Change - Functional Genomics of Ageing & DR

Created on Sept. 3, 2012, 8:19 p.m. by Hevok & updated on Nov. 16, 2012, 1:01 p.m. by Hevok

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 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 those DR-essential genes were investigate on the level of molecular evolution, interactions and expressions. This lead to the discovery DR that 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 majorly 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.

List of Figures and Tables

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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

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Comment: Added rest tag.

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