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Cholesterol is indispensable for tissues and cells of human beings. It is not only an important substance participating in the formation of cell membranes but also a kind of material for the synthesis of bile acids, vitamin D, and steroid hormones. A human being can get cholesterol from routine diet. But the main source of cholesterol is synthesized by the liver. Cholesterol is transported through the blood by the apolipoprotein to vessels, adrenal gland, ovary, and other oranges or tissues. However, excessive cholesterol can be deposited in the vascular wall, leading to a variety of cardiovascular diseases. LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) are two main components of plasma cholesterol. High total cholesterol and high LDL-C levels are widely regarded as casual predicted factors for cardiovascular events. However, the relevance of HDL-C level to cardiovascular disease is not certain (Holmes et al. 2018). Cardiovascular disease is a leading cause of death worldwide, and it has now surpassed tumor diseases as the main killer of human beings. Monitoring and maintaining cholesterol homeostasis is an important means of preventing cardiovascular disease.
Aging is a natural process of human life. The functions of multiple organs and systems decline gradually, and the metabolism changes correspondingly, including cholesterol metabolism. The changes in plasma cholesterol levels cause various physiological and pathological effects, which in turn affect various organs of the body and interfere with normal physiological functions. As a result, it causes multiple diseases further, especially cardiovascular diseases. Very low-density lipoprotein cholesterol (VLDL-C) is formed from the liver cholesterol pool. Lipoprotein lipase (LPL) partially hydrolyzes VLDL-C to form medium-density lipoprotein cholesterol (IDL-C), a kind of low-density lipoprotein cholesterol (LDL-C) precursor. IDL-C is further hydrolyzed by liver lipase to form LDL-C. VLDL, IDL, and LDL transport triacylglycerol and cholesterol to tissues. High-density lipoprotein (HDL) can remove cholesterol from tissues and transport it back to the liver for metabolism. Elevated plasma level of LDL-C is a good predictive factor for cardiovascular disease risk (Ference et al. 2017), while the plasma level of high-density lipoprotein cholesterol (HDL-C) is negatively correlated with cardiovascular risk. There have been many simple and effective methods to reduce the level of LDL-C, and they can effectively decrease the risk of cardiovascular disease. However, elevating HDL-C level in the prevention and treatment of cardiovascular diseases is not necessarily effective as that we expected. Cardiovascular risk is not reduced by solely elevating plasma HDL-C level (Soria-Florido et al. 2020). It is necessary to improve the function of HDL while raising HDL-C level. Cholesterol level management is a simple and effective strategy to maintain the health of older people.
Key Research Findings
Changes in Cholesterol Metabolism During Aging
An abnormal feature of aging is the dysregulation of cholesterol metabolism of the whole body (Mc Auley and Mooney 2014; also see “Aging and Cholesterol Metabolism” in this volume). The clinical manifestation of this process is an age-related rise in the plasma levels of VLDL-C, IDL-C, and LDL-C (Abbott et al. 1983; Dayimu et al. 2019). VLDL-C, IDL-C, and LDL-C in the circulation can be absorbed into the hepatic cells by the LDL receptor (LDLr) (Veniant et al. 1998; Spolitu et al. 2019). However, the hepatic LDLr decreases with age, which results in the accumulation of LDL-C in the circulation (Millar et al. 1995; Mc Auley et al. 2012). On the contrary, the level of HDL-C decreases with age (Wilson et al. 1994; Cho et al. 2020). It has been reported that estrogen deficiency can cause female dyslipidemia (van Beresteijn et al. 1993; Taylor et al. 2017). In addition, the level of follicle-stimulating hormone (FSH) in peripheral blood circulation increases during menopause. Blocking the effect of FSH can inhibit hepatic cholesterol synthesis and reduces plasma cholesterol (Guo et al. 2019). Metabolism of cholesterol can be affected by the decline of organ function in the aging process of human body, and it is an important index to judge whether the aging process is normal.
