Volume 3, Issue 9

Steroid boost for sirtuin research

Tobias Rumpf, Manfred Jung,

https://doi.org/10.18632/aging.100386 pp 818

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Rumpf T, Jung M, . Steroid boost for sirtuin research. . 3:818-818. https://doi.org/10.18632/aging.100386

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Identification of specific and semi-specific SIRT inhibitors through computer-aided studies

Antonello Mai,

https://doi.org/10.18632/aging.100387 pp 819—820

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Hormesis, cell death and aging

Isabelle Martins, Lorenzo Galluzzi, Guido Kroemer,

https://doi.org/10.18632/aging.100380 pp 821—828

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Martins I, Galluzzi L, Kroemer G, . Hormesis, cell death and aging. . 3:821-828. https://doi.org/10.18632/aging.100380

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                TY  - JOUR
                AU  - Martins, Isabelle 
                AU  - Galluzzi, Lorenzo 
                AU  - Kroemer, Guido 
                TI  - Hormesis, cell death and aging
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100380
                DO  - 10.18632/aging.100380
                SP  - 821
                EP  - 828
                PY  - 
                AB  - Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress response that raise the resistance of the organism against high doses of the same agent. This phenomenon, which is known as “hormesis”, is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction.
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Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair

Michael Van Meter, Zhiyong Mao, Vera Gorbunova, Andrei Seluanov,

https://doi.org/10.18632/aging.100389 pp 829—835

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Van Meter M, Mao Z, Gorbunova V, Seluanov A, . Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair. . 3:829-835. https://doi.org/10.18632/aging.100389

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                TY  - JOUR
                AU  - Van Meter, Michael 
                AU  - Mao, Zhiyong 
                AU  - Gorbunova, Vera 
                AU  - Seluanov, Andrei 
                TI  - Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100389
                DO  - 10.18632/aging.100389
                SP  - 829
                EP  - 835
                PY  - 
                AB  - The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies. To date, most of these studies have focused on the deacetylase activity of sirtuins, and relatively little is known about the other biochemical activity of sirtuins, mono-ADP ribosylation. We recently reported that the mammalian sirtuin, SIRT6, mono-ADP ribosylates PARP1 to promote DNA repair in response to oxidative stress. In this research perspective we review the role of SIRT6 in DNA repair and discuss the emerging implications for sirtuin directed mono-ADP ribosylation in aging and age-related diseases.
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53BP1 contributes to a robust genomic stability in human fibroblasts

Lauren S. Fink, Michaela Roell, Emanuela Caiazza, Chad Lerner, Thomas Stamato, Silvana Hrelia, Antonello Lorenzini, Christian Sell,

https://doi.org/10.18632/aging.100381 pp 836—845

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Fink LS, Roell M, Caiazza E, Lerner C, Stamato T, Hrelia S, Lorenzini A, Sell C, . 53BP1 contributes to a robust genomic stability in human fibroblasts. . 3:836-845. https://doi.org/10.18632/aging.100381

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                TY  - JOUR
                AU  - Fink, Lauren S. 
                AU  - Roell, Michaela 
                AU  - Caiazza, Emanuela 
                AU  - Lerner, Chad 
                AU  - Stamato, Thomas 
                AU  - Hrelia, Silvana 
                AU  - Lorenzini, Antonello 
                AU  - Sell, Christian 
                TI  - 53BP1 contributes to a robust genomic stability in human fibroblasts
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100381
                DO  - 10.18632/aging.100381
                SP  - 836
                EP  - 845
                PY  - 
                AB  - Faithful repair of damaged DNA is a crucial process in maintaining cell viability and function. A multitude of factors and pathways guides this process and includes repair proteins and cell cycle checkpoint factors. Differences in the maintenance of genomic processes are one feature that may contribute to species-specific differences in lifespan. We predicted that 53BP1, a key transducer of the DNA damage response and cell cycle checkpoint control, is highly involved in maintaining genomic stability and may function differently in cells from different species. We demonstrate a difference in the levels and recruitment of 53BP1 in mouse and human cells following DNA damage. In addition, we show that unresolved DNA damage persists more in mouse cells than in human cells, as evidenced by increased numbers of micronuclei. The difference in micronuclei seems to be related to the levels of 53BP1 present in cells. Finally, we present evidence that unresolved DNA damage correlates with species lifespan. Taken together, these studies suggest a link between recruitment of 53BP1, resolution of DNA damage, and increased species lifespan.
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Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer's disease

