Volume 8, Issue 2

The longevity transporter mIndy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance

Diana M. Willmes, Stephen L. Helfand, Andreas L. Birkenfeld,

https://doi.org/10.18632/aging.100907 pp 208—209

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Willmes DM, Helfand SL, Birkenfeld AL, . The longevity transporter mIndy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance. . 8:208-209. https://doi.org/10.18632/aging.100907

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Copper that cancer with lysosomal love!

Zaklina Kovacevic, Sumit Sahni, Des R. Richardson,

https://doi.org/10.18632/aging.100910 pp 210—211

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Mitochondria operate as signaling platforms in yeast aging

Younes Medkour, Vladimir I. Titorenko,

https://doi.org/10.18632/aging.100914 pp 212—213

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MKP1: Jekyll and Hyde for E1A

Francisco J. Cimas, Juan Luis Callejas-Valera, Ricardo Sanchez-Prieto,

https://doi.org/10.18632/aging.100918 pp 214—215

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Placental membrane aging and HMGB1 signaling associated with human parturition

Ramkumar Menon, Faranak Behnia, Jossimara Polettini, George R Saade, Judith Campisi, Michael Velarde,

https://doi.org/10.18632/aging.100891 pp 216—230

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Menon R, Behnia F, Polettini J, Saade GR, Campisi J, Velarde M, . Placental membrane aging and HMGB1 signaling associated with human parturition. . 8:216-230. https://doi.org/10.18632/aging.100891

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                TY  - JOUR
                AU  - Menon, Ramkumar 
                AU  - Behnia, Faranak 
                AU  - Polettini, Jossimara 
                AU  - Saade, George R 
                AU  - Campisi, Judith 
                AU  - Velarde, Michael 
                TI  - Placental membrane aging and HMGB1 signaling associated with human parturition
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100891
                DO  - 10.18632/aging.100891
                SP  - 216
                EP  - 230
                PY  - 
                AB  - Aging is associated with the onset of several diseases in various organ systems; however, different tissues may age differently, rendering some of them dysfunctional sooner than others. Placental membranes (fetal amniochorionic membranes) protect the fetus throughout pregnancy, but their longevity is limited to the duration of pregnancy. The age-associated dysfunction of these membranes is postulated to trigger parturition. Here, we investigated whether cellular senescence—the loss of cell division potential as a consequence of stress—is involved in placental membrane function at term. We show telomere reduction, p38 MAPK activation, increase in p21 expression, loss of lamin B1 loss, increase in SA-β-galactosidase, and senescence-associated secretory phenotype (SASP) gene expression in placental membranes after labor and delivery (term labor [TL]) compared to membranes prior to labor at term (term, not-in-labor [TNIL]). Exposing TNIL placental membranes to cigarette smoke extract, an oxidative stress inducer, also induced markers of cellular senescence similar to those in TL placental membranes. Bioinformatics analysis of differentially expressed SASP genes revealed HMGB1 signaling among the top pathways involved in labor. Further, we show that recombinant HMGB1 upregulates the expression of genes associated with parturition in myometrial cells. These data suggest that the natural physiologic aging of placental tissues is associated with cellular senescence and human parturition.
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Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

Hannah E. Walters, Sylwia Deneka-Hannemann, Lynne S. Cox,

https://doi.org/10.18632/aging.100872 pp 231—244

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Walters HE, Deneka-Hannemann S, Cox LS, . Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. . 8:231-244. https://doi.org/10.18632/aging.100872

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                TY  - JOUR
                AU  - Walters, Hannah E. 
                AU  - Deneka-Hannemann, Sylwia 
                AU  - Cox, Lynne S. 
                TI  - Reversal of phenotypes of cellular senescence by pan-mTOR inhibition
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100872
                DO  - 10.18632/aging.100872
                SP  - 231
                EP  - 244
                PY  - 
                AB  - Cellular senescence, a state of essentially irreversible proliferation arrest, serves as a potent tumour suppressor mechanism. However, accumulation of senescent cells with chronological age is likely to contribute to loss of tissue and organ function and organismal aging. A crucial biochemical modulator of aging is mTOR; here, we have addressed the question of whether acute mTORC inhibition in near-senescent cells can modify phenotypes of senescence. We show that acute short term treatment of human skin fibroblasts with low dose ATP mimetic pan-mTORC inhibitor AZD8055 leads to reversal of many phenotypes that develop as cells near replicative senescence, including reduction in cell size and granularity, loss of SA-β-gal staining and reacquisition of fibroblastic spindle morphology. AZD8055 treatment also induced rearrangement of the actin cytoskeleton, providing a possible mechanism of action for the observed rejuvenation. Importantly, short-term drug exposure had no detrimental effects on cell proliferation control across the life-course of the fibroblasts. Our findings suggest that combined inhibition of both mTORC1 and mTORC2 may provide a promising strategy to reverse the development of senescence-associated features in near-senescent cells.
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Hexokinase is a key regulator of energy metabolism and ROS activity in insect lifespan extension

