Encyclopedia of Gerontology and Population Aging

Living Edition
| Editors: Danan Gu, Matthew E. Dupre

Aging and Cholesterol Metabolism

  • Mark T. Mc AuleyEmail author
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-69892-2_122-1

Synonyms

Introduction

Diet is the only known intervention which has been conclusively shown to extend life span. It can be argued the key role diet has to play in the aging process came to prominence as a result of the seminal studies of Mc Cay and colleagues in the 1930s (Mc Cay et al. 1935). These studies revealed that caloric restriction (CR), without inducing malnutrition or nutrient deficiency in rats, could significantly extend their life span. Almost a century on from this pioneering work, it has been shown that CR extends both the median and maximal life span of Drosophila melanogaster and in the nematode Caenorhabditis elegans (Lopez-Lluch and Navas 2016). In addition, CR extends the life span of certain primates (Colman and Anderson 2011) and possibly humans (Fontana et al. 2004). The studies in humans are intriguing because they raise the question, does CR in humans simply improve overall metabolic health, which in turn augments health span? Or more significantly, does CR invoke key intracellular regulators of the aging process? This is an important distinction to make because studies in humans have revealed that subjects who have undergone CR benefit from an overall improvement in their metabolic health (Golbidi et al. 2017). Specifically, these individuals have improved insulin sensitivity, blood glucose levels, and blood lipid levels. The fact there is an improvement in blood lipid levels in these subjects is of significance to understanding health span. This is because a favorable lipid profile is inexorably connected to health. To emphasize this, the dysregulation of cholesterol metabolism correlates strongly with cardiovascular disease (CVD) risk (Mc Auley and Mooney 2014, Mooney and Mc Auley 2015). Moreover, CVD is the main cause of morbidity and mortality in older people (individuals >65 years) (Mc Auley and Mooney 2014). Thus, the role cholesterol metabolism has to play in health span is clear, and monitoring the parameters of cholesterol metabolism is key to aging successfully. The aim of this chapter is to provide a brief overview of the mechanisms which regulate cholesterol in the body, secondly to discuss how aging effects cholesterol metabolism, and thirdly to unveil how systems biology is leading to an improved understanding of the intersection between aging and the dysregulation of cholesterol metabolism.

A Very Simplified Account of Whole-Body Cholesterol Metabolism

It is necessary to emphasize the biological value of cholesterol to the body. Cholesterol is an essential cell membrane enforcer, is the precursor to steroid hormones, and is used for the manufacture of bile acids and vitamin D. Cholesterol metabolism is regulated on several levels. A pivotal regulatory point is the small intestine, where endogenously derived cholesterol mixes with dietary cholesterol and is absorbed into the body. During the absorption process, cholesterol is packaged with triglycerides into chylomicrons which then enter the lymph (Dawson and Rudel 1999; Hussain 2000). On leaving the lymph chylomicrons are acted on by lipoprotein lipase, generating chylomicron remnants which are removed from the circulation by the liver. Cholesterol from the chylomicrons joins a pool of hepatic cholesterol. The liver is the central hub which regulates cholesterol metabolism and is responsible for the majority of cholesterol synthesized by the body (Nguyen et al. 2008). Cholesterol biosynthesis involves a complex metabolic cascade which culminates with the production of cholesterol. Key to this pathway is HMG-CoA reductase (HMGCR), an enzyme responsible for regulating intracellular cholesterol biosynthesis (Friesen and Rodwell 2004). Consequently HMGCR is the target of statins, which are the primary pharmacological agents used to lower blood cholesterol levels (Cerqueira et al. 2016). Cholesterol enters the circulation from the liver as part of very low-density lipoproteins (VLDL). VLDL is enzymatically acted upon, in a process culminating with the formation of low-density lipoprotein (LDL), a lipoprotein which carries the majority of blood cholesterol to where it is needed throughout the body. LDL-C is removed from the circulation by LDL receptors (LDLRs), the synthesis of which is tightly controlled by intracellular cholesterol levels (Brown and Goldstein 1986). This is a crucial regulatory point in cholesterol metabolism, a fact underscored by a mutation in the LDLR gene which leads to hypercholesterolemia (Marais 2004). Hypercholesterolemia is associated with premature atherosclerotic CVD, with the LDL particle central to the paradigm which accounts for the etiology of atherosclerosis (Riccioni and Sblendorio 2012). In contrast to LDL-C, high-density lipoprotein cholesterol (HDL-C) is widely regarded as being anti-atherogenic (Rye et al. 2009). The reason for this is HDL-C is the focal point of reverse cholesterol transport (RCT) (Wang et al. 2017). RCT is a multistep process, whereby excess cholesterol from peripheral tissue is transported to the liver, where it joins a hepatic pool of cholesterol, and can be removed from the body during the enterohepatic circulation of bile acids. Central to RCT is lecithin: cholesterol acyltransferase which generates cholesteryl esters in plasma and promotes the assembly of HDL (Rousset et al. 2009). Another key enzyme involved in RCT is cholesteryl ester transfer protein (CETP), which mediates the transfer of triglycerides from VLDL or LDL in exchange for cholesteryl esters from HDL (Charles and Kane 2012). The discovery of genetic deficiencies in CETP has resulted in this enzyme being therapeutically targeted using pharmacologically inhibitors, in a bid to raise HDL levels (Kosmas et al. 2016, Wang et al. 2018). In summary, the processes we have discussed, which have included cholesterol absorption, synthesis, and RCT, act together to regulate whole-body cholesterol metabolism. In the next section, we discuss how aging affects these mechanisms and what the implications of this are for health span.