Bing Song, Korbin Davis, X. Shawn Liu, Hyoung-gon Lee, Mark Smith, Xiaoqi Liu,

https://doi.org/10.18632/aging.100382 pp 846—851

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Song B, Davis K, Liu XS, Lee H, Smith M, Liu X, . Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer's disease. . 3:846-851. https://doi.org/10.18632/aging.100382

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                TY  - JOUR
                AU  - Song, Bing 
                AU  - Davis, Korbin 
                AU  - Liu, X. Shawn 
                AU  - Lee, Hyoung-gon 
                AU  - Smith, Mark 
                AU  - Liu, Xiaoqi 
                TI  - Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer's disease
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100382
                DO  - 10.18632/aging.100382
                SP  - 846
                EP  - 851
                PY  - 
                AB  - Alzheimer's disease (AD) is a progressive and fatal brain disease, but the pathogenesis of AD is still not understood. Aberrant cell-cycle re-entry of neuronal cells is emerging as a potential pathological mechanism in AD. Polo-like kinase 1 (Plk1) is an established regulator of many cell cycle-related events. Interestingly, Plk1 is present in susceptible hippocampal and cortical neurons of AD patients but not age-matched controls. However, whether Plk1 is involved in the pathogenesis of AD remains elusive. In this study, we showed that Plk1 activity is elevated in AD patient brain as indicated by the increased phosphorylation signal of p150Glued, a Plk1-specific substrate. Furthermore, we demonstrated that Plk1 is elevated during the cell-cycle re-entry of neuronal cells in an in vitro cell-culture model. Significantly, inhibition of Plk1 kinase activity or depletion of Plk1 by RNAi reduces β-amyloid (Aβ)-induced neuronal cell death. These results validate Plk1 as a possible target for AD therapy.
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Structure-based development of novel sirtuin inhibitors

Christine Schlicker, Gina Boanca, Mahadevan Lakshminarasimhan, Clemens Steegborn,

https://doi.org/10.18632/aging.100388 pp 852—872

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Schlicker C, Boanca G, Lakshminarasimhan M, Steegborn C, . Structure-based development of novel sirtuin inhibitors. . 3:852-872. https://doi.org/10.18632/aging.100388

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                TY  - JOUR
                AU  - Schlicker, Christine 
                AU  - Boanca, Gina 
                AU  - Lakshminarasimhan, Mahadevan 
                AU  - Steegborn, Clemens 
                TI  - Structure-based development of novel sirtuin inhibitors
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100388
                DO  - 10.18632/aging.100388
                SP  - 852
                EP  - 872
                PY  - 
                AB  - Sirtuins are NAD+-dependent protein deacetylases regulating metabolism, stress responses, and aging processes. Mammalia possess seven Sirtuin isoforms, Sirt1-7, which differ in their subcellular localization and in the substrate proteins they deacetylate. The physiological roles of Sirtuins and their potential use as therapeutic targets for metabolic and aging-related diseases have spurred interest in the development of small-molecule Sirtuin modulators. Here, we describe an approach exploiting the structures available for four human Sirtuins for the development of isoform-specific inhibitors. Virtual docking of a compound library into the peptide binding pockets of crystal structures of Sirt2, 3, 5 and 6 yielded compounds potentially discriminating between these isoforms. Further characterization in activity assays revealed several inhibitory compounds with little isoform specificity, but also two compounds with micromolar potency and high specificity for Sirt2. Structure comparison and the predicted, shared binding mode of the Sirt2-specific compounds indicate a pocket extending from the peptide-binding groove as target side enabling isoform specificity. Our family-wide structure-based approach thus identified potent, Sirt2-specific inhibitors as well as lead structures and a target site for the development of compounds specific for other Sirtuin isoform, constituting an important step toward the identification of a complete panel of isoform-specific Sirtuin inhibitors.
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Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks

Anne Schellenberg, Qiong Lin, Herdit Schüler, Carmen M. Koch, Sylvia Joussen, Bernd Denecke, Gudrun Walenda, Norbert Pallua, Christoph V. Suschek, Martin Zenke, Wolfgang Wagner,

https://doi.org/10.18632/aging.100391 pp 873—888

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Schellenberg A, Lin Q, Schüler H, Koch CM, Joussen S, Denecke B, Walenda G, Pallua N, Suschek CV, Zenke M, Wagner W, . Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks. . 3:873-888. https://doi.org/10.18632/aging.100391