Xian-Wu Lin, Wei-Hua Xu,

https://doi.org/10.18632/aging.100885 pp 245—259

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Lin X, Xu W, . Hexokinase is a key regulator of energy metabolism and ROS activity in insect lifespan extension. . 8:245-259. https://doi.org/10.18632/aging.100885

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                TY  - JOUR
                AU  - Lin, Xian-Wu 
                AU  - Xu, Wei-Hua 
                TI  - Hexokinase is a key regulator of energy metabolism and ROS activity in insect lifespan extension
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100885
                DO  - 10.18632/aging.100885
                SP  - 245
                EP  - 259
                PY  - 
                AB  - Developmental arrest (diapause) is a ‘non-aging’ state that is similar to the Caenorhabditis elegans dauer stage and Drosophila lifespan extension. Diapause results in low metabolic activity and a profound extension of insect lifespan. Here, we cloned the Helicoverpa armigera Hexokinase (HK) gene, a gene that is critical for the developmental arrest of this species. HK expression and activity levels were significantly increased in nondiapause-destined pupae compared with those of diapause-destined pupae. Downregulation of HK activity reduced cell viability and delayed pupal development by reducing metabolic activity and increasing ROS activity, which suggests that HK is a key regulator of insect development. We then identified the transcription factors Har-CREB, -c-Myc, and -POU as specifically binding the Har-HK promoter and regulating its activity. Intriguingly, Har-POU and -c-Myc are specific transcription factors for HK expression, whereas Har-CREB is nonspecific. Furthermore, Har-POU and -c-Myc could respond to ecdysone, which is an upstream hormone. Therefore, low ecdysone levels in diapause-destined individuals lead to low Har-POU and -c-Myc expression levels, ultimately repressing Har-HK expression and inducing entry into diapause or lifespan extension.
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Genomes of Strongylocentrotus franciscanus and Lytechinus variegatus: are there any genomic explanations for the two order of magnitude difference in the lifespan of sea urchins?

Petr V. Sergiev, Artem A. Artemov, Egor B. Prokhortchouk, Olga A. Dontsova, Grigory V. Berezkin,

https://doi.org/10.18632/aging.100889 pp 260—271

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Sergiev PV, Artemov AA, Prokhortchouk EB, Dontsova OA, Berezkin GV, . Genomes of Strongylocentrotus franciscanus and Lytechinus variegatus: are there any genomic explanations for the two order of magnitude difference in the lifespan of sea urchins?. . 8:260-271. https://doi.org/10.18632/aging.100889

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Provider: 
 TY - JOUR
 AU - Sergiev, Petr V. 
 AU - Artemov, Artem A. 
 AU - Prokhortchouk, Egor B. 
 AU - Dontsova, Olga A. 
 AU - Berezkin, Grigory V. 
 TI - Genomes of Strongylocentrotus franciscanus and Lytechinus variegatus: are there any genomic explanations for the two order of magnitude difference in the lifespan of sea urchins?
 JO - 
 JA - 
 VL - 8
 IS - 2
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100889
 DO - 10.18632/aging.100889
 SP - 260
 EP - 271
 PY - 
 AB - Sea urchins are marine invertebrates of extreme diversity of life span. Red sea urchin S. franciscanus is among the longest living creatures of the Ocean. Its lifetime is estimated to exceed a century, while the green sea urchin L. variegatus hardly survives more than four years. We sequenced and compared the genomes of these animals aiming at determination of the genetic basis of their longevity difference. List of genes related to the longevity of other animal species was created and used for homology search among the genomic data obtained in this study. Aminoacid sequences of longevity related proteins of S. franciscanus and L. variegatus as well as from a set of model species, were aligned and grouped on the basis of the species lifespan. Aminoacid residues specific for a longevity group were identified. Proteins containing aminoacids whose identity correlated with the lifespan were clustered on the basis of their function.
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Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease

Chi Zhang, Jie Lu, Bing Liu, Qinghua Cui, Yun Wang,

https://doi.org/10.18632/aging.100887 pp 272—290

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Zhang C, Lu J, Liu B, Cui Q, Wang Y, . Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease. . 8:272-290. https://doi.org/10.18632/aging.100887

