Volume 9, Issue 12

Chen G, Du C, Shen Z, Peng L, Xie H, Zang R, Li H, Xia Y, Tang W, . MicroRNA-939 inhibits cell proliferation via targeting LRSAM1 in Hirschsprung’s disease. . 9:2471-2479. https://doi.org/10.18632/aging.101331

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                TY  - JOUR
                AU  - Chen, Guanglin 
                AU  - Du, Chunxia 
                AU  - Shen, Ziyang 
                AU  - Peng, Lei 
                AU  - Xie, Hua 
                AU  - Zang, Rujin 
                AU  - Li, Hongxing 
                AU  - Xia, Yankai 
                AU  - Tang, Weibing 
                TI  - MicroRNA-939 inhibits cell proliferation via targeting LRSAM1 in Hirschsprung’s disease
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101331
                DO  - 10.18632/aging.101331
                SP  - 2471
                EP  - 2479
                PY  - 
                AB  - BackgroundHirschsprung's disease (HSCR) is a common digestive disease caused by impaired development of neural crest cells. Some studies have revealed the roles of microRNA (miRNA) in various diseases. But the function of miRNA in HSCR needs further investigation.MethodsWe adopted qRT-PCR and immunoblot analyses to explore the relative expression of miR-939 and LRSAM1 in 80 HSCR bowel tissues and 80 normal bowel tissues. CCK-8 assay, transwell assay and flow cytometry were used to evaluate the function of miR-939 by overexpression of miR-939 in 293T, SK-N-BE(2), SH-SY5Y cell lines. The direct connection between miR-939 and LRSAM1 was validated by dual-luciferase reporter assay. We also investigated the autophagy level via immunoblot analyses.ResultsMir-939 was significantly upregulated in HSCR tissues with decreased expression of LRSAM1. Overexpression of miR-939 suppressed cell proliferation without affecting cell apoptosis, cell cycle or cell migration. And LRSAM1 exerted similar function. Autophagy was impaired in HSCR tissues compared with control samples. Mir-939 did not inhibit the autophagy although it decreased the expression of LRSAM1.ConclusionsOur study shows the potential function of mir-939 through regulating LRSAM1 in HSCR and infers that autophagy may also confer the risk of HSCR.
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Transfer of autologous mitochondria from adipose tissue-derived stem cells rescues oocyte quality and infertility in aged mice

Zhen-Bo Wang, Jian-Xiu Hao, Tie-Gang Meng, Lei Guo, Ming-Zhe Dong, Li-Hua Fan, Ying-Chun Ouyang, Guopeng Wang, Qing-Yuan Sun, Xiang-Hong Ou, Yuan-Qing Yao,

https://doi.org/10.18632/aging.101332 pp 2480—2488

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Wang Z, Hao J, Meng T, Guo L, Dong M, Fan L, Ouyang Y, Wang G, Sun Q, Ou X, Yao Y, . Transfer of autologous mitochondria from adipose tissue-derived stem cells rescues oocyte quality and infertility in aged mice. . 9:2480-2488. https://doi.org/10.18632/aging.101332

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                TY  - JOUR
                AU  - Wang, Zhen-Bo 
                AU  - Hao, Jian-Xiu 
                AU  - Meng, Tie-Gang 
                AU  - Guo, Lei 
                AU  - Dong, Ming-Zhe 
                AU  - Fan, Li-Hua 
                AU  - Ouyang, Ying-Chun 
                AU  - Wang, Guopeng 
                AU  - Sun, Qing-Yuan 
                AU  - Ou, Xiang-Hong 
                AU  - Yao, Yuan-Qing 
                TI  - Transfer of autologous mitochondria from adipose tissue-derived stem cells rescues oocyte quality and infertility in aged mice
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101332
                DO  - 10.18632/aging.101332
                SP  - 2480
                EP  - 2488
                PY  - 
                AB  - Elder women suffer from low or loss of fertility because of decreasing oocyte quality as maternal aging. As energy resource, mitochondria play pivotal roles in oocyte development, determining oocyte quality. With advanced maternal age, increased dysfunctions emerge in oocyte mitochondria, which decrease oocyte quality and its developmental potential. Mitochondria supplement as a possible strategy for improving egg quality has been in debate due to ethnic problems. Heterogeneity is an intractable problem even transfer of germinal vesicle, spindle, pronuclei or polar body is employed. We proposed that the autologous adipose tissue-derived stem cell (ADSC) mitochondria could improve the fertility in aged mice. We found that autologous ADSC mitochondria could promote oocyte quality, embryo development and fertility in aged mice, which may provide a promising strategy for treatment of low fertility or infertility in elder women.
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Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936