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                TY  - JOUR
                AU  - Schellenberg, Anne 
                AU  - Lin, Qiong 
                AU  - Schüler, Herdit 
                AU  - Koch, Carmen M. 
                AU  - Joussen, Sylvia 
                AU  - Denecke, Bernd 
                AU  - Walenda, Gudrun 
                AU  - Pallua, Norbert 
                AU  - Suschek, Christoph V. 
                AU  - Zenke, Martin 
                AU  - Wagner, Wolfgang 
                TI  - Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100391
                DO  - 10.18632/aging.100391
                SP  - 873
                EP  - 888
                PY  - 
                AB  - Cells in culture undergo replicative senescence. In this study, we analyzed functional, genetic and epigenetic sequels of long-term culture in human mesenchymal stem cells (MSC). Already within early passages the fibroblastoid colonyforming unit (CFU-f) frequency and the differentiation potential of MSC declined significantly. Relevant chromosomal aberrations were not detected by karyotyping and SNP-microarrays. Subsequently, we have compared DNA-methylation profiles with the Infinium HumanMethylation27 Bead Array and the profiles differed markedly in MSC derived from adipose tissue and bone marrow. Notably, all MSC revealed highly consistent senescence-associated modifications at specific CpG sites. These DNA-methylation changes correlated with histone marks of previously published data sets, such as trimethylation of H3K9, H3K27 and EZH2 targets. Taken together, culture expansion of MSC has profound functional implications - these are hardly reflected by genomic instability but they are associated with highly reproducible DNA-methylation changes which correlate with repressive histone marks. Therefore replicative senescence seems to be epigenetically controlled.
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Accelerated aging syndromes, are they relevant to normal human aging?

Oliver Dreesen, Colin L. Stewart,

https://doi.org/10.18632/aging.100383 pp 889—895

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Dreesen O, Stewart CL, . Accelerated aging syndromes, are they relevant to normal human aging?. . 3:889-895. https://doi.org/10.18632/aging.100383

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                TY  - JOUR
                AU  - Dreesen, Oliver 
                AU  - Stewart, Colin L. 
                TI  - Accelerated aging syndromes, are they relevant to normal human aging?
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100383
                DO  - 10.18632/aging.100383
                SP  - 889
                EP  - 895
                PY  - 
                AB  - Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in theLMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging? Much of what we know stems from the study of patient derived fibroblasts with both mutations resulting in increased DNA damage, primarily at telomeres. However, in vivo patients with Werner's develop arteriosclerosis, among other pathologies. In HGPS patients, including iPS derived cells from HGPS patients, as well as some mouse models for Progeria, vascular smooth muscle (VSM) appears to be among the most severely affected tissues. Defective Lamin processing, associated with DNA damage, is present in VSM from old individuals, indicating processing defects may be a factor in normal aging. Whether persistent DNA damage, particularly at telomeres, is the root cause for these pathologies remains to be established, since not all progeroid Lmna mutations result in DNA damage and genome instability.
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Epidermal growth factor and aging: A signaling molecule reveals a new eye opening function

Christopher Rongo,

https://doi.org/10.18632/aging.100384 pp 896—905

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Rongo C, . Epidermal growth factor and aging: A signaling molecule reveals a new eye opening function. . 3:896-905. https://doi.org/10.18632/aging.100384