Cholesterol Metabolism and the Impact of Aging

The aging process has a pervasive impact on cholesterol metabolism (Morgan et al. 2016b; Mc Auley 2018). Aging has been shown to increase the efficiency of cholesterol absorption (Wang 2002). This has clear implications for the other components of cholesterol metabolism. For instance, a change in cholesterol absorption can elicit an increase in cholesterol synthesis (Cohen 2008). Additionally, from the perspective of cholesterol absorption, bile acid synthesis diminishes with age in humans (Bertolotti et al. 2007). It has been posited this is due to a decrease in the hepatic expression of CYP7AI, which is the rate limiting enzyme for bile acid synthesis (Bertolotti et al. 2007). HDL-C levels are also impacted by aging. It has been observed that HDL-C can decrease by 1% per year (Ferrara et al. 1997). In contrast to HDL-C, it has been found that LDL-C increases up until the midpoint of life in males and females (Carroll et al. 2005). An interesting adjunct to this observation has revealed possible differences in the biology of the oldest old (individuals ≥85 years). In the Leiden 85-Plus Study, it was observed that both high and low levels of LDL-C had a similar impact on mortality risk (Weverling-Rijnsburger et al. 2003). Paradoxically, this finding occurred despite CVD being the main cause of mortality in these subjects. Similar observations have been identified in several other studies which have examined the lipoprotein profile of the oldest old (Al-Mallah et al. 2009; Ravnskov et al. 2016). Interestingly, during a 3-year follow-up study involving the Chinese oldest old, it was found that for each 1 mmol/L increase of LDL-C concentration, there was a corresponding 19% decrease in 3-year all-cause mortality (Lv et al. 2015). These findings are intriguing and necessitate a mechanistic biological explanation. Very controversially it has been suggested high levels of plasma cholesterol could confer a beneficial cardiovascular effect in older people (Ravnskov et al. 2016). However, given the overwhelming evidence to contrary, this is a distinctly remote possibility. A more plausible explanation was recently suggested (Mc Auley and Mooney 2017). In short, aging is associated with a rise in hepatic reactive oxygen species (ROS) levels (Dai et al. 2014). Consequently ROS can increase HMGCR activity (Pallottini et al. 2007). Normally this would result in a rise in LDL-C due to the downregulation of LDLR synthesis and increased production of VLDL-C. However, if there is also an age-associated decrease in the conversion of free cholesterol to cholesterol esters, this would result in a drop in the secretion of VLDL-C (Shiomi et al. 2000). Consequently, plasma LDL-C levels would drop also. As hepatic free cholesterol accumulates, this state could result in nonalcoholic fatty liver disease (NAFLD) (Zhao et al. 2011), a condition associated with CVD (Francque et al. 2016). This provides a mechanistic explanation for the association between low levels of LDL-C and mortality, which has been observed in the oldest old.

