Volume 10, Issue 10

Angenendt A, Steiner R, Knörck A, Schwär G, Konrad M, Krause E, Lis A, . Memory and menopause: an unsolved puzzle. . 10:2541-2543. https://doi.org/10.18632/aging.101596

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Mutant ubiquitin reduces Aβ plaques

Bert M. Verheijen, Fred W. van Leeuwen,

https://doi.org/10.18632/aging.101598 pp 2544—2546

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Frontotemporal dementia: a neurophysiological study

Flavio Di Stasio, Antonio Suppa, Alfredo Berardelli,

https://doi.org/10.18632/aging.101604 pp 2547—2548

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Identifying ubiquitinated proteins and aggregates

Nathan Basisty, Birgit Schilling, Peter S. Rabinovitch,

https://doi.org/10.18632/aging.101605 pp 2549—2550

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Age-related changes in 'hub' neurons

Abbi R. Hernandez, Sara N. Burke,

https://doi.org/10.18632/aging.101606 pp 2551—2552

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Why do on-pump patients live longer?

Nicola King, Val Mann,

https://doi.org/10.18632/aging.101607 pp 2553—2554

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Accelerated atherosclerosis in HGPS

Magda R. Hamczyk, Vicente Andrés,

https://doi.org/10.18632/aging.101608 pp 2555—2556

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Aging and aging-associated diseases: a microRNA-based endocrine regulation hypothesis

Samuil Umansky,

https://doi.org/10.18632/aging.101612 pp 2557—2569

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Umansky S, . Aging and aging-associated diseases: a microRNA-based endocrine regulation hypothesis. . 10:2557-2569. https://doi.org/10.18632/aging.101612

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                TY  - JOUR
                AU  - Umansky, Samuil 
                TI  - Aging and aging-associated diseases: a microRNA-based endocrine regulation hypothesis
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101612
                DO  - 10.18632/aging.101612
                SP  - 2557
                EP  - 2569
                PY  - 
                AB  - Although there are numerous hypotheses explaining the nature of aging and associated processes, two concepts are dominant: (i) aging is a result of cell-autonomous processes, such as the accumulation of DNA mutations, aberrant methylations, protein defects, and shortening of telomeres, leading to either inhibition of cellular proliferation and death of non-dividing terminally differentiated cells or tumor development; (ii) aging is a result of a central program that is switched on at a specific stage of organismic development. The microRNA-based endocrine regulation hypothesis combines the two above concepts by proposing central regulation of cell death occurrences via hypothalamus-pituitary gland (PG)-secreted miRNA hormones, the expression and/or secretion of which are regulated by sex hormones. This hypothesis explains such well-known phenomena as inverse comorbidity of either cancer or Alzheimer’s (AD) and other neurodegenerative diseases; higher AD morbidity and lower frequency of many common types of cancer in women vs. men; higher risk of early AD and lower risk of cancer in subjects with Down syndrome; longer life expectancy in women vs. men and much lower sex-dependent differences, if any, in other mammals; increased lifespans due to hypophysectomy or PG hypofunction; and parabiotic effects of blood or plasma transfusions between young and old animals.
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CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling

Zhao Liu, Mi Chen, Lin-Ka Xie, Ting Liu, Zhen-Wei Zou, Yong Li, Peng Chen, Xin Peng, Charlie Ma, Wen-Jie Zhang, Pin-Dong Li,

https://doi.org/10.18632/aging.101571 pp 2570—2584

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Liu Z, Chen M, Xie L, Liu T, Zou Z, Li Y, Chen P, Peng X, Ma C, Zhang W, Li P, . CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling. . 10:2570-2584. https://doi.org/10.18632/aging.101571

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                TY  - JOUR
                AU  - Liu, Zhao 
                AU  - Chen, Mi 
                AU  - Xie, Lin-Ka 
                AU  - Liu, Ting 
                AU  - Zou, Zhen-Wei 
                AU  - Li, Yong 
                AU  - Chen, Peng 
                AU  - Peng, Xin 
                AU  - Ma, Charlie 
                AU  - Zhang, Wen-Jie 
                AU  - Li, Pin-Dong 
                TI  - CLCA4 inhibits cell proliferation and invasion of hepatocellular carcinoma by suppressing epithelial-mesenchymal transition via PI3K/AKT signaling
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101571
                DO  - 10.18632/aging.101571
                SP  - 2570
                EP  - 2584
                PY  - 
                AB  - Calcium activated Chloride Channel A4 (CLCA4), as a tumor suppressor, was reported to contribute to the progression of several malignant tumors, yet little is known about the significance of CLCA4 in invasion and prognosis of hepatocellular carcinoma (HCC). CLCA4 expression was negatively correlated with tumor size, vascular invasion and TNM stage. Kaplan-Meier analysis showed that CLCA4 was an independent predictor for overall survival (OS) and time to recurrence (TTR). In addition, CLCA4 status could act as prognostic predictor in different risk of subgroups. Moreover, combination of CLCA4 and serum AFP could be a potential predictor for survival in HCC patients. Furthermore, CLCA4 may inhibit cell migration and invasion by suppressing epithelial-mesenchymal transition (EMT) via PI3K/ATK signaling. Knockdown of CLCA4 significantly increased the migration and invasion of HCC cells and changed the expression pattern of EMT markers and PI3K/AKT phosphorylation. An opposite expression pattern of EMT markers and PI3K/AKT phosphorylation was observed in CLCA4-transfected cells. Additionally, immunohistochemistry and RT-PCR results further confirmed this correlation. Taken together, CLCA4 contributes to migration and invasion by suppressing EMT via PI3K/ATK signaling and predicts favourable prognosis of HCC. CLCA4/AFP expression may help to distinguish different risks of HCC patients after hepatectomy.
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H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions

Alena Svobodová Kovaříková, Soňa Legartová, Jana Krejčí, Eva Bártová,

https://doi.org/10.18632/aging.101572 pp 2585—2605

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Svobodová Kovaříková A, Legartová S, Krejčí J, Bártová E, . H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions. . 10:2585-2605. https://doi.org/10.18632/aging.101572

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                TY  - JOUR
                AU  - Svobodová Kovaříková, Alena 
                AU  - Legartová, Soňa 
                AU  - Krejčí, Jana 
                AU  - Bártová, Eva 
                TI  - H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101572
                DO  - 10.18632/aging.101572
                SP  - 2585
                EP  - 2605
                PY  - 
                AB  - Methylation of histones H4 at lysine 20 position (H4K20me), which is functional in DNA repair, represents a binding site for the 53BP1 protein. Here, we show a radiation-induced increase in the level of H4K20me3 while the levels of H4K20me1 and H4K20me2 remained intact. H4K20me3 was significantly pronounced at DNA lesions in only the G1 phase of the cycle, while this histone mark was reduced in very late S and G2 phases when PCNA was recruited to locally micro-irradiated chromatin. H4K20me3 was diminished in locally irradiated Suv39h1/h2 double knockout (dn) fibroblasts, and the same phenomenon was observed for H3K9me3 and its binding partner, the HP1β protein. Immunoprecipitation showed the existence of an interaction between H3K9me3-53BP1 and H4K20me3-53BP1; however, HP1β did not interact with 53BP1. Together, H3K9me3 and H4K20me3 represent epigenetic markers that are important for the function of the 53BP1 protein in non-homologous end joining (NHEJ) repair. The very late S phase represents the cell cycle breakpoint when a DDR function of the H4K20me3-53BP1 complex is abrogated due to recruitment of the PCNA protein and other DNA repair factors of homologous recombination to DNA lesions.
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Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer

Hongwei Liu, Dongliang Chen, Junming Bi, Jinli Han, Meihua Yang, Wei Dong, Tianxin Lin, Jian Huang,

https://doi.org/10.18632/aging.101573 pp 2606—2623

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Liu H, Chen D, Bi J, Han J, Yang M, Dong W, Lin T, Huang J, . Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer. . 10:2606-2623. https://doi.org/10.18632/aging.101573

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                TY  - JOUR
                AU  - Liu, Hongwei 
                AU  - Chen, Dongliang 
                AU  - Bi, Junming 
                AU  - Han, Jinli 
                AU  - Yang, Meihua 
                AU  - Dong, Wei 
                AU  - Lin, Tianxin 
                AU  - Huang, Jian 
                TI  - Circular RNA circUBXN7 represses cell growth and invasion by sponging miR-1247-3p to enhance B4GALT3 expression in bladder cancer
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101573
                DO  - 10.18632/aging.101573
                SP  - 2606
                EP  - 2623
                PY  - 
                AB  - Circular RNAs (circRNAs) have recently been confirmed to participate in different pathological processes, including cancer progression. However, the role and precise mechanism of action of the majority of circRNAs have not been elucidated in bladder cancer (BC). Here, we identified a novel circular RNA, termed circUBXN7, which was significantly downregulated in BC tissues compared with matched nontumor tissues. Importantly, we found that decreased circUBXN7 expression was associated with pathological stage, grade and poor prognosis of BC patients. Functional experiments showed that circUBXN7 overexpression dramatically inhibited proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Mechanistically, circUBXN7 could directly bind to miR-1247-3p and reverse the oncogenic effects induced by miR-1247-3p. Furthermore, B4GALT3 was predicted and confirmed to be a target of miR-1247-3p. Rescue experiments demonstrated that circUBXN7 abrogated miR-1247-3p-mediated inhibition of B4GALT3 expression. Finally, silencing of B4GALT3 promoted proliferation and invasion of BC cells; and partially abolished the tumor suppressive effects caused by circUBXN7. Taken together, our study revealed that circUBXN7 serves as a competitive endogenous RNA of miR-1247-3p to elevate B4GALT3 expression, consequently inhibiting cell viability and invasion in BC. The circUBXN7-miR-1247-3p-B4GALT3 regulatory network may provide a new perspective for gene-based treatment strategies for BC.
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A joint analysis of metabolomic profiles associated with muscle mass and strength in Caucasian women

