The following article is from Life Extension Magazine
|Emerging research into underappreciated aspects of cholesterol biochemistry has revealed that levels of cholesterol account for only a portion of the cardiovascular risk profile, while the properties of the molecules responsible for transporting cholesterol through the blood, called lipoproteins, offer important insights into the development ofatherosclerosis.
In fact, the size and density of lipoproteins are important factors for cardiovascular risk – for example, large, buoyant LDL (“bad cholesterol”) particles are much less dangerous than small, dense LDL particles; likewise large, buoyant HDL (“good cholesterol”) particles offer greater vascular protection than smaller, more dense HDL. The development of advanced lipid testing strategies that take the importance of lipoprotein particle size into consideration, such as the Vertical Auto Profile (VAP) or NMR (nuclear magnetic resonance) tests, allows a far deeper assessment of cardiovascular risk than a conventional lipid profile utilized by most mainstream medical practitioners.
Furthermore, metabolic processes, such as oxidation and glycation, modify the functionality of lipoproteins, transforming them from cholesterol transport vehicles into highly reactive molecules capable of damaging the delicate endothelial cellsthat line our arterial walls. This endothelial damage both initiates and promotes atherogenesis. Scientifically supported natural interventions can target the formation of these modified lipoproteins and help avert deadly cardiovascular diseases such as heart attack and stroke.
The pharmaceutical industry has been very successful in promoting cholesterol reduction with statin drugs as essentially the most important strategy for reducing cardiovascular risk. However, although the use of pharmaceutical treatment has saved lives, Life Extension has long recognized that optimal cardiovascular protection involves a multifactorial strategythat includes at least 17 different factors responsible for vascular disease.
Life Extension believes that innovative strategies for decreasing vascular risk should incorporate thorough cholesterol and lipoprotein testing, as well as strategic nutrient and pharmaceutical intervention, for optimal health effects and vascular support.
The Blood Lipids: Cholesterol and Triglycerides
CHOLESTEROL is a wax-like steroid molecule that plays a critical role in metabolism. It is a major component of cellular membranes, where its concentration varies depending on the function of the particular cell. For example, the membrane of liver cells contains fairly large fractions of cholesterol (~30%).1
The cholesterol in cell membranes serves two primary functions. First, it modulates the fluidity of membranes, allowing them to maintain their function over a wide range of temperatures. Second, it prevents leakage of ions (molecules used by the cell to interact with its environment) by acting as a cellular insulator.2 This effect is critical for the proper function of neuronal cells, because the cholesterol-rich myelin sheath insulates neurons and allows them to transmit electrical impulses rapidly over distances.
Cholesterol has other important roles in human metabolism. Cholesterol serves as a precursor to the steroid hormones,which include the sex hormones (androgens and estrogens), mineral-corticoids, which control the balance of water and minerals in the kidney, and glucocorticoids, which control protein and carbohydrate metabolism, immune suppression, and inflammation. Cholesterol is also the precursor to vitamin D. Finally, cholesterol provides the framework for the synthesis of bile acids, which emulsify dietary fats for absorption.
TRIGLYCERIDES are storage lipids that have a critical role in metabolism and energy production. They are molecular complexes of glycerol (glycerin) and three fatty acids.
While glucose is the preferred energy source for most cells, it is a bulky molecule that contains little energy for the amount of space it occupies. Glucose is primarily stored in the liver and muscles as glycogen. Fatty acids, on the other hand, when packaged as triglycerides, are denser sources of energy than carbohydrates, which make them superior for long-term energy storage (the average human can only store enough glucose in the liver for about 12 hours worth of energy without food, but can store enough fat to power the body for significantly longer).
Lipoproteins: Blood Lipid Transporters
Lipids (cholesterol and fatty acids) are unable to move independently through the blood stream, and so must be transported throughout the body as lipid particles. The lipid particles that transport cholesterol in circulation are calledlipoproteins. Contained within these lipoproteins are one or more proteins, called apolipoproteins, which act as molecular “signals” to facilitate the movement of lipid-filled lipoproteins throughout the body. Lipoproteins can also carry fat-soluble antioxidants, like CoQ10, vitamin E, and carotenoids, which protect the transported lipids from oxidative damage. This is why vitamin E and CoQ10 have performed so well in cardiovascular studies – because they prevent the oxidative modification of LDL particles, which in turn protects the blood vessel lining from damage. This will be discussed in greater detail in forthcoming sections in this protocol.
