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Ausstellung Der Urkunde: 23 System Biology of Aging -- Exploring the System Nature of Aging employing Reliability Theory Dr. rer. nat. Lei Mao, M.Comp.Sc.(Bioinformatics) Habilitationsschrift an der Fakultät III Prozesswissenschaften Der Technischen Universität Berlin Lehrgebiet: Mikrobiologie und Genetik Eröffnung des Verfahrens: 9. September 2009 Verleihung der Lehrbefähigung: 15. Dezember 2010 Ausstellung der Urkunde: 23. Januar 2011 Aushändigung der Urkunde: 10. Februar 2011 Gutachter: Professor Dr. Jens Kurreck Professor Dr. Karl Sperling Professor Jiri Ferejt Professor Dr. Peter Hammerstein Berlin, 2010 D83 Diese kumulative Schrift gründet sich auf die folgenden Originalarbeiten: Kasper, G., Mao, L., Geissler, S., Trippens, J., Kuehnisch, J., Tschirschmann, M., Kaspar, K., Perka, C., Duda, G. N., and Klose, J. (2009). Insights into mesenchymal stem cell ageing: Involvement of antioxidant defence and actin cytoskeleton. Stem Cells. Feb;26;27(6):1288- 1297. Nebrich, G., Herrmann, M., Hartl, D., Diedrich, M., Kreitler, T., Wierling, C., Klose, J., Giavalisco, P., Zabel, C., and Mao, L. (2009). PROTEOMER: A workflow-optimized laboratory information management system for 2-D electrophoresis-centered proteomics. Proteomics Apr;9(7):1795-808. Mao, L., Hartl, D., Nolden, T., Koppelstatter, A., Klose, J., Himmelbauer, H., and Zabel, C. (2008). Pronounced alterations of cellular metabolism and structure due to hyper- or hypo- osmosis. J Proteome Res 2008 Sep;7(9):3968-83 Epub 2008 Jul 23. Zabel, C., Mao, L., Woodman, B., Rohe, M., Wacker, M. A., Klaere, Y., Koppelstaetter, A., Nebrich, G., Klein, O., Grams, S., et al. (2009). A large number of protein expression changes occur early in life and precede phenotype onset in a mouse model for Huntington's disease. Mol Cell Proteomics Apr;8(4):720-34. Diedrich, M., Mao, L., Bernreuther, C., Zabel, C., Nebrich, G., Kleene, R., and Klose, J. (2008). Proteome analysis of ventral midbrain in MPTP-treated normal and L1cam transgenic mice. Proteomics Mar;8(6):1266-75. Hartl, D., Irmler, M., Romer, I., Mader, M. T., Mao, L., Zabel, C., de Angelis, M. H., Beckers, J., and Klose, J. (2008a). Transcriptome and proteome analysis of early embryonic mouse brain development. Proteomics Mar;8(6):1257-65. Hartl, D., Rohe, M., Mao, L., Staufenbiel, M., Zabel, C., and Klose, J. (2008b). Impairment of adolescent hippocampal plasticity in a mouse model for Alzheimer's disease precedes disease phenotype. PLoS ONE Jul 23;3(7):e2759. Mao, L., Zabel, C., Herrmann, M., Nolden, T., Mertes, F., Magnol, L., Chabert, C., Hartl, D., Herault, Y., Delabar, J. M., et al. (2007). Proteomic shifts in embryonic stem cells with gene dose modifications suggest the presence of balancer proteins in protein regulatory networks. PLoS ONE Nov 28;2(11):e1218. Mao, L., Zabel, C., Wacker, M. A., Nebrich, G., Sagi, D., Schrade, P., Bachmann, S., Kowald, A., and Klose, J. (2006). Estimation of the mtDNA mutation rate in aging mice by proteome analysis and mathematical modeling. Exp Gerontol Jan;41(1):11-24. Epub 2005 Nov 2022. Zabel, C., Sagi, D., Kaindl, A. M., Steireif, N., Klare, Y., Mao, L., Peters, H., Wacker, M. A., Kleene, R., and Klose, J. (2006). Comparative proteomics in neurodegenerative and non- neurodegenerative diseases suggest nodal point proteins in regulatory networking. J Proteome Res Aug;5(8):1948-58. Erklärungen a) Ich versichere hiermit an Eidesstatt, dass die vorliegende Habilitationsschrift ohne fremde Hilfe verfasst, die beschriebene Ergebnisse selbst gewonnen, die Angaben über die Zusammenarbeit mit anderen Wissenschaftern und die zugrunde liegende Literatur vollständig sind. b) Ich erkläre hiermit, dass ich nicht bereits in einem Habilitationsverfahren, für das Fachgebiet, für das die Lehrbefähigung festgestellt werden soll, oder für ein verwandtes Fachgebiet gescheitert bin. c) Ein akademischer Grad wurde mir nicht entzogen und es liegen keine Tatsachen vor, die die Entziehung eines akademischen Grades rechtfertigen. d) An einer anderen Hochschule wurde von mir kein Habilitationsgesuch eingereicht. e) Ich erkläre hiermit, dass ein Strafverfahren beim Gericht nicht anhängig ist. f) Ich erkläre hiermit, dass mir die Habilitationsordnung vom 13.6.1993 bekannt ist. g) Ich erkläre hiermit, dass die Lehrveranstaltungen selbständig vorbereitet und abgehalten wurden. ……………………………… (Unterschrift) Abkürzungsverzeichnis: AD: Alzheimer disease HD: Huntington disease MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene hydrochloride MSC: mesenchymal stem cells ND: neurodegenerative disease PD: Parkinson diseases ROS: reactive oxygen species System Biology of Aging Exploring the System Nature of Aging employing Reliability Theory Table of contents 1 Introduction ........................................................................................................................ 