Qi Zhao, Hui Shen, Kuan-Jui Su, Qing Tian, Lan-Juan Zhao, Chuan Qiu, Timothy J. Garrett, Jiawang Liu, David Kakhniashvili, Hong-Wen Deng,

https://doi.org/10.18632/aging.101574 pp 2624—2635

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Zhao Q, Shen H, Su K, Tian Q, Zhao L, Qiu C, Garrett TJ, Liu J, Kakhniashvili D, Deng H, . A joint analysis of metabolomic profiles associated with muscle mass and strength in Caucasian women. . 10:2624-2635. https://doi.org/10.18632/aging.101574

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                TY  - JOUR
                AU  - Zhao, Qi 
                AU  - Shen, Hui 
                AU  - Su, Kuan-Jui 
                AU  - Tian, Qing 
                AU  - Zhao, Lan-Juan 
                AU  - Qiu, Chuan 
                AU  - Garrett, Timothy J. 
                AU  - Liu, Jiawang 
                AU  - Kakhniashvili, David 
                AU  - Deng, Hong-Wen 
                TI  - A joint analysis of metabolomic profiles associated with muscle mass and strength in Caucasian women
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101574
                DO  - 10.18632/aging.101574
                SP  - 2624
                EP  - 2635
                PY  - 
                AB  - Both loss of muscle mass and strength are important sarcopenia-related traits. In this study, we investigated both specific and shared serum metabolites associated with these two traits in 136 Caucasian women using a liquid chromatography-mass spectrometry method. A joint analysis of multivariate traits was used to examine the associations of individual metabolites with muscle mass measured by the body mass index-adjusted appendicular lean mass (ALM/BMI) and muscle strength measured by hand grip strength (HGS). After adjusting for multiple testing, nine metabolites including two amino acids (aspartic acid and glutamic acid) and an amino acid derive (pipecolic acid), one peptide (phenylalanyl-threonine), one carbohydrate (methyl beta-D-glucopyranoside), and four lipids (12S-HETRE, arachidonic acid, 12S-HETE, and glycerophosphocholine) were significant in the joint analysis. Of them, the two amino acids (aspartic acid and glutamic acid) and two lipids (12S-HETRE and 12S-HETE) were associated with both ALM/BMI and HGS, and the other five were only associated with ALM/BMI. The pathway analysis showed the amino acid metabolism pathways (aspartic acid and glutamic acid) might play important roles in the regulation of muscle mass and strength. In conclusion, our study identified novel metabolites associated with sarcopenia-related traits, suggesting novel metabolic pathways for muscle regulation.
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Inflammation markers are associated with frailty in elderly patients with coronary heart disease

Ping Hou, Hui-Ping Xue, Xin-E Mao, Yong-Nan Li, Lin-Feng Wu, Yong-Bing Liu,

https://doi.org/10.18632/aging.101575 pp 2636—2645

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Hou P, Xue H, Mao X, Li Y, Wu L, Liu Y, . Inflammation markers are associated with frailty in elderly patients with coronary heart disease. . 10:2636-2645. https://doi.org/10.18632/aging.101575

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                TY  - JOUR
                AU  - Hou, Ping 
                AU  - Xue, Hui-Ping 
                AU  - Mao, Xin-E 
                AU  - Li, Yong-Nan 
                AU  - Wu, Lin-Feng 
                AU  - Liu, Yong-Bing 
                TI  - Inflammation markers are associated with frailty in elderly patients with coronary heart disease
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101575
                DO  - 10.18632/aging.101575
                SP  - 2636
                EP  - 2645
                PY  - 
                AB  - The neutrophil-to-lymphocyte ratio (NLR) and red blood cell distribution width (RDW) are important indicators of adverse outcomes and have predictive value for many diseases; however, the relationships between frailty, and the NLR and RDW in patients with coronary heart disease (CHD) have not been determined. In this cross-sectional study, we investigated the association between frailty, and the NLR and RDW in elderly CHD patients ≥ 60 years of age. Frailty was defined according to frailty phenotype. Of 345 patients enrolled in the study, 22.6%, 58.3%, and 19.1% were characterized as robust, pre-frail, and frail, respectively. A significant positive correlation was observed between frailty and the NLR (r = 0.169) and RDW (r = 0.196). After adjusting for confounders, linear regression analyses showed that participants in the 4th quartile of the NLR or RDW were more likely to have a higher frailty phenotype score. Based on multivariable logistic regression, patients in the 4th quartile of the NLR and RDW, the fully-adjusted odds ratios for incident frailty were 2.894 (p = 0.011) and 2.494 (p = 0.040), respectively. Our findings indicate that frailty is associated with the NLR and RDW in elderly patients with CHD.
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The fasting blood glucose and long non-coding RNA SNHG8 predict poor prognosis in patients with gastric carcinoma after radical gastrectomy

Yunchai Lin, Dan Hu, Qiang Zhou, Xiangdong Lin, Jinxiu Lin, Feng Peng,

https://doi.org/10.18632/aging.101576 pp 2646—2656

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Lin Y, Hu D, Zhou Q, Lin X, Lin J, Peng F, . The fasting blood glucose and long non-coding RNA SNHG8 predict poor prognosis in patients with gastric carcinoma after radical gastrectomy. . 10:2646-2656. https://doi.org/10.18632/aging.101576

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                TY  - JOUR
                AU  - Lin, Yunchai 
                AU  - Hu, Dan 
                AU  - Zhou, Qiang 
                AU  - Lin, Xiangdong 
                AU  - Lin, Jinxiu 
                AU  - Peng, Feng 
                TI  - The fasting blood glucose and long non-coding RNA SNHG8 predict poor prognosis in patients with gastric carcinoma after radical gastrectomy
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101576
                DO  - 10.18632/aging.101576
                SP  - 2646
                EP  - 2656
                PY  - 
                AB  - This prospective study sought to evaluate the prediction of fasting blood glucose and long non-coding RNA (lncRNA) SNHG8 for the risk of gastric carcinoma mortality. A total of 217 gastric carcinoma patients underwent radical gastrectomy were included during 2012-16. The final follow-up was finished in January 2017. The aggregate hazard ratio(HR) demonstrated that poor prognosis of gastric carcinoma was associated with fasting blood glucose (HR= 1.29, P=0.037), SNHG8 expression(HR = 1.10, P= 0.009), positive distant metastasis(HR = 2.99, P= 0.020), EBV positive (HR = 3.40, P=0.002), and tumor size more than 5.0 cm (HR = 3.36, P= 0.005). In survival analysis, elevated fasting blood glucose (P =0.007) and high SNHG8 expression (P =0.007) were significantly associated with shorter survival times in gastric cancer. Significant multiplicative interaction was shown between fasting blood glucose and SNHG8 expression (chi-squared=7.81, Pmultiplicative =0.005), without statistical additive interaction. Fasting blood glucose and SNHG8 expression could predict poor prognosis after radical gastrectomy. LncRNA SNHG8 could be applied as a novel epigenetic molecular target in gastric carcinoma.
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A high glucose diet induces autophagy in a HLH-30/TFEB-dependent manner and impairs the normal lifespan of C. elegans

Berenice Franco-Juárez, Fanny Mejía-Martínez, Elizabeth Moreno-Arriola, Alain Hernández-Vázquez, Saul Gómez-Manzo, Jaime Marcial-Quino, Roberto Arreguín-Espinosa, Antonio Velázquez-Arellano, Daniel Ortega-Cuellar,

https://doi.org/10.18632/aging.101577 pp 2657—2667

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Franco-Juárez B, Mejía-Martínez F, Moreno-Arriola E, Hernández-Vázquez A, Gómez-Manzo S, Marcial-Quino J, Arreguín-Espinosa R, Velázquez-Arellano A, Ortega-Cuellar D, . A high glucose diet induces autophagy in a HLH-30/TFEB-dependent manner and impairs the normal lifespan of C. elegans. . 10:2657-2667. https://doi.org/10.18632/aging.101577