Four main classes of lipoproteins exist, and each has a different, important function:
Amongst its myriad of functions, the liver has a central role in the distribution of cellular fuel throughout the body. Following a meal, and after its own requirements for glucose have been satisfied, the liver converts excess glucose and fatty acids into triglycerides for storage, and packages them into VLDL particles for transit to fat cells. VLDLs travel from the liver to fat cells, where they transfer triglycerides/fatty acids to the cell for storage. VLDLs carry between 10 and 15% of the total cholesterol normally found in the blood.3
As VLDLs release their triglycerides to fat cells, their cholesterol content becomes proportionally higher (which also causes the VLDL particle to become smaller and denser). The loss of triglycerides causes the VLDL to transition to a low-density lipoprotein (LDL). The LDL particle, which averages about 45% cholesterol, is the primary particle for the transport of cholesterol from the liver to other cells of the body; about 60-70% of serum cholesterol is carried by LDL.4
During the VLDL to LDL transition, an apolipoprotein buried just below the surface of the VLDL called ApoB-100, becomes exposed. ApoB-100 identifies the lipoprotein as an LDL particle to other cells. Cells which require cholesterol recognize ApoB-100 and capture the LDL, so that the cholesterol it contains can be brought into the cell. Each LDL particle expresses exactly one ApoB-100 molecule, so measurement of Apo-B100 levels serves as a much more accurate indicator of LDL number than LDL-C (LDL cholesterol) level.
Because of the correlation between elevated blood levels of cholesterol carried in LDL and the risk of heart disease, LDL is commonly referred to as the “bad cholesterol”. LDL is, however, more than just cholesterol, and its contribution to disease risk involves more than just the cholesterol it carries.
All LDL particles are not created equal. In fact, LDL subfractions are divided into several classes based on size (diameter) and density, and are generally represented from largest to smallest in numerical order beginning with 1. The lower numbered classes are larger and more buoyant (less dense); size gradually decreases and density increases as the numbers progress. Smaller, denser LDLs are significantly more atherogenic for two reasons; they are much more susceptible to oxidation,5,6,7 and they pass from the blood stream into the blood vessel wall much more efficiently than large buoyant LDL particles.8 A more comprehensive lipid test, such as The Verticle Auto Profile (VAP) Test or NMR (nuclear magnetic resonance), allows for assessment of the size and density of LDL particles, a feature that dramatically increases the prognostic value and sets these advanced tests apart from conventional lipid tests. If an individual is found to have a greater number of small dense LDLs they are said to express LDL pattern B and are at greater risk for heart disease than an individual with more large buoyant LDL particles, which is referred to as pattern A.
HDLs are small, dense lipoprotein particles that are assembled in the liver, and carry about 20-30% of the total serum cholesterol.9 Cholesterol carried in the HDL particle is called “good cholesterol,” in reference to the protective effect HDL particles can have on cardiovascular disease risk. HDL particles can pick up cholesterol from other tissues and transport it back to the liver for re-processing and/or disposal as bile salts. HDL can also transport cholesterol to the testes, ovaries and adrenals to serve as precursors to steroid hormones. HDLs are identified by their apolipoproteins ApoA-I and ApoA-II,which allow the particles to interact with cell surface receptors and other enzymes.
The movement of cholesterol from tissues to the liver for clearance, mediated by HDLs, is called reverse cholesterol transport. If the reverse cholesterol transport process is not functioning efficiently, lipids can build up in tissues such as the arterial wall. Thus, reverse cholesterol transport is critical for avoiding atherosclerosis. Interestingly, a link between the male hormone testosterone and reverse cholesterol transport has been discovered – testosterone enhances reverse cholesterol transport.10 Though it is known that testosterone decreases levels of HDL, it also improves HDL function. This effect is mediated by a protein in the liver called scavenger receptor B1 that acts to stimulate cholesterol uptake for processing and disposal. Testosterone beneficially increases scavenger receptor B1.11 Testosterone also increases the activity of an enzyme called hepatic lipase, another facilitator of reverse cholesterol transport.12
Aging men experience a decline in testosterone levels, as well as a simultaneous increase in heart disease risk, which suggests that these phenomena may be related. Indeed, studies have shown that men with even slightly lower testosterone levels were over three times as likely to exhibit signs of early coronary artery disease.13 In order to maintain optimal reverse cholesterol transport efficiency, aging men should strive to maintain a free testosterone in the youthful range of 20 – 25 pg/ml. Those men interested in learning more about the link between heart disease and declining testosterone levels and ways to boost testosterone naturally should read Life Extension’s Male Hormone Restoration protocol.
