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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 ¶
| November 2012 ¶
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: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 be 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. ¶
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C Preliminary in an introduction the potential causes of ageing are discussed from an evolutionary perspective. Subsequently, first of all a class of genes which mediate the lifespan extension effect of a restricted diet was defined and thos ¶
e DR----essential genes were investigate on the level of molecular evolution, interactions and expression. This lead to the discovery 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 to totally different processes. 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 was 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. Comparative Interactomics of DR ¶
3. Ageing Genes Classification ¶
4. Tissue-Specific DR-Effects ¶
5. Ndt80 Target Genes ¶
6. Longevity by Ultradian Oscillations ¶
7. Circadian Clock Controls Ageing ¶
8. A Unified Explanation of Ageing ¶
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List of Figures and Tables ¶
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Glossary ¶
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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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