Sarah E. Harris, Valentina Riggio, Louise Evenden, Tamara Gilchrist, Sarah McCafferty, Lee Murphy, Nicola Wrobel, Adele M. Taylor, Janie Corley, Alison Pattie, Simon R. Cox, Carmen Martin-Ruiz, James Prendergast, John M. Starr, Riccardo E. Marioni, Ian J. Deary,

https://doi.org/10.18632/aging.101333 pp 2489—2503

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Harris SE, Riggio V, Evenden L, Gilchrist T, McCafferty S, Murphy L, Wrobel N, Taylor AM, Corley J, Pattie A, Cox SR, Martin-Ruiz C, Prendergast J, et al, . Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936. . 9:2489-2503. https://doi.org/10.18632/aging.101333

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                TY  - JOUR
                AU  - Harris, Sarah E. 
                AU  - Riggio, Valentina 
                AU  - Evenden, Louise 
                AU  - Gilchrist, Tamara 
                AU  - McCafferty, Sarah 
                AU  - Murphy, Lee 
                AU  - Wrobel, Nicola 
                AU  - Taylor, Adele M. 
                AU  - Corley, Janie 
                AU  - Pattie, Alison 
                AU  - Cox, Simon R. 
                AU  - Martin-Ruiz, Carmen 
                AU  - Prendergast, James 
                AU  - Starr, John M. 
                AU  - Marioni, Riccardo E. 
                AU  - Deary, Ian J. 
                TI  - Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101333
                DO  - 10.18632/aging.101333
                SP  - 2489
                EP  - 2503
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Harris, Sarah E. 
                AU  - Riggio, Valentina 
                AU  - Evenden, Louise 
                AU  - Gilchrist, Tamara 
                AU  - McCafferty, Sarah 
                AU  - Murphy, Lee 
                AU  - Wrobel, Nicola 
                AU  - Taylor, Adele M. 
                AU  - Corley, Janie 
                AU  - Pattie, Alison 
                AU  - Cox, Simon R. 
                AU  - Martin-Ruiz, Carmen 
                AU  - Prendergast, James 
                AU  - Starr, John M. 
                AU  - Marioni, Riccardo E. 
                AU  - Deary, Ian J. 
                TI  - Age-related gene expression changes, and transcriptome wide association study of physical and cognitive aging traits, in the Lothian Birth Cohort 1936
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101333
                DO  - 10.18632/aging.101333
                SP  - 2489
                EP  - 2503
                PY  - 
                AB  - Gene expression is influenced by both genetic variants and the environment. As individuals age, changes in gene expression may be associated with decline in physical and cognitive abilities. We measured transcriptome-wide expression levels in lymphoblastoid cell lines derived from members of the Lothian Birth Cohort 1936 at mean ages 70 and 76 years. Changes in gene expression levels were identified for 1,741 transcripts in 434 individuals. Gene Ontology enrichment analysis indicated an enrichment of biological processes involved in the immune system. Transcriptome-wide association analysis was performed for eleven cognitive, fitness, and biomedical aging-related traits at age 70 years (N=665 to 781) and with mortality. Transcripts for genes (F2RL3, EMILIN1 and CDC42BPA) previously identified as being differentially methylated or expressed in smoking or smoking-related cancers were overexpressed in smokers compared to non-smokers and the expression of transcripts for genes (HERPUD1, GAB2, FAM167A and GLS) previously associated with stress response, autoimmune disease and cancer were associated with telomere length. No associations between expression levels and other traits, or mortality were identified.
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Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

Luke C. Pilling, Chia-Ling Kuo, Kamil Sicinski, Jone Tamosauskaite, George A. Kuchel, Lorna W. Harries, Pamela Herd, Robert Wallace, Luigi Ferrucci, David Melzer,

https://doi.org/10.18632/aging.101334 pp 2504—2520

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Pilling LC, Kuo C, Sicinski K, Tamosauskaite J, Kuchel GA, Harries LW, Herd P, Wallace R, Ferrucci L, Melzer D, . Human longevity: 25 genetic loci associated in 389,166 UK biobank participants. . 9:2504-2520. https://doi.org/10.18632/aging.101334

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                TY  - JOUR
                AU  - Pilling, Luke C. 
                AU  - Kuo, Chia-Ling 
                AU  - Sicinski, Kamil 
                AU  - Tamosauskaite, Jone 
                AU  - Kuchel, George A. 
                AU  - Harries, Lorna W. 
                AU  - Herd, Pamela 
                AU  - Wallace, Robert 
                AU  - Ferrucci, Luigi 
                AU  - Melzer, David 
                TI  - Human longevity: 25 genetic loci associated in 389,166 UK biobank participants
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101334
                DO  - 10.18632/aging.101334
                SP  - 2504
                EP  - 2520
                PY  - 
                AB  - We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p&lt;5*10-8), including 8 previously identified for traits including survival, Alzheimer’s and cardiovascular disease. Of these, 4 were also associated with longest 10% survival (mothers age ≥90 years, fathers ≥87 years), with 2 additional associations including MC2R intronic variants (coding for the adrenocorticotropic hormone receptor). Mother’s age at death was associated with 3 additional loci (2 linked to autoimmune conditions), and 8 for fathers only. An attained age genetic risk score associated with parental survival in the US Health and Retirement Study and the Wisconsin Longitudinal Study and with having a centenarian parent (n=1,181) in UK Biobank. The results suggest that human longevity is highly polygenic with prominent roles for loci likely involved in cellular senescence and inflammation, plus lipid metabolism and cardiovascular conditions. There may also be gender specific routes to longevity.
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Sexually dimorphic effects of dietary sugar on lifespan, feeding and starvation resistance in Drosophila