Changes in Cholesterol Levels Affect Aging
Cardiovascular and cerebrovascular diseases are common diseases in older people. They are the leading cause of mortality internationally (Lozano et al. 2012). VLDL transports cholesterol in the circulation, where it is hydrolyzed to form IDL, a precursor of LDL. Then, IDL is further hydrolyzed to form LDL. Plasma VLDL-C is closely related to cardiovascular disease and it can be a predictor of coronary events (Sacks et al. 2000). Similarly, decreasing plasma IDL-C can effectively improve cardiovascular health (Zambon et al. 2014). Hirowatari introduced the anion-exchange chromatographic method to obtain IDL-C, which may serve as useful markers for risk of cardiovascular disease in chronic kidney disease patients with hemodialysis treatment (Hirowatari et al. 2012). Apolipoprotein (Apo)C-II, ApoC-III, and ApoE are three VLDL-associated apolipoproteins in de novo lipogenesis, glucose metabolism, complement activation, blood coagulation, and inflammation. In addition, ApoC-II/ApoC-III/ApoE correlated with a pattern of lipid species previously linked to coronary vascular disease (CVD) risk (Pechlaner et al. 2017). ApoC-III is a vital apolipoprotein for ApoB lipoproteins, which may contribute directly to atherogenesis by activating endothelial cells and recruiting monocytes to them (Kawakami et al. 2006a, b). Drug targeting ApoC-III succeeds in lowering plasma levels of ApoC-II, ApoC-III, triacylglycerols, and diacylglycerols, but increasing ApoA-I, ApoA-II, and ApoM without affecting ApoB-100 (Pechlaner et al. 2017). This supports the concept of targeting triacylglycerol-rich lipoproteins to reduce the risk of CVD.
Elevated plasma total cholesterol or LDL-C level is an important risk factor for cardiovascular events (Wadhera et al. 2016). LDL-C level is positively correlated with the risk of cardiovascular diseases. Atherosclerosis is the basic vasculopathy of multiple cardiovascular diseases, characterized by cholesterol deposition in macrophages in large and medium-sized arteries. Elevated plasma LDL-C level leads to increased adhesion of circulating monocytes to arterial endothelial cells. In addition, under various pathological stresses, LDL can undergo chemical modifications, turn to modified LDL or caused oxidized LDL. Modified LDL is cytotoxic, which makes LDL particles more proatherogenic, contributing to the damage of endothelial cells. Decreasing LDL-C level has been proved to be effective in reducing the incidence of cardiovascular diseases (Cannon et al. 2015).
High-density lipoprotein (HDL) can reversely transport cholesterol back to the liver for metabolism and excrete them from bile or stool to prevent lipid oxidation and deposition in the peripheral blood vessel wall (van Vlijmen and Herz 1999). In addition, HDL has been proved to be of anti-oxidative, anti-inflammatory, and protective for vascular endothelium (Nofer et al. 2002; Norata et al. 2005). The level of plasma HDL-C is negatively correlated with the risk of cardiovascular disease (Castelli et al. 1986). However, solely elevating plasma HDL-C level cannot effectively reduce the occurrence of cardiovascular events. Cholesteryl ester transfer protein (CETP) can promote the transport of cholesterol esters from HDL to LDL and VLDL (Ohashi et al. 2005). CETP inhibitors significantly increase the plasma HDL-C levels, but the risk of cardiovascular disease does not decrease accordingly (Schwartz et al. 2012). On the contrary, statins and exercise effectively reduce the cardiovascular risk while elevating plasma HDL-C level. But statin has limited effect on the increase of HDL-C level (Grundy et al. 2001). It is now believed that statins may play a protective role in improving the function of HDL. Similarly, exercise can not only increase the level of plasma HDL-C (Igarashi and Nogami 2019) but also improve the function of HDL (Blazek et al. 2013). Compared with HDL-C level, the function of HDL may be more critical. While suffering from pathological stress, HDL may lose its normal physiological function. At present, there is a lack of easy and effective methods to evaluate the function of HDL.
Examples of Application
Cholesterol level is of great importance for health. There are many clinical treatments for cholesterol dysregulation.
Application of Reducing LDL-C Level
A number of approaches for LDL-C lowering have been well studied, such as lifestyle interventions, pharmacologic treatment, and surgical therapy. When the baseline level of plasma LDL-C is high, lowering LDL-C can reduce cardiovascular mortality more effectively (Navarese et al. 2018).
Statin is an inhibitor of rate-limiting enzyme for cholesterol synthesis, hydroxy methylglutaryl coenzyme A reductase. It can reduce the production of endogenous cholesterol by inhibiting the synthesis of cholesterol, thus reducing LDL-C. A 1 mmol/L of LDL-C reduction was associated with 38% and 31% decreases in the relative risk of major vascular events (nonfatal myocardial infarction, coronary death, coronary revascularization, or stroke) in subgroups of 5-year predicted risk <5% and ≥5% to <10%, respectively (Mihaylova et al. 2012).