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                TY  - JOUR
                AU  - Zhang, Chi 
                AU  - Lu, Jie 
                AU  - Liu, Bing 
                AU  - Cui, Qinghua 
                AU  - Wang, Yun 
                TI  - Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100887
                DO  - 10.18632/aging.100887
                SP  - 272
                EP  - 290
                PY  - 
                AB  - Alzheimer's disease (AD) is a serious neurodegenerative disease, and microRNAs (miRNAs) have been linked to its pathogenesis. miR-603, a novel primate-specific miRNA and an intronic miRNA of a human brain highly expressed gene KIAA1217, is implicated in the risk and pathogenesis of AD. The rs11014002 single nucleotide polymorphism (SNP) (C/U), which locates in miR-603 precursor (pre-miR-603), exhibits a protective effect towards AD risk. Additionally, the rs11014002 SNP promotes the biogenesis of mature miR-603. miR-603 downregulates LRPAP1 mRNA and protein levels through directly binding the 3′ untranslated region (3′UTR) of LRPAP1. Moreover, miR-603 increases LRP1 protein expression. LRPAP1 and LRP1, playing opposite roles, are involved in Aβ clearance and pathogenesis of AD. Strikingly, miR-603 exhibits a relatively higher expression and there is a loss of a negative correlation between miR-603 and LRPAP1/RND1 mRNA levels in the hippocampi of patients with AD. In addition, miR-603 directly downregulates a key neuronal apoptotic component-E2F1, and prevents HeLa cells from undergoing H2O2-induced apoptosis. This work suggests that miR-603 may be a novel AD-relevant miRNA and that its rs11014002 SNP may serve as a protective factor against AD.
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The signaling pathways by which the Fas/FasL system accelerates oocyte aging

Jiang Zhu, Fei-Hu Lin, Jie Zhang, Juan Lin, Hong Li, You-Wei Li, Xiu-Wen Tan, Jing-He Tan,

https://doi.org/10.18632/aging.100893 pp 291—303

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Zhu J, Lin F, Zhang J, Lin J, Li H, Li Y, Tan X, Tan J, . The signaling pathways by which the Fas/FasL system accelerates oocyte aging. . 8:291-303. https://doi.org/10.18632/aging.100893

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                TY  - JOUR
                AU  - Zhu, Jiang 
                AU  - Lin, Fei-Hu 
                AU  - Zhang, Jie 
                AU  - Lin, Juan 
                AU  - Li, Hong 
                AU  - Li, You-Wei 
                AU  - Tan, Xiu-Wen 
                AU  - Tan, Jing-He 
                TI  - The signaling pathways by which the Fas/FasL system accelerates oocyte aging
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100893
                DO  - 10.18632/aging.100893
                SP  - 291
                EP  - 303
                PY  - 
                AB  - In spite of great efforts, the mechanisms for postovulatory oocyte aging are not fully understood. Although our previous work showed that the FasL/Fas signaling facilitated oocyte aging, the intra-oocyte signaling pathways are unknown. Furthermore, the mechanisms by which oxidative stress facilitates oocyte aging and the causal relationship between Ca2+ rises and caspase-3 activation and between the cell cycle and apoptosis during oocyte aging need detailed investigations. Our aim was to address these issues by studying the intra-oocyte signaling pathways for Fas/FasL to accelerate oocyte aging. The results indicated that sFasL released by cumulus cells activated Fas on the oocyte by increasing reactive oxygen species via activating NADPH oxidase. The activated Fas triggered Ca2+ release from the endoplasmic reticulum by activating phospholipase C-γ pathway and cytochrome c pathway. The cytoplasmic Ca2+ rises activated calcium/calmodulin-dependent protein kinase II (CaMKII) and caspase-3. While activated CaMKII increased oocyte susceptibility to activation by inactivating maturation-promoting factor (MPF) through cyclin B degradation, the activated caspase-3 facilitated further Ca2+ releasing that activates more caspase-3 leading to oocyte fragmentation. Furthermore, caspase-3 activation and fragmentation were prevented in oocytes with a high MPF activity, suggesting that an oocyte must be in interphase to undergo apoptosis.
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Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic

Dale E. Bredesen,

https://doi.org/10.18632/aging.100896 pp 304—313

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Bredesen DE, . Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic. . 8:304-313. https://doi.org/10.18632/aging.100896

