Volume 11, Issue 4

Zhu Y, Yang T, Duan J, Mu N, Zhang T, . MALAT1/miR-15b-5p/MAPK1 mediates endothelial progenitor cells autophagy and affects coronary atherosclerotic heart disease via mTOR signaling pathway. . 11:1089-1109. https://doi.org/10.18632/aging.101766

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 TY - JOUR
 AU - Zhu, Ying 
 AU - Yang, Tianrui 
 AU - Duan, Jinlan 
 AU - Mu, Ninghui 
 AU - Zhang, Tong 
 TI - MALAT1/miR-15b-5p/MAPK1 mediates endothelial progenitor cells autophagy and affects coronary atherosclerotic heart disease via mTOR signaling pathway
 JO - 
 JA - 
 VL - 11
 IS - 4
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101766
 DO - 10.18632/aging.101766
 SP - 1089
 EP - 1109
 PY - 
 AB - Objective: Present study focused on the influence of lncRNA MALAT1 on coronary atherosclerotic heart disease (CAD) by regulating miR-15b-5p/MAPK1 and mTOR signaling pathway.Method: Differentially expressed genes and activated pathway were investigated through bioinformatics analysis. QRT-PCR was conducted to verify expression of MALAT1, miR-15b-5p and MAPK1 in CAD blood samples and endothelial progenitor cells (EPCs). In addition, the interactions among MALAT1, miR-15b-5p and MAPK1 were revealed by Luciferase reporter assay. Cell autophagy of EPCs was examined by Cyto-ID Autophagy Detection Kit and transmission electron microscope. MTT assay and flow cytometry were carried out to assess cell viability and apoptosis in different interference conditions. Western blot was performed to testify the expression of pERK1/2 (MAPK1), phosphorylated mTOR, ATG1 and LC3-II. Vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were detected by qRT-PCR. Finally, the effect of lncRNA MALAT1 on cell autophagy and atherogenesis was tested in vivo.Results: MALAT1 was overexpressed in CAD blood samples and EPCs. Knockdown of MALAT1 and MAPK1 promoted cell viability, autophagy and further suppressed the development of CAD. AntagoMALAT1 protects mice against atherosclerosis.Conclusion: LncRNA MALAT1 inhibited EPCs autophagy and increased cell viability while repressed apoptosis of CAD via activating mTOR signaling pathway.
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The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality

Yan-Ru Li, Rui-Rui Peng, Wen-Yi Gao, Peng Liu, Liang-Jian Chen, Xiao-Lan Zhang, Na-Na Zhang, Yang Wang, Lei Du, Feng-Yu Zhu, Li-Li Wang, Cong-Rong Li, Wen-Tao Zeng, Jian-Min Li, Fan Hu, Dong Zhang, Zhi-Xia Yang,

https://doi.org/10.18632/aging.101802 pp 1110—1128

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Li Y, Peng R, Gao W, Liu P, Chen L, Zhang X, Zhang N, Wang Y, Du L, Zhu F, Wang L, Li C, Zeng W, et al, . The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality. . 11:1110-1128. https://doi.org/10.18632/aging.101802