Nonstatin Pharmacologic Therapies
Many drugs have been used clinically to reduce LDL-C levels such as bile sequestrant resins, fibrates, nicotinic acid drugs, ezetimibe, and ω-3 fatty acid drugs. Cholestyramine, a bile acid sequestrant, 24 g/d lowers LDL-C levels by 53.4 mg/dL and TC levels by 50.7 mg/dL compared with matching placebo, with a trend toward reduced risk of CAD (odds ratio 0.81) (Ross et al. 2015). Fibrates can reduce triglycerides by 20–50%, LDL-C levels by up to 20% (Wierzbicki 2009). Fibrates alone can reduce cardiovascular events by 10–15% (Jun et al. 2010). The study of heart and renal protection (SHRP) trial shows that simvastatin, combined with ezetimibe, is able to significantly reduce the mortality of primary endpoint events such as nonfatal heart failure or coronary events and nonhemorrhagic stroke, and that the combined group did not show any adverse reactions like increased cancers, myolysis, or liver damage (Baigent et al. 2011).
The partial ileal bypass has been shown to reduce LDL-C levels before statins appear. Liver transplantation has become the most effective method to implant LDLr in homozygous family hypercholesterolemia patients with gene mutations affecting the LDLr (Ishigaki et al. 2019). However, surgical therapy will inevitably cause great damage and many complications.
Application of Improving HDL Function
Several clinical studies have reported that elevating plasma HDL-C levels by CETP inhibitors fail to reduce cardiovascular risk. Currently, more attention has been paid to improve HDL function.
Apolipoprotein A-I (ApoA-I) Mimetic Peptide
ApoA-I, a major component protein of HDL, is an important carrier of ABCA1-mediated reverse cholesterol transport (Wang and Tall 2003). Rubin reported that the overexpression of ApoA-I increased the plasma levels of ApoA-I and HDL. As a result, the progress of arterial lipid plaque was impeded (Rubin et al. 1991). Studies have shown that ApoA-I mimetic peptide can improve HDL function, which not only inhibits the formation of atherosclerosis but also prevents the development of pulmonary hypertension (Sharma et al. 2014; Ou et al. 2005; Navab et al. 2002).
Otocka-Kmiecik and colleagues suggested that statins may play a role in improving HDL function and delaying the progression of atherosclerosis (Otocka-Kmiecik et al. 2012). Patients accepting simvastatin therapy, who were with noncoronary heart disease and scheduled to undergo heart operation, had a significant improvement in cardiac function, oxidative stress, and inflammatory reaction after cardiac surgery compared with the control group. Subgroup analysis showed that simvastatin significantly decreased HDL pro-inflammatory index in patients with valvular heart disease (Almansob et al. 2012). HDL of patients treated with simvastatin was improved significantly, suggesting that simvastatin promotes recovery of patients after cardiac surgery at least partially by improving HDL function (Chang et al. 2014).
Future Directions of Research
Many studies have achieved great success in reducing the level of LDL-C. New drugs for lowering LDL-C have been put on the market gradually, while HDL research is still in its infancy. More attention should be paid to the changes in HDL function and its subcomponents while suffering from diseases, and we should think about how to prevent new HDL from becoming pro-inflammatory HDL and improve the functions of pro-inflammatory HDL. There have been some methods to detect the function of HDL, such as its ability to reverse cholesterol transport, anti-apoptotic activity, the number of HDL particles in circulation, and so on. However, these methods have their own disadvantages, such as lack of standardization and unstable clinical correlation, which makes it impossible to integrate these indicators into risk prediction model or to evaluate the clinical efficacy of new lipid-lowering drugs. It is an urgent need to develop an easy and reliable method to accurately evaluate the function of HDL in clinical practice.
Cholesterol is an important nutrient. It not only participates in the composition and renewal of cell structure but also plays an important part in the signal transmission between human cells through the synthesis of steroid hormones. Cholesterol that ingested from food or synthesized by the liver is then transported to peripheral tissues by combining with apolipoproteins to form VLDL, IDL, and LDL. The excessive cholesterol from peripheral tissues is transported back to the liver to be discharged from the body through HDL, thus maintaining the delicate balance of cholesterol metabolism in the human body. If excessive cholesterol synthesis is ingested or peripheral cholesterol cannot be removed in time, excessive cholesterol will be deposited in peripheral tissues and organs, resulting in organ dysfunction and even disease. Aging is accompanied by the functional decline of organs, which affects the normal metabolism of cholesterol. Therefore, older people are prone to suffer from various lipid metabolic dysregulation, as well as cardiovascular and cerebrovascular diseases, which seriously threaten the health in older people. Various interventions have been applied to regulate the metabolism balance of cholesterol in clinical practice, and plasma cholesterol level has been used as a diagnosis reference of cardiovascular diseases. It is of great benefit to judge and utilize cholesterol levels in the prevention and treatment of various cardiovascular and cerebrovascular diseases in older people.
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