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                TY  - JOUR
                AU  - Bredesen, Dale E. 
                TI  - Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100896
                DO  - 10.18632/aging.100896
                SP  - 304
                EP  - 313
                PY  - 
                AB  - Alzheimer's disease is one of the most significant healthcare problems today, with a dire need for effective treatment. Identifying subtypes of Alzheimer's disease may aid in the development of therapeutics, and recently three different subtypes have been described: type 1 (inflammatory), type 2 (non-inflammatory or atrophic), and type 3 (cortical). Here I report that type 3 Alzheimer's disease is the result of exposure to specific toxins, and is most commonly inhalational (IAD), a phenotypic manifestation of chronic inflammatory response syndrome (CIRS), due to biotoxins such as mycotoxins. The appropriate recognition of IAD as a potentially important pathogenetic condition in patients with cognitive decline offers the opportunity for successful treatment of a large number of patients whose current prognoses, in the absence of accurate diagnosis, are grave.
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Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts

Ying Ann Chiao, Stephen C. Kolwicz, Nathan Basisty, Arni Gagnidze, Julia Zhang, Haiwei Gu, Danijel Djukovic, Richard P. Beyer, Daniel Raftery, Michael MacCoss, Rong Tian, Peter S. Rabinovitch,

https://doi.org/10.18632/aging.100881 pp 314—327

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Chiao YA, Kolwicz SC, Basisty N, Gagnidze A, Zhang J, Gu H, Djukovic D, Beyer RP, Raftery D, MacCoss M, Tian R, Rabinovitch PS, . Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts. . 8:314-327. https://doi.org/10.18632/aging.100881

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                TY  - JOUR
                AU  - Chiao, Ying Ann 
                AU  - Kolwicz, Stephen C. 
                AU  - Basisty, Nathan 
                AU  - Gagnidze, Arni 
                AU  - Zhang, Julia 
                AU  - Gu, Haiwei 
                AU  - Djukovic, Danijel 
                AU  - Beyer, Richard P. 
                AU  - Raftery, Daniel 
                AU  - MacCoss, Michael 
                AU  - Tian, Rong 
                AU  - Rabinovitch, Peter S. 
                TI  - Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100881
                DO  - 10.18632/aging.100881
                SP  - 314
                EP  - 327
                PY  - 
                AB  - Rapamycin, an inhibitor of mTOR signaling, has been shown to reverse diastolic dysfunction in old mice in 10 weeks, highlighting its therapeutic potential for a poorly treatable condition. However, the mechanisms and temporal regulation of its cardiac benefits remain unclear. We show that improved diastolic function in old mice begins at 2-4 weeks, progressing over the course of 10-week treatment. While TORC1-mediated S6 phosphorylation and TORC2 mediated AKT and PKCα phosphorylation are inhibited throughout the course of treatment, rapamycin inhibits ULK phosphorylation and induces autophagy during just the first week of treatment, returning to baseline at two weeks and after. Concordantly, markers of mitochondrial biogenesis increase over the first two weeks of treatment and return to control levels thereafter. This transient induction of autophagy and mitochondrial biogenesis suggests that damaged mitochondria are replaced by newly synthesized ones to rejuvenate mitochondrial homeostasis. This remodeling is shown to rapidly reverse the age-related reduction in fatty acid oxidation to restore a more youthful substrate utilization and energetic profile in old isolated perfused hearts, and modulates the myocardial metabolome in vivo. This study demonstrates the differential and dynamic mechanisms following rapamycin treatment and highlights the importance of understanding the temporal regulation of rapamycin effects.
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NKG2D ligands mediate immunosurveillance of senescent cells

Adi Sagiv, Dominick G. A. Burton, Zhana Moshayev, Ezra Vadai, Felix Wensveen, Shifra Ben-Dor, Ofra Golani, Bojan Polic, Valery Krizhanovsky,

https://doi.org/10.18632/aging.100897 pp 328—344

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Sagiv A, Burton DGA, Moshayev Z, Vadai E, Wensveen F, Ben-Dor S, Golani O, Polic B, Krizhanovsky V, . NKG2D ligands mediate immunosurveillance of senescent cells. . 8:328-344. https://doi.org/10.18632/aging.100897