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                TY  - JOUR
                AU  - Li, Yan-Ru 
                AU  - Peng, Rui-Rui 
                AU  - Gao, Wen-Yi 
                AU  - Liu, Peng 
                AU  - Chen, Liang-Jian 
                AU  - Zhang, Xiao-Lan 
                AU  - Zhang, Na-Na 
                AU  - Wang, Yang 
                AU  - Du, Lei 
                AU  - Zhu, Feng-Yu 
                AU  - Wang, Li-Li 
                AU  - Li, Cong-Rong 
                AU  - Zeng, Wen-Tao 
                AU  - Li, Jian-Min 
                AU  - Hu, Fan 
                AU  - Zhang, Dong 
                AU  - Yang, Zhi-Xia 
                TI  - The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101802
                DO  - 10.18632/aging.101802
                SP  - 1110
                EP  - 1128
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Li, Yan-Ru 
                AU  - Peng, Rui-Rui 
                AU  - Gao, Wen-Yi 
                AU  - Liu, Peng 
                AU  - Chen, Liang-Jian 
                AU  - Zhang, Xiao-Lan 
                AU  - Zhang, Na-Na 
                AU  - Wang, Yang 
                AU  - Du, Lei 
                AU  - Zhu, Feng-Yu 
                AU  - Wang, Li-Li 
                AU  - Li, Cong-Rong 
                AU  - Zeng, Wen-Tao 
                AU  - Li, Jian-Min 
                AU  - Hu, Fan 
                AU  - Zhang, Dong 
                AU  - Yang, Zhi-Xia 
                TI  - The ubiquitin ligase KBTBD8 regulates PKM1 levels via Erk1/2 and Aurora A to ensure oocyte quality
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101802
                DO  - 10.18632/aging.101802
                SP  - 1110
                EP  - 1128
                PY  - 
                AB  - Tight control of energy metabolism is essential for normal cell function and organism survival. PKM (pyruvate kinase, muscle) isoforms 1 and 2 originate from alternative splicing of PKM pre-mRNA. They are key enzymes in oxidative phosphorylation and aerobic glycolysis, respectively, and are essential for ATP generation. The PKM1:PKM2 expression ratio changes with development and differentiation, and may also vary under metabolic stress and other conditions. Until now, there have been no reports about the function and regulation of PKM isozymes in oocytes. Here, we demonstrate that PKM1 or PKM2 depletion significantly disrupts ATP levels and mitochondrial integrity, and exacerbates free-radical generation and apoptosis in mouse oocytes. We also show that KBTBD8, a female fertility factor in the KBTBD ubiquitin ligase family, selectively regulates PKM1 levels through a signaling cascade that includes Erk1/2 and Aurora A kinases as intermediates. Finally, using RNA sequencing and protein network analysis, we identify several regulatory proteins that may be govern generation of mature PKM1 mRNA. These results suggest KBTBD8 affects PKM1 levels in oocytes via a KBTBD8→Erk1/2→Aurora A axis, and may also affect other essential processes involved in maintaining oocyte quality.
                ER  -

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Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies

Lihong Yang, Jialu Zhu, Cong Zhang, Juntao Wang, Fengyang Yue, Xingtai Jia, Hongzhi Liu,

https://doi.org/10.18632/aging.101814 pp 1129—1150

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Yang L, Zhu J, Zhang C, Wang J, Yue F, Jia X, Liu H, . Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies. . 11:1129-1150. https://doi.org/10.18632/aging.101814

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                TY  - JOUR
                AU  - Yang, Lihong 
                AU  - Zhu, Jialu 
                AU  - Zhang, Cong 
                AU  - Wang, Juntao 
                AU  - Yue, Fengyang 
                AU  - Jia, Xingtai 
                AU  - Liu, Hongzhi 
                TI  - Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101814
                DO  - 10.18632/aging.101814
                SP  - 1129
                EP  - 1150
                PY  - 
                AB  - AimsStem cell-derived extracellular vesicles (EVs) have emerged as a promising therapy for myocardial infarction, but its effects remain incompletely understood. We aim to systematically review the efficacy of EVs on myocardial infarction in both small and large animals.MethodsOn April 5, 2018, we searched the PubMed, Embase and Web of Science databases using variations of “myocardial infarction” and “extracellular vesicle”. Controlled studies about the treatment effects of stem cell-derived EVs in myocardial infarction animal model were included. Meta-regression analysis was used to reveal the factors affecting the EVs treatments.ResultsOf 1210 studies retrieved, 24 were eligible for meta-analysis. EVs injection was associated with the improvements of left ventricular ejection fraction (12.65%), fractional shortening (7.54%) and the reduction of infarct size/area at risk (-15.55%). Meta-regression analysis did not reveal the association between treatment efficacy and type of stem cell, ligation-to-injection interval, route of delivery, dosage of delivery or follow-up period (all P values &gt; 0.05). The median quality score of eligible studies was only 1, indicating potential risks of bias.ConclusionStem cell-derived EVs improve cardiac function and reduce infarct size in myocardial infarction animals, but current pool-up study reveals no associations between common factors and treatment effects.
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DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways

Juan Wang, Sayyed Hanif Ullah, Meihe Li, Miao Zhang, Fujun Zhang, Jin Zheng, Xiaofei Yan,

https://doi.org/10.18632/aging.101815 pp 1151—1162

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Wang J, Ullah SH, Li M, Zhang M, Zhang F, Zheng J, Yan X, . DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways. . 11:1151-1162. https://doi.org/10.18632/aging.101815

