BASIS: an internet resource for network modelling Gillespie, Colin S.; Wilkinson, Darren J.; Shanley, Daryl P. ...
Journal of integrative bioinformatics,
12/2006, Volume:
3, Issue:
2
Journal Article
Peer reviewed
Open access
There is a growing realisation that complex biological processes cannot be understood through the application of ever more reductionist experimental programs alone. Recognising this, we have a ...constructed a flexible web-service based modelling system called BASIS (Biology of Ageing e-Science Integration and Simulation), which facilitates model construction and development. In particular it allows users to store, share and simulate their models. The system is accessed through web-services using any language (e.g. Python or Java) or under any operating system (e.g. Linux or Windows).
A central problem in biology is the optimal allocation of metabolic resources among activities such as growth, reproduction and maintenance. The disposable soma theory of senescence suggests that ...because of the competing demands of growth and reproduction, less effort is invested in maintenance of the somatic tissues than is necessary for indefinite survival. It follows that ageing is an inevitable result of optimal decisions of resource allocation taken throughout life. In this thesis, evolutionary models are developed to examine how rates of ageing are altered in response to environmental variation, and how the characteristics of reproductive effort alter in response to age-related change. A reduction in dietary intake is the only environmental manipulation that is known to consistently extend lifespan in mammals. An evolutionary explanation is that this represents an adaptive response to periods of food shortage whereby a greater fraction of the available energy is invested in maintenance at the expense of reproduction. The advantage is that reproductive potential is preserved for when more favourable conditions resume. This hypothesis is tested for the house mouse. It is found that levels of maintenance are indeed enhanced in periods of food shortage, but only in the presence of important ecological or physiological constraints. The constraints identified are: (1) when juvenile survival is particularly depressed in periods of food shortage, adult animals divert more energy to individual survival; (2) when substantial physiological savings can be made by shutting down reproduction completely, such as by reducing the production of reproductive hormones, levels of maintenance may be enhanced. Reproductive decisions are influenced by a number of factors including the age of the organism and the survival prospects of offspring once produced. Human females are capable of producing children at two year intervals, but in traditional populations a typical interval is 4 years which increases with maternal age. A dynamic model for optimal reproductive decisions, parameterised with life table data, demonstrates that the observed interbirth interval can be explained by the negative impact that newborn children have on their siblings. With the addition of each child to the family, a mother must distribute resources more widely, which has a detrimental effect on family survival. The age-related increase in the interbirth interval is accounted for by a combination of an increased risk to the mother in childbirth and the fact that the larger families of older mothers are more sensitive to the addition of further siblings. A further characteristic of human reproduction is the universal cessation of reproduction in mid-life that occurs with the menopause. It has been suggested that at some age maternal mortality in childbirth is sufficiently high that it may be beneficial for females to terminate their own reproductive effort and invest in existing offspring. Certainly, care extends beyond childhood and older females, particularly post-reproductive females, can provide for adult offspring and grandchildren. By contrasting hypothetical life tables of populations following different reproductive strategies it was found that menopause was favoured even if only a small increase in the fecundity of adult daughters and survival of grandchildren results from the assistance provided by a post-reproductive female.
Mother cell-specific ageingageing is a well-known phenomenon in budding yeast Saccharomyces cerevisiae. Asymmetric segregationsegregation of damagedamage and its accumulation in the mother cell has ...been proposed as one important mechanism. There are, however, unicellular organisms such as the fission yeast Schizosaccharomyces pombe, which replicates with almost no asymmetry of segregationsegregation of damagedamage and the pathogenic yeast Candida albicans, which falls around the middle of the segregationsegregation spectrum far from both complete symmetry and complete asymmetryasymmetry. The ultimate evolutionary cause that determines the way damagedamage segregates in a given organism is not known. Here we develop a mathematical model to examine the selective forces that drive the evolutionevolution of asymmetryasymmetry and discover the conditions in which symmetry is the optimal strategy. Three main processes are included in the model: protein synthesis (growth), protein damagedamage, and degradation of damagedamage. We consider, for the first time, the costs to the cell that might accompany the evolutionevolution of asymmetryasymmetry and incorporate them into the model along with known trade-offs between reproductive and maintenance investments and their energy requirements. The model provides insight into the relationship between ecology and cellular trade-off physiology in the context of unicellular ageingageing, and applications of the model may extend to multicellular organisms.
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FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Pancreatic beta-cells are unique among other cells in possessing an extremely weak antioxidant defence system. Furthermore, beta-cell defences against oxidative stress in both mice and humans are ...weaker in females than in males. These observations need an evolutionary explanation given that oxidative stress in beta-cells has an important contribution to the pathogenesis of type 2 diabetes. It turns out that a satisfactory explanation is feasible only by a systems-level approach to the glucose homeostatic system and beta-cell physiology. The connection between physiology and ecology is particularly important in major transitions in the evolutionary history of beta-cells. We have proposed that beta-cells evolved weak antioxidant protection to allow for reactive oxygen species (ROS) to exert a regulatory function directly linked with reproductive fitness of the organism. By down-regulating insulin synthesis and secretion, ROS in beta-cells cooperate with the stress-induced whole-body insulin resistance to divert glucose from insulin-dependent organs to an important insulin-independent structure: the evolving brain. Mammalian evolution provoked further reduction of beta-cell antioxidant defences in females in order to provide the fetus (through the insulin-independent placenta) with a reliable energy supply in pregnancy. The stress response has driven, within physiological constraints, the co-evolution of beta-cells, the brain and placenta and shaped their current status. We review the hypothesis and explore its implications.
This chapter examines the rationale for the use of computer models in studying the aging process and reviews the range of models that have been developed. There are many ways to develop a model—from ...using traditional programming languages such as C, Fortran, and Java to mathematical packages such as Mathematica, Matlab, and R. One standard that has been widely adopted for representing mathematical models is the Systems Biology Markup Language (SBML). It provides a computer-readable format for representing models of biochemical reaction networks. Other tools, such as JigCell, allow the user to construct a model using chemical equations combined with a spreadsheet approach. There are a large number of models currently available that focus on individual intracellular mechanisms. Currently, the models that relate directly to aging have been mainly concerned with telomere shortening, the accumulation of somatic mutations, and the accumulation of defective mitochondria. There are only a very limited number of models dealing with whole-organism aging and these are limited to unicellular organisms.
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