• Aging and computational systems biology

      Mooney, Kathleen M.; Morgan, Amy; Mc Auley, Mark T.; Edgehill University, University of Chester (John Wiley & Sons, 2016-01-29)
      Aging research is undergoing a paradigm shift, which has led to new and innovative methods of exploring this complex phenomenon. The systems biology approach endeavors to understand biological systems in a holistic manner, by taking account of intrinsic interactions, while also attempting to account for the impact of external inputs, such as diet. A key technique employed in systems biology is computational modeling, which involves mathematically describing and simulating the dynamics of biological systems. Although a large number of computational models have been developed in recent years, these models have focused on various discrete components of the aging process, and to date no model has succeeded in completely representing the full scope of aging. Combining existing models or developing new models may help to address this need and in so doing could help achieve an improved understanding of the intrinsic mechanisms which underpin aging.
    • Cardiovascular disease and healthy ageing

      Mooney, Kathleen M.; Mc Auley, Mark T.; University of Chester, Edgehill University (Open Access Text, 2016-06-16)
      Cardiovascular diseases are main cause of morbidity and mortality in the Western World. Cardiovascular disease increases in its prevalence with age and the burden of this condition is set to increase with an Ageing global population. There are many factors that impact cardiovascular disease risk. The aim of this brief commentary is to explore some of these factors; specifically, we will examine the role of social status, nutrition and, psychological stress in modulating cardiovascular disease risk. Our aim is to emphasise the multidimensional nature of this condition and to stress that a more complete understanding of the mechanisms which underpin its pathology can only be achieved by adopting an integrated approach which treats the progression of this disease in a more holistic fashion.
    • Cholesterol metabolism: A review of how ageing disrupts the biological mechanisms responsible for its regulation

      Morgan, Amy; Mooney, Kathleen M.; Wilkinson, Stephen J.; Pickles, Neil; Mc Auley, Mark T.; University of Chester, Edgehill University (Elsevier, 2016-04-01)
      Cholesterol plays a vital role in the human body as a precursor of steroid hormones and bile acids, in addition to providing structure to cell membranes. Whole body cholesterol metabolism is maintained by a highly coordinated balancing act between cholesterol ingestion, synthesis, absorption, and excretion. The aim of this review is to discuss how ageing interacts with these processes. Firstly, we will present an overview of cholesterol metabolism. Following this, we discuss how the biological mechanisms which underpin cholesterol metabolism are effected by ageing. Included in this discussion are lipoprotein dynamics, cholesterol absorption/synthesis and the enterohepatic circulation/synthesis of bile acids. Moreover, we discuss the role of oxidative stress in the pathological progression of atherosclerosis and also discuss how cholesterol biosynthesis is effected by both the mammalian target of rapamycin and sirtuin pathways. Next, we examine how diet and alterations to the gut microbiome can be used to mitigate the impact ageing has on cholesterol metabolism. We conclude by discussing how mathematical models of cholesterol metabolism can be used to identify therapeutic interventions.
    • Computational Modelling Folate Metabolism and DNA Methylation: Implications for Understanding Health and Ageing

      Mc Auley, Mark T.; Mooney, Kathleen M.; Salcedo-Sora, J. Enrique; University of Chester; Edge Hill University; Liverpool Hope University (Oxford University Press, 2016-12-21)
      Dietary folates have a key role to play in health as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms which underpin these processes are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date no model has represented the full scope of the interaction between the folate cycle and the reactions which govern the DNA methylation cycle. In this review we will discuss several of the models which have been developed to represent these systems. In addition we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.
    • Computer Modelling for Nutritionists