Bhakti Chandegra, Jocelyn Lok Yee Tang, Haoyu Chi, Nazif Alic,

https://doi.org/10.18632/aging.101335 pp 2521—2528

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Chandegra B, Tang JLY, Chi H, Alic N, . Sexually dimorphic effects of dietary sugar on lifespan, feeding and starvation resistance in Drosophila. . 9:2521-2528. https://doi.org/10.18632/aging.101335

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                TY  - JOUR
                AU  - Chandegra, Bhakti 
                AU  - Tang, Jocelyn Lok Yee 
                AU  - Chi, Haoyu 
                AU  - Alic, Nazif 
                TI  - Sexually dimorphic effects of dietary sugar on lifespan, feeding and starvation resistance in <i>Drosophila</i>
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101335
                DO  - 10.18632/aging.101335
                SP  - 2521
                EP  - 2528
                PY  - 
                AB  - Lifespan and health in older age are strongly influenced by diet. Feeding Drosophila melanogaster diets high in sugar has increasingly been used as an experimental model to understand the physiological effects of unhealthy, contemporary human diets. Several metabolic parameters and physiological responses to nutrition are known to be dependent on the sex of the animal. However, sexual dimorphism in the responses to high-sugar diets in fruit flies has not been examined. Here we show that a high-sugar diet in Drosophila melanogaster elicits sexually dimorphic effects on feeding behaviour, starvation resistance and lifespan. Females feed less on such diets, while males feed more, and these feeding responses may have secondary consequences. Females, more than males, gain the ability to resist periods of starvation from high-sugar diets, indicating that the female response to excess sugar may be geared towards surviving food shortages in early life. At the same time, female lifespan is more susceptible to the detrimental effects of high sugar diets. Our study reveals differences between Drosophila sexes in their responses to sugar-rich diets, indicating the fruit fly could be used as a model to understand the sexually dimorphic features of human metabolic health.
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POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions

Yang Yu, Rong Tan, Qian Ren, Boya Gao, Zhejin Sheng, Juanlian Zhang, Xiaoqing Zheng, Ying Jiang, Li Lan, Zhiyong Mao,

https://doi.org/10.18632/aging.101339 pp 2529—2543

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Yu Y, Tan R, Ren Q, Gao B, Sheng Z, Zhang J, Zheng X, Jiang Y, Lan L, Mao Z, . POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions. . 9:2529-2543. https://doi.org/10.18632/aging.101339

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                TY  - JOUR
                AU  - Yu, Yang 
                AU  - Tan, Rong 
                AU  - Ren, Qian 
                AU  - Gao, Boya 
                AU  - Sheng, Zhejin 
                AU  - Zhang, Juanlian 
                AU  - Zheng, Xiaoqing 
                AU  - Jiang, Ying 
                AU  - Lan, Li 
                AU  - Mao, Zhiyong 
                TI  - POT1 inhibits the efficiency but promotes the fidelity of nonhomologous end joining at non-telomeric DNA regions
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101339
                DO  - 10.18632/aging.101339
                SP  - 2529
                EP  - 2543
                PY  - 
                AB  - Robust DNA double strand break (DSB) repair and stabilized telomeres help maintain genome integrity, preventing the onset of aging or tumorigenesis. POT1 is one of the six factors in the shelterin complex, which protects telomeres from being recognized as DNA damages. TRF1 and TRF2, two other shelterin proteins, have been shown to participate in DNA DSB repair at non-telomeric regions, but whether POT1, which binds to single strand telomeric DNA at chromosomal ends, is involved in DNA DSB repair has not been assessed. Here we found that POT1 arrives at DNA damage sites upon the occurrence of DNA DSBs. It suppresses the efficiency of nonhomologous end joining (NHEJ), the major pathway for fixing DNA DSBs in mammals, but surprisingly promotes NHEJ fidelity. Mechanistic studies indicate that POT1 facilitates the recruitment of Artemis, which is a nuclease and promotes fidelity of NHEJ, to DNA damage sites. In addition, we found that overexpression of POT1 inhibits the protein stability of Lig3, which is the major regulator of alternative NHEJ (alt-NHEJ), therefore suppressing the efficiency of alt-NHEJ. Taken together we propose that POT1 is a key factor regulating the balance between the efficiency and fidelity of NHEJ at non-telomeric DNA regions.
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The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research