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                TY  - JOUR
                AU  - Sagiv, Adi 
                AU  - Burton, Dominick G. A. 
                AU  - Moshayev, Zhana 
                AU  - Vadai, Ezra 
                AU  - Wensveen, Felix 
                AU  - Ben-Dor, Shifra 
                AU  - Golani, Ofra 
                AU  - Polic, Bojan 
                AU  - Krizhanovsky, Valery 
                TI  - NKG2D ligands mediate immunosurveillance of senescent cells
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100897
                DO  - 10.18632/aging.100897
                SP  - 328
                EP  - 344
                PY  - 
                AB  - Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood. Here we show that ligands of an activating Natural Killer (NK) cell receptor (NKG2D), MICA and ULBP2 are consistently up-regulated following induction of replicative senescence, oncogene-induced senescence and DNA damage - induced senescence. MICA and ULBP2 proteins are necessary for efficient NK-mediated cytotoxicity towards senescent fibroblasts. The mechanisms regulating the initial expression of NKG2D ligands in senescent cells are dependent on a DNA damage response, whilst continuous expression of these ligands is regulated by the ERK signaling pathway. In liver fibrosis, the accumulation of senescent activated stellate cells is increased in mice lacking NKG2D receptor leading to increased fibrosis. Overall, our results provide new insights into the mechanisms regulating the expression of immune ligands in senescent cells and reveal the importance of NKG2D receptor-ligand interaction in protecting against liver fibrosis.
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p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function

Zijun Y. Xu-Monette, Shanxiang Zhang, Xin Li, Ganiraju C. Manyam, Xiao-xiao Wang, Yi Xia, Carlo Visco, Alexandar Tzankov, Li Zhang, Santiago Montes-Moreno, Karen Dybkaer, April Chiu, Attilio Orazi, Youli Zu, Govind Bhagat, Kristy L. Richards, Eric D. Hsi, William W.L. Choi, J. Han van Krieken, Jooryung Huh, Maurilio Ponzoni, Andrés J.M. Ferreri, Xiaoying Zhao, Michael B. Møller, Ben M. Parsons, Jane N. Winter, Miguel A. Piris, L. Jeffrey Medeiros, Ken H. Young,

https://doi.org/10.18632/aging.100898 pp 345—365

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Xu-Monette ZY, Zhang S, Li X, Manyam GC, Wang X, Xia Y, Visco C, Tzankov A, Zhang L, Montes-Moreno S, Dybkaer K, Chiu A, Orazi A, et al, . p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function. . 8:345-365. https://doi.org/10.18632/aging.100898

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                TY  - JOUR
                AU  - Xu-Monette, Zijun Y. 
                AU  - Zhang, Shanxiang 
                AU  - Li, Xin 
                AU  - Manyam, Ganiraju C. 
                AU  - Wang, Xiao-xiao 
                AU  - Xia, Yi 
                AU  - Visco, Carlo 
                AU  - Tzankov, Alexandar 
                AU  - Zhang, Li 
                AU  - Montes-Moreno, Santiago 
                AU  - Dybkaer, Karen 
                AU  - Chiu, April 
                AU  - Orazi, Attilio 
                AU  - Zu, Youli 
                AU  - Bhagat, Govind 
                AU  - Richards, Kristy L. 
                AU  - Hsi, Eric D. 
                AU  - Choi, William W.L. 
                AU  - van Krieken, J. Han 
                AU  - Huh, Jooryung 
                AU  - Ponzoni, Maurilio 
                AU  - Ferreri, Andrés J.M. 
                AU  - Zhao, Xiaoying 
                AU  - Møller, Michael B. 
                AU  - Parsons, Ben M. 
                AU  - Winter, Jane N. 
                AU  - Piris, Miguel A. 
                AU  - Medeiros, L. Jeffrey 
                AU  - Young, Ken H. 
                TI  - p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100898
                DO  - 10.18632/aging.100898
                SP  - 345
                EP  - 365
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Xu-Monette, Zijun Y. 
                AU  - Zhang, Shanxiang 
                AU  - Li, Xin 
                AU  - Manyam, Ganiraju C. 
                AU  - Wang, Xiao-xiao 
                AU  - Xia, Yi 
                AU  - Visco, Carlo 
                AU  - Tzankov, Alexandar 
                AU  - Zhang, Li 
                AU  - Montes-Moreno, Santiago 
                AU  - Dybkaer, Karen 
                AU  - Chiu, April 
                AU  - Orazi, Attilio 
                AU  - Zu, Youli 
                AU  - Bhagat, Govind 
                AU  - Richards, Kristy L. 
                AU  - Hsi, Eric D. 
                AU  - Choi, William W.L. 
                AU  - van Krieken, J. Han 
                AU  - Huh, Jooryung 
                AU  - Ponzoni, Maurilio 
                AU  - Ferreri, Andrés J.M. 
                AU  - Zhao, Xiaoying 
                AU  - Møller, Michael B. 
                AU  - Parsons, Ben M. 
                AU  - Winter, Jane N. 
                AU  - Piris, Miguel A. 
                AU  - Medeiros, L. Jeffrey 
                AU  - Young, Ken H. 
                TI  - p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100898
                DO  - 10.18632/aging.100898
                SP  - 345
                EP  - 365
                PY  - 
                AB  - The role of p53 family member, p63 in oncogenesis is the subject of controversy. Limited research has been done on the clinical implications of p63 expression in diffuse large B-cell lymphoma (DLBCL). In this study, we assessed p63 expression in de novo DLBCL samples (n=795) by immunohistochemistry with a pan-p63-monoclonal antibody and correlated it with other clinicopathologic factors and clinical outcomes. p63 expression was observed in 42.5% of DLBCL, did not correlate with p53 levels, but correlated with p21, MDM2, p16INK4A, Ki-67, Bcl-6, IRF4/MUM-1 and CD30 expression, REL gains, and BCL6 translocation. p63 was an independent favorable prognostic factor in DLBCL, which was most significant in patients with International Prognostic Index (IPI) &gt;2, and in activated-B-cell–like DLBCL patients with wide-type TP53. The prognostic impact in germinal-center-B-cell–like DLBCL was not apparent, which was likely due to the association of p63 expression with high-risk IPI, and potential presence of ∆Np63 isoform in TP63 rearranged patients (a mere speculation). Gene expression profiling suggested that p63 has both overlapping and distinct functions compared with p53, and that p63 and mutated p53 antagonize each other. In summary, p63 has p53-like and p53-independent functions and favorable prognostic impact, however this protective effect can be abolished by TP53 mutations.
                ER  -