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                TY  - JOUR
                AU  - Rongo, Christopher 
                TI  - Epidermal growth factor and aging: A signaling molecule reveals a new eye opening function
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100384
                DO  - 10.18632/aging.100384
                SP  - 896
                EP  - 905
                PY  - 
                AB  - Epidermal Growth Factor (EGF) is known for its role in promoting cell division and cellular differentiation in developing animals, but we know surprising little about what EGF does in vivo in mature adult animals. Here I review EGF signaling, emphasizing several recent studies that uncovered an unexpected role for EGF in promoting longevity and healthspan in mature adult C. elegans. EGF, acting through phospholipase Cγ and the IP3 receptor signaling, maintains pharyngeal and body wall muscle function in aging adults, and delays the accumulation of lipofuscin-enriched aging pigments within intestinal cells. EGF also acts through the Ras/ERK pathway to regulate protein homeostasis by promoting the expression of antioxidant genes, stimulating the activity of the Ubiquitin Proteasome System (UPS), and repressing the expression of small heat shock protein chaperones. The effects of EGF signaling on lifespan are largely independent of Insulin/IGF-like Signaling (IIS), as the effects of EGF signaling mutants on lifespan and heathspan are not affected by mutations in the DAF-2 insulin receptor or the DAF-16 FOXO transcription factor. Nevertheless, these two signal pathways have multiple points of overlap, coordination, and cross regulation. I propose that the IIS and EGF signaling pathways respond to environment and to developmental timing, respectively, so as to coordinate the appropriate physiological strategy that cells use to maintain protein homeostasis.
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Oxidation as “The Stress of Life”

Nikolay L. Malinin, Xiaoxia Z. West, Tatiana V. Byzova,

https://doi.org/10.18632/aging.100385 pp 906—910

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Malinin NL, West XZ, Byzova TV, . Oxidation as “The Stress of Life”. . 3:906-910. https://doi.org/10.18632/aging.100385

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                TY  - JOUR
                AU  - Malinin, Nikolay L. 
                AU  - West, Xiaoxia Z. 
                AU  - Byzova, Tatiana V. 
                TI  - Oxidation as “The Stress of Life”
                JO  - 
                JA  - 
                VL  - 3
                IS  - 9
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100385
                DO  - 10.18632/aging.100385
                SP  - 906
                EP  - 910
                PY  - 
                AB  - Multiple biological consequences of oxidative stress are known to contribute to aging and aging-related pathologies. It was recently shown that (carboxyalkyl)pyrroles (CAPs), the end products of phospholipid oxidation serve as a novel class of endogenous ligands for Toll-like receptors (TLRs) and promote the process of angiogenesis. In this review, we discuss implications of these findings in the context of age-related pathologies, including tumorigenesis. Accumulation of oxidation products in tissues of aging organisms might create conditions for uncontrolled pathological angiogenesis as seen in patients with age related macular degeneration. CAPs and their receptors, TLRs might also promote the progression of atherosclerotic lesions. Importantly, besides their role in a number of pathologies, oxidative products of phospholipids contribute to tissue repair processes thereby antagonizing the destructive effects of oxidation.
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Volume 3, Issue 9

Steroid boost for sirtuin research

Tobias Rumpf, Manfred Jung,

Identification of specific and semi-specific SIRT inhibitors through computer-aided studies

Antonello Mai,

Reviews

Hormesis, cell death and aging

Isabelle Martins, Lorenzo Galluzzi, Guido Kroemer,

Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair

Michael Van Meter, Zhiyong Mao, Vera Gorbunova, Andrei Seluanov,

Research Papers

53BP1 contributes to a robust genomic stability in human fibroblasts

Lauren S. Fink, Michaela Roell, Emanuela Caiazza, Chad Lerner, Thomas Stamato, Silvana Hrelia, Antonello Lorenzini, Christian Sell,

Inhibition of Polo-like kinase 1 reduces beta-amyloid-induced neuronal cell death in Alzheimer's disease

Bing Song, Korbin Davis, X. Shawn Liu, Hyoung-gon Lee, Mark Smith, Xiaoqi Liu,

Structure-based development of novel sirtuin inhibitors

Christine Schlicker, Gina Boanca, Mahadevan Lakshminarasimhan, Clemens Steegborn,

Replicative senescence of mesenchymal stem cells causes DNA-methylation changes which correlate with repressive histone marks

Anne Schellenberg, Qiong Lin, Herdit Schüler, Carmen M. Koch, Sylvia Joussen, Bernd Denecke, Gudrun Walenda, Norbert Pallua, Christoph V. Suschek, Martin Zenke, Wolfgang Wagner,

Research Perspectives

Accelerated aging syndromes, are they relevant to normal human aging?

Oliver Dreesen, Colin L. Stewart,

Epidermal growth factor and aging: A signaling molecule reveals a new eye opening function

Christopher Rongo,

Oxidation as “The Stress of Life”

Nikolay L. Malinin, Xiaoxia Z. West, Tatiana V. Byzova,

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