Blood Lipids and Lipoproteins and Disease Risk
The initial association between cholesterol and cardiovascular disease was born out of the detection of lipid and cholesterol deposits in atherosclerotic lesions during the progression of atherosclerosis.14 Subsequently, studies have elucidated a role of LDLs in cardiovascular disease development, particularly the role of oxidized LDL (ox-LDL; LDL particles that contain oxidized fatty acids) in infiltrating and damaging arterial walls, and leading to development of lesions and arterial plaques.15,16
Upon exposure of the fatty acid components of LDL particles to free radicals, they become oxidized and structural and functional changes occur to the entire LDL particle. The oxidized LDL (ox-LDL) particle can damage the delicate endothelial lining of the inside of blood vessels.17 Once the ox-LDL particle has disrupted the integrity of the endothelial barrier additional LDL particles flood into the arterial wall (intima). Upon recognition of the presence of the ox-LDL within the intima, immune cells (macrophages) respond by engulfing it in an effort to remove it. But, the immune cells have then become too enlarged (by engulfing multiple ox-LDL particles) to escape back through the endothelial layer and become trapped within the intima, where they continually release cytokines, causing oxidative and inflammatory reactions to occur, resulting in the oxidation of additional native LDL particles and recruitment of more immune cells. This accumulative cycle results in the formation of atherosclerotic plaque deposits, which cause the arterial wall to protrude and disrupt blood flow, a process referred to as stenosis.
The recognition that ox-LDL is an initiator of endothelial damage allows for a clearer understanding of LDL’s role in the grand scheme of heart disease. Though an elevated number of native LDL particles does not directly endanger endothelial cells, it does mean that there are more LDL particles available to become oxidized (or otherwise modified), which then become more likely to damage endothelial cells.
Lowering serum cholesterol to an “optimal” range (total cholesterol 160 – 180; LDL-C 50-99) is one of the most frequently used strategies for reducing heart disease risk in persons without CHD.18 This approach, however, only addresses a portion of the risk. The actual predictive power of high LDL cholesterol for cardiovascular risk is likely much more complex, and has been the subject of several investigations. (Standard therapy for those at increased risk for heart disease is to keep LDL below 70 mg/dl.)
The Multifactorial Pathology of Vascular Disease
Analysis of the decline in CHD death rates from 1980 to 2000 by mathematical modeling highlighted the need to address multiple risk factors to protect against the end result of heart disease – mortality. In this study, cholesterol reduction accounted for only 34% of the reduction in death rate in individuals with heart disease. To put this into context, the same model estimated that reductions in systolic blood pressure were responsible for 53% of the death rate reduction, and smoking cessation accounted for 13%.19 In another comprehensive review of studies of CHD risk factors, non-HDL cholesterol increased the risk of CHD less than either elevated C-reactive protein (CRP; a marker of systemic inflammation) levels or high systolic blood pressure.20 In the Copenhagen Heart Study, which tracked 12,000 participants for 21 years, high cholesterol was the 6th most relevant risk factor for developing CHD in both men and women; diabetes, hypertension, smoking, physical inactivity and no daily alcohol intake (light alcohol consumption is heart-healthy) presented larger risks for the disease.21 The controversial JUPITER trial, which examined prevention of CHD by statin drugs in persons with very low LDL-C (but elevated hs-CRP) supported the conclusion that non-LDL-C risk factors (such as inflammation) represent enough risk for CHD to warrant treatment, even if lipids are within low-risk ranges.22
In order to reduce risk, there must be a systematic approach and understanding of the multiple factors of cardiovascular risk and atherosclerosis. Optimal cholesterol management is important for risk reduction, but so are the multiple risk factors that Life Extension has long identified. Accordingly, efforts to lower cholesterol to mitigate cardiovascular risk will only be met with optimal success if paired with measures to reduce other risk factors such as inflammation, oxidation, hypertension, excess plasma glucose, excess body weight, fibrinogen, excess homocysteine, low vitamin K, insufficient vitamin D, hormone imbalance; etc. Mainstream medicine is quick to point out that 10-15% of patients with coronary heart disease have no apparent major risk factors.23
Life Extension members are well aware of the need to address every risk factor for heart disease to improve outcome. The 17 Daggers of Arterial Disease graphic has been published in Life Extension Magazine and illustrates the risk factors that Life Extension has identified as being critical to address in order to maintain optimal vascular health.