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                TY  - JOUR
                AU  - Wang, Juan 
                AU  - Ullah, Sayyed Hanif 
                AU  - Li, Meihe 
                AU  - Zhang, Miao 
                AU  - Zhang, Fujun 
                AU  - Zheng, Jin 
                AU  - Yan, Xiaofei 
                TI  - DR region specific antibody ameliorated but ouabain worsened renal injury in nephrectomized rats through regulating Na,K-ATPase mediated signaling pathways
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101815
                DO  - 10.18632/aging.101815
                SP  - 1151
                EP  - 1162
                PY  - 
                AB  - Reduced Na+-K+-ATPase function is reported in various renal diseases. This implies that increase of Na+-K+-ATPase function may be a new target in treatment of renal injury. We previously reported that Na+-K+-ATPase was stabilized by DRm217, a specific antibody against DR region of Na+-K+-ATPase. In this study, we compared the protective effect of DRm217 and ouabain on kidney in a chronic kidney disease rat model and investigated the mechanism under it. We found that DRm217 improved renal function, alleviated glomerulus atrophy, inhibited renal tubular cells apoptosis, tubulointerstitial injury and renal fibrosis in 5/6 nephrectomized rats. Contrary to DRm217, ouabain worsened renal damage. Activated Na+-K+-ATPase /Src signaling pathway, increased oxidant stress and activated inflammasome were responsible for nephrectomized or ouabain-induced renal injury. DRm217 inhibited Na+-K+-ATPase /Src signaling pathway, retarded oxidant stress, suppressed inflammasome activation, and improved renal function, suggesting a novel approach to prevent renal damage.
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Alzheimer’s disease as a multistage process: an analysis from a population-based cohort study

Silvan Licher, Kimberly D. van der Willik, Elisabeth J. Vinke, Pinar Yilmaz, Lana Fani, Sanne B. Schagen, M. Arfan Ikram, M. Kamran Ikram,

https://doi.org/10.18632/aging.101816 pp 1163—1176

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Licher S, van der Willik KD, Vinke EJ, Yilmaz P, Fani L, Schagen SB, Ikram MA, Ikram MK, . Alzheimer’s disease as a multistage process: an analysis from a population-based cohort study. . 11:1163-1176. https://doi.org/10.18632/aging.101816

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                TY  - JOUR
                AU  - Licher, Silvan 
                AU  - van der Willik, Kimberly D. 
                AU  - Vinke, Elisabeth J. 
                AU  - Yilmaz, Pinar 
                AU  - Fani, Lana 
                AU  - Schagen, Sanne B. 
                AU  - Ikram, M. Arfan 
                AU  - Ikram, M. Kamran 
                TI  - Alzheimer’s disease as a multistage process: an analysis from a population-based cohort study
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101816
                DO  - 10.18632/aging.101816
                SP  - 1163
                EP  - 1176
                PY  - 
                AB  - In cancer research, multistage models are used to assess the multistep process that leads to the onset of cancer. In view of biological and clinical similarities between cancer and dementia, we used these models to study Alzheimer’s disease (AD). From the population-based Rotterdam Study, we included 9,362 non-demented participants, of whom 1,124 developed AD during up to 26 years of follow-up. Under a multistage model, we regressed the logarithm of AD incidence rate against the logarithm of five-year age categories. The slope in this model reflects the number of steps (n–1) required for disease onset before the final step leading to disease manifestation. A linear relationship between log incidence rate and log age was observed, with a slope of 12.82 (95% confidence interval: 9.01-16.62), equivalent to 14 steps. We observed fewer steps for those at high genetically determined risk: 12 steps for APOE-ε4 carriers, and 10 steps for those at highest genetic risk based on APOE and a genetic risk score. The pathogenesis of AD complies with a multistage disease-model, requiring 14 steps before disease manifestation. Genetically predisposed individuals require fewer steps indicating that they already inherited multiple of these steps. Unravelling these steps in AD pathogenesis could benefit the development of intervention strategies.
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Nutraceutical effects of Emblica officinalis in age-related macular degeneration

Sonali Nashine, Raj Kanodia, Anthony B. Nesburn, Girish Soman, Baruch D. Kuppermann, M. Cristina Kenney,

https://doi.org/10.18632/aging.101820 pp 1177—1188

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Nashine S, Kanodia R, Nesburn AB, Soman G, Kuppermann BD, Kenney MC, . Nutraceutical effects of Emblica officinalis in age-related macular degeneration. . 11:1177-1188. https://doi.org/10.18632/aging.101820