      Mc Auley, Mark Tomás; University of Chester
      This book is about computational modelling of nutrient focused biological systems. The book is aimed at students, researchers, and those with an interest in learning how to build a computational model. The book is the product of many years of teaching computational modelling to undergraduates, postgraduates, and researchers with limited, or no background in computational modelling. What I learned from these experiences is those new to modelling are invariably apprehensive about it, and approach it with a degree of trepidation, or even scepticism. However, from tentative initial steps, they quickly realize that modelling is not as challenging, or as academically intimidating as they initially perceive it; and after gaining familiarity with the essential components of model building they rapidly become cognisant, that it offers an alternative lens to view a biological system, and learn new insights about its underlying dynamic behaviour. In this book I provide a practical introduction to modelling, for those who are interested in exploring the dynamics of nutrient based systems. My rationale for undertaking this project is based on my experience of interacting with nutritionists in recent years. As a result of many fruitful discussions I identified a growing need for a book of this nature, which is specifically tailored to nutritionists. My aims are to provide the reader with a solid grounding in computational modelling, and how it dovetails within the burgeoning field of systems biology. For the reader this will involve learning how a model is assembled, what software tools are available for model building, what the different paradigms are for simulating a model, and how to analyse and interpret the output from in silico simulations. The only expectation I make of you, as a reader, is that you are enthusiastic about learning how to use new software tools. In exchange for your engagement I will provide you with ample practical exercises, which will help to consolidate your learning, and will make your computational modelling journey a rewarding and enjoyable experience.
    • Effects of obesity on cholesterol metabolism and its implications for healthy ageing.

      Mc Auley, Mark Tomás; University of Chester (Cambridge University Press, 2020-01-27)
      The last few decades have witnessed a global rise in the number of older people. Despite this demographic shift, morbidity within this population group is high. Many factors influence healthspan; however an obesity pandemic is emerging as a significant determinant of older peoples’ health. It is well established obesity adversely effects several metabolic systems. However, due to its close association with overall cardiometabolic health, the impact obesity has on cholesterol metabolism needs to be recognised. The aim of this review is to critically discuss the effects obesity has on cholesterol metabolism and to reveal its significance for healthy ageing.
    • Investigating Cholesterol Metabolism and Ageing Using a Systems Biology Approach

      Morgan, Amy; Mooney, Kathleen M.; Wilkinson, Stephen J.; Pickles, Neil; Mc Auley, Mark T.; University of Chester (Cambridge University Press, 2016-11-02)
      CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.
    • LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge

      Mc Auley, Mark T.; Mooney, Kathleen M.; Univeristy of Chester; Edge Hill University (Elsevier, 2017-05-17)
      The cardiovascular disease (CVD) risk factor, low density lipoprotein cholesterol (LDL-C) increases with age, up until the midpoint of life in males and females. However, LDL-C can decrease with age in older men and women. Intriguingly, a recent systematic review also revealed an inverse association between LDL-C levels and cardiovascular mortality in older people; low levels of LDL-C were associated with reduced risk of mortality. Such findings are puzzling and require a biological explanation. In this paper a hypothesis is proposed to explain these observations. We hypothesize that the free radical theory of ageing (FRTA) together with disrupted cholesterol homeostasis can account for these observations. Based on this hypothesis, dysregulated hepatic cholesterol homeostasis in older people is characterised by two distinct metabolic states. The first state accounts for an older person who has elevated plasma LDL-C. This state is underpinned by the FRTA which suggests there is a decrease in cellular antioxidant capacity with age. This deficiency enables hepatic reactive oxidative species (ROS) to induce the total activation of HMG-CoA reductase, the key rate limiting enzyme in cholesterol biosynthesis. An increase in cholesterol synthesis elicits a corresponding rise in LDL-C, due to the downregulation of LDL receptor synthesis, and increased production of very low density lipoprotein cholesterol (VLDL-C). In the second state of dysregulation, ROS also trigger the total activation of HMG-CoA reductase. However, due to an age associated decrease in the activity of cholesterol-esterifying enzyme, acyl CoA: cholesterol acyltransferase, there is restricted conversion of excess free cholesterol (FC) to cholesterol esters. Consequently, the secretion of VLDL-C drops, and there is a corresponding decrease in LDL-C. As intracellular levels of FC accumulate, this state progresses to a pathophysiological condition akin to nonalcoholic fatty liver disease. It is our conjecture this deleterious state has the potential to account for the inverse association between LDL-C level and CVD risk observed in older people.
    • Mathematically modelling the dynamics of cholesterol metabolism and ageing