Blood Lipid Measurement
The determination of the relative levels of the blood lipids and their lipoprotein carriers is an important step for assessing cardiovascular disease, as well as determining appropriate measures for attenuating this risk. Most physicians conduct a routine, fasting blood chemistry panel during a patient’s annual physical. This test includes the classic lipid panel or lipid profile, which measures total cholesterol, HDL, and triglycerides from a fasting blood sample; levels of LDL-C are calculated from this data.30 An extended lipid profile may also include tests for non-HDL and VLDL.
The recognition of the relative risks of the different subclasses of lipoprotein particles has led to the development of advanced lipid testing, which may have an improved prognostic power over conventional lipid panels in its ability to assess additional risk factors for CHD (such LDL particle size, VLDL remnants, lipoprotein(a), or ApoB). The Vertical Auto Profile (VAP) Test is a comprehensive advanced lipid test that uses advanced techniques to separate and quantify lipoproteins from a blood sample. The standard VAP can directly measure LDL-C levels; can subclassify LDLs by particle size and density,and HDL, VLDL subclasses, as well as apolipoprotein B-100 (ApoB).
A comparison between standard lipid tests and the VAP test is provided in the table below.
Other lipid tests include: 1) A gradient gel technique developed by Berkeley HeartLab,31 which, while not as comprehensive as the VAP test, is able to quantify all seven LDL subclasses. 2) Nuclear magnetic resonance (NMR) spectroscopy,32 which determines much of the same information as the other two techniques (VAP and Berkeley), but it is the only one test that can quantitate LDL particle number (though this is not necessarily an advantage over the VAP test, since this is functionally the same as directly quantitating ApoB-100).
Conventional Approaches to Managing Blood Lipids and Lipoproteins
Reduction of total- and LDL-cholesterol (and/or triglycerides) by conventional medical therapies usually involves inhibiting cellular cholesterol production in the body, or preventing the absorption/reabsorption of cholesterol from the gut. By reducing the availability of cholesterol to cells, they are forced to pull cholesterol from the blood (which is contained in LDL particles). This has the net effect of lowering LDL-C. Therapies which increase the breakdown of fatty acids in the liver or lower the amount of VLDL in the blood (like fibrate drugs or high-dose niacin)33 also result in lower serum cholesterol levels. Often, complementary strategies (such as statin to lower cholesterol production plus a bile acid sequesterant to lower cholesterol absorption) are combined to meet cholesterol-lowering goals.
Reduction of cellular cholesterol production is the most frequent strategy for reducing cardiovascular disease risk, with HMG-CoA reductase inhibitors (statins) being the most commonly prescribed cholesterol-lowering treatments. Statins inhibit the activity of the enzyme HMG-CoA reductase, a key regulatory step in cholesterol synthesis. Since cholesterol levels in cells are tightly controlled (cholesterol is critical to many cellular functions), the shutdown of cellular cholesterol synthesis causes the cell to respond by increasing the activity of the LDL receptor on the cell surface, which has the net effect of pulling LDL particles out of the bloodstream and into the cell. Statins may also reduce CHD risk by other mechanisms, such as by reducing inflammation.34
Statins may induce serious side effects in some individuals; most common being muscle pain or weakness (myopathy). The prevalence of myopathy is fairly low in clinical trials (1.5-3.0%), but can be as high as 33% in community based studies and may rise dramatically in statin users who are active (up to 75% in statin-treated athletes.)35,36 Occasionally, statins may cause an elevation of the liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT). These enzymes can be monitored by doing a routine chemistry panel blood test. Additionally, by inhibiting HMG-CoA reductase (an enzyme not only required for the production of cholesterol, but other metabolites as well), statins may also reduce levels of the critically important antioxidant molecule CoQ10.