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Provider: 
 TY - JOUR
 AU - Franco-Juárez, Berenice 
 AU - Mejía-Martínez, Fanny 
 AU - Moreno-Arriola, Elizabeth 
 AU - Hernández-Vázquez, Alain 
 AU - Gómez-Manzo, Saul 
 AU - Marcial-Quino, Jaime 
 AU - Arreguín-Espinosa, Roberto 
 AU - Velázquez-Arellano, Antonio 
 AU - Ortega-Cuellar, Daniel 
 TI - A high glucose diet induces autophagy in a HLH-30/TFEB-dependent manner and impairs the normal lifespan of C. elegans
 JO - 
 JA - 
 VL - 10
 IS - 10
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101577
 DO - 10.18632/aging.101577
 SP - 2657
 EP - 2667
 PY - 
 AB - A high-glucose diet (HGD) is associated with the development of metabolic diseases that decrease life expectancy, including obesity and type-2 diabetes (T2D); however, the mechanism through which a HGD does so is still unclear. Autophagy, an evolutionarily conserved mechanism, has been shown to promote both cell and organismal survival. The goal of this study was to determine whether exposure of Caenorhabditis elegans to a HGD affects autophagy and thus contributes to the observed lifespan reduction under a HGD. Unexpectedly, nematodes exposed to a HGD showed increased autophagic flux via an HLH-30/TFEB-dependent mechanism because animals with loss of HLH-30/TFEB, even those with high glucose exposure, had an extended lifespan, suggesting that HLH-30/TFEB might have detrimental effects on longevity through autophagy under this stress condition. Interestingly, pharmacological treatment with okadaic acid, an inhibitor of the PP2A and PP1 protein phosphatases, blocked HLH-30 nuclear translocation, but not TAX-6/calcineurin suppression by RNAi, during glucose exposure. Together, our data support the suggested dual role of HLH-30/TFEB and autophagy, which, depending on the cellular context, may promote either organismal survival or death.
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High expression of the breast cancer susceptibility gene BRCA1 in long-lived termite kings

Eisuke Tasaki, Yuki Mitaka, Tomonari Nozaki, Kazuya Kobayashi, Kenji Matsuura, Yoshihito Iuchi,

https://doi.org/10.18632/aging.101578 pp 2668—2683

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Tasaki E, Mitaka Y, Nozaki T, Kobayashi K, Matsuura K, Iuchi Y, . High expression of the breast cancer susceptibility gene BRCA1 in long-lived termite kings. . 10:2668-2683. https://doi.org/10.18632/aging.101578

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                TY  - JOUR
                AU  - Tasaki, Eisuke 
                AU  - Mitaka, Yuki 
                AU  - Nozaki, Tomonari 
                AU  - Kobayashi, Kazuya 
                AU  - Matsuura, Kenji 
                AU  - Iuchi, Yoshihito 
                TI  - High expression of the breast cancer susceptibility gene BRCA1 in long-lived termite kings
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101578
                DO  - 10.18632/aging.101578
                SP  - 2668
                EP  - 2683
                PY  - 
                AB  - Aging is associated with the accumulation of DNA damage. High expression of DNA repair genes has been suggested to contribute to prolonged lifespan in several organisms. However, the crucial DNA repair genes contributing to longevity remain unknown. Termite kings have an extraordinary long lifespan compared with that of non-reproductive individuals such as workers despite being derived from the same genome, thus providing a singular model for identifying longevity-related genes. In this study, we demonstrated that termite kings express higher levels of the breast cancer susceptibility gene BRCA1 than other castes. Using RNA sequencing, we identified 21 king-specific genes among 127 newly annotated DNA repair genes in the termite Reticulitermes speratus. Using quantitative PCR, we revealed that some of the highly expressed king-specific genes were significantly upregulated in reproductive tissue (testis) compared to their expression in somatic tissue (fat body). Notably, BRCA1 gene expression in the fat body was more than 4-fold higher in kings than in workers. These results suggest that BRCA1 partly contributes to DNA repair in somatic and reproductive tissues in termite kings. These findings provide important insights into the linkage between BRCA1 gene expression and the extraordinary lifespan of termite kings.
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Searching for longevity hotspots in Denmark

Anne Vinkel Hansen, Laust Hvas Mortensen, Rudi Westendorp,

https://doi.org/10.18632/aging.101579 pp 2684—2694

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Hansen AV, Mortensen LH, Westendorp R, . Searching for longevity hotspots in Denmark. . 10:2684-2694. https://doi.org/10.18632/aging.101579

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                TY  - JOUR
                AU  - Hansen, Anne Vinkel 
                AU  - Mortensen, Laust Hvas 
                AU  - Westendorp, Rudi 
                TI  - Searching for longevity hotspots in Denmark
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101579
                DO  - 10.18632/aging.101579
                SP  - 2684
                EP  - 2694
                PY  - 
                AB  - While existing research on regions with high prevalence of centenarians has focused on selected candidate geographical regions, we explore the existence of hotspots in the whole of Denmark.We performed a Kulldorff spatial scan, searching for regions of birth, and of residence at age 71, where an increased percentage of the cohort born 1906-1915 became centenarians. We then compared mortality hazards for these regions to the rest of the country.We found a birth hotspot of 222 centenarians, 1.37 times more than expected, centered on a group of rural islands. Lower mortality hazards from age 71 onwards were confined to those born within the hotspot and persisted over a period of at least 30 years. At age 71, we found two residence-based hotspots of 348 respectively 238 centenarians, 1.46 and 1.44 times the expected numbers. One hotspot, located in high-income suburbs of the Danish capital, seems driven by selective in-migration of low-mortality individuals. The other hotspot seems driven by selective migration and lower morality among those born and residing in the hotspot.Thus, Danish centenarian hotspots do exist. The locations and interpretation depend on whether we look at place of birth or of residence late in life.
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Role of alternative splicing of VEGF-A in the development of atherosclerosis

Naishi Zhao, Jianfeng Zhang,

https://doi.org/10.18632/aging.101580 pp 2695—2708

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Zhao N, Zhang J, . Role of alternative splicing of VEGF-A in the development of atherosclerosis. . 10:2695-2708. https://doi.org/10.18632/aging.101580

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                TY  - JOUR
                AU  - Zhao, Naishi 
                AU  - Zhang, Jianfeng 
                TI  - Role of alternative splicing of VEGF-A in the development of atherosclerosis
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101580
                DO  - 10.18632/aging.101580
                SP  - 2695
                EP  - 2708
                PY  - 
                AB  - Vascular endothelial cell growth factor A (VEGF-A) signaling promotes the endothelial cell proliferation, macrophage infiltration and foam cell formation, which play pivotal roles in the pathogenesis of atherosclerosis (AS). However, the role of alternative splicing of VEGF here is not known. Here, ApoE (-/-) mice supplied high-fat diet (HFD mice) were used to generate AS, while ApoE (-/-) mice supplied with normal diet (NOR mice) were used as a control. Aortic endothelial cells (AECs) and infiltrated macrophages were purified and quantified by flow cytometry. Alternative splicing of VEGF and the regulator of VEGF splicing, SRPK1, were assessed by RT-qPCR and immunoblotting in both AECs and aortic macrophages. We found that HFD mice developed AS in 12 weeks, while the NOR did not. Compared to NOR mice, HFD mice possessed significantly more AECs and AEC proliferation, and had significantly more aortic infiltrated macrophages and more apoptosis of them. Significant shift of VEGF-A splicing to pro-angiogenic VEGF165 was detected in both AECs and macrophages from HFD mice, seemingly through upregulation of SRPK1. In vitro, SRPK1 overexpression significantly increased EC proliferation and macrophage apoptosis. Thus, our data suggest that alternative splicing of VEGF-A to pro-angiogenic VEGF165 may contribute to the development of AS.
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Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice

Justin Darcy, Samuel McFadden, Yimin Fang, Darlene E. Berryman, Edward O. List, Nicholas Milcik, Andrzej Bartke,

https://doi.org/10.18632/aging.101582 pp 2709—2722

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Darcy J, McFadden S, Fang Y, Berryman DE, List EO, Milcik N, Bartke A, . Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice. . 10:2709-2722. https://doi.org/10.18632/aging.101582

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                TY  - JOUR
                AU  - Darcy, Justin 
                AU  - McFadden, Samuel 
                AU  - Fang, Yimin 
                AU  - Berryman, Darlene E. 
                AU  - List, Edward O. 
                AU  - Milcik, Nicholas 
                AU  - Bartke, Andrzej 
                TI  - Increased environmental temperature normalizes energy metabolism outputs between normal and Ames dwarf mice
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101582
                DO  - 10.18632/aging.101582
                SP  - 2709
                EP  - 2722
                PY  - 
                AB  - Ames dwarf (Prop1df) mice possess a loss-of-function mutation that results in deficiency of growth hormone, prolactin, and thyroid-stimulating hormone, as well as exceptional longevity. Work in other laboratories suggests that increased respiration and lipid utilization are important for maximizing mammalian longevity. Interestingly, these phenotypes are observed in Ames dwarf mice. We recently demonstrated that Ames dwarf mice have hyperactive brown adipose tissue (BAT), and hypothesized that this may in part be due to their increased surface to mass ratio leading to increased heat loss and an increased demand for thermogenesis. Here, we used increased environmental temperature (eT) to interrogate this hypothesis. We found that increased eT diminished BAT activity in Ames dwarf mice, and led to the normalization of both VO2 and respiratory quotient between dwarf and normal mice, as well as partial normalization (i.e. impairment) of glucose homeostasis in Ames dwarf mice housed at an increased eT. Together, these data suggest that an increased demand for thermogenesis is partially responsible for the improved energy metabolism and glucose homeostasis which are observed in Ames dwarf mice.
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Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice