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Provider: 
 TY - JOUR
 AU - Nashine, Sonali 
 AU - Kanodia, Raj 
 AU - Nesburn, Anthony B. 
 AU - Soman, Girish 
 AU - Kuppermann, Baruch D. 
 AU - Kenney, M. Cristina 
 TI - Nutraceutical effects of Emblica officinalis in age-related macular degeneration
 JO - 
 JA - 
 VL - 11
 IS - 4
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101820
 DO - 10.18632/aging.101820
 SP - 1177
 EP - 1188
 PY - 
 AB - Emblica officinalis Gaetrn (i.e., Phyllanthus emblica/ Indian gooseberry/ Amla) (EO) has been used extensively as a nutraceutical in several diseases since it is known to boost immunity and offers numerous health benefits such as antioxidant, anti-inflammatory, and anti-aging effects. The goal of our study was to test the hypothesis that EO will rescue human AMD RPE transmitochondrial cells from mitochondria-induced cellular damage. AMD RPE transmitochondrial cell lines were created by fusion of mitochondria DNA-deficient APRE-19 (Rho0) cells with platelets isolated from AMD patients, and therefore had identical nuclei but differed in mitochondrial DNA content. These AMD RPE cells were treated with EO extract followed by characterization of effects of EO using cellular and molecular assays. Herein, EO significantly improved live cell number and mitochondrial membrane potential, reduced apoptosis and oxidative stress, down-regulated VEGF, and up-regulated PGC-1α. In conclusion, EO improved cellular and mitochondrial health, thereby playing a key cytoprotective role in AMD in vitro. Further studies are required to examine the mechanisms that mediate the cytoprotective effects of EO.
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Age and poverty status alter the coding and noncoding transcriptome

Nicole Noren Hooten, Michele K. Evans,

https://doi.org/10.18632/aging.101823 pp 1189—1203

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Noren Hooten N, Evans MK, . Age and poverty status alter the coding and noncoding transcriptome. . 11:1189-1203. https://doi.org/10.18632/aging.101823

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                TY  - JOUR
                AU  - Noren Hooten, Nicole 
                AU  - Evans, Michele K. 
                TI  - Age and poverty status alter the coding and noncoding transcriptome
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101823
                DO  - 10.18632/aging.101823
                SP  - 1189
                EP  - 1203
                PY  - 
                AB  - Emerging evidence indicates that noncoding RNAs play regulatory roles in aging and disease. The functional roles of long noncoding RNAs (lncRNAs) in physiology and disease are not completely understood. Little is known about lncRNAs in the context of human aging and socio-environmental conditions. Microarray profiling of lncRNAs and mRNAs from peripheral blood mononuclear cells from young and old white (n=16) and African American (AA) males (n=16) living above or below poverty from the Healthy Aging in Neighborhoods of Diversity across the Life Span study revealed changes in both lncRNAs and mRNAs with age and poverty status in white males, but not in AA males. We validated lncRNA changes in an expanded cohort (n=40); CTD-3247F14.2, GAS5, H19, TERC and MEG3 changed significantly with age, whereas AK022914, GAS5, KB-1047C11.2, MEG3 and XLOC_003262 changed with poverty. Mitochondrial function and response to DNA damage and stress were pathways enriched in younger individuals. Response to stress, viral infection, and immune signals were pathways enriched in individuals living above poverty. These data show that both human age and a marker of social adversity influence lncRNA expression, which may provide insight about molecular pathways underlying aging and social factors that affect disparities in aging and disease.
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m⁶A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas

Rui-Chao Chai, Fan Wu, Qi-Xue Wang, Shu Zhang, Ke-Nan Zhang, Yu-Qing Liu, Zheng Zhao, Tao Jiang, Yong-Zhi Wang, Chun-Sheng Kang,

https://doi.org/10.18632/aging.101829 pp 1204—1225

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Chai R, Wu F, Wang Q, Zhang S, Zhang K, Liu Y, Zhao Z, Jiang T, Wang Y, Kang C, . m⁶A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas. . 11:1204-1225. https://doi.org/10.18632/aging.101829

