Investigating cholesterol metabolism and ageing using a systems biology approach

Abstract

CVD accounted for 27 % of all deaths in the UK in 2014, and was responsible for 1·7 million hospital admissions in 2013/2014. This condition becomes increasingly prevalent with age, affecting 34·1 and 29·8 % of males and females over 75 years of age respectively in 2011. The dysregulation of cholesterol metabolism with age, often observed as a rise in LDL-cholesterol, has been associated with the pathogenesis of CVD. To compound this problem, it is estimated by 2050, 22 % of the world's population will be over 60 years of age, in culmination with a growing resistance and intolerance to pre-existing cholesterol regulating drugs such as statins. Therefore, it is apparent research into additional therapies for hypercholesterolaemia and CVD prevention is a growing necessity. However, it is also imperative to recognise this complex biological system cannot be studied using a reductionist approach; rather its biological uniqueness necessitates a more integrated methodology, such as that offered by systems biology. In this review, we firstly discuss cholesterol metabolism and how it is affected by diet and the ageing process. Next, we describe therapeutic strategies for hypercholesterolaemia, and finally how the systems biology paradigm can be utilised to investigate how ageing interacts with complex systems such as cholesterol metabolism. We conclude by emphasising the need for nutritionists to work in parallel with the systems biology community, to develop novel approaches to studying cholesterol metabolism and its interaction with ageing.

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

“…It is possible that obesity superimposed on ageing could expedite the age-associated dysregulation of cholesterol metabolism (103)(104)(105) . Taking LDL-C as an example, increasing age is associated with a rise in LDL-C in males and females, in both cross-sectional (106,107) and prospective studies (108,109) .…”

Lactobacillus mediates the expression of NPC1L1, CYP7A1, and ABCG5 genes to regulate cholesterol

“…It is not only an important component of biofilms, but also the precursor of substances, such as vitamin D and bile acid (Liong & Shah, 2005 ). Cholesterol metabolism in the body is shown in Figure 1 (Morgan et al., 2017 ).…”

“…SREBP‐1c preferentially activates the transcription of genes required for fatty acid synthesis, but not cholesterol synthesis. Similarly, SREBP‐2 has a transcription activation domain, but preferentially activates LDL receptor genes and genes required for cholesterol synthesis (Morgan et al., 2017 ). LDL receptor levels are regulated by the negative feedback of SREBP‐2 (Shin & Osborne, 2003 ).…”

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

“…However, a significant obstacle to this is that the human liver is subject to a multitude of dynamic processes. Recently, ageing research and lipid metabolism have benefited from adopting the systems biology paradigm (45)(46)(47)(48). This framework provides a means of handling the complexities of hepatic cholesterol metabolism and ageing.…”