Yuji Morita, Kenta Jounai, Akihiko Sakamoto, Yasuyuki Tomita, Yoshihiko Sugihara, Hiroaki Suzuki, Konomi Ohshio, Masato Otake, Daisuke Fujiwara, Osamu Kanauchi, Mitsuo Maruyama,

https://doi.org/10.18632/aging.101583 pp 2723—2740

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Morita Y, Jounai K, Sakamoto A, Tomita Y, Sugihara Y, Suzuki H, Ohshio K, Otake M, Fujiwara D, Kanauchi O, Maruyama M, . Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice. . 10:2723-2740. https://doi.org/10.18632/aging.101583

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 TY - JOUR
 AU - Morita, Yuji 
 AU - Jounai, Kenta 
 AU - Sakamoto, Akihiko 
 AU - Tomita, Yasuyuki 
 AU - Sugihara, Yoshihiko 
 AU - Suzuki, Hiroaki 
 AU - Ohshio, Konomi 
 AU - Otake, Masato 
 AU - Fujiwara, Daisuke 
 AU - Kanauchi, Osamu 
 AU - Maruyama, Mitsuo 
 TI - Long-term intake of Lactobacillus paracasei KW3110 prevents age-related chronic inflammation and retinal cell loss in physiologically aged mice
 JO - 
 JA - 
 VL - 10
 IS - 10
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101583
 DO - 10.18632/aging.101583
 SP - 2723
 EP - 2740
 PY - 
 AB - Age-related chronic inflammation is a major risk factor for the incidence and prevalence of age-related diseases, including infectious and neurodegenerative diseases. We previously reported that a lactic acid bacteria, Lactobacillus paracasei KW3110, activated macrophages and suppressed inflammation in mice and humans. In this study, we investigated whether long-term intake of heat-killed L. paracasei KW3110 modulated age-related inflammation and altered the gut microbiota in physiologically aged mice. Compared with age-matched control mice, fecal analyses of gut microbiota revealed that intake of L. paracasei KW3110 mitigated age-related changes of beneficial bacterial composition, including the Bifidobacteriaceae family. L. paracasei KW3110 intake also mitigated age-related immune defects by reducing the prevalence of interferon-gamma (IFN-γ) -producing inflammatory CD4-positive T cells in the lamina propia of the small intestine, and reduced serum levels of proinflammatory cytokines. Furthermore, L. paracasei KW3110 intake suppressed retinal inflammation by reducing proinflammatory cytokine-producing macrophage, and age-related retinal cell loss. Taken together, these findings suggested that L. paracasei KW3110 mitigated age-related chronic inflammation through modulation of gut microbiota composition and immune system functions in aged mice, and also reduced age-related retinal ganglion cell (RGC) loss. Further studies are needed to evaluate the effect in age-related senescent changes of the retina.
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A single-nucleotide polymorphism (rs1805087) in the methionine synthase (METH) gene increases the risk of prostate cancer

Xiaosong Zhang, Jilei Tang, Nan Shen, Kewei Ren,

https://doi.org/10.18632/aging.101584 pp 2741—2754

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Zhang X, Tang J, Shen N, Ren K, . A single-nucleotide polymorphism (rs1805087) in the methionine synthase (METH) gene increases the risk of prostate cancer. . 10:2741-2754. https://doi.org/10.18632/aging.101584

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                TY  - JOUR
                AU  - Zhang, Xiaosong 
                AU  - Tang, Jilei 
                AU  - Shen, Nan 
                AU  - Ren, Kewei 
                TI  - A single-nucleotide polymorphism (rs1805087) in the methionine synthase (METH) gene increases the risk of prostate cancer
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101584
                DO  - 10.18632/aging.101584
                SP  - 2741
                EP  - 2754
                PY  - 
                AB  - Methionine synthase (METH, i.e., MTR) is a key enzyme in the folate pathway, which plays a critical role in the synthesis, repair, and methylation of DNA. The association between METH gene polymorphisms and prostate cancer susceptibility remains ambiguous. Thus, we performed an updated meta-analysis of METH single-nucleotide polymorphism rs1805087 involving 12 independent case-control studies comprising 9986 prostate cancer patients and 40134 controls. The odds ratio and 95% confidence intervals were applied to evaluate the relation of this single-nucleotide polymorphism with prostate cancer. Statistical analysis was performed in STATA 11.0. A significant association was found between rs1805087 and increased prostate cancer risk, overall and with Hardy–Weinberg equilibrium. In subgroup analyses (based on ethnicity, source of control, genotyping methods, or publication status), similar associations were observed (e.g., genotype GA vs. AA: odds ratio 1.19, 95% confidence interval 1.01–1.40 among whites; G allele vs. A allele: odds ratio 1.14, 95% confidence interval 1.02–1.28 among hospital-based controls). Thus, the common polymorphism (rs1805087) of METH may be associated with increased prostate cancer risk. Further studies with a larger sample size and detailed gene–environment interactions should be conducted to identify the role of METH polymorphisms in prostate cancer susceptibility.
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Pretreatment TACC3 expression in locally advanced rectal cancer decreases the response to neoadjuvant chemoradiotherapy

Wen-juan Ma, Yang-kui Gu, Jian-hong Peng, Xue-cen Wang, Xin Yue, Zhi-zhong Pan, Gong Chen, Hai-neng Xu, Zhong-guo Zhou, Rong-xin Zhang,

https://doi.org/10.18632/aging.101585 pp 2755—2771

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Ma W, Gu Y, Peng J, Wang X, Yue X, Pan Z, Chen G, Xu H, Zhou Z, Zhang R, . Pretreatment TACC3 expression in locally advanced rectal cancer decreases the response to neoadjuvant chemoradiotherapy. . 10:2755-2771. https://doi.org/10.18632/aging.101585

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                TY  - JOUR
                AU  - Ma, Wen-juan 
                AU  - Gu, Yang-kui 
                AU  - Peng, Jian-hong 
                AU  - Wang, Xue-cen 
                AU  - Yue, Xin 
                AU  - Pan, Zhi-zhong 
                AU  - Chen, Gong 
                AU  - Xu, Hai-neng 
                AU  - Zhou, Zhong-guo 
                AU  - Zhang, Rong-xin 
                TI  - Pretreatment TACC3 expression in locally advanced rectal cancer decreases the response to neoadjuvant chemoradiotherapy
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101585
                DO  - 10.18632/aging.101585
                SP  - 2755
                EP  - 2771
                PY  - 
                AB  - Chemoradiotherapy combined with surgical resection is the standard treatment for locally advanced rectal cancer, but not all the patients respond to neoadjuvant treatment. Transforming acidic coiled-coil protein-3 (TACC3) is frequently aberrantly expressed in rectal cancer tissue. In this study, we investigated whether TACC3 could serve as a biomarker predictive of the efficacy of chemoradiotherapy. In all, 152 rectal cancer patients with tumor tissue collected at biopsy and set aside before treatment were enrolled in this study. All patients received chemoradiotherapy and surgical resection. Immunohistochemically detected tumoral TACC3 expression significantly decreased sensitivity to chemoradiotherapy [risk ratio (RR) = 2.236, 95% confidence interval (CI): 1.447–3.456; P = 0.001] and thus the pathological complete response rate (P = 0.001). TACC3 knockdown using specific siRNA enhanced radiotherapy-induced decreases in proliferation and colony formation by HCT116 and SW480 cells and increased the incidence of radiotherapy-induced apoptosis. Cox multivariate analysis showed that TACC3 was a significant prognostic factor for overall survival (P = 0.017) and disease-free survival (P = 0.020). These findings suggest TACC3 expression may be predictive of chemoradiotherapy sensitivity and prognosis in locally advanced rectal cancer.
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Autophagy of macrophages is regulated by PI3k/Akt/mTOR signalling in the development of diabetic encephalopathy

Beiyun Wang, Yuan Zhong, Qinjie Li, Liang Cui, Gaozhong Huang,

https://doi.org/10.18632/aging.101586 pp 2772—2782

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Wang B, Zhong Y, Li Q, Cui L, Huang G, . Autophagy of macrophages is regulated by PI3k/Akt/mTOR signalling in the development of diabetic encephalopathy. . 10:2772-2782. https://doi.org/10.18632/aging.101586

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                TY  - JOUR
                AU  - Wang, Beiyun 
                AU  - Zhong, Yuan 
                AU  - Li, Qinjie 
                AU  - Cui, Liang 
                AU  - Huang, Gaozhong 
                TI  - Autophagy of macrophages is regulated by PI3k/Akt/mTOR signalling in the development of diabetic encephalopathy
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101586
                DO  - 10.18632/aging.101586
                SP  - 2772
                EP  - 2782
                PY  - 
                AB  - The development of diabetic encephalopathy (DE) is enhanced by inflammatory macrophages, and is suppressed by macrophage autophagy. However, the molecular signaling that controls macrophage autophagy in DE remains ill-defined. Here, DE is induced in rats that received intraperitoneal injection of streptozotocin (STZ). In macrophages isolated from the brain of the rats, we detected downregulated autophagy activity and enhanced PI3k/Akt/mTOR/S6K1 signaling. In order to examine the role of autophagy and PI3k/Akt/mTOR signaling in DE development, an mTOR inhibitor, rapamycin, or an autophagy inhibitor, chloroquine (CQ), were administered to the rats that that received STZ. We found that rapamycin significantly enhanced DE development through mTOR suppression-induced augmentation of macrophage autophagy, while CQ significantly decreased DE development through suppression of macrophage autophagy. Together, our data suggest that PI3k/Akt/mTOR signaling may promote the development of DE through suppression of macrophage autophagy.
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Ubiquitin-speciﬁc protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition

Chan Qiu, Yan Liu, Ying Mei, Min Zou, Zhibo Zhao, Mingxin Ye, Xiaoling Wu,

https://doi.org/10.18632/aging.101587 pp 2783—2799

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Qiu C, Liu Y, Mei Y, Zou M, Zhao Z, Ye M, Wu X, . Ubiquitin-speciﬁc protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition. . 10:2783-2799. https://doi.org/10.18632/aging.101587

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                TY  - JOUR
                AU  - Qiu, Chan 
                AU  - Liu, Yan 
                AU  - Mei, Ying 
                AU  - Zou, Min 
                AU  - Zhao, Zhibo 
                AU  - Ye, Mingxin 
                AU  - Wu, Xiaoling 
                TI  - Ubiquitin-speciﬁc protease 4 promotes metastasis of hepatocellular carcinoma by increasing TGF-β signaling-induced epithelial-mesenchymal transition
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101587
                DO  - 10.18632/aging.101587
                SP  - 2783
                EP  - 2799
                PY  - 
                AB  - Invasion and metastasis are the main cause of recurrence and death in advanced hepatocellular carcinoma (HCC). Revealing the mechanisms of HCC metastasis is important for developing new therapeutic approaches and reducing patient mortality. Ubiquitin specific protease 4 (USP4), is involved in tumorigenesis by deubiquitinating some important oncogenic proteins and impacting their degradation. In the present study, we found that USP4 was significantly upregulated in HCC tumor tissues and the high expression of USP4 was associated with distant metastasis and poor survival in patients. Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results. In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis. Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-β receptor type I (TGFR-1) to activate the TGF-β signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells. Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-β signaling-Induced EMT. These results could provide a new therapeutic target for the treatment of HCC.
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Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression

Sylwia Kabacik, Steve Horvath, Howard Cohen, Kenneth Raj,

https://doi.org/10.18632/aging.101588 pp 2800—2815

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Kabacik S, Horvath S, Cohen H, Raj K, . Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression. . 10:2800-2815. https://doi.org/10.18632/aging.101588

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                TY  - JOUR
                AU  - Kabacik, Sylwia 
                AU  - Horvath, Steve 
                AU  - Cohen, Howard 
                AU  - Raj, Kenneth 
                TI  - Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101588
                DO  - 10.18632/aging.101588
                SP  - 2800
                EP  - 2815
                PY  - 
                AB  - The paramount role of senescent cells in ageing has prompted suggestions that re-expression of telomerase may prevent ageing; a proposition that is predicated on the assumption that senescent cells are the sole cause of ageing. Recently, several DNA methylation-based age estimators (epigenetic clocks) have been developed and they revealed that increased epigenetic age is associated with a host of age-related conditions, and is predictive of lifespan. Employing these clocks to measure epigenetic age in vitro, we interrogated the relationship between epigenetic ageing and telomerase activity. Although hTERT did not induce any perceptible change to the rate of epigenetic ageing, hTERT-expressing cells, which bypassed senescence, continued to age epigenetically. Employment of hTERT mutants revealed that neither telomere synthesis nor immortalisation is necessary for the continued increase in epigenetic age by these cells. Instead, the extension of their lifespan is sufficient to support continued epigenetic ageing of the cell. These characteristics, observed in cells from numerous donors and cell types, reveal epigenetic ageing to be distinct from replicative senescence. Hence, while re-activation of hTERT may stave off physical manifestation of ageing through avoidance of replicative senescence, it would have little impact on epigenetic ageing which continues in spite of telomerase activity.
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Re-exploring the core genes and modules in the human frontal cortex during chronological aging: insights from network-based analysis of transcriptomic studies

Mulin Xu, Yu Liu, Yi Huang, Jinli Wang, Jinhua Yan, Le Zhang, Cuntai Zhang,

https://doi.org/10.18632/aging.101589 pp 2816—2831

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Xu M, Liu Y, Huang Y, Wang J, Yan J, Zhang L, Zhang C, . Re-exploring the core genes and modules in the human frontal cortex during chronological aging: insights from network-based analysis of transcriptomic studies. . 10:2816-2831. https://doi.org/10.18632/aging.101589

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                TY  - JOUR
                AU  - Xu, Mulin 
                AU  - Liu, Yu 
                AU  - Huang, Yi 
                AU  - Wang, Jinli 
                AU  - Yan, Jinhua 
                AU  - Zhang, Le 
                AU  - Zhang, Cuntai 
                TI  - Re-exploring the core genes and modules in the human frontal cortex during chronological aging: insights from network-based analysis of transcriptomic studies
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101589
                DO  - 10.18632/aging.101589
                SP  - 2816
                EP  - 2831
                PY  - 
                AB  - Frontal cortical dysfunction is a fundamental pathology contributing to age-associated behavioral and cognitive deficits that predispose older adults to neurodegenerative diseases. It is established that aging increases the risk of frontal cortical dysfunction; however, the underlying molecular mechanism remains elusive. Here, we used an integrative meta-analysis to combine five frontal cortex microarray studies with a combined sample population of 161 younger and 155 older individuals. A network-based analysis was used to describe an outline of human frontal cortical aging to identify core genes whose expression changes with age and to reveal the interrelationships among these genes. We found that histone deacetylase 1 (HDAC1) and YES proto-oncogene 1 (YES1) are the two most upregulated genes, while cell division cycle 42 (CDC42) is the central regulatory gene decreased in the aged human frontal cortex. Quantitative PCR assays revealed corresponding changes in frontal cortical Hdac1, Yes1 and Cdc42 mRNA levels in an established aging mouse model. Moreover, analysis of the GSE48350 dataset confirmed similar changes in HDAC1, CDC42 and YES1 expression in Alzheimer's disease, thereby providing a molecular connection between aging and Alzheimer's disease (AD). This framework of network-based analysis could provide novel strategies for detecting and monitoring aging in the brain.
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A multi-tissue full lifespan epigenetic clock for mice

Michael J. Thompson, Karolina Chwiałkowska, Liudmilla Rubbi, Aldons J. Lusis, Richard C. Davis, Anuj Srivastava, Ron Korstanje, Gary A. Churchill, Steve Horvath, Matteo Pellegrini,

https://doi.org/10.18632/aging.101590 pp 2832—2854

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Thompson MJ, Chwiałkowska K, Rubbi L, Lusis AJ, Davis RC, Srivastava A, Korstanje R, Churchill GA, Horvath S, Pellegrini M, . A multi-tissue full lifespan epigenetic clock for mice. . 10:2832-2854. https://doi.org/10.18632/aging.101590

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                TY  - JOUR
                AU  - Thompson, Michael J. 
                AU  - Chwiałkowska, Karolina 
                AU  - Rubbi, Liudmilla 
                AU  - Lusis, Aldons J. 
                AU  - Davis, Richard C. 
                AU  - Srivastava, Anuj 
                AU  - Korstanje, Ron 
                AU  - Churchill, Gary A. 
                AU  - Horvath, Steve 
                AU  - Pellegrini, Matteo 
                TI  - A multi-tissue full lifespan epigenetic clock for mice
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101590
                DO  - 10.18632/aging.101590
                SP  - 2832
                EP  - 2854
                PY  - 
                AB  - Human DNA-methylation data have been used to develop highly accurate biomarkers of aging ("epigenetic clocks"). Recent studies demonstrate that similar epigenetic clocks for mice (Mus Musculus) can be slowed by gold standard anti-aging interventions such as calorie restriction and growth hormone receptor knock-outs. Using DNA methylation data from previous publications with data collected in house for a total 1189 samples spanning 193,651 CpG sites, we developed 4 novel epigenetic clocks by choosing different regression models (elastic net- versus ridge regression) and by considering different sets of CpGs (all CpGs vs highly conserved CpGs). We demonstrate that accurate age estimators can be built on the basis of highly conserved CpGs. However, the most accurate clock results from applying elastic net regression to all CpGs. While the anti-aging effect of calorie restriction could be detected with all types of epigenetic clocks, only ridge regression based clocks replicated the finding of slow epigenetic aging effects in dwarf mice. Overall, this study demonstrates that there are trade-offs when it comes to epigenetic clocks in mice. Highly accurate clocks might not be optimal for detecting the beneficial effects of anti-aging interventions.
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The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells

Angelica Giuliani, Ilenia Cirilli, Francesco Prattichizzo, Emanuela Mensà, Gianluca Fulgenzi, Jacopo Sabbatinelli, Laura Graciotti, Fabiola Olivieri, Antonio Domenico Procopio, Luca Tiano, Maria Rita Rippo,

https://doi.org/10.18632/aging.101591 pp 2855—2873

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Giuliani A, Cirilli I, Prattichizzo F, Mensà E, Fulgenzi G, Sabbatinelli J, Graciotti L, Olivieri F, Procopio AD, Tiano L, Rippo MR, . The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells. . 10:2855-2873. https://doi.org/10.18632/aging.101591

