BioModelsapplication/xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.pdfhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434-biopax2.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434-biopax3.owlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434_url.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434_urn.xmlhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.mhttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.xpphttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.scihttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.pnghttps://www.ebi.ac.uk/biomodels/model/download/BIOMD0000000434?filename=BIOMD0000000434.vcmlprimaryOK200Mark Mc AuleyManually curatedCholesterol Ester Storage DiseaseL2V4https://www.ebi.ac.uk/biomodels/BIOMD000000043423046614falseBioModelsSBMLModelsMcAuley2012 Whole body Cholesterol Metabolism2012MODEL1206010000Mc Auley MT, Wilkinson DJ, Jones JJ, Kirkwood TBMc Auley MT23046614,
BACKGROUND: 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). 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. RESULTS: The 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. CONCLUSIONS: Our 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.. null, 6.
Campus for Ageing and Vitality, Newcastle University, Henry Wellcome Biogerontology Building, Newcastle upon Tyne NE4 5PL, United Kingdom. mcaulem@hope.ac.ukmcaulem@hope.ac.ukLiverpool Hope UniversityBIOMD0000000434<h4>Background</h4>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). 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.<h4>Results</h4>The 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.<h4>Conclusions</h4>Our 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.A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation.Mc Auley Mark T MT, Wilkinson Darren J DJ, Jones Janette J L JJ, Kirkwood Thomas B L TBorganism, whole body, multi-cellular organism, whole organism, animal, cholesterol metabolism., body, Koerperprojections, Other diseases of pericardium (disorder), nucleocytoplasm, Cardiovascular disease, HSN1E, Period Prevalence, Other pericardial disease NOS (disorder), Blood, cardiovascular system disease or disorder, Other heart disease NOS (disorder), Cardiovascular disorder, Biochemical, PAPILLARY MUSCLE DIS NEC, 116, Aging, cholesterol, Cardiovascular Disease (CVD), [X]Other specified diseases of pericardium (disorder), CG11121, Relative, School-Age, Readability, Point Prevalence, unspecified, old, Risk Factors, diseases, Disease of cardiovascular system (disorder), Biological, Point Prevalences, cardiovascular disorder, Other heart disease NOS, disease or disorder of cardiovascular system, CVD, 17alpha)-cholest-5-en-3-ol, diseases and disorders, (2Z)-but-2-enedioate, animal, 14beta, male, Senescence, Cardiovascular Diseases, Fresh Frozen Plasmas, Fresh Frozen, human disease, (3beta, Biology, Prevalences, FACT, activation inducer molecule, Molecular, long, [X]Other forms of heart disease (disorder), Other ill-defined heart disease (disorder), hypoplasia, Cholest-5-en-3beta-ol, Other diseases of endocardium, Cardiovascular Disorder, elevated, W, number of, circulatory system disease, SO, Epicholesterol, Biological Aging, Low Density Lipoprotein Cholesterol, Disorder of cardiovascular system, papilla, Cholesterol, Homo sapiens disease, So, plasma, intracellular, ratio, Prevalence, Circulatory system disease NOS (disorder), CHOLESTEROL, Frozen Plasma, anatomical protrusion, wide/broad, 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disease, ASCVD, Cardiovascular system disease, multi-cellular organism, Fresh Frozen Plasma, cholesterol metabolism., LDL Cholesterol, lamellae, disorder of cardiovascular system, Other heart disease (disorder), number, EA1, Period Prevalences, Other diseases of pericardium, broad, Other disorders of papillary muscle, MLR-3, Ximpact, process of organ, unspecified (disorder), protrusion, lamella, Disorder of cardiovascular system (disorder), [X]Cardiovascular disease, AIM, Certain sequelae of myocardial infarction, reduced, DmelCG11121, Cholest-5-en-3-ol (3beta)-, Metabolism, Diets, disease or disorder, low-density lipoproteins, tiny, Other ill-defined heart disease NOS (disorder), early activation antigen CD69, Unspecified circulatory system disorder, protoplasm, School-Age Populations, FACT80, Blood Plasma, proportion, Other diseases of endocardium (disorder), somda, lipid metabolism, [X]Other specified diseases of pericardium, DISEASES OF THE CIRCULATORY