Functional Genomics of Ageing and Its Modulation by Diet
| | Thesis submitted in accordance with the requirements of the | University of Liverpool for the degree of Doctor in Philosophy | by | Daniel Wuttke | November 2012
:Abstract: Ageing is a widespread phenomenon limiting the lifespan of many species. Ageing is here, there, almost everywhere, besides a few interesting exceptions. However what controls this process remains enigmatic. Biological information is increasing with a exponential pace, information technology is also advancing with an fast-pacing speed. The marriage of these two will certainly enable to re-engineering biological processes such as ageing. Here functional genomics approaches were applied on ageing and dietary restriction (DR), the most powerful non-genetic intervention known to counteract the basic ageing process. Preliminary in an introduction the potential causes of ageing and its slow down by dietary restriction (DR) are discussed from an evolutionary perspective as well as methodologies to decipher it. Subsequently, first of all a class of genes which mediate the lifespan extension effect of a restricted diet was defined and those DR-essential genes were investigate on the level of molecular evolution, interactions and expressions. This lead to the discovery that DR evokes a light form of rejuvenation by potentially employing recycling machineries such as autophagy. Then all the ageing genes were classified into gerontogenes and ageing-suppressors, which promote and counteract the ageing process, respectively. Those classes are compared on the network and functional level and found to be associated totally different processes and clusters, although they also share certain functionalities. Then tissue-specific gene expression profiles were employed to investigate the activities of these defined classes in individual tissues upon DR. Following this, transcriptional regulation given rise to observed gene expression changes were reconstructed and specifically exemplified by predicting the potential target genes of a rejuvenating transcription factor found to be invoked by DR. Among the identified targets were telomerase and autophagy-related genes. Subsequently autophagy was investigated in more detail which revealed evidence that autophagic process oscillate on in ultradian-scale. Moreover, transcriptional signatures of defined processes, namely juvenile growth, ageing, and DR were found to be commonly connected via circadian cycles. Finally, an integrated unified explanation of ageing is presented.
:Dedication: For the singularity.
================= Table of Contents ================= 1. The Cause of Ageing 2. Dietary Restriction 3. Functional Genomics 4. Systems Biology 5. Semantic Web 6. Comparative Interactomics of DR 7. Ageing Genes Classification 8. Tissue-Specific DR-Effects 9. Ndt80 Target Genes 10. Longevity by Ultradian Oscillations 11. Circadian Clock Controls Ageing 12. A Unified Explanation of Ageing
======== Glossary ======== PAS Phagophore assembly site ILP Insulin like peptide GSH Glutathione SPS Ssy1p-Ptr3p-Ssy5p GH Grwoth hormone FKHR FOXO1a IPC Inositol phosphorylceramide NPC Nuclear pore complex UBA Ubiquitin associated domain APC Anaphase promoting complex BESTO Beta-cell specific Sirt1-overexpressing CMA Chaperone mediated autophagy HA High amplitude TSS Transcription start site NLS Nuclear localisation signal SCN Suprachiasmatic nucleus EGF Epidermal growth factor MHC Thoracic muscle bZIP Basic leucine zipper UPR Mitochondrial unfolded protein response UPS Ubiquitin proteasome system ER Endoplasmic reticulum UTR Upstream translated region CDEI Centromere DNA element I STRE Stress-response element ETC Mitochondrial electron transport chain HSE Heat shock elements NES Nuclear export signal ECM Extracellular matrix PLZF Promyelocytic leukemia zinc finger protein SPC Spermatogonial progenitor cell KEGG Kyoto of Enyclopdia of Genes and Genomes ORF Open reading frame PDS Post-diauxic shift MVB Multi-vesicular body NMN nicotinamid adenine dinucleotide ALR Autophagic lysosome reformation TOR Target of rapamycin SP Short period MSE Meiotic middle genes LA Low amplitude MBF MCB binding factor GAP GTPase Activating Protein LP Long period TF Transcription factor SGD Saccharomyces Genome Database AG Ageing AR Arrythymicity SSC Spermatogonial stem cell GFP green fluorescent protein SDL Simple Directmedia Layer SCPD Saccharomyces Cerevisiae Promoter Database DR Dietary restriction CR Caloric/calorie restriction AL Ad libitum LA α-Lipoic acid CC Circadian clock RLS Replicative lifespan CLS Chronological lifespan DNMT DNA methyl transferase sDR solid-state DR bDR bacterial dilution/depletion DR TSS Transcription start site TF Transcription factor TFBS Transcription factor binding site NAD Nicotinamide adenine dinucleotide NADH NAD hydrogen MVB Multi-vesicular body NMN Nicotinamid adenine dinucleotide BESTO Beta-cell specific Sirt1-overexpressing GABA Gamma-aminobutyric acid CMA Chaperone mediated autophagy RA Retinoic acid SPC Spermatogonial progenitor cell ROS Reactive oxygen species