Systems Biology: Its Role in Understanding Cholesterol Metabolism and Aging

In the last 20 years, the systems biology paradigm has made a significant contribution to the way in which biological research is being conducted (Mc Auley et al. 2013; Mc Auley et al. 2015a; Mc Auley and Mooney 2015a; Kilner et al. 2016; Larson et al. 2019). Systems biology is grounded within a philosophy which believes in studying an organism in a holistic manner (Mooney et al. 2016). This contrasts with the reductionist approach which has been the mainstay of biological research (Morgan et al. 2017). Due to the complex and multifaceted nature of aging, systems biology is an ideal framework for investigating this intriguing phenomenon (Mc Auley et al. 2017b, Mc Auley and Mooney 2018). Computational and mathematical biology are core components of systems biology and have been used to shine light on many aspects of aging and health (Mc Auley et al. 2009, Mc Auley et al. 2017a, Mc Auley et al. 2018, Zagkos et al. 2019). Our research centers on creating computational models of cholesterol metabolism, which incorporate the effects of aging. Our overarching goal is to use our findings to infer novel biological insights into health span (Mc Auley and Mooney 2015b, Mc Auley et al. 2015b). Using this approach we created a whole-body mechanistic computational model to investigate why there is an increase in LDL-C with age (Mc Auley et al. 2005, Mc Auley et al. 2012). Moreover, the goal was to test the hypothesis that intrinsic age-related changes to cholesterol absorption and the removal of LDL-C from the circulation were the primary drivers of this rise. We were able to show that gradually raising the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years results in an increase of LDL-C by as much as 34 mg/dL in a male subject. Furthermore, the model suggested that dropping the rate of hepatic LDL-C clearance incrementally to 50% by age 65 years resulted in an increase of LDL-C by as much as 116 mg/dL. Thus, the model revealed that age-related changes to the hepatic clearance rate of LDL-C have the most significant impact on cholesterol metabolism, with even small changes to the number of hepatic LDLRs having a significant impact on LDL-C levels. In 2016 this model was updated to include a number of additional key regulatory mechanisms and to explore the aging process in greater depth (Morgan et al. 2016c). This involved incorporating into the model further biological detail, including, cholesterol absorption, cholesterol synthesis, RCT, bile acid synthesis, and enterohepatic circulation. Imbued with this additional mechanistic detail, it was found cholesterol feeding resulted in a significant rise in cholesterol, in hepatic and peripheral tissue. Moreover, the in silico individual was used to investigate aging in tandem with three different cholesteryl ester transfer protein (CETP) genotypes. Aging in the presence of an atheroprotective CETP genotype, conferring low CETP activity, resulted in a 0.6% rise in LDL-C. In contrast, aging with a genotype indicative of elevated CETP activity was associated with a 1.6% increase in LDL-C levels. This finding demonstrates the significance of CETP genotypes to cardiovascular health and emphasizes the utility of computational modelling to studying cholesterol metabolism and its intersection with aging.

Conclusions

Many aspects of aging remain an enduring mystery. However, there is little doubt diet is key to health span and could even shape the trajectory of aging (Morgan et al. 2016a). In particular CR has a beneficial effect on metabolic health in humans. Cholesterol metabolism benefits from CR, and an improvement to blood lipid profile is a hallmark of CR. The significance of this relationship cannot be overlooked, because the dysregulation of cholesterol metabolism is intrinsically associated with increased risk of CVD. Integrated techniques, such as computational systems biology, are vital to the study of cholesterol metabolism and its intersection with aging. It is possible this technique could be employed to investigate the biology of the oldest old, because we have highlighted that cholesterol metabolism in the oldest old is an area which necessitates greater exploration. In so doing it may be possible to unravel the mechanisms responsible for the association between low LDL-C levels and increased risk of mortality, which has been observed in a number of studies involving this age group.

Cross-References

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Authors and Affiliations

  1. 1.Faculty of Science and Engineering, Department of Chemical EngineeringUniversity of ChesterChesterUK

Section editors and affiliations

  • Virginia Boccardi
    • 1
  1. 1.Institute of Gerontology and GeriatricsUniversità degli Studi di PerugiaPerugiaItaly