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
Daniel Wuttke
August 2013

Abstract:Ageing is a widespread phenomenon limiting the lifespan of almost all species. Virtually all organisms age, besides a few interesting exceptions. However what controls this process remains a great, but not insurmountable, challenge. Biological information is increasing with a exponential pace. Similar information technology is also advancing with an fast-pacing speed. The marriage of these two will certainly enable to re-engineer biological processes such as ageing. In this thesis, functional genomics approaches are applied on ageing. Particular attention 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 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.

Dedication:For the singularity.

List of Figures and Tables


Keywords: rest, structure, thesis

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