Lowering cholesterol absorption from the intestines reduces LDL-C in a different fashion; by preventing uptake of intestinal cholesterol, cells respond by making more LDL receptor, which pulls LDL particles out of the blood stream. Ezetimibe and bile acid sequestrants (colesevelam, cholestyramine, cholestopol) are two classes of prescription treatment that work in this fashion. Ezetimibe acts on the cells lining the intestines (enterocytes) to reduce their ability to take up cholesterol from the intestines. While ezetimibe does reduce LDL levels, the results of several major trials37,38,39 failed to show the benefit of ezetimibe as part of a combination therapy for reducing risk of cardiovascular disease, and it may actually increase the risk of atherosclerosis if prescribed to patients already on statins for reasons that are not clear.40 Bile acid sequestrants bind to bile acids in the intestine, which reduces their ability to emulsify fats and cholesterol. This has the net effect of preventing intestinal cholesterol absorption. Bile acid sequestrants may also increase HDL production in the liver, which is usually inhibited by the reabsorption of bile acids.41
Nutritional Approaches to Managing Blood Lipids and Lipoproteins
Nutritional approaches to blood lipid and lipoprotein management mirror many of the strategies of conventional therapies. Dietary modifications aim to reduce the intake and uptake of fats and cholesterol from the diet. The inclusion of specific dietary compounds with cholesterol-lowering (hypocholesterolemic) or cardioprotective properties may also reduce cardiovascular disease risk by several different mechanisms.
Diet is an important determinant of cardiovascular disease risk; both conventional and alternative approaches advocate dietary and lifestyle changes as the first step in meeting lipid management goals. The National Cholesterol Education Program (NCEP) developed the Therapeutic Lifestyle Changes (TLC) diet42 for medical professionals to help patients pursue nutritional options for lowering cholesterol. The TLC diet recommends no more than 25 to 35 percent of daily calories from total fat, with up to 20 percent as monounsaturated, 10 percent as polyunsaturated, and less than 7 percent as saturated fats. This relatively high allotment of fat calories allows for increased unsaturated fat intake like omega-3 fatty acids in place of carbohydrates for patients with metabolic syndrome.
Carbohydrates and proteins should provide 50-60 percent and 15 percent, of total calories, respectively. Dietary cholesterol intake should be less than 200 mg per day. Optional dietary guidelines include the addition of 10-25 grams of soluble fiber,and 2 grams of plant sterols per day. Total calories are adjusted to maintain body weight and prevent weight gain, and enough moderate exercise to burn at least 250 calories per day is recommended.
Although not designed as a hypocholesterolemic diet, the DASH (Dietary Approaches to Stop Hypertension) eating plan encourages many of the same heart-healthy eating habits.43 The first DASH eating plan (originally called the “combination diet”) focused on fruits, vegetables, and whole grains, and was especially high in fiber (31 grams/day) and potassium (4.7 grams / day), and low in animal products. Ironically, the original DASH was not a low sodium diet (allowing up to 3 grams/day), but was nonetheless hypotensive44. The low-sodium DASH diet has demonstrated even greater hypotensive effects when limiting sodium to 1.5 grams/day.45 Recall that hypertension is a major coronary heart disease factor. Hypertension magnifies the danger posed by excess LDL by damaging the endothelial barrier, allowing increased permeability.
Caloric restriction (CR) is the dramatic reduction of dietary calories (by up to 40%), to a level short of malnutrition.46Restriction in energy intake slows down the body’s growth processes, causing it to instead focus on protective repair mechanisms; the overall effect is an improvement in several measures of wellbeing. Observational studies have tracked the effects of CR on lean, healthy individuals, and have demonstrated that moderate CR (22-30% decreases in caloric intake from normal levels) improves heart function, reduces markers of inflammation (C-reactive protein, tumor necrosis factor (TNF)), reduces risk factors for cardiovascular disease (LDL-C, triglycerides, blood pressure) and reduces diabetes risk factors (fasting blood glucose and insulin levels).47,48,49,50 Preliminary results of the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) study, a long-term multicenter trial on the effects of calorie-restricted diets in healthy, overweight volunteers51 has shown that moderate CR can reduce several cardiovascular risk factors (LDL-C, triglycerides, and blood pressure, C-reactive protein).52
Replacing Lost Hormones to Achieve Optimal Cholesterol Levels
Due to the role of cholesterol as a precursor to steroid hormones, some researchers have speculated that the elevation in cholesterol seen with advancing age is a compensatory effort by the body to restore levels of hormones to more youthful levels.
In a small clinical trial, Dr. Sergey Dzugan, and Dr. Arnold Smith, found that restoring youthful hormone levels with the use of bioidentical hormone replacement therapy (BHRT) resulted in a significant reduction in cholesterol levels in 20 individuals with high cholesterol.53
Hormone replacement therapy has been shown to reduce cardiovascular risk in aging women,54 and aging men with lower testosterone levels are at significantly greater risk for heart disease.55 Thus, aging individuals should consider optimizing their hormone levels in order to reduce cardiovascular risk. More information on this topic can be found in Life Extension’s Hormone Replacement Therapy protocols for Men and Women.