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                TY  - JOUR
                AU  - Giuliani, Angelica 
                AU  - Cirilli, Ilenia 
                AU  - Prattichizzo, Francesco 
                AU  - Mensà, Emanuela 
                AU  - Fulgenzi, Gianluca 
                AU  - Sabbatinelli, Jacopo 
                AU  - Graciotti, Laura 
                AU  - Olivieri, Fabiola 
                AU  - Procopio, Antonio Domenico 
                AU  - Tiano, Luca 
                AU  - Rippo, Maria Rita 
                TI  - The mitomiR/Bcl-2 axis affects mitochondrial function and autophagic vacuole formation in senescent endothelial cells
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101591
                DO  - 10.18632/aging.101591
                SP  - 2855
                EP  - 2873
                PY  - 
                AB  - During senescence, cells undergo distinctive biochemical and morphological changes and become dysfunctional. MiRNAs are involved in the senescence process and specific miRNAs can localize to mitochondria (mitomiRs). We hypothesized that part of the typical alterations of senescence may depends on mitomiRs deregulation. Therefore, we thoroughly explored the phenotype of human endothelial cells undergoing replicative senescence (sHUVECs) and observed elongated/branched mitochondria, accumulation of autophagic vacuoles (AVs), increased ROS and IL-1β production and reduced expression of Bcl-2 compared to younger cells (yHUVECs). Despite these pro-apoptotic features, sHUVECs are more resistant to serum deprivation, conceivably due to development of pro-survival strategies such as upregulation of Bcl-xL and Survivin. We demonstrate that mitomiR-181a, -34a, and -146a, are overexpressed and localize to mitochondria in sHUVECs compared with yHUVECs and that they: i) down-regulate Bcl-2, ii) induce permeability transition pore opening and activation of caspase-1 and 3, iii) affect sensitivity to apoptosis and iv) promote the conversion of LC3-I to LC3-II. Overall, we document for the first time that some mitomiRs can act as mediators of the multiple but functionally linked biochemical and morphological changes that characterize aging cells and that they can promote different cellular outcomes according to the senescence status of the cell.
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Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism

Junxiang Yin, Shiping Li, Megan Nielsen, Tanner Carcione, Winnie S. Liang, Jiong Shi,

https://doi.org/10.18632/aging.101592 pp 2874—2883

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Yin J, Li S, Nielsen M, Carcione T, Liang WS, Shi J, . Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism. . 10:2874-2883. https://doi.org/10.18632/aging.101592

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                TY  - JOUR
                AU  - Yin, Junxiang 
                AU  - Li, Shiping 
                AU  - Nielsen, Megan 
                AU  - Carcione, Tanner 
                AU  - Liang, Winnie S. 
                AU  - Shi, Jiong 
                TI  - Sirtuin 3 attenuates amyloid-β induced neuronal hypometabolism
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101592
                DO  - 10.18632/aging.101592
                SP  - 2874
                EP  - 2883
                PY  - 
                AB  - Alzheimer’s disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-β (Aβ)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aβ-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aβ. Sirt3 plays an important role in regulating Aβ-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.
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Radiogenomics of lower-grade gliomas: a radiomic signature as a biological surrogate for survival prediction

Zenghui Qian, Yiming Li, Zhiyan Sun, Xing Fan, Kaibin Xu, Kai Wang, Shaowu Li, Zhong Zhang, Tao Jiang, Xing Liu, Yinyan Wang,

https://doi.org/10.18632/aging.101594 pp 2884—2899

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Qian Z, Li Y, Sun Z, Fan X, Xu K, Wang K, Li S, Zhang Z, Jiang T, Liu X, Wang Y, . Radiogenomics of lower-grade gliomas: a radiomic signature as a biological surrogate for survival prediction. . 10:2884-2899. https://doi.org/10.18632/aging.101594

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                TY  - JOUR
                AU  - Qian, Zenghui 
                AU  - Li, Yiming 
                AU  - Sun, Zhiyan 
                AU  - Fan, Xing 
                AU  - Xu, Kaibin 
                AU  - Wang, Kai 
                AU  - Li, Shaowu 
                AU  - Zhang, Zhong 
                AU  - Jiang, Tao 
                AU  - Liu, Xing 
                AU  - Wang, Yinyan 
                TI  - Radiogenomics of lower-grade gliomas: a radiomic signature as a biological surrogate for survival prediction
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101594
                DO  - 10.18632/aging.101594
                SP  - 2884
                EP  - 2899
                PY  - 
                AB  - Objective: We aimed to identify a radiomic signature to be used as a noninvasive biomarker of prognosis in patients with lower-grade gliomas (LGGs) and to reveal underlying biological processes through comprehensive radiogenomic investigation. Methods: We extracted 55 radiomic features from T2-weighted images of 233 patients with LGGs (training cohort: n = 85; validation cohort: n = 148). Univariate Cox regression and linear risk score formula were applied to generate a radiomic-based signature. Gene ontology analysis of highly expressed genes in the high-risk score group was conducted to establish a radiogenomic map. A nomogram was constructed for individualized survival prediction.Results: The six-feature radiomic signature stratified patients in the training cohort into low- or high-risk groups for overall survival (P = 0.0018). This result was successfully verified in the validation cohort (P = 0.0396). Radiogenomic analysis revealed that the prognostic radiomic signature was associated with hypoxia, angiogenesis, apoptosis, and cell proliferation. The nomogram resulted in high prognostic accuracy (C-index: 0.92, C-index: 0.70) and favorable calibration for individualized survival prediction in the training and validation cohorts.Conclusions: Our results suggest a great potential for the use of radiomic signature as a biological surrogate in providing prognostic information for patients with LGGs.
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Can mesenchymal stem cell lysate reverse aging?

Ming-Fen Hsu, Szu-Hsien Yu, Sheng-Ju Chuang, Tom Kwang-Chun Kuo, Pawan K. Singal, Chih-Yang Huang, Chung-Lan Kao, Chia-Hua Kuo,

https://doi.org/10.18632/aging.101595 pp 2900—2910

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Hsu M, Yu S, Chuang S, Kuo TK, Singal PK, Huang C, Kao C, Kuo C, . Can mesenchymal stem cell lysate reverse aging?. . 10:2900-2910. https://doi.org/10.18632/aging.101595

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                TY  - JOUR
                AU  - Hsu, Ming-Fen 
                AU  - Yu, Szu-Hsien 
                AU  - Chuang, Sheng-Ju 
                AU  - Kuo, Tom Kwang-Chun 
                AU  - Singal, Pawan K. 
                AU  - Huang, Chih-Yang 
                AU  - Kao, Chung-Lan 
                AU  - Kuo, Chia-Hua 
                TI  - Can mesenchymal stem cell lysate reverse aging?
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101595
                DO  - 10.18632/aging.101595
                SP  - 2900
                EP  - 2910
                PY  - 
                AB  - Recent findings regarding uses of adipose-derived mesenchymal stem cell (MSC)-lysate on weight loss and improved glucose tolerance in mice on a high-fat diet suggest an encouraging possibility of using MSC lysate for an anti-aging intervention in humans. However, weight loss and lipopenia during late life can be as life-threatening as hyperglycemia during early adulthood. For this 3-year lifelong experiment, a total of 92 rats were randomized into the vehicle-injected group (F=22; M=24) and the MSC lysate injected group (F=22, M=24). We examined longevity, spontaneous locomotor activity, and body composition in rats maintained on a normal diet and received an intermittent treatment of human adipose-derived MSC lysate (3 times a week, 11 times a month given every second month), starting at 12 months of age until natural death. In substantiating previous knowledge regarding the effects of long-term MSC lysate treatments on fat loss and insulin resistance, the present findings also highlighted a shortened average lifespan, a longer inactive time, and a greater bone loss with a relative increase of lean mass in MSC lysate rats with respect to controls. Conclusion: Our data suggest that MSC lysate treatments stimulate disparity in tissue development and produce a cachexia-like effect to decrease longevity.
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Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging

Francesca Casciaro, Francesca Beretti, Manuela Zavatti, James A. McCubrey, Stefano Ratti, Sandra Marmiroli, Matilde Y. Follo, Tullia Maraldi,

https://doi.org/10.18632/aging.101599 pp 2911—2934

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Casciaro F, Beretti F, Zavatti M, McCubrey JA, Ratti S, Marmiroli S, Follo MY, Maraldi T, . Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging. . 10:2911-2934. https://doi.org/10.18632/aging.101599