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 TY - JOUR
 AU - Chai, Rui-Chao 
 AU - Wu, Fan 
 AU - Wang, Qi-Xue 
 AU - Zhang, Shu 
 AU - Zhang, Ke-Nan 
 AU - Liu, Yu-Qing 
 AU - Zhao, Zheng 
 AU - Jiang, Tao 
 AU - Wang, Yong-Zhi 
 AU - Kang, Chun-Sheng 
 TI - m6A RNA methylation regulators contribute to malignant progression and have clinical prognostic impact in gliomas
 JO - 
 JA - 
 VL - 11
 IS - 4
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101829
 DO - 10.18632/aging.101829
 SP - 1204
 EP - 1225
 PY - 
 AB - N6-methyladenosine (m6A) RNA methylation, associated with cancer initiation and progression, is dynamically regulated by the m6A RNA methylation regulators (“writers”, “erasers” and “readers”). Here, we demonstrate that most of the thirteen main m6A RNA methylation regulators are differentially expressed among gliomas stratified by different clinicopathological features in 904 gliomas. We identified two subgroups of gliomas (RM1/2) by applying consensus clustering to m6A RNA methylation regulators. Compared with the RM1 subgroup, the RM2 subgroup correlates with a poorer prognosis, higher WHO grade, and lower frequency of IDH mutation. Moreover, the hallmarks of epithelial-mesenchymal transition and TNFα signaling via NF-κB are also significantly enriched in the RM2 subgroup. This finding indicates that m6A RNA methylation regulators are closely associated with glioma malignancy. Based on this finding, we derived a risk signature, using seven m6A RNA methylation regulators, that is not only an independent prognostic marker but can also predict the clinicopathological features of gliomas. Moreover, m6A regulators are associated with the mesenchymal subtype and TMZ sensitivity in GBM. In conclusion, m6A RNA methylation regulators are crucial participants in the malignant progression of gliomas and are potentially useful for prognostic stratification and treatment strategy development.
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Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: in vivo and in vitro experiments

Zeyu Li, Yifan Jia, Yang Feng, Ruixia Cui, Runchen Miao, Xing Zhang, Kai Qu, Chang Liu, Jingyao Zhang,

https://doi.org/10.18632/aging.101831 pp 1226—1239

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Li Z, Jia Y, Feng Y, Cui R, Miao R, Zhang X, Qu K, Liu C, Zhang J, . Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: in vivo and in vitro experiments. . 11:1226-1239. https://doi.org/10.18632/aging.101831

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                TY  - JOUR
                AU  - Li, Zeyu 
                AU  - Jia, Yifan 
                AU  - Feng, Yang 
                AU  - Cui, Ruixia 
                AU  - Miao, Runchen 
                AU  - Zhang, Xing 
                AU  - Qu, Kai 
                AU  - Liu, Chang 
                AU  - Zhang, Jingyao 
                TI  - Methane alleviates sepsis-induced injury by inhibiting pyroptosis and apoptosis: in vivo and in vitro experiments
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101831
                DO  - 10.18632/aging.101831
                SP  - 1226
                EP  - 1239
                PY  - 
                AB  - Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Methane has been reported to have anti-oxidative, anti-apoptotic and anti-inﬂammatory properties. We investigated the potential protective effects of methane on sepsis-induced injury and determined the related mechanisms. C57BL/6 mice received laparotomy with cecal ligation and puncture (CLP) to create a septic model, followed by methane-rich saline (MRS) treatment after CLP. MRS treatment improved the 5-day survival rate and organ functions and alleviated pathological damage of the mice, as well as reduced excessive inflammatory mediators, such as tumor necrosis factor-α and interleukin-6. MRS treatment also decreased the levels of oxidative stress index proteins, decreased the apoptosis of cells and inhibited nod-liker receptor protein (NLRP)3-mediated pyroptosis in the lung and intestine. In in vitro experiments, RAW264.7 and primary peritoneal macrophages were treated with lipopolysaccharide (LPS) plus adenosine-triphosphate (ATP) to induce inflammation and pyroptosis. Consistent with the in vivo results, methane-rich medium (MRM) treatment also reduced the levels of excessive inflammatory mediators, and decreased the levels of ROS, inhibited apoptosis and pyroptosis. Our results indicate that methane offers a protective effect for septic mice via its anti-inflammation, anti-oxidation, anti-pyroptosis and anti-apoptosis properties.
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Epigenetic signature: implications for mitochondrial quality control in human aging

Patrizia D’Aquila, Alberto Montesanto, Francesco De Rango, Francesco Guarasci, Giuseppe Passarino, Dina Bellizzi,

https://doi.org/10.18632/aging.101832 pp 1240—1251

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D’Aquila P, Montesanto A, De Rango F, Guarasci F, Passarino G, Bellizzi D, . Epigenetic signature: implications for mitochondrial quality control in human aging. . 11:1240-1251. https://doi.org/10.18632/aging.101832