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Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase

Olga Moiseeva, Stéphane Lopes-Paciencia, Geneviève Huot, Frédéric Lessard, Gerardo Ferbeyre,

https://doi.org/10.18632/aging.100903 pp 366—381

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Moiseeva O, Lopes-Paciencia S, Huot G, Lessard F, Ferbeyre G, . Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase. . 8:366-381. https://doi.org/10.18632/aging.100903

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Provider: 
                TY  - JOUR
                AU  - Moiseeva, Olga 
                AU  - Lopes-Paciencia, Stéphane 
                AU  - Huot, Geneviève 
                AU  - Lessard, Frédéric 
                AU  - Ferbeyre, Gerardo 
                TI  - Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100903
                DO  - 10.18632/aging.100903
                SP  - 366
                EP  - 381
                PY  - 
                AB  - Mutants of lamin A cause diseases including the Hutchinson-Gilford progeria syndrome (HGPS) characterized by premature aging. Lamin A undergoes a series of processing reactions, including farnesylation and proteolytic cleavage of the farnesylated C-terminal domain. The role of cleavage is unknown but mutations that affect this reaction lead to progeria. Here we show that interphase serine 22 phosphorylation of endogenous mutant lamin A (progerin) is defective in cells from HGPS patients. This defect can be mimicked by expressing progerin in human cells and prevented by inhibition of farnesylation. Furthermore, serine 22 phosphorylation of non-farnesylated progerin was enhanced by a mutation that disrupts lamin A head to tail interactions. The phosphorylation of lamin A or non-farnesylated progerin was associated to the formation of spherical intranuclear lamin A droplets that accumulate protein kinases of the CDK family capable of phosphorylating lamin A at serine 22. CDK inhibitors compromised the turnover of progerin, accelerated senescence of HGPS cells and reversed the effects of FTI on progerin levels. We discuss a model of progeria where faulty serine 22 phosphorylation compromises phase separation of lamin A polymers, leading to accumulation of functionally impaired lamin A structures.
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Telomere shortening leads to earlier age of onset in ALS mice

Birgit Linkus, Diana Wiesner, Martina Meßner, Alexander Karabatsiakis, Annika Scheffold, K. Lenhard Rudolph, Dietmar R. Thal, Jochen H. Weishaupt, Albert C. Ludolph, Karin M. Danzer,

https://doi.org/10.18632/aging.100904 pp 382—393

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Linkus B, Wiesner D, Meßner M, Karabatsiakis A, Scheffold A, Rudolph KL, Thal DR, Weishaupt JH, Ludolph AC, Danzer KM, . Telomere shortening leads to earlier age of onset in ALS mice. . 8:382-393. https://doi.org/10.18632/aging.100904

