A systems-level approach to the evolution of ageing

Abstract

Ageing as a biological process is ubiquitous in life. In humans, ageing and its related conditions are revealed with improvements in health care conditions. Evidence for ageing is also apparent in most other organisms including unicellular species. Many of the pathways and mechanisms involved in ageing are evolutionarily conserved across the tree of life which provides an exceptional opportunity to study simpler organisms and extend the results to more complex forms of life. There is a rapidly growing body of data from organisms of varying levels of complexity, but there is a shortage of attempts in coherently making use of these data. A systems-level approach is necessary to bridge the gap between different biological levels, integrate the available information, and enable the synthesis of unifying hypotheses. Also, given the evolutionary nature of the question at hand (i.e. ageing), a successful hypothesis needs to be able to account for evolutionary considerations. In this thesis, I take a theoretical approach and try to explain a number of aspects of ageing from a systems-level perspective in an evolutionary context. Among the topics that will be covered are the following: (i) intra-islet pancreatic beta-cell dynamics, (ii) antioxidant defence system in pancreatic beta-cells, (iii) metabolic evolution of the glucose homeostatic system, and (iv) asymmetric damage segregation in unicellular organisms. In (i), I investigate the dynamics of beta-cell number within pancreatic islets and link the results to pathophysiology of diabetes and its various stages. In (ii) and (iii), I provide a unifying hypothesis for the paradoxical and unequivocal observation that metabolically active beta-cells have a weak antioxidant defence system and interestingly, that they are particularly weak in females. In (iv), I show how asymmetric segregation of damage at the time of mitosis is a fundamental step toward ageing and then evaluate whether and by how much asymmetry is optimal in a given organism under certain environmental conditions. I use a variety of techniques including deterministic and stochastic modelling in this thesis. The shared essence of these projects is an attempt to put data of various sources together in a unifying, systems-level evolutionary framework in order to better understand some aspects of the ageing process and its consequences.