Corinna N. Ross, Steven Austad, Kathy Brasky, Celeste J. Brown, Larry J. Forney, Jonathan A. Gelfond, Robert Lanford, Arlan Richardson, Suzette D. Tardif,

https://doi.org/10.18632/aging.101340 pp 2544—2558

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Ross CN, Austad S, Brasky K, Brown CJ, Forney LJ, Gelfond JA, Lanford R, Richardson A, Tardif SD, . The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research. . 9:2544-2558. https://doi.org/10.18632/aging.101340

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                TY  - JOUR
                AU  - Ross, Corinna N. 
                AU  - Austad, Steven 
                AU  - Brasky, Kathy 
                AU  - Brown, Celeste J. 
                AU  - Forney, Larry J. 
                AU  - Gelfond, Jonathan A. 
                AU  - Lanford, Robert 
                AU  - Richardson, Arlan 
                AU  - Tardif, Suzette D. 
                TI  - The development of a specific pathogen free (SPF) barrier colony of marmosets (<i>Callithrix jacchus</i>) for aging research
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101340
                DO  - 10.18632/aging.101340
                SP  - 2544
                EP  - 2558
                PY  - 
                AB  - A specific pathogen free (SPF) barrier colony of breeding marmosets (Callithrix jacchus) was established at the Barshop Institute for Longevity and Aging Studies. Rodent and other animal models maintained as SPF barrier colonies have demonstrated improved health and lengthened lifespans enhancing the quality and repeatability of aging research. The marmosets were screened for two viruses and several bacterial pathogens prior to establishing the new SPF colony. Twelve founding animals successfully established a breeding colony with increased reproductive success, improved health parameters, and increased median lifespan when compared to a conventionally housed, open colony. The improved health and longevity of marmosets from the SPF barrier colony suggests that such management can be used to produce a unique resource for future studies of aging processes in a nonhuman primate model.
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Central role of the p53 pathway in the noncoding-RNA response to oxidative stress

Paola Fuschi, Matteo Carrara, Christine Voellenkle, Jose Manuel Garcia-Manteiga, Paolo Righini, Biagina Maimone, Elena Sangalli, Francesco Villa, Claudia Specchia, Mario Picozza, Giovanni Nano, Carlo Gaetano, Gaia Spinetti, Annibale A. Puca, Alessandra Magenta, Fabio Martelli,

https://doi.org/10.18632/aging.101341 pp 2559—2586

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Fuschi P, Carrara M, Voellenkle C, Garcia-Manteiga JM, Righini P, Maimone B, Sangalli E, Villa F, Specchia C, Picozza M, Nano G, Gaetano C, Spinetti G, et al, . Central role of the p53 pathway in the noncoding-RNA response to oxidative stress. . 9:2559-2586. https://doi.org/10.18632/aging.101341

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                TY  - JOUR
                AU  - Fuschi, Paola 
                AU  - Carrara, Matteo 
                AU  - Voellenkle, Christine 
                AU  - Garcia-Manteiga, Jose Manuel 
                AU  - Righini, Paolo 
                AU  - Maimone, Biagina 
                AU  - Sangalli, Elena 
                AU  - Villa, Francesco 
                AU  - Specchia, Claudia 
                AU  - Picozza, Mario 
                AU  - Nano, Giovanni 
                AU  - Gaetano, Carlo 
                AU  - Spinetti, Gaia 
                AU  - Puca, Annibale A. 
                AU  - Magenta, Alessandra 
                AU  - Martelli, Fabio 
                TI  - Central role of the p53 pathway in the noncoding-RNA response to oxidative stress
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101341
                DO  - 10.18632/aging.101341
                SP  - 2559
                EP  - 2586
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Fuschi, Paola 
                AU  - Carrara, Matteo 
                AU  - Voellenkle, Christine 
                AU  - Garcia-Manteiga, Jose Manuel 
                AU  - Righini, Paolo 
                AU  - Maimone, Biagina 
                AU  - Sangalli, Elena 
                AU  - Villa, Francesco 
                AU  - Specchia, Claudia 
                AU  - Picozza, Mario 
                AU  - Nano, Giovanni 
                AU  - Gaetano, Carlo 
                AU  - Spinetti, Gaia 
                AU  - Puca, Annibale A. 
                AU  - Magenta, Alessandra 
                AU  - Martelli, Fabio 
                TI  - Central role of the p53 pathway in the noncoding-RNA response to oxidative stress
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101341
                DO  - 10.18632/aging.101341
                SP  - 2559
                EP  - 2586
                PY  - 
                AB  - Oxidative stress plays a fundamental role in many conditions. Specifically, redox imbalance inhibits endothelial cell (EC) growth, inducing cell death and senescence. We used global transcriptome profiling to investigate the involvement of noncoding-RNAs in these phenotypes. By RNA-sequencing, transcriptome changes were analyzed in human ECs exposed to H2O2, highlighting a pivotal role of p53-signaling. Bioinformatic analysis and validation in p53-silenced ECs, identified several p53-targets among both mRNAs and long noncoding-RNAs (lncRNAs), including MALAT1 and NEAT1. Among microRNAs (miRNAs), miR-192-5p was the most induced by H2O2 treatment, in a p53-dependent manner. Down-modulated mRNA-targets of miR-192-5p were involved in cell cycle, DNA repair and stress response. Accordingly, miR-192-5p overexpression significantly decreased EC proliferation, inducing cell death. A central role of the p53-pathway was also confirmed by the analysis of differential exon usage: Upon H2O2 treatment, the expression of p53-dependent 5’-isoforms of MDM2 and PVT1 increased selectively. The transcriptomic alterations identified in H2O2-treated ECs were also observed in other physiological and pathological conditions where redox control plays a fundamental role, such as ECs undergoing replicative senescence, skeletal muscles of critical limb-ischemia patients and the peripheral-blood mononuclear cells of long-living individuals. Collectively, these findings indicate a prominent role of noncoding-RNAs in oxidative stress response.
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Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast

