LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge

Hdl Handle:
http://hdl.handle.net/10034/620523
Title:
LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge
Authors:
Mc Auley, Mark T.; Mooney, Kathleen M.
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.
Affiliation:
Univeristy of Chester; Edge Hill University
Citation:
Mc Auley, M. T., & Mooney, K. M. (2017). LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge. Medical Hypotheses, 104, 15-19. DOI: 10.1016/j.mehy.2017.05.013
Publisher:
Elsevier
Journal:
Medical Hypotheses
Publication Date:
17-May-2017
URI:
http://hdl.handle.net/10034/620523
DOI:
10.1016/j.mehy.2017.05.013
Additional Links:
http://www.sciencedirect.com/science/article/pii/S0306987717303614
Type:
Article
Language:
en
EISSN:
1532-2777
Appears in Collections:
Chemical Engineering

Full metadata record

DC FieldValue Language
dc.contributor.authorMc Auley, Mark T.en
dc.contributor.authorMooney, Kathleen M.en
dc.date.accessioned2017-06-05T16:04:24Z-
dc.date.available2017-06-05T16:04:24Z-
dc.date.issued2017-05-17-
dc.identifier.citationMc Auley, M. T., & Mooney, K. M. (2017). LDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Converge. Medical Hypotheses, 104, 15-19. DOI: 10.1016/j.mehy.2017.05.013en
dc.identifier.doi10.1016/j.mehy.2017.05.013-
dc.identifier.urihttp://hdl.handle.net/10034/620523-
dc.description.abstractThe 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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://www.sciencedirect.com/science/article/pii/S0306987717303614en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectAgeingen
dc.subjectCholesterol metabolismen
dc.titleLDL-C levels in older people: Cholesterol Homeostasis and the Free Radical Theory of Ageing Convergeen
dc.typeArticleen
dc.identifier.eissn1532-2777-
dc.contributor.departmentUniveristy of Chester; Edge Hill Universityen
dc.identifier.journalMedical Hypothesesen
dc.date.accepted2017-05-15-
or.grant.openaccessYesen
rioxxterms.funderUnfundeden
rioxxterms.identifier.projectUnfundeden
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2018-05-17-
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