1 1.1 Mankind is growing older worldwide....................................................................... 1 1.2 What is aging? .......................................................................................................... 1 1.3 Descriptive laws on aging phenomenon ................................................................... 2 1.4 Current view of aging mechanism............................................................................ 4 1.5 Shortcoming of existing aging theories .................................................................... 7 1.6 Evolutionary theories explore aging at the system level .......................................... 7 1.6.1 Mutation accumulation theory ..................................................................... 8 1.6.2 Antagonistic pleiotropy theory..................................................................... 8 1.7 Limitations of evolutionary theories......................................................................... 8 2 Aim of the Study .............................................................................................................. 10 3 Methods............................................................................................................................ 11 3.1 Exploration of relevant theory from system engineering ....................................... 11 3.2 Genetic and proteomics analyses at selected levels of detail ................................. 11 3.3 System analyses on experimental data ................................................................... 11 4 Results and Discussion..................................................................................................... 13 4.1 Reliability theory treats aging as a system phenomenon........................................ 13 4.2 Is reliability theory applicable on biological systems?........................................... 14 4.2.1 Biological organisms are redundant at different levels.............................. 14 4.2.2 Biological systems show extensive error accumulation ............................ 15 4.2.3 Biological systems are tolerant against genetic perturbations ................... 17 4.2.4 System redundancy is established during organogenesis .......................... 20 4.3 Reliability model: simulation and implementations............................................... 21 4.4 Possible common fatal origin for aging and age-related diseases .......................... 23 4.4.1 Impairment of neuronal plasticity proceeds Alzheimer pathology............ 23 4.4.2 Initial decrease of system redundancy leads to Huntington pathology...... 24 4.4.3 Transgenic mice are more vulnerable to Parkinson pathology.................. 25 4.5 Anti-aging should target quantitative aspects......................................................... 26 4.5.1 Proteasome Reduction represents a chief quantitative aspect in aging...... 27 4.5.2 Cellular dehydration could be responsible for proteasome function decline. .................................................................................................................... 27 4.6 Possible Intervention on aging................................................................................ 28 4.7 Ethical aspects of aging interventions .................................................................... 29 5 Conclusion and Outlook................................................................................................... 31 6 Summary .......................................................................................................................... 32 7 Zusammenfassung............................................................................................................ 33 8 Acknowledgments............................................................................................................ 34 9 References ........................................................................................................................ 35 1 Introduction 1.1 Mankind is growing older worldwide Human life expectancy has been constantly and almost linearly rising during the last 160 years (Oeppen and Vaupel, 2002) (Fig.1). According to a recent report from the United Nations, the number of old people (age 60 and over) will exceed the number of children worldwide for the first time in human history by year 2047 (Nature collections September 2007). Indeed, the fastest growing population among the elderly is the oldest – those aged 80 years and beyond. Fig. 1: Record female life expectancy from 1840 to 2002. The linear regression trend is depicted by a bold black line and the extrapolated trends by dashed lines (Oeppen and Vaupel, 2002).
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