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Functional Genomics of Ageing and Its Modulation by Diet ¶
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| Thesis submitted in accordance with the requirements of the ¶
| University of Liverpool for the degree of Doctor in Philosophy ¶
| by ¶
| Daniel Wuttke ¶
| August 2013 ¶
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:Abstract: Ageing is a widespread phenomenon limiting the lifespan of many species. Ageing Vis here, there,ually alml organistms everywherage, besides a few interesting exceptions. However what controls this process remains largely unkown (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. HerIn this thesis, functional genomics approaches weare applied on ageing. Particular attentiond is given to dietary restriction (DR), the most powerful non-genetic intervention now known to counteract the basic ageing process. Other therapeutics and methods are under development. 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 mediates the lifespan extension effect of a restricted diet was defined and those DR-essential genes were investigated 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. ¶
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:Dedication: For the singularity. ¶
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Table of Contents ¶
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1. The Cause of Ageing ¶
2. Dietary Restriction ¶
3. Functional Genomics ¶
4. Systems Biology ¶
5. Comparative Interactomics of DR ¶
6. Ageing Gene Classification ¶
7. Tissue-Specific DR-Effects ¶
8. Ndt80 Target Genes ¶
9. Longevity by Ultradian Oscillations ¶
10. Circadian Clock Controls Ageing ¶
11. A Unified Explanation of Ageing ¶
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List of Figures and Tables ¶
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Glossary ¶
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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 ¶
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