Maneesha Aluru, Tori McKinney, Anne-Kathryn L. Venero, Shilpa Choudhury, Matthew Torres,

https://doi.org/10.18632/aging.101350 pp 2587—2609

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Aluru M, McKinney T, Venero AL, Choudhury S, Torres M, . Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast. . 9:2587-2609. https://doi.org/10.18632/aging.101350

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                TY  - JOUR
                AU  - Aluru, Maneesha 
                AU  - McKinney, Tori 
                AU  - Venero, Anne-Kathryn L. 
                AU  - Choudhury, Shilpa 
                AU  - Torres, Matthew 
                TI  - Mitogen-activated protein kinases, Fus3 and Kss1, regulate chronological lifespan in yeast
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101350
                DO  - 10.18632/aging.101350
                SP  - 2587
                EP  - 2609
                PY  - 
                AB  - Using a systems-based approach, we have identified several genes not previously evaluated for a role(s) in chronological aging. Here, we have thoroughly investigated the chronological lifespan (CLS) of three of these genes (FUS3, KSS1 and HOG1) and their protein products, each of which have well-defined cell signaling roles in young cells. The importance of FUS3 and KSS1 in CLS are largely unknown and analyzed here for the first time. Using both qualitative and quantitative CLS assays, we show that deletion of any of the three MAPK’s increases yeast lifespan. Furthermore, combined deletion of any MAPK and TOR1, most prominently fus3Δ/tor1Δ, produces a two-stage CLS response ending in lifespan increase greater than that of tor1Δ. Similar effects are achieved upon endogenous expression of a non-activatable form of Fus3. We speculate that the autophagy-promoting role of FUS3, which is inherently antagonistic to the role of TOR1, may in part be responsible for the differential aging phenotype of fus3Δ/tor1Δ. Consistent with this notion we show that nitrogen starvation, which promotes autophagy by deactivating Tor1, results in decreased CLS if FUS3 is deleted. Taken together, these results reveal a previously unrealized effect of mating-specific MAPKs in the chronological lifespan of yeast.
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Targeting flavin-containing enzymes eliminates cancer stem cells (CSCs), by inhibiting mitochondrial respiration: Vitamin B2 (Riboflavin) in cancer therapy

Bela Ozsvari, Gloria Bonuccelli, Rosa Sanchez-Alvarez, Richard Foster, Federica Sotgia, Michael P. Lisanti,

https://doi.org/10.18632/aging.101351 pp 2610—2628

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Ozsvari B, Bonuccelli G, Sanchez-Alvarez R, Foster R, Sotgia F, Lisanti MP, . Targeting flavin-containing enzymes eliminates cancer stem cells (CSCs), by inhibiting mitochondrial respiration: Vitamin B2 (Riboflavin) in cancer therapy. . 9:2610-2628. https://doi.org/10.18632/aging.101351

