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Cholesterol transport in blood, lipoproteins, and cholesterol metabolism.The aim of this chapter is to critically discuss recent work which has focused on the dynamics of cholesterol transport and its intersection with health. Firstly, we provide an overview of the main lipoproteins, and their role in whole-body cholesterol metabolism. We then focus on low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), paying particular attention to a diverse array of evidence which associates perturbations to these lipoproteins with cardiovascular disease (CVD). Next, we explain how aging and obesity disrupt the biological mechanisms that regulate cholesterol metabolism. Crucially, we reveal the parallels between aging and obesity, underscoring that obesity superimposed on the aging process has the potential to exacerbate the age-related dysregulation of cholesterol metabolism. Following this, we unveil how mathematical modeling can be used to deepen our understanding of cholesterol metabolism. We conclude the chapter by discussing the future of this area; in doing so, we reveal how recent experimental findings could open the way for novel therapeutic approaches which could help maintain optimal blood lipoprotein levels and thus increase health span.
The Interplay Between Cholesterol Metabolism and Intrinsic AgeingThe last few decades have witnessed remarkable progress in our understanding of ageing. From an evolutionary standpoint it is generally accepted that ageing is a non-adaptive process which is underscored by a decrease in the force of natural selection with time. From a mechanistic perspective ageing is characterized by a wide variety of cellular mechanisms, including processes such as cellular senescence, telomere attrition, oxidative damage, molecular chaperone activity, and the regulation of biochemical pathways by sirtuins. These biological findings have been accompanied by an unrelenting rise in both life expectancy and the number of older people globally. However, despite age being recognized demographically as a risk factor for healthspan, the processes associated with ageing are routinely overlooked in disease mechanisms. Thus, a central goal of biogerontology is to understand how diseases such as cardiovascular disease (CVD) are shaped by ageing. This challenge cannot be ignored because CVD is the main cause of morbidity in older people. A worthwhile way to examine how ageing intersects with CVD is to consider the effects ageing has on cholesterol metabolism, because dysregualted cholesterol metabolism is the key factor which underpins the pathology of CVD. The aim of this chapter is to outline a hypothesis which accounts for how ageing intersects with intracellular cholesterol metabolism. Moreover, we discuss the implications of this relationship for the onset of disease in the 'oldest old' (individuals ≥85 years of age). We conclude the chapter by discussing the important role mathematical modelling has to play in improving our understanding of cholesterol metabolism and ageing.
Modelling Cholesterol Metabolism and AtherosclerosisAtherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among Western populations. Many risk factors have been identified for ASCVD; however, elevated low-density lipoprotein cholesterol (LDL-C) remains the gold standard. Cholesterol metabolism at the cellular and whole-body level is maintained by an array of interacting components. These regulatory mechanisms have complex behavior. Likewise, the mechanisms which underpin atherogenesis are nontrivial and multifaceted. To help overcome the challenge of investigating these processes mathematical modeling, which is a core constituent of the systems biology paradigm has played a pivotal role in deciphering their dynamics. In so doing models have revealed new insights about the key drivers of ASCVD. The aim of this review is fourfold; to provide an overview of cholesterol metabolism and atherosclerosis, to briefly introduce mathematical approaches used in this field, to critically discuss models of cholesterol metabolism and atherosclerosis, and to highlight areas where mathematical modeling could help to investigate in the future.