Nutrients for Lipid Management
There are several nutrients that have been identified as potential agents for promoting a favorable lipid profile; many of them work by the same principles as conventional therapies (such as reducing cholesterol synthesis, or interfering with cholesterol absorption in the gut). Several also have additional activities (antihypertensive, inhibition of LDL-oxidation, antiinflammatory) that complement their cholesterol-lowering activity and lend to their overall reductions in fatal and non-fatal cardiovascular events.
Inhibiting Cholesterol Synthesis
Pantethine and its metabolites appear to act on the body’s fat and cholesterol metabolism pathways. Pantethine is a derivative of pantothenic acid (vitamin B5), and can serve as a source of the vitamin. One notable function of vitamin B5 is its conversion into coenzyme A, a necessary factor in the metabolism of fatty acids into cellular energy. The pantethine derivative cysteamine may also function to reduce the activity of liver enzymes that produce cholesterol and triglycerides.56Studies of pantethine consumption have demonstrated significant reductions in total- and LDL cholesterol (up to 13.5%), triglycerides, and elevation of HDL-C in hypercholesterolemic subjects (individuals with high cholesterol)57,58 and diabetic subjects59 when taken at 900-1,200mg/day, although significant effects on triglycerides have been observed at dosages as low as 600 mg / day.60
Red yeast rice is a traditional preparation of rice fermented by the yeast Monascus purpureus. The yeast produces metabolites (monacolins) that are naturally-occuring HMG-CoA Reductase inhibitors (one of these, monacolin K, is chemically identical to lovastatin61). A comprehensive review of 93 randomized trials including nearly 10,000 patients has demonstrated that commercial preparations of red yeast rice produced reduction in total cholesterol, LDL-C, triglycerides, and an increase in HDL-cholesterol.62 A long-term (4.5 year) multicenter study of nearly 5,000 patients with a previous heart attack and high total cholesterol levels demonstrated that a commercial red yeast rice preparation reduced the incidence of major coronary events, including nonfatal heart attack and cardiovascular mortality, when compared to placebo63. Red yeast rice extracts have also been shown to be well tolerated and effective in lowering LDL in patients with statin intolerance.64,65
Due to regulations regarding their labeling in the US, standardization of commercial red yeast rice preparations for monacolins is problematic, thus levels of monacolins can vary dramatically between red yeast rice products.66 There are some standardized red yeast rice products that are standardized for monacolin K content.
Garlic has been substantiated by several human trials, particularly its ability to support favorable blood lipid profiles. Three separate analyses of 32 blinded, controlled human trials of garlic consumption in healthy or patients with high cholesterol and trigylcerides confirm significant reductions in total cholesterol by an average of 7.3 mg/dL, and triglycerides by an average of 4.2 mg/dL. 67,68,69 While the average cholesterol reductions across all human studies are modest, greater reductions in total cholesterol were realized in patients who were initially hyperlipidemic or hypertriglycemic (>11 mg/dL reduction), took the extract for over 12 weeks (11 mg/dL reduction), or took a garlic powder (as opposed to an oil or aged extract; 12 mg/dL reduction).70
Garlic also reduces systolic- and diastolic- blood pressure (SBP and DBP) in hypertensive individuals, and systolic blood pressure in persons with normal blood pressure. A recent review and analysis of 11 controlled human trials of garlic showed a mean decrease of 4.6 ± 2.8 mm Hg for SBP in the garlic group compared to placebo, while the mean decrease in the hypertensive subgroup was 8.4 mm Hg for SBP and 7.3 mm Hg for DBP.71
Indian Gooseberry (Amla; Emblica officinalis) has been used traditionally as a nutrient-dense food in Indian regions, and in Ayurvedic medicine for treating a variety of conditions. Modern scientific inquiry has revealed considerable evidence in support of the medicinal use of this nutritional powerhouse. Analytical studies on extracts of Indian Gooseberry highlight its potent antioxidant properties;72 animal studies carry these findings forward by showing that orally administered amla extract significantly reduce levels of oxidized LDL.73,74 In human studies, extracts of amla have been shown to attenuate elevations in LDL, total cholesterol, and triglycerides, and boost levels of protective HDL.75 In a study examining the antioxidant activity of amla extract in subjects with metabolic abnormalities, four months of supplementation was shown to dramatically bolster plasma antioxidant power and suppress oxidative stress.76
Studies suggest that amla extract may also protect against LDL glycation by modulating blood glucose levels. In diabetic patients amla not only significantly reduced post-prandial glucose levels, but also lowered lipid and triglyceride levels over a 21 day period77. In an animal model of metabolic syndrome induced by a high fructose diet, concomitant administration of amla extract reined in rising cholesterol and triglyceride levels, and also significantly repressed the expression of inflammation-related genes, which are typically elevated in metabolic syndrome models.78 Extracts of the antioxidant-rich fruit also reduce levels of advanced glycation end products (AGEs), which are formed by the same process as glycated LDL.79By limiting the amount of LDL particles that become glycated, amla may help maintain proper cellular uptake of cholesterol and reduce the amount of LDL-C available to infiltrate the arterial wall.