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                TY  - JOUR
                AU  - Ozsvari, Bela 
                AU  - Bonuccelli, Gloria 
                AU  - Sanchez-Alvarez, Rosa 
                AU  - Foster, Richard 
                AU  - Sotgia, Federica 
                AU  - Lisanti, Michael P. 
                TI  - Targeting flavin-containing enzymes eliminates cancer stem cells (CSCs), by inhibiting mitochondrial respiration: Vitamin B2 (Riboflavin) in cancer therapy
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101351
                DO  - 10.18632/aging.101351
                SP  - 2610
                EP  - 2628
                PY  - 
                AB  - Here, we performed high-throughput drug-screening to identify new non-toxic mitochondrial inhibitors. This screening platform was specifically designed to detect compounds that selectively deplete cellular ATP levels, but have little or no toxic side effects on cell viability. Using this approach, we identified DPI (Diphenyleneiodonium chloride) as a new potential therapeutic agent. Mechanistically, DPI potently blocks mitochondrial respiration by inhibiting flavin-containing enzymes (FMN and FAD-dependent), which form part of Complex I and II. Interestingly, DPI induced a chemo-quiescence phenotype that potently inhibited the propagation of CSCs, with an IC-50 of 3.2 nano-molar. Virtually identical results were obtained using CSC markers, such as CD44 and CD24. We further validated the effects of DPI on cellular metabolism. At 10 nM, DPI inhibited oxidative mitochondrial metabolism (OXPHOS), reducing mitochondrial driven ATP production by &gt;90%. This resulted in a purely glycolytic phenotype, with elevated L-lactate production. We show that this metabolic inflexibility could be rapidly-induced, after only 1 hour of DPI treatment. Remarkably, the mitochondrial inhibitory effects of DPI were reversible, and DPI did not induce ROS production. Cells maintained in DPI for 1 month showed little or no mitochondrial activity, but remained viable. Thus, it appears that DPI behaves as a new type of mitochondrial inhibitor, which maintains cells in a state of metabolic-quiescence or “suspended animation”.In conclusion, DPI treatment can be used to acutely confer a mitochondrial-deficient phenotype, which we show effectively depletes CSCs from the heterogeneous cancer cell population. These findings have significant therapeutic implications for potently targeting CSCs, while minimizing toxic side effects. We also discuss the possible implications of DPI for the aging process. Interestingly, previous studies in C. elegans have shown that DPI prevents the accumulation of lipofuscin (an aging-associated hallmark), during the response to oxidative stress. Our current results are consistent with data showing that flavins (FAD, FMN and/or Riboflavin) are auto-fluorescent markers of i) increased mitochondrial “power” (OXPHOS) and ii) elevated CSC activity.Finally, we believe that DPI is one of the most potent and highly selective CSC inhibitors discovered to date. Therefore, our current findings suggest a new impetus to create novel analogues of i) DPI (Diphenyleneiodonium chloride) and ii) DPI-related compounds (Diphenyliodonium chloride), using medicinal chemistry, to optimize this very promising and potent anti-CSC activity. We propose to call these new molecules “Mitoflavoscins”.For example, DPI is ~30 times more potent than Palbociclib (IC-50 = 100 nM), which is an FDA-approved CDK4/6 inhibitor, that broadly targets proliferation in any cell type, including CSCs.
                ER  -

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Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort

Miao Jiang, Andrea Dawn Foebel, Ralf Kuja-Halkola, Ida Karlsson, Nancy Lee Pedersen, Sara Hägg, Juulia Jylhävä,

https://doi.org/10.18632/aging.101352 pp 2629—2646

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Jiang M, Foebel AD, Kuja-Halkola R, Karlsson I, Pedersen NL, Hägg S, Jylhävä J, . Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort. . 9:2629-2646. https://doi.org/10.18632/aging.101352

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                TY  - JOUR
                AU  - Jiang, Miao 
                AU  - Foebel, Andrea Dawn 
                AU  - Kuja-Halkola, Ralf 
                AU  - Karlsson, Ida 
                AU  - Pedersen, Nancy Lee 
                AU  - Hägg, Sara 
                AU  - Jylhävä, Juulia 
                TI  - Frailty index as a predictor of all-cause and cause-specific mortality in a Swedish population-based cohort
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101352
                DO  - 10.18632/aging.101352
                SP  - 2629
                EP  - 2646
                PY  - 
                AB  - Frailty is a complex manifestation of aging and associated with increased risk of mortality and poor health outcomes. However, younger individuals (under 65 years) are less-studied in this respect. Also, the relationship between frailty and cause-specific mortality in community settings is understudied. We used a 42-item Rockwood-based frailty index (FI) in the Swedish Adoption/Twin Study of Aging (n=1477; 623 men, 854 women; aged 29-95 years) and analyzed its association with all-cause and cause-specific mortality in up to 30-years of follow-up. Deaths due to cardiovascular disease (CVD), cancer, dementia and other causes were considered as competing risks. The FI was independently associated with increased risk for all-cause mortality in younger (&lt;65 years; HR per increase in one deficit 1.11, 95%CI 1.07-1.17) and older (≥65 years; HR 1.07, 95%CI 1.04-1.10) women and in younger men (HR 1.05, 95%CI 1.01-1.10). In cause-specific mortality analysis, the FI was strongly predictive of CVD mortality in women (HR per increase in one deficit 1.13, 95%CI 1.09-1.17), whereas in men the risk was restricted to deaths from other causes (HR 1.07, 95%CI 1.01-1.13). In conclusion, the FI is a strong mortality predictor especially among younger individuals and its associations with cause-specific mortality are sex-specific.
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Clock mediates liver senescence by controlling ER stress

Gongsheng Yuan, Bingxuan Hua, Tingting Cai, Lirong Xu, Ermin Li, Yiqing Huang, Ning Sun, Zuoqin Yan, Chao Lu, Ruizhe Qian,

https://doi.org/10.18632/aging.101353 pp 2647—2665

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Yuan G, Hua B, Cai T, Xu L, Li E, Huang Y, Sun N, Yan Z, Lu C, Qian R, . Clock mediates liver senescence by controlling ER stress. . 9:2647-2665. https://doi.org/10.18632/aging.101353