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                TY  - JOUR
                AU  - Linkus, Birgit 
                AU  - Wiesner, Diana 
                AU  - Meßner, Martina 
                AU  - Karabatsiakis, Alexander 
                AU  - Scheffold, Annika 
                AU  - Rudolph, K. Lenhard 
                AU  - Thal, Dietmar R. 
                AU  - Weishaupt, Jochen H. 
                AU  - Ludolph, Albert C. 
                AU  - Danzer, Karin M. 
                TI  - Telomere shortening leads to earlier age of onset in ALS mice
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100904
                DO  - 10.18632/aging.100904
                SP  - 382
                EP  - 393
                PY  - 
                AB  - Telomere shortening has been linked to a variety of neurodegenerative diseases. Recent evidence suggests that reduced telomerase expression results in shorter telomeres in leukocytes from sporadic patients with amyotrophic lateral sclerosis (ALS) compared with healthy controls. Here, we have characterized telomere length in microglia, astroglia and neurons in human post mortem brain tissue from ALS patients and healthy controls. Moreover, we studied the consequences of telomerase deletion in a genetic mouse model for ALS. We found a trend towards longer telomeres in microglia in the brains of ALS patients compared to non-neurologic controls. Knockout of telomerase leading to telomere shortening accelerated the ALS phenotype in SOD1G93A–transgenic mice. Our results suggest that telomerase dysfunction might contribute to the age-related risk for ALS.
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DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy

Qiong Lin, Carola I. Weidner, Ivan G. Costa, Riccardo E. Marioni, Marcelo R. P. Ferreira, Ian J. Deary, Wolfgang Wagner,

https://doi.org/10.18632/aging.100908 pp 394—401

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Lin Q, Weidner CI, Costa IG, Marioni RE, Ferreira MRP, Deary IJ, Wagner W, . DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy. . 8:394-401. https://doi.org/10.18632/aging.100908

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                TY  - JOUR
                AU  - Lin, Qiong 
                AU  - Weidner, Carola I. 
                AU  - Costa, Ivan G. 
                AU  - Marioni, Riccardo E. 
                AU  - Ferreira, Marcelo R. P. 
                AU  - Deary, Ian J. 
                AU  - Wagner, Wolfgang 
                TI  - DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy
                JO  - 
                JA  - 
                VL  - 8
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100908
                DO  - 10.18632/aging.100908
                SP  - 394
                EP  - 401
                PY  - 
                AB  - DNA-methylation (DNAm) levels at age-associated CpG sites can be combined into epigenetic aging signatures to estimate donor age. It has been demonstrated that the difference between such epigenetic age-predictions and chronological age is indicative for of all-cause mortality in later life. In this study, we tested alternative epigenetic signatures and followed the hypothesis that even individual age-associated CpG sites might be indicative for life-expectancy. Using a 99-CpG aging model, a five-year higher age-prediction was associated with 11% greater mortality risk in DNAm profiles of the Lothian Birth Cohort 1921 study. However, models based on three CpGs, or even individual CpGs, generally revealed very high offsets in age-predictions if applied to independent microarray datasets. On the other hand, we demonstrate that DNAm levels at several individual age-associated CpGs seem to be associated with life expectancy – e.g., at CpGs associated with the genes PDE4C and CLCN6. Our results support the notion that small aging signatures should rather be analysed by more quantitative methods, such as site-specific pyrosequencing, as the precision of age-predictions is rather low on independent microarray datasets. Nevertheless, the results hold the perspective that simple epigenetic biomarkers, based on few or individual age-associated CpGs, could assist the estimation of biological age.
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Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan

Charles A. Schumpert, Craig Anderson, Jeffry L. Dudycha, Rekha C. Patel,

https://doi.org/10.18632/aging.100909 pp 402—417

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Schumpert CA, Anderson C, Dudycha JL, Patel RC, . Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan. . 8:402-417. https://doi.org/10.18632/aging.100909

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 TY - JOUR
 AU - Schumpert, Charles A. 
 AU - Anderson, Craig 
 AU - Dudycha, Jeffry L. 
 AU - Patel, Rekha C. 
 TI - Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan
 JO - 
 JA - 
 VL - 8
 IS - 2
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100909
 DO - 10.18632/aging.100909
 SP - 402
 EP - 417
 PY - 
 AB - The ability to appropriately respond to proteotoxic stimuli is a major determinant of longevity and involves induction of various heat shock response (HSR) genes, which are essential to cope with cellular and organismal insults throughout lifespan. The activity of NAD+-dependent deacetylase Sir2, originally discovered in yeast, is known to be essential for effective HSR and longevity. Our previous work on HSR in Daphnia pulicaria indicated a drastic reduction of the HSR in older organisms. In this report we investigate the role of Sir2 in regulating HSR during the lifespan of D. pulicaria. We cloned Daphnia Sir2 open reading frame (ORF) to characterize the enzyme activity and confirmed that the overall function of Sir2 was conserved in Daphnia. The Sir2 mRNA levels increased while the enzyme activity declined with age and considering that Sir2 activity regulates HSR, this explains the previously observed age-dependent decline in HSR. Finally, we tested the effect of Sir2 knockdown throughout adult life by using our new RNA interference (RNAi) method by feeding. Sir2 knockdown severely reduced both the median lifespan as well as significantly increased mortality following heat shock. Our study provides the first characterization and functional study of Daphnia Sir2.
 ER -

