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Cholesterol metabolism: A review of how ageing disrupts the biological mechanisms responsible for its regulationCholesterol 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.
Effects of obesity on cholesterol metabolism and its implications for healthy ageing.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.
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.
LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing ConvergeThe 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.