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                TY  - JOUR
                AU  - Yuan, Gongsheng 
                AU  - Hua, Bingxuan 
                AU  - Cai, Tingting 
                AU  - Xu, Lirong 
                AU  - Li, Ermin 
                AU  - Huang, Yiqing 
                AU  - Sun, Ning 
                AU  - Yan, Zuoqin 
                AU  - Lu, Chao 
                AU  - Qian, Ruizhe 
                TI  - Clock mediates liver senescence by controlling ER stress
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101353
                DO  - 10.18632/aging.101353
                SP  - 2647
                EP  - 2665
                PY  - 
                AB  - Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood. Here, we show that Clock-mediated Pdia3 expression is required to sustain reactive oxidative reagents and ER stress. First, ER stress and ROS are strongly activated in the liver tissue of Clock∆19 mutant mice, which exhibit a significant aging phenotype. Next, transcription of Pdia3 is mediated by the circadian gene Clock, but this process is affected by the Clock∆19 mutant due to the low affinity of the E-box motif in the promoter. Finally, ablation of Pdia3 with siRNA causes ER stress with sustained phosphorylation of PERK and eIF1α, resulting in exaggerated up-regulation of UPR target genes and increased apoptosis as well as ROS. Moreover, the combined effects result in an imbalance of cell homeostasis and ultimately lead to cell damage and senescence. Taken together, this study identified the circadian gene Clock as a regulator of ER stress and senescence, which will provide a reference for the clinical prevention of aging.
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Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression

Rahul Bhome, Rebecca W. Goh, Marc D. Bullock, Nir Pillar, Stephen M. Thirdborough, Massimiliano Mellone, Reza Mirnezami, Dieter Galea, Kirill Veselkov, Quan Gu, Timothy J. Underwood, John N. Primrose, Olivier De Wever, Noam Shomron, A. Emre Sayan, Alex H. Mirnezami,

https://doi.org/10.18632/aging.101355 pp 2666—2694

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Bhome R, Goh RW, Bullock MD, Pillar N, Thirdborough SM, Mellone M, Mirnezami R, Galea D, Veselkov K, Gu Q, Underwood TJ, Primrose JN, De Wever O, et al, . Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. . 9:2666-2694. https://doi.org/10.18632/aging.101355

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                TY  - JOUR
                AU  - Bhome, Rahul 
                AU  - Goh, Rebecca W. 
                AU  - Bullock, Marc D. 
                AU  - Pillar, Nir 
                AU  - Thirdborough, Stephen M. 
                AU  - Mellone, Massimiliano 
                AU  - Mirnezami, Reza 
                AU  - Galea, Dieter 
                AU  - Veselkov, Kirill 
                AU  - Gu, Quan 
                AU  - Underwood, Timothy J. 
                AU  - Primrose, John N. 
                AU  - De Wever, Olivier 
                AU  - Shomron, Noam 
                AU  - Sayan, A. Emre 
                AU  - Mirnezami, Alex H. 
                TI  - Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101355
                DO  - 10.18632/aging.101355
                SP  - 2666
                EP  - 2694
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Bhome, Rahul 
                AU  - Goh, Rebecca W. 
                AU  - Bullock, Marc D. 
                AU  - Pillar, Nir 
                AU  - Thirdborough, Stephen M. 
                AU  - Mellone, Massimiliano 
                AU  - Mirnezami, Reza 
                AU  - Galea, Dieter 
                AU  - Veselkov, Kirill 
                AU  - Gu, Quan 
                AU  - Underwood, Timothy J. 
                AU  - Primrose, John N. 
                AU  - De Wever, Olivier 
                AU  - Shomron, Noam 
                AU  - Sayan, A. Emre 
                AU  - Mirnezami, Alex H. 
                TI  - Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101355
                DO  - 10.18632/aging.101355
                SP  - 2666
                EP  - 2694
                PY  - 
                AB  - Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal-tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells.
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A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas

Djihad Hadjadj, Su-Jung Kim, Thomas Denecker, Laura Ben Driss, Jean-Charles Cadoret, Chrystelle Maric, Giuseppe Baldacci, Fabien Fauchereau,

https://doi.org/10.18632/aging.101356 pp 2695—2716

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Hadjadj D, Kim S, Denecker T, Ben Driss L, Cadoret J, Maric C, Baldacci G, Fauchereau F, . A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas. . 9:2695-2716. https://doi.org/10.18632/aging.101356