      Morgan, Amy; Mooney, Kathleen M.; Wilkinson, Stephen J.; Pickles, Neil; Mc Auley, Mark T.; University of Chester, Edgehill University (Elsevier, 2016-07-30)
      Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the UK. This conditionbecomes increasingly prevalent during ageing; 34.1% and 29.8% of males and females respectively, over 75years of age have an underlying cardiovascular problem. The dysregulation of cholesterol metabolism isinextricably correlated with cardiovascular health and for this reason low density lipoprotein cholesterol(LDL-C) and high density lipoprotein cholesterol (HDL-C) are routinely used as biomarkers of CVD risk. Theaim of this work was to use mathematical modelling to explore how cholesterol metabolism is affectedby the ageing process. To do this we updated a previously published whole-body mathematical model ofcholesterol metabolism to include an additional 96 mechanisms that are fundamental to this biologicalsystem. Additional mechanisms were added to cholesterol absorption, cholesterol synthesis, reversecholesterol transport (RCT), bile acid synthesis, and their enterohepatic circulation. The sensitivity of themodel was explored by the use of both local and global parameter scans. In addition, acute cholesterolfeeding was used to explore the effectiveness of the regulatory mechanisms which are responsible formaintaining whole-body cholesterol balance. It was found that our model behaves as a hypo-responderto cholesterol feeding, while both the hepatic and intestinal pools of cholesterol increased significantly.The model was also used to explore the effects of ageing in tandem with three different cholesterolester transfer protein (CETP) genotypes. Ageing in the presence of an atheroprotective CETP genotype,conferring low CETP activity, resulted in a 0.6% increase in LDL-C. In comparison, ageing with a genotypereflective of high CETP activity, resulted in a 1.6% increase in LDL-C. Thus, the model has illustrated theimportance of CETP genotypes such as I405V, and their potential role in healthy ageing.
    • Modelling the molecular mechanisms of ageing

      Mc Auley, Mark T.; Martinez Guimera, Alvaro; Hodgson, David; McDonald, Neil; Mooney, Kathleen M.; Morgan, Amy; Proctor, Carole; University of Chester; Edgehill University; Newcastle University (Portland Press, 2017-02-23)
      The ageing process is driven at the cellular level by random molecular damage which slowly accumulates with age. Although cells possess mechanisms to repair or remove damage, they are not 100% efficient and their efficiency declines with age. There are many molecular mechanisms involved and exogenous factors such as stress also contribute to the ageing process. The complexity of the ageing process has stimulated the use of computational modelling in order to increase our understanding of the system, test hypotheses and make testable predictions. As many different mechanisms are involved, a wide range of models have been developed. This paper gives an overview of the types of models that have been developed, the range of tools used, modelling standards, and discusses many specific examples of models which have been grouped according to the main mechanisms that they address. We conclude by discussing the opportunities and challenges for future modelling in this field.
    • Obesity and the Dysregulation of Fatty Acid Metabolism: Implications for Healthy Aging

      Morgan, Amy; Mooney, Kathleen M.; Mc Auley, Mark T.; University of Chester; Edge Hill University (Taylor & Francis, 2016-10-17)
      The population of the world is aging. In 2010, an estimated 524 million people were aged 65 years or older presenting eight percent of the global population. By 2050, this number is expected to nearly triple to approximately 1.5 billion, 16 percent of the world’s population. Although people are living longer, the quality of their lives are often compromised due to ill-health. Areas covered. Of the conditions which compromise health as we age, obesity is at the forefront. Over half of the global older population were overweight or obese in 2010, significantly increasing the risk of a range of metabolic diseases. Although, it is well recognised excessive calorie intake is a fundamental driver of adipose tissue dysfunction, the relationship between obesity; intrinsic aging; and fat metabolism is less understood. In this review we discuss the intersection between obesity, aging and the factors which contribute to the dysregulation of whole-body fat metabolism. Expert Commentary. Being obese disrupts an array of physiological systems and there is significant crosstalk among these. Moreover it is imperative to acknowledge the contribution intrinsic aging makes to the dysregulation of these systems and the onset of disease.