LDL-C levels in older people: Cholesterol homeostasis and the free radical theory of ageing converge

Abstract

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.

Effects of obesity on cholesterol metabolism and its implications for healthy ageing

“…Consequently, oxidative stress results in IR within adipose and peripheral tissue (133) . It has been suggested that high levels of ROS impinge on intracellular cholesterol homeostasis (134) . ROS have been found to upregulate the activity of hepatic HMGCR in rodent hepatic tissue, leading to an increase in cholesterol synthesis (80; 135; 136; 137) ROS are also implicated in the pathogenesis of atherosclerosis, where oxidation of LDL is regarded as a key event in the initial stages of atherosclerosis formation (138) .…”

“…Consequently, oxidative stress results in IR within adipose and peripheral tissue (131) . It has been suggested that high levels of ROS impinge on intracellular cholesterol homeostasis (132) . ROS have been found to up-regulate the activity of hepatic HMGCR in rodent hepatic tissue, leading to an increase in cholesterol synthesis (80,(133)(134)(135) .…”

U-shaped association between low-density lipid cholesterol and diabetes mellitus in patients with hypertension

“…Changes in TC, TG and LDL-C levels that occur in the geriatric population have been inversely associated with all-cause mortality. The association might be a result of decreased cellular antioxidant capacity and LDL-C production described in the free-radical theory of aging (FRTA) [25–28]. However, the relationship between LDL-C levels and DM in geriatric populations has not been reported.…”

Cholesterol Homeostasis: An In Silico Investigation into How Aging Disrupts Its Key Hepatic Regulatory Mechanisms

“…However, it is challenging to see how this is plausible mechanistically. An alternative explanation for these findings could reside within the biochemical mechanisms which govern hepatic cholesterol homeostasis, and how these processes are affected by aging [ 35 , 36 ].…”

“…In this work, a previously enunciated hypothesis is outlined and examined [ 35 ]. It is hoped the examination of this idea will help to explain why low levels of LDL-C have been associated with an increased rate of mortality in the oldest old.…”