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                TY  - JOUR
                AU  - Casciaro, Francesca 
                AU  - Beretti, Francesca 
                AU  - Zavatti, Manuela 
                AU  - McCubrey, James A. 
                AU  - Ratti, Stefano 
                AU  - Marmiroli, Sandra 
                AU  - Follo, Matilde Y. 
                AU  - Maraldi, Tullia 
                TI  - Nuclear Nox4 interaction with prelamin A is associated with nuclear redox control of stem cell aging
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101599
                DO  - 10.18632/aging.101599
                SP  - 2911
                EP  - 2934
                PY  - 
                AB  - Mesenchymal stem cells have emerged as an important tool that can be used for tissue regeneration thanks to their easy preparation, differentiation potential and immunomodulatory activity. However, an extensive culture of stem cells in vitro prior to clinical use can lead to oxidative stress that can modulate different stem cells properties, such as self-renewal, proliferation, differentiation and senescence. The aim of this study was to investigate the aging process occurring during in vitro expansion of stem cells, obtained from amniotic fluids (AFSC) at similar gestational age.The analysis of 21 AFSC samples allowed to classify them in groups with different levels of stemness properties. In summary, the expression of pluripotency genes and the proliferation rate were inversely correlated with the content of reactive oxygen species (ROS), DNA damage signs and the onset premature aging markers, including accumulation of prelamin A, the lamin A immature form. Interestingly, a specific source of ROS, the NADPH oxidase isoform 4 (Nox4), can localize into PML nuclear bodies (PML-NB), where it associates to prelamin A. Besides, Nox4 post translational modification, involved in PML-NB localization, is linked to its degradation pathway, as it is also for prelamin A, thus possibly modulating the premature aging phenotype occurrence.
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The influence of the TNFα rs1800629 polymorphism on some inflammatory biomarkers in 45-60-year-old women with metabolic syndrome

Małgorzata Szkup, Elżbieta Chełmecka, Anna Lubkowska, Aleksander Jerzy Owczarek, Elżbieta Grochans,

https://doi.org/10.18632/aging.101600 pp 2935—2943

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Szkup M, Chełmecka E, Lubkowska A, Owczarek AJ, Grochans E, . The influence of the TNFα rs1800629 polymorphism on some inflammatory biomarkers in 45-60-year-old women with metabolic syndrome. . 10:2935-2943. https://doi.org/10.18632/aging.101600

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Provider: 
 TY - JOUR
 AU - Szkup, Małgorzata 
 AU - Chełmecka, Elżbieta 
 AU - Lubkowska, Anna 
 AU - Owczarek, Aleksander Jerzy 
 AU - Grochans, Elżbieta 
 TI - The influence of the TNFα rs1800629 polymorphism on some inflammatory biomarkers in 45-60-year-old women with metabolic syndrome
 JO - 
 JA - 
 VL - 10
 IS - 10
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101600
 DO - 10.18632/aging.101600
 SP - 2935
 EP - 2943
 PY - 
 AB - Introduction: There are reports that the TNFα gene (rs1800629) can be involved in the pathogenesis of metabolic syndrome through an increased production of pro-inflammatory cytokines. Therefore, we have decided to search for the relationship between the TNFα gene polymorphisms and serum levels of proinflammatory cytokines (IL-1α, IL-1β, IL-6, TNFα, IFNγ) and CRP in women with metabolic syndrome.Material and methods: The study sample consisted of 416 women aged 45-60 years, including 118 with metabolic syndrome. The participants were surveyed and subjected to anthropometric, biochemical and genetic analysis.Results: We noticed that in the group meeting the criteria for metabolic syndrome, the G/G genotype of the TNFα gene was related to higher IL-6 levels than in the remainder group. The carriers of the A/G genotype in the metabolic syndrome group had significantly higher levels of IFNγ than those in the group without this syndrome. CRP was significantly higher in the group with metabolic syndrome, irrespective of the women’s genotypes.Conclusions: The upregulation of IFNγ and IL-6 and CRP suggests that autoinflammatory process may play a significant role in the pathogenesis of metabolic syndrome. However, a direct relationship between the TNFα gene polymorphisms and inflammatory biomarkers analyzed in our study was not confirmed.
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XRCC1 gene polymorphisms and risk of neuroblastoma in Chinese children

Jiao Zhang, Zhenjian Zhuo, Wenya Li, Jinhong Zhu, Jing He, Jinsong Su,

https://doi.org/10.18632/aging.101601 pp 2944—2953

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Zhang J, Zhuo Z, Li W, Zhu J, He J, Su J, . XRCC1 gene polymorphisms and risk of neuroblastoma in Chinese children. . 10:2944-2953. https://doi.org/10.18632/aging.101601

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 TY - JOUR
 AU - Zhang, Jiao 
 AU - Zhuo, Zhenjian 
 AU - Li, Wenya 
 AU - Zhu, Jinhong 
 AU - He, Jing 
 AU - Su, Jinsong 
 TI - XRCC1 gene polymorphisms and risk of neuroblastoma in Chinese children
 JO - 
 JA - 
 VL - 10
 IS - 10
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101601
 DO - 10.18632/aging.101601
 SP - 2944
 EP - 2953
 PY - 
 AB - Neuroblastoma is a common pediatric extra-cranial tumor of the sympathetic nervous system. XRCC1 is a scaffold protein that participates in DNA single-strand break repair by complexing with other proteins. XRCC1 gene polymorphisms are being increasingly explored in cancer epidemiology studies. However, the contribution of XRCC1 gene polymorphisms to neuroblastoma risk remains unclarified. Herein, we conducted a case-control study with 393 neuroblastoma patients and 812 controls to explore the association of XRCC1 gene polymorphisms (rs1799782 G&gt;A, rs25487 C&gt;T, rs25489 C&gt;T and rs915927 T&gt;C) with neuroblastoma risk. Results showed that none of the studied polymorphisms was associated with neuroblastoma risk. However, individuals with 2 risk genotypes seemed to be at significantly higher risk for neuroblastoma compared with those without risk genotype (adjusted odds ratio=1.69; 95% confidence interval=1.06-2.69). Stratified analysis revealed that the XRCC1 rs25489 CT/TT was strongly associated with reduced risk of neuroblastoma in the children ≤ 18 months of age and subgroup with clinical stage I+II+4s diseases, compared with CC genotypes. We also identified an increased neuroblastoma risk for carrier of 2-3 risk genotypes among children ≤ 18 months of age and subgroup with clinical stage I+II+4s. More evidence of the association between XRCC1 gene polymorphisms and neuroblastoma risk is needed.
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Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress

Jia Fang, Yuan Yan, Xin Teng, Xinyu Wen, Na Li, Sha Peng, Wenshuai Liu, F. Xavier Donadeu, Shanting Zhao, Jinlian Hua,

https://doi.org/10.18632/aging.101602 pp 2954—2972

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Fang J, Yan Y, Teng X, Wen X, Li N, Peng S, Liu W, Donadeu FX, Zhao S, Hua J, . Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress. . 10:2954-2972. https://doi.org/10.18632/aging.101602

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                TY  - JOUR
                AU  - Fang, Jia 
                AU  - Yan, Yuan 
                AU  - Teng, Xin 
                AU  - Wen, Xinyu 
                AU  - Li, Na 
                AU  - Peng, Sha 
                AU  - Liu, Wenshuai 
                AU  - Donadeu, F. Xavier 
                AU  - Zhao, Shanting 
                AU  - Hua, Jinlian 
                TI  - Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101602
                DO  - 10.18632/aging.101602
                SP  - 2954
                EP  - 2972
                PY  - 
                AB  - Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during in vitro expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages in vitro, we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-κB signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-κB and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.
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Quantitative characterization of biological age and frailty based on locomotor activity records

Timothy V. Pyrkov, Evgeny Getmantsev, Boris Zhurov, Konstantin Avchaciov, Mikhail Pyatnitskiy, Leonid Menshikov, Kristina Khodova, Andrei V. Gudkov, Peter O. Fedichev,

https://doi.org/10.18632/aging.101603 pp 2973—2990

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Pyrkov TV, Getmantsev E, Zhurov B, Avchaciov K, Pyatnitskiy M, Menshikov L, Khodova K, Gudkov AV, Fedichev PO, . Quantitative characterization of biological age and frailty based on locomotor activity records. . 10:2973-2990. https://doi.org/10.18632/aging.101603

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                TY  - JOUR
                AU  - Pyrkov, Timothy V. 
                AU  - Getmantsev, Evgeny 
                AU  - Zhurov, Boris 
                AU  - Avchaciov, Konstantin 
                AU  - Pyatnitskiy, Mikhail 
                AU  - Menshikov, Leonid 
                AU  - Khodova, Kristina 
                AU  - Gudkov, Andrei V. 
                AU  - Fedichev, Peter O. 
                TI  - Quantitative characterization of biological age and frailty based on locomotor activity records
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101603
                DO  - 10.18632/aging.101603
                SP  - 2973
                EP  - 2990
                PY  - 
                AB  - We performed a systematic evaluation of the relationships between locomotor activity and signatures of frailty, morbidity, and mortality risks using physical activity records from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) and UK BioBank (UKB). We proposed a statistical description of the locomotor activity tracks and transformed the provided time series into vectors representing physiological states for each participant. The Principal Component Analysis of the transformed data revealed a winding trajectory with distinct segments corresponding to subsequent human development stages. The extended linear phase starts from 35−40 years old and is associated with the exponential increase of mortality risks according to the Gompertz mortality law. We characterized the distance traveled along the aging trajectory as a natural measure of biological age and demonstrated its significant association with frailty and hazardous lifestyles, along with the remaining lifespan and healthspan of an individual. The biological age explained most of the variance of the log-hazard ratio that was obtained by fitting directly to mortality and the incidence of chronic diseases. Our findings highlight the intimate relationship between the supervised and unsupervised signatures of the biological age and frailty, a consequence of the low intrinsic dimensionality of the aging dynamics.
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Sirt1/Nrf2 pathway is involved in oocyte aging by regulating Cyclin B1

