Abstract
BackgroundGlobal demographic changes have stimulated marked interest in the process of aging. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD) has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C) has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion.ResultsThe model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34 mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116 mg/dL.ConclusionsOur model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism.
Highlights
Global demographic changes have stimulated marked interest in the process of aging
We were of the opinion that existing models of cholesterol metabolism were limited and could not offer a sufficiently deep understanding of how an entire biological system changes with age, in this work a conscious effort was made to represent the interactions throughout the body
Results from the sensitivity analysis of the model indicated that the model requires further fine-tuning in the future before it could be used as a comprehensive tool for predicting changes to Low Density Lipoprotein Cholesterol (LDL-C) in response to dietary cholesterol/ fats and intrinsic aging
Summary
Global demographic changes have stimulated marked interest in the process of aging. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Lipid metabolism has a key role to play in human longevity and healthy ageing This has been emphasized by recent genetic studies examining the lipoprotein phenotype in individuals with exceptional longevity [1,2]. Understanding why LDL-C rises with age is complex; rodent studies have indicated that increases in intestinal cholesterol absorption or possibly a decrease in the plasma clearance rate of LDL-C may have a mechanistic role to play [8,9,10]. It was necessary to study both intestinal cholesterol absorption and LDL-C plasma clearance within an integrative framework which incorporated the other fundamental biological components of this complex system [11,12] This required incorporating the interactions of the individual elements of this system. Whole-body cholesterol metabolism is a complex system with a variety of non-linear interactions among its various components, including both positive and negative feedback and complex crosstalk between elements such as cholesterol synthesis and absorption [14]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