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Volume 8, Issue 2

About the Cover

The longevity transporter mIndy (Slc13a5) as a target for treating hepatic steatosis and insulin resistance

Diana M. Willmes, Stephen L. Helfand, Andreas L. Birkenfeld,

Editorials

Copper that cancer with lysosomal love!

Zaklina Kovacevic, Sumit Sahni, Des R. Richardson,

Mitochondria operate as signaling platforms in yeast aging

Younes Medkour, Vladimir I. Titorenko,

MKP1: Jekyll and Hyde for E1A

Francisco J. Cimas, Juan Luis Callejas-Valera, Ricardo Sanchez-Prieto,

Research Papers

Placental membrane aging and HMGB1 signaling associated with human parturition

Ramkumar Menon, Faranak Behnia, Jossimara Polettini, George R Saade, Judith Campisi, Michael Velarde,

Reversal of phenotypes of cellular senescence by pan-mTOR inhibition

Hannah E. Walters, Sylwia Deneka-Hannemann, Lynne S. Cox,

Hexokinase is a key regulator of energy metabolism and ROS activity in insect lifespan extension

Xian-Wu Lin, Wei-Hua Xu,

Genomes of Strongylocentrotus franciscanus and Lytechinus variegatus: are there any genomic explanations for the two order of magnitude difference in the lifespan of sea urchins?

Petr V. Sergiev, Artem A. Artemov, Egor B. Prokhortchouk, Olga A. Dontsova, Grigory V. Berezkin,

Primate-specific miR-603 is implicated in the risk and pathogenesis of Alzheimer's disease

Chi Zhang, Jie Lu, Bing Liu, Qinghua Cui, Yun Wang,

The signaling pathways by which the Fas/FasL system accelerates oocyte aging

Jiang Zhu, Fei-Hu Lin, Jie Zhang, Juan Lin, Hong Li, You-Wei Li, Xiu-Wen Tan, Jing-He Tan,

Inhalational Alzheimer's disease: an unrecognized—and treatable—epidemic

Dale E. Bredesen,

Rapamycin transiently induces mitochondrial remodeling to reprogram energy metabolism in old hearts

Ying Ann Chiao, Stephen C. Kolwicz, Nathan Basisty, Arni Gagnidze, Julia Zhang, Haiwei Gu, Danijel Djukovic, Richard P. Beyer, Daniel Raftery, Michael MacCoss, Rong Tian, Peter S. Rabinovitch,

NKG2D ligands mediate immunosurveillance of senescent cells

Adi Sagiv, Dominick G. A. Burton, Zhana Moshayev, Ezra Vadai, Felix Wensveen, Shifra Ben-Dor, Ofra Golani, Bojan Polic, Valery Krizhanovsky,

p63 expression confers significantly better survival outcomes in high-risk diffuse large B-cell lymphoma and demonstrates p53-like and p53-independent tumor suppressor function

Permanent farnesylation of lamin A mutants linked to progeria impairs its phosphorylation at serine 22 during interphase

Olga Moiseeva, Stéphane Lopes-Paciencia, Geneviève Huot, Frédéric Lessard, Gerardo Ferbeyre,

Telomere shortening leads to earlier age of onset in ALS mice

Birgit Linkus, Diana Wiesner, Martina Meßner, Alexander Karabatsiakis, Annika Scheffold, K. Lenhard Rudolph, Dietmar R. Thal, Jochen H. Weishaupt, Albert C. Ludolph, Karin M. Danzer,

DNA methylation levels at individual age-associated CpG sites can be indicative for life expectancy

Qiong Lin, Carola I. Weidner, Ivan G. Costa, Riccardo E. Marioni, Marcelo R. P. Ferreira, Ian J. Deary, Wolfgang Wagner,

Involvement of Daphnia pulicaria Sir2 in regulating stress response and lifespan

Charles A. Schumpert, Craig Anderson, Jeffry L. Dudycha, Rekha C. Patel,

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