Rujun Ma, Wei Liang, Qin Sun, Xuhua Qiu, Ying Lin, Xie Ge, Kadiliya Jueraitetibaike, Min Xie, Ji Zhou, Xuan Huang, Qiang Wang, Li Chen, Bing Yao,

https://doi.org/10.18632/aging.101609 pp 2991—3004

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Ma R, Liang W, Sun Q, Qiu X, Lin Y, Ge X, Jueraitetibaike K, Xie M, Zhou J, Huang X, Wang Q, Chen L, Yao B, . Sirt1/Nrf2 pathway is involved in oocyte aging by regulating Cyclin B1. . 10:2991-3004. https://doi.org/10.18632/aging.101609

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                TY  - JOUR
                AU  - Ma, Rujun 
                AU  - Liang, Wei 
                AU  - Sun, Qin 
                AU  - Qiu, Xuhua 
                AU  - Lin, Ying 
                AU  - Ge, Xie 
                AU  - Jueraitetibaike, Kadiliya 
                AU  - Xie, Min 
                AU  - Zhou, Ji 
                AU  - Huang, Xuan 
                AU  - Wang, Qiang 
                AU  - Chen, Li 
                AU  - Yao, Bing 
                TI  - Sirt1/Nrf2 pathway is involved in oocyte aging by regulating Cyclin B1
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101609
                DO  - 10.18632/aging.101609
                SP  - 2991
                EP  - 3004
                PY  - 
                AB  - Nuclear factor erythroid 2-related factor 2 (Nrf2) is capable of inducing a variety of biological effects, and the regulation of the Nrf2 signaling pathway is closely related to longevity. To find out whether the nuclear factor erythroid 2-related factor 2 (Nrf2) is involved in oocyte aging or not which may cause reduced female fertility, a series of biological methods was applied, including oocyte collection and culture, micro injection, RNA interference, western blotting, immunofluorescence and confocal microscopy, and quantitative real-time PCR.Our data demonstrated that Nrf2 depletion disrupted oocyte maturation and spindle/chromosome organization by suppressing Cyclin B1 expression. Sirtuin 1 (Sirt1) depletion reduced Nrf2 expression, which indicated the existence of the Sirt1-Nrf2-Cyclin B1 signaling pathway in mouse oocytes. Additionally, immunoblotting results reflected a lower Nrf2 protein level in oocytes from aged mice, and maternal age-associated meiotic defects can be ameliorated through overexpression of Nrf2, which supported the hypothesis that decreased Nrf2 is an important factor contributing toward oocyte age-dependent deﬁcits. Furthermore, we show that the expression of Nrf2 is related to female age in ovarian granular cells, suggesting that the decreased expression of Nrf2 may be related to the decline in the reproductive capacity of older women.
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Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men

Xiaotian Yuan, Magnus Kronström, Mai-Lis Hellenius, Tommy Cederholm, Dawei Xu, Per Sjögren,

https://doi.org/10.18632/aging.101611 pp 3005—3016

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Yuan X, Kronström M, Hellenius M, Cederholm T, Xu D, Sjögren P, . Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men. . 10:3005-3016. https://doi.org/10.18632/aging.101611

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                TY  - JOUR
                AU  - Yuan, Xiaotian 
                AU  - Kronström, Magnus 
                AU  - Hellenius, Mai-Lis 
                AU  - Cederholm, Tommy 
                AU  - Xu, Dawei 
                AU  - Sjögren, Per 
                TI  - Longitudinal changes in leukocyte telomere length and mortality in elderly Swedish men
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101611
                DO  - 10.18632/aging.101611
                SP  - 3005
                EP  - 3016
                PY  - 
                AB  - Telomere length (TL) is considered an indicator of aging and age-related diseases, but longitudinal studies on TL changes and mortality are few. We therefore analyzed TL and longitudinal changes in TL in relation to all-cause, cardiovascular, and cancer mortality in 247 elderly Swedish men. TL was determined by the qPCR method at ages 71 and 81 and subsequent mortality cases were identified from the Swedish cause-of-death registry. Cox proportional hazard ratios were calculated during a mean follow-up of 7.4 years, during which 178 deaths occurred. Short telomeres at baseline was strongly associated with mortality risks, with a 40 to 70% increased risk of all-cause mortality, and a 2-fold increased risk of cancer mortality. Longitudinal changes in TL revealed shortening in 83% of individuals, whilst 10% extended their telomeres. TL attrition did not predict all-cause or cancer mortality, but we found a 60% decreased risk for cardiovascular mortality in those who shortened their telomeres. Our data show an increased risk of mortality in individuals with short baseline telomeres, but no relations to all-cause, and cancer mortality for changes in TL. Intriguingly, our data indicate lower risk of cardiovascular mortality with shortening of telomeres. The latter should be interpreted cautiously.
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Age- and sex-dependent changes in levels of circulating brain-enriched microRNAs during normal aging

Kira Sheinerman, Vladimir Tsivinsky, Aabhas Mathur, Debra Kessler, Beth Shaz, Samuil Umansky,

https://doi.org/10.18632/aging.101613 pp 3017—3041

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Sheinerman K, Tsivinsky V, Mathur A, Kessler D, Shaz B, Umansky S, . Age- and sex-dependent changes in levels of circulating brain-enriched microRNAs during normal aging. . 10:3017-3041. https://doi.org/10.18632/aging.101613

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                TY  - JOUR
                AU  - Sheinerman, Kira 
                AU  - Tsivinsky, Vladimir 
                AU  - Mathur, Aabhas 
                AU  - Kessler, Debra 
                AU  - Shaz, Beth 
                AU  - Umansky, Samuil 
                TI  - Age- and sex-dependent changes in levels of circulating brain-enriched microRNAs during normal aging
                JO  - 
                JA  - 
                VL  - 10
                IS  - 10
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101613
                DO  - 10.18632/aging.101613
                SP  - 3017
                EP  - 3041
                PY  - 
                AB  - Aging is a major risk factor for many common and life-threatening pathologies. The development of reliable biomarkers of aging should lead to a better understanding of aging-associated processes and facilitate the development of therapeutic regimens that delay aging. Levels of 38 brain-enriched microRNAs (miRNA) circulating in plasma were measured by quantitative RT-PCR in two age groups: 26-35 and 56-65 years old. An miRNA-pair approach was used for data normalization and determination of effective miRNA biomarker ratios. Nineteen miRNAs, comprising miRNA pairs and pair combinations (classifiers) that effectively differentiated the age and sex (individual pairs: 74-95% and 68-95%, respectively; classifiers: up to 100% accuracy) groups, were selected for further analysis of plasma samples from 5 donor age groups: 26-35, 36-45, 46-55, 56-65 and 66-75 years old. Dynamic changes in the plasma concentrations of certain miRNAs occurred at different ages in females and males, with peaks in the 46-55-year-old and 56-65-year-old groups, respectively. This finding suggests that the changes in miRNA levels can reflect centrally regulated processes, including changes in hormone levels during menopause. Certain miRNAs and miRNA pairs correlated with age in the sex-stratified groups at different ages and should be investigated further as potentially promising biomarkers of brain aging.
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Volume 10, Issue 10

About the Cover

Editorials

Yusuke Takatsuru,

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Stefano L. Sensi,

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Tamir Ben-Hur, Nina Fainstein,

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Research Papers

Adrian Angenendt, Romy Steiner, Arne Knörck, Gertrud Schwär, Maik Konrad, Elmar Krause, Annette Lis,

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Bert M. Verheijen, Fred W. van Leeuwen,

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Flavio Di Stasio, Antonio Suppa, Alfredo Berardelli,

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Nathan Basisty, Birgit Schilling, Peter S. Rabinovitch,

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Abbi R. Hernandez, Sara N. Burke,

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Nicola King, Val Mann,

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Magda R. Hamczyk, Vicente Andrés,

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Theory Article

Samuil Umansky,

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Zhao Liu, Mi Chen, Lin-Ka Xie, Ting Liu, Zhen-Wei Zou, Yong Li, Peng Chen, Xin Peng, Charlie Ma, Wen-Jie Zhang, Pin-Dong Li,

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Alena Svobodová Kovaříková, Soňa Legartová, Jana Krejčí, Eva Bártová,

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Hongwei Liu, Dongliang Chen, Junming Bi, Jinli Han, Meihua Yang, Wei Dong, Tianxin Lin, Jian Huang,

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Qi Zhao, Hui Shen, Kuan-Jui Su, Qing Tian, Lan-Juan Zhao, Chuan Qiu, Timothy J. Garrett, Jiawang Liu, David Kakhniashvili, Hong-Wen Deng,

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Ping Hou, Hui-Ping Xue, Xin-E Mao, Yong-Nan Li, Lin-Feng Wu, Yong-Bing Liu,

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Yunchai Lin, Dan Hu, Qiang Zhou, Xiangdong Lin, Jinxiu Lin, Feng Peng,

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Berenice Franco-Juárez, Fanny Mejía-Martínez, Elizabeth Moreno-Arriola, Alain Hernández-Vázquez, Saul Gómez-Manzo, Jaime Marcial-Quino, Roberto Arreguín-Espinosa, Antonio Velázquez-Arellano, Daniel Ortega-Cuellar,

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Eisuke Tasaki, Yuki Mitaka, Tomonari Nozaki, Kazuya Kobayashi, Kenji Matsuura, Yoshihito Iuchi,

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