Modeling of Human Aging using a Systems Approach A Thesis Submitted to the Faculty of Drexel University by Glenn R. Booker in partial fulfillment of the requirements for the degree of Doctor of Philosophy October 2011 © Copyright 2011 Glenn R. Booker. All Rights Reserved. ii Acknowledgments Thanks to: My advisor, Dr. Andres Kriete Members of Dr. Kriete’s research team o Dr. Ulrich Rodeck, William Beggs, Nirupama Yalamanchili, Kelli Mayo, Drew Clearfield, David Boorman, Mariam Albahrani, Ryan Danowski , and Visish Srinivasan The team of Dr. Albert-László Barabási (Northeastern University) for data sharing Dr. William Bosl (Harvard Medical School) for Bionet And thanks to my dissertation committee: Dr. Fred Allen (Biomed) Dr. Uri Hershberg (Biomed) Dr. Longjian Liu (Public Health) Dr. Daniel Marenda (Bioscience) Dr. Ahmet Sacan (Biomed) iii TABLE OF CONTENTS LIST OF TABLES ..................................................................................................................... x LIST OF FIGURES ................................................................................................................ xiii ABSTRACT ......................................................................................................................... xvii INTRODUCTION ................................................................................................................... 1 Systems Approach to Aging ............................................................................................ 3 What is Aging? ................................................................................................................ 6 Aging Theories ................................................................................................................ 8 Energy consumption theories of aging ..................................................................... 10 Evolutionary theories of aging .................................................................................. 11 Programmed theories of aging ................................................................................. 12 Damage accumulation theories of aging .................................................................. 14 Network theories of aging ........................................................................................ 16 Gaps in existing theories of aging ............................................................................. 16 Scope ............................................................................................................................. 16 Scope Exclusions ........................................................................................................... 17 Research Hypotheses .................................................................................................... 18 Novel Elements ............................................................................................................. 18 REVIEW OF COMPUTATIONAL APPROACHES ................................................................... 20 Model Species and Tissues ........................................................................................... 20 iv Differential Equations ................................................................................................... 22 Bayesian and Boolean Logic .......................................................................................... 24 Fuzzy Logic .................................................................................................................... 27 Reliability Modeling ...................................................................................................... 30 Multi‐scale Modeling .................................................................................................... 31 METHODS .......................................................................................................................... 34 Experimental Data ........................................................................................................ 34 Scope of Samples .......................................................................................................... 34 Cell Lines and Culture Procedures ................................................................................ 35 Methodology ................................................................................................................. 35 Microarray Analysis ................................................................................................... 35 NF‐κB DNA Binding Activity Assay ............................................................................ 36 Other Data .................................................................................................................... 36 Data Summary ............................................................................................................... 37 CELL MODELING ................................................................................................................ 38 The Vicious Cycle Model ............................................................................................... 38 Physiological mechanisms in the Vicious Cycle Model ............................................. 38 Mitochondrial respiration ..................................................................................... 38 Generation of ROS and Oxidized Proteins ............................................................ 41 Bionet Vicious Cycle model ....................................................................................... 41 Vicious Cycle versus Retrograde Response model ................................................... 42 Discussion of the Bionet Vicious Cycle Model .......................................................... 43 v Documentation of Bionet Application ...................................................................... 44 Conclusion from the Vicious Cycle Model ................................................................ 46 The Adaptive Response Model ..................................................................................... 47 Physiological mechanisms in the Adaptive Response model ................................... 47 Retrograde response ............................................................................................ 47 Inflammation ......................................................................................................... 47 Superoxide dismutases (SOD) ............................................................................... 49 Calcium pathways ................................................................................................. 49 Feedback via mTOR ............................................................................................... 50 UPR and EOR ......................................................................................................... 50 Bionet Adaptive Response model ............................................................................. 51 Sensitivity Analysis .................................................................................................... 52 Introduction and Criteria ...................................................................................... 52 Baseline results ..................................................................................................... 53 Input parameters .................................................................................................. 53 Analysis ................................................................................................................. 53 Discussion of Adaptive Response models ................................................................. 57 Transcription factors and gene expression candidates ............................................ 58 Conclusion from the Adaptive Response Model ...................................................... 59 POPULATION STUDIES ...................................................................................................... 60 Physiology of aging ....................................................................................................... 60 The Gompertz Model ................................................................................................ 60 vi ABC studies ............................................................................................................... 61 Aging and Disease ..................................................................................................... 61 Diseasome ................................................................................................................. 62 Linear decline ............................................................................................................ 65 Stochastic component studies ...................................................................................... 69 The Weitz & Fraser model ........................................................................................ 69 Implementation of Weitz & Fraser viability equation .............................................. 71 Analysis of Weitz & Fraser viability equation ........................................................... 72 Gene Expression Variability ...................................................................................... 74 Changes in Stochastic Component ..........................................................................