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                TY  - JOUR
                AU  - D’Aquila, Patrizia 
                AU  - Montesanto, Alberto 
                AU  - De Rango, Francesco 
                AU  - Guarasci, Francesco 
                AU  - Passarino, Giuseppe 
                AU  - Bellizzi, Dina 
                TI  - Epigenetic signature: implications for mitochondrial quality control in human aging
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101832
                DO  - 10.18632/aging.101832
                SP  - 1240
                EP  - 1251
                PY  - 
                AB  - Maintenance of functional mitochondria is essential to prevent damage leading to aging and diseases. What is more, the research of biomarkers of aging is focusing on better predicting functional capability along the lifetime beyond chronological age. Aim of this study was to identify novel CpG sites the methylation of which might be correlated to the chronological and biological age. We performed methylation analyses of the CpG sites in candidate genes involved in mitochondrial biogenesis, mitophagy, fusion, and fission, all key quality control mechanisms to ensure maintenance of healthy mitochondria and homeostasis during aging, using DNA samples from two independent datasets composed by 381 and 468 differently-aged individuals, respectively. Twelve potential CpG predictors resulted associated with aging in the discovery dataset. Of these, two sites located within RAB32 and RHOT2 genes were replicated in the second dataset. What is more, individuals exhibiting methylation levels of the RAB32 CpG site higher than 10% were observed more prone to disability than people with lower levels.These results seem to provide the first evidence that epigenetic modifications of genes involved in mitochondrial quality control occur over time according to the aging decline, and may then represent potential biomarkers of both chronological and biological age.
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Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma

Jinglu Zhao, Yun Zhu, Xiaoli Xie, Yuxiao Yao, Jiao Zhang, Ruizhong Zhang, Lihua Huang, Jiwen Cheng, Huimin Xia, Jing He, Yan Zhang,

https://doi.org/10.18632/aging.101834 pp 1252—1261

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Zhao J, Zhu Y, Xie X, Yao Y, Zhang J, Zhang R, Huang L, Cheng J, Xia H, He J, Zhang Y, . Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma. . 11:1252-1261. https://doi.org/10.18632/aging.101834

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Provider: 
 TY - JOUR
 AU - Zhao, Jinglu 
 AU - Zhu, Yun 
 AU - Xie, Xiaoli 
 AU - Yao, Yuxiao 
 AU - Zhang, Jiao 
 AU - Zhang, Ruizhong 
 AU - Huang, Lihua 
 AU - Cheng, Jiwen 
 AU - Xia, Huimin 
 AU - He, Jing 
 AU - Zhang, Yan 
 TI - Pleiotropic effect of common PHOX2B variants in Hirschsprung disease and neuroblastoma
 JO - 
 JA - 
 VL - 11
 IS - 4
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.101834
 DO - 10.18632/aging.101834
 SP - 1252
 EP - 1261
 PY - 
 AB - Hirschsprung disease (HSCR) is a heterogeneous congenital disorder that affects the enteric nervous system, while neuroblastoma is an embryonal tumor of the sympathetic nervous system. Familial cases of both HSCR and neuroblastoma appear to be functionally linked to PHOX2B, which plays a key role in the development of neural crest derivatives. However, the association between common PHOX2B variants and disease risk is contested. Additionally, large-scale examination for pleiotropy or shared genetic susceptibility in sporadic HSCR and neuroblastoma cases lacks theoretical support. Here, we report the first examination of PHOX2B in 1470 HSCR and 469 neuroblastoma patients with matched healthy controls. The PHOX2B rs28647582 polymorphism was found to be associated with HSCR (P = 2.21E-03, OR = 1.26), and each subtype of the ailment (3.22E-03 ≤ P ≤ 0.43, 1.11 ≤ OR ≤ 2.32). The association between rs28647582 and NB risk was consistent with HSCR in a recessive model, though the P value was marginal (P = 0.06). These new genetic findings indicate the potential pleiotropic effects of PHOX2B in both HSCR and neuroblastoma, which could guide the development of therapeutic targets for the treatment of related neurodevelopmental disorders.
 ER -

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Longitudinal plasma metabolomics of aging and sex

Burcu F. Darst, Rebecca L. Koscik, Kirk J. Hogan, Sterling C. Johnson, Corinne D. Engelman,

https://doi.org/10.18632/aging.101837 pp 1262—1282

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Darst BF, Koscik RL, Hogan KJ, Johnson SC, Engelman CD, . Longitudinal plasma metabolomics of aging and sex. . 11:1262-1282. https://doi.org/10.18632/aging.101837