Inhibiting Absorption of Dietary Cholesterol
Soluble Fibers include non-digestable and fermentable carbohydrates, and their sufficient intake has been associated with lower prevalence of cardiovascular disease.81 When included as part of a low-saturated fat/low cholesterol diet, they can lower LDL-C by 5-10% in hypercholesterolemic and diabetic patients, and may reduce LDL-C in healthy individuals as well.82The cholesterol-lowering properties of soluble oat fiber, psyllium, pectin, guar gum, ß-glucans from barley, and chitosan are substantiated by dozens of controlled human clinical trials. 83,84,85 Soluble fibers lower cholesterol by several potential mechanisms.86 They may directly bind bile acids or dietary cholesterol, preventing/disrupting their absorption. Their high viscosities (measure of a liquids thickness) and effects on intestinal motility may slow or limit macronutrient uptake. They can also increase satiety, which can limit overall energy intake.
Prebiotics, a subset of solube fiber, have gained attention in recent years in their ability to be selectively fermented by gut flora for a diversity of potential health-promoting benefits. The fermentation of prebiotic fibers into short-chain fatty acids such as acetate, butyrate, or propionate may inhibit cholesterol synthesis in the liver.87 In human trials, the prebiotic fibers inulin and dextrin have induced reductions in serum levels of total cholesterol (-9% and -2% for inulin and dextrin, respectively), LDL-C (-1 % for dextrin), and triglycerides (-21% for inulin).88,89
Plant sterols (phytosterols) are steroid compounds found in plants that function similarly to cholesterol in animals (as components of plant cell membranes, and precursors to plant hormones). Like cholesterol, they can exist as free molecules or as sterol- esters. Esters of sterols have a higher activity and better fat solubility, which allows for lower effective dosages (2-3 g/day as opposed to 5-10 g/day for unesterified sterols).90 Sterols themselves are poorly absorbed from the diet, but because of their chemical similarity to cholesterol, they are thought to compete with cholesterol for absorption in the intestines, which has the net effect of reducing LDL levels.91 Sterols may also reduce cholesterol production in the liver, reduce the synthesis of VLDLs, increase LDL particle size, and increase LDL uptake from the blood92,93 HDL and/or very low-density lipoproteins are generally not affected by sterol intake.94
There have been numerous studies of the effects of sterol esters on reducing mean total cholesterol and LDL-C cholesterol in healthy, hypercholesterolemic, and diabetic individuals. An analysis of 57 trials involving over 3600 individuals has reported an average LDL-C reduction of 9.9% at a mean intake of 2.4 g sterol esters/day.95 Sufficient evidence of the cholesterol-lowering effects of sterols has prompted the US Food and Drug Administration to permit the health claim that sterol esters may be associated with a reduced risk of coronary heart disease, when taken at sufficient levels in the context of a healthy diet, one of only 12 permissible health claims granted by this organization96 The NCEP97 and American Heart Association98 both support the use of sterols in their dietary recommendations.
