A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation

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.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.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]. It is highly probable such subjects with exceptional longevity and favourable lipoprotein profiles have avoided CVD. CVD is the primary cause of mortality in developed countries, with almost 40% of males and 30% of females in the United Kingdom over the age of 85 years living with the condition [3]. Of the components of lipid metabolism, elevated LDL-C has consistently stood out as a risk factor for CVD [4]. This cholesterol sub-frac