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Provider: 
                TY  - JOUR
                AU  - Darst, Burcu F. 
                AU  - Koscik, Rebecca L. 
                AU  - Hogan, Kirk J. 
                AU  - Johnson, Sterling C. 
                AU  - Engelman, Corinne D. 
                TI  - Longitudinal plasma metabolomics of aging and sex
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101837
                DO  - 10.18632/aging.101837
                SP  - 1262
                EP  - 1282
                PY  - 
                AB  - Understanding how metabolites are longitudinally influenced by age and sex could facilitate the identification of metabolomic profiles and trajectories that indicate disease risk. We investigated the metabolomics of age and sex using longitudinal plasma samples from the Wisconsin Registry for Alzheimer’s Prevention (WRAP), a cohort of participants who were dementia free at enrollment. Metabolomic profiles were quantified for 2,344 fasting plasma samples among 1,212 participants, each with up to three study visits. Of 1,097 metabolites tested, 623 (56.8%) were associated with age and 695 (63.4%) with sex after correcting for multiple testing. Approximately twice as many metabolites were associated with age in stratified analyses of women versus men, and 68 metabolite trajectories significantly differed by sex, most notably including sphingolipids, which tended to increase in women and decrease in men with age. Using genome-wide genotyping, we also report the heritabilities of metabolites investigated, which ranged dramatically (0.2–99.2%); however, the median heritability of 36.2% suggests that many metabolites are highly influenced by a complex combination of genomic and environmental influences. These findings offer a more profound description of the aging process and may inform many new hypotheses regarding the role metabolites play in healthy and accelerated aging.
                ER  -

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Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction

Dae Hyun Kim, Min Hi Park, Sugyeong Ha, Eun Jin Bang, Yujeong Lee, A Kyoung Lee, Jaewon Lee, Byung Pal Yu, Hae Young Chung,

https://doi.org/10.18632/aging.101838 pp 1283—1304

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Kim DH, Park MH, Ha S, Bang EJ, Lee Y, Lee AK, Lee J, Yu BP, Chung HY, . Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction. . 11:1283-1304. https://doi.org/10.18632/aging.101838

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                TY  - JOUR
                AU  - Kim, Dae Hyun 
                AU  - Park, Min Hi 
                AU  - Ha, Sugyeong 
                AU  - Bang, Eun Jin 
                AU  - Lee, Yujeong 
                AU  - Lee, A Kyoung 
                AU  - Lee, Jaewon 
                AU  - Yu, Byung Pal 
                AU  - Chung, Hae Young 
                TI  - Anti-inflammatory action of β-hydroxybutyrate via modulation of PGC-1α and FoxO1, mimicking calorie restriction
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101838
                DO  - 10.18632/aging.101838
                SP  - 1283
                EP  - 1304
                PY  - 
                AB  - β-Hydroxybutyrate (HB) is a ketone body used as an energy source that has shown anti-inflammatory effects similar to calorie restriction (CR); Here, PGC-1α, an abundantly expressed co-factor in the kidney, was reported to interact with both FoxO1 and NF-κB although the definitive interactive mechanism has not yet been reported. In this study, we investigated whether renal aging-related inflammation is modulated by HB. We compared aged rats administered with HB to calorie restricted rats and examined the modulation of FoxO1 and the NF-κB pathway through interactions with PGC-1α. We found that in aged rats treated with HB, pro-inflammatory signaling changes were reversed and showed effects comparable to CR. As FoxO1 and its target genes catalase/MnSOD were upregulated by HB treatment and PGC-1α selectively interacted with FoxO1, not with NF-κB, and ameliorated the renal inflammatory response. These findings were further confirmed using FoxO1 overexpression and siRNA transfection in vitro. Our findings suggest that HB suppressed aging-related inflammation as a CR mimetic by enabling the co-activation and selective interaction between FoxO1 and PGC-1α. This study demonstrates the potential therapeutic role of HB as a CR mimetic, which ameliorates inflammation by a novel mechanism where FoxO1 outcompetes NF-κB by interacting with PGC-1α in aging kidneys.
                ER  -

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Towards a more precise and individualized assessment of breast cancer risk

Marie E. Wood, Nicholas H. Farina, Thomas P. Ahern, Melissa E. Cuke, Janet L. Stein, Gary S. Stein, Jane B. Lian,

https://doi.org/10.18632/aging.101803 pp 1305—1316

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Wood ME, Farina NH, Ahern TP, Cuke ME, Stein JL, Stein GS, Lian JB, . Towards a more precise and individualized assessment of breast cancer risk. . 11:1305-1316. https://doi.org/10.18632/aging.101803