SYSTEM, Genetic, protoplast, 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Ximpact, process of organ, presence, unspecified (disorder), protrusion, lamella, Disorder of cardiovascular system (disorder), [X]Cardiovascular disease, AIM, Certain sequelae of myocardial infarction, reduced, DmelCG11121, Cholest-5-en-3-ol (3beta)-, Metabolism, Diets, low-density lipoproteins, disease or disorder, tiny, Other ill-defined heart disease NOS (disorder), early activation antigen CD69, Enterprises, Unspecified circulatory system disorder, Toy, protoplasm, School-Age Populations, FACT80, proportion, Blood Plasma, Other diseases of endocardium (disorder), somda, lipid metabolism, [X]Other specified diseases of pericardium, DISEASES OF THE CIRCULATORY SYSTEM, Genetic, protoplast, Playthings, Other heart disease, 2810428A13Rik, Other forms of heart disease, Cholesteryl Linoleate, ridges, Population, disease of cardiovascular system, Public Enterprises, man, Other specified pericardial disease NOS, non-neoplastic, cardiovascular disease, leukocyte surface antigen Leu-23, Abstract, Puppets, Blood Plasmas, has or lacks parts of type, C-type lectin domain family 2 member C, Play, disorder, Disease of cardiovascular system, School Age Population, Enterprise, laminae, high elevation, Circulatory system disease NOS, Puppet, Lifespan, Drl, OTHER SEQUELAE OF MI NEC, small, Molecular Genetics, Disease, data, Other ill-defined heart diseases, Life Spans, body, Males, Molecular Genetic, anatomical process, not elsewhere classified, disorders, DNMT, whole body, medical condition, Factor, function, Disease affecting entire cardiovascular system (disorder), MCMT, Genetics, beta-Lipoprotein Cholesterol, AA589422, Other ill-defined heart disease, impact-a, cardiovascular disease (CVD), Mdu, Concept, mereological quality, Frozen Plasmas, BL-AC/P26, count in organism, Period, beta Lipoprotein Cholesterol, mda, Public, condition, background, Cholesterin, Other forms of heart disease (disorder), Other ill-defined heart disease NOS, PERICARDIAL DISEASE NEC, flange, ami, organ process, Data Base, Relative Risk, CXXC9, Plasma, Other specified diseases of pericardium, Cardiovascular, underdeveloped, Biochemical Genetic, [X]Other ill-defined heart diseases, med, Dietary, Risks, cholest-5-en-3beta-ol, portion of plasma, LDL, [X]Other forms of heart disease, Understanding, Other sequelae of myocardial infarction, School Age Populations, Healthy, introduction, CVS disease, male human body, processes, process, ageing, cardiovascular system disease, Other specified pericardial disease NOS (disorder), cholesterol metabolism, GP32/28, Point, cardinality, quotient, T160, processus, Biochemical Genetics, Public., quantitative, CLEC2C, RWDD5, hypothesis, presence or absence in organismassociated., organism, whole body, cholesterol metabolism, multi-cellular organism, whole organism, animal, body, KoerperfalseMcAuley2012 - Whole-body Cholesterol Metabolism
McAuley2012 - Whole-body Cholesterol Metabolism
Lipid metabolism has a key role to play in human longevity and healthy aging. A whole-body mathematical model of cholesterol metabolism that explores the changes in both the rate of intestinal cholesterol absorption and the hepatic rate of clearance of LDL-C from the plasma, has been presented here. The model showed that of these two mechanisms, changes to the rate of LDL-C removal from the plasma with age had the most significant effect on cholesterol metabolism.
The original SBML model file was generated using MathSBML 2.5.1.
This model is described in the article:
A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation.
Mc Auley MM, Wilkinson DJ, Jones JJ, Kirkwood TT.
BMC Syst Biol. 2012 Oct 10;6(1):130.
Abstract:
BACKGROUND: Global demographic changes have stimulated marked interest in the process of ageing. 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.
RESULTS: The 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 34mg/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 116mg/dL.
CONCLUSIONS: Our 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.
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2014-10-092012-11-272012-06-01BIOMD000000043423046614CHEBI:16113CHEBI:22868CHEBI:17002CHEBI:17984CHEBI:61995MODEL1206010000BIOMD0000000434GO:0007571GO:0008203GO:0070508GO:0006695GO:0015721GO:0006699GO:0030299GO:0033344GO:0042158GO:0030301GO:0043691FMA:15815FMA:96379606BTO:0000648BTO:0000131Q00341P04180Q6PIU2P98155P01130P06858Q05469P11597Q8WTV0