大学化学系段昊泓
自然科研论文编辑服务
中国科学院大学楚甲祥
中国科学院微生物研究所潘国辉
中国科学院化学研究所
课题组网站
X-MOL
北京大学分子工程苏南研究院
华东师范大学分子机器及功能材料
中山大学化学工程与技术学院
试剂库存
天合科研
down
wechat
bug