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                TY  - JOUR
                AU  - Wood, Marie E. 
                AU  - Farina, Nicholas H. 
                AU  - Ahern, Thomas P. 
                AU  - Cuke, Melissa E. 
                AU  - Stein, Janet L. 
                AU  - Stein, Gary S. 
                AU  - Lian, Jane B. 
                TI  - Towards a more precise and individualized assessment of breast cancer risk
                JO  - 
                JA  - 
                VL  - 11
                IS  - 4
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101803
                DO  - 10.18632/aging.101803
                SP  - 1305
                EP  - 1316
                PY  - 
                AB  - Many clinically based models are available for breast cancer risk assessment; however, these models are not particularly useful at the individual level, despite being designed with that intent. There is, therefore, a significant need for improved, precise individualized risk assessment. In this Research Perspective, we highlight commonly used clinical risk assessment models and recent scientific advances to individualize risk assessment using precision biomarkers. Genome-wide association studies have identified &gt;100 single nucleotide polymorphisms (SNPs) associated with breast cancer risk, and polygenic risk scores (PRS) have been developed by several groups using this information. The ability of a PRS to improve risk assessment is promising; however, validation in both genetically and ethnically diverse populations is needed. Additionally, novel classes of biomarkers, such as microRNAs, may capture clinically relevant information based on epigenetic regulation of gene expression. Our group has recently identified a circulating-microRNA signature predictive of long-term breast cancer in a prospective cohort of high-risk women. While progress has been made, the importance of accurate risk assessment cannot be understated. Precision risk assessment will identify those women at greatest risk of developing breast cancer, thus avoiding overtreatment of women at average risk and identifying the most appropriate candidates for chemoprevention or surgical prevention.
                ER  -

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Volume 11, Issue 4

About the Cover

Editorials

Ameenathul M. Fawzy, Tse-Fan Chao, Gregory Y.H. Lip,

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Vincent A. Pallazola, Vasanth Sathiyakumar, Seth S. Martin,

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Valentina Sala, Mingchuan Li, Alessandra Ghigo,

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Daniela Puzzo,

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Juan Ureña, María del Carmen González-Montelongo, Francisco Murillo-Cabezas,

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Mario Ezquerra, María-José Martí, Rubén Fernández-Santiago,

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Jacqueline Taylor, Andreas Fischer,

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Nancy Côté, Philippe Pibarot, Marie-Annick Clavel,

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Rumana Akhter, Lynn M. Bekris,

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Research Papers

Ying Zhu, Tianrui Yang, Jinlan Duan, Ninghui Mu, Tong Zhang,

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Yan-Ru Li, Rui-Rui Peng, Wen-Yi Gao, Peng Liu, Liang-Jian Chen, Xiao-Lan Zhang, Na-Na Zhang, Yang Wang, Lei Du, Feng-Yu Zhu, Li-Li Wang, Cong-Rong Li, Wen-Tao Zeng, Jian-Min Li, Fan Hu, Dong Zhang, Zhi-Xia Yang,

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Lihong Yang, Jialu Zhu, Cong Zhang, Juntao Wang, Fengyang Yue, Xingtai Jia, Hongzhi Liu,

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Juan Wang, Sayyed Hanif Ullah, Meihe Li, Miao Zhang, Fujun Zhang, Jin Zheng, Xiaofei Yan,

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Silvan Licher, Kimberly D. van der Willik, Elisabeth J. Vinke, Pinar Yilmaz, Lana Fani, Sanne B. Schagen, M. Arfan Ikram, M. Kamran Ikram,

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Sonali Nashine, Raj Kanodia, Anthony B. Nesburn, Girish Soman, Baruch D. Kuppermann, M. Cristina Kenney,

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Nicole Noren Hooten, Michele K. Evans,

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Rui-Chao Chai, Fan Wu, Qi-Xue Wang, Shu Zhang, Ke-Nan Zhang, Yu-Qing Liu, Zheng Zhao, Tao Jiang, Yong-Zhi Wang, Chun-Sheng Kang,

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Zeyu Li, Yifan Jia, Yang Feng, Ruixia Cui, Runchen Miao, Xing Zhang, Kai Qu, Chang Liu, Jingyao Zhang,

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Patrizia D’Aquila, Alberto Montesanto, Francesco De Rango, Francesco Guarasci, Giuseppe Passarino, Dina Bellizzi,

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