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                TY  - JOUR
                AU  - Hadjadj, Djihad 
                AU  - Kim, Su-Jung 
                AU  - Denecker, Thomas 
                AU  - Ben Driss, Laura 
                AU  - Cadoret, Jean-Charles 
                AU  - Maric, Chrystelle 
                AU  - Baldacci, Giuseppe 
                AU  - Fauchereau, Fabien 
                TI  - A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas
                JO  - 
                JA  - 
                VL  - 9
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.101356
                DO  - 10.18632/aging.101356
                SP  - 2695
                EP  - 2716
                PY  - 
                AB  - High proliferation rate and high mutation density are both indicators of poor prognosis in adrenocortical carcinomas. We performed a hypothesis-driven association study between clinical features in adrenocortical carcinomas and the expression levels of 136 genes involved in DNA metabolism and G1/S phase transition. In 79 samples downloaded from The Cancer Genome Atlas portal, high Cyclin Dependent Kinase 6 (CDK6) mRNA levels gave the most significant association with shorter time to relapse and poorer survival of patients. A hierarchical clustering approach assembled most tumors with high levels of CDK6 mRNA into one group. These tumors tend to cumulate mutations activating the Wnt/β-catenin pathway and show reduced MIR506 expression. Actually, the level of MIR506 RNA is inversely correlated with the levels of both CDK6 and CTNNB1 (encoding β-catenin). Together these results indicate that high CDK6 expression is found in aggressive tumors with activated Wnt/β-catenin pathway. Thus we tested the impact of Food and Drug Administration-approved CDK4 and CDK6 inhibitors, namely palbociclib and ribociclib, on SW-13 and NCI-H295R cells. While both drugs reduced viability and induced senescence in SW-13 cells, only palbociclib was effective on the retinoblastoma protein (pRB)-negative NCI-H295R cells, by inducing apoptosis. In NCI-H295R cells, palbociclib induced an increase of the active form of Glycogen Synthase Kinase 3β (GSK3β) responsible for the reduced amount of active β-catenin, and altered the amount of AXIN2 mRNA. Taken together, these data underline the impact of CDK4 and CDK6 inhibitors in treating adrenocortical carcinomas.
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Volume 9, Issue 12

About the Cover

Editorials

Jolien S. de Groot, Paul J. van Diest, Patrick W.B. Derksen,

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Manish V. Bais,

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Fernando Ferreira,

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Mihwa Kim, Liza D. Morales, Dae Joon Kim,

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Elizabeth R. Murray, Angus J.M. Cameron,

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Cara Green, Sharon Mitchell, John Speakman,

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Hongwei Liao, Fang Ji, Songmin Ying,

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Timothy A. Donlon, Bradley J. Willcox, Brian J. Morris,

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Ning Zhou, Shaunrick Stoll, Hongyu Qiu,

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Research Papers

Guanglin Chen, Chunxia Du, Ziyang Shen, Lei Peng, Hua Xie, Rujin Zang, Hongxing Li, Yankai Xia, Weibing Tang,

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Zhen-Bo Wang, Jian-Xiu Hao, Tie-Gang Meng, Lei Guo, Ming-Zhe Dong, Li-Hua Fan, Ying-Chun Ouyang, Guopeng Wang, Qing-Yuan Sun, Xiang-Hong Ou, Yuan-Qing Yao,

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Sarah E. Harris, Valentina Riggio, Louise Evenden, Tamara Gilchrist, Sarah McCafferty, Lee Murphy, Nicola Wrobel, Adele M. Taylor, Janie Corley, Alison Pattie, Simon R. Cox, Carmen Martin-Ruiz, James Prendergast, John M. Starr, Riccardo E. Marioni, Ian J. Deary,

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Luke C. Pilling, Chia-Ling Kuo, Kamil Sicinski, Jone Tamosauskaite, George A. Kuchel, Lorna W. Harries, Pamela Herd, Robert Wallace, Luigi Ferrucci, David Melzer,

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Bhakti Chandegra, Jocelyn Lok Yee Tang, Haoyu Chi, Nazif Alic,

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Yang Yu, Rong Tan, Qian Ren, Boya Gao, Zhejin Sheng, Juanlian Zhang, Xiaoqing Zheng, Ying Jiang, Li Lan, Zhiyong Mao,

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Corinna N. Ross, Steven Austad, Kathy Brasky, Celeste J. Brown, Larry J. Forney, Jonathan A. Gelfond, Robert Lanford, Arlan Richardson, Suzette D. Tardif,

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Paola Fuschi, Matteo Carrara, Christine Voellenkle, Jose Manuel Garcia-Manteiga, Paolo Righini, Biagina Maimone, Elena Sangalli, Francesco Villa, Claudia Specchia, Mario Picozza, Giovanni Nano, Carlo Gaetano, Gaia Spinetti, Annibale A. Puca, Alessandra Magenta, Fabio Martelli,

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Maneesha Aluru, Tori McKinney, Anne-Kathryn L. Venero, Shilpa Choudhury, Matthew Torres,

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Bela Ozsvari, Gloria Bonuccelli, Rosa Sanchez-Alvarez, Richard Foster, Federica Sotgia, Michael P. Lisanti,

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