Guggul/Gum guggul, the resin of the Commiphora mukul tree, has a history of traditional usage in Ayurvedic medicine and is widely used in Asia as a cholesterol-lowering agent. Guggulipid is a lipid extract of the gum that contains plant sterols (guggulsterones E and Z), the proposed bioactive compounds.99 In an analysis of 20 human studies on guggulipid, most of the evidence support a significant reduction in serum total cholesterol, LDL, and triglycerides, as well as an elevation in HDL.100 However, most of these studies were small, and had significant design flaws (such as lack of controls or statistical analysis). More recent studies, with better designs, have produced conflicting results. The first, a 36 week study of the effects of 25 mg of guggulsterones on 61 hypercholesterolemic patients demonstrated significant reductions of total cholesterol by 11.7%, LDL by 12.5%, and triglycerides by 15%.101 A second study revealed an opposite effect; this larger (103 patient) study looked at low- (25 mg) and high- (50 mg) dose guggulsterones on blood lipid parameters for eight weeks, and observed increases in LDL-C (4% and 5% for the low and high dose groups, respectively).102 In the most recent study, 12 week administration of 540 mg raw guggul demonstrated modest reductions in both total cholesterol and HDL (3-6%), although the clinical significance of this outcome is not clear.103
Soy protein has value as an anti-hypercholesterolemic agent not only because of the potential lipid-lowering effects of its included isoflavones (which may increase the amount of LDL receptors and help to clear LDL particles from the blood), but also for its potential as an alternative to other high fat/high cholesterol protein sources. A 1995 meta-analysis of 38 controlled human clinical trials (30 conducted on hypercholesterolemic patients) revealed that compared to animal protein, an average intake of 47g/day of soy protein resulted in significant improvements in blood lipid/lipoprotein parameters. Across the studies there were observable average reductions in total cholesterol (9%), LDL-C (12.9%), triglycerides (10.5%), and VLDL-C (2.6%), as well as a non-significant increase in HDL-C (2.4%)104 These data were the foundation for the FDA approval of the food-labeling health claim for soy protein in the prevention of CHD.105
More recently, a second meta-analysis of 41 soy protein studies (including 32 new studies performed after 1995) confirmed the anti-hypercholesterolemic properties of soy protein. The average reductions in blood lipids were smaller (5.3% for total cholesterol, 4.3% for LDL-C, 6.3% for triglycerides, and a 0.8% increase in HDL-C), but this analysis was limited to studies that used soy protein isolates (which contain no cholesterol-lowering fiber).106 Some of this difference may also be explained by baseline lipid levels; persons with moderate to severe hypercholesterolemia showed the largest decreases in serum cholesterol when soy is added to the diet.107
Isoflavone-enriched soy proteins may have additiona lipid-lowering benefits. In the 11 human trials that compare isoflavone-enriched soy to isoflavone-free soy, the enriched soy products (which delivered an average of 102 mg isoflavones/day) lowered total and LDL cholesterol more than isoflavone-free soy, by 1.7% and 3.5%, respectively.108
Inhibiting Oxidation and Glycation of LDL
Coenzyme Q10 (CoQ10). The generation of chemical energy in the form of ATP by the mitochondrial electron transport chain is essential for the existence of life as we know it. Delicate endothelial cells that line the arterial walls depend on healthy mitochondrial function to control blood pressure and vascular tone. Oxidized or glycated LDL can sabotage endothelial mitochondrial function and damage the endothelial barrier, setting the stage for the atherosclerotic cascade to initiate.109,110CoQ10 is an integral component of mitochondrial metabolism, serving as an intermediary transporter between two major check points along the road to ATP production. Interestingly, CoQ10 is also the only known endogenously synthesized lipid soluble antioxidant,111 and is thus incorporated into LDL particles, where it serves to protect against oxidation. Because of these dual roles insufficient levels of CoQ10 expedite atherogenesis from two angles – by limiting mitochondrial efficiency in endothelial cells and leaving LDL particles vulnerable to oxidative damage.
As noted above, statin drugs, which are typically used to treat high cholesterol, ironically also suppress levels of CoQ10 in the blood.112 Individuals taking a statin drug should always supplement with CoQ10.
Carotenoids are common constituents of the LDL particle. ß-carotene is the second most abundant antioxidant in LDL; other common dietary carotenoids (lycopene, lutein) may be transported by LDL particles as well.113 Together, these three carotenoids have an indispensable role in the protection of LDL particles from oxidative damage; their serum levels have been demonstrated to be the most predictive of the degree of LDL oxidation in humans.114 Carotenoids may also possess additional lipid-lowering activities independent of their antioxidant potential. The best-studied in this respect is lycopene; an analysis of 12 human trials of lycopene reveals an average reduction in LDL-C of approximately 12%.115 Potential mechanisms for this action are suppression of cholesterol synthesis by the inhibition of the HMG-CoA reductase enzyme, or an increase in the rate of LDL degradation.116 Astaxanthin, a carotenoid found in some fish and marine oils, can increase HDL.117
Vitamin E. Natural tocopherols and tocotrienols together form vitamin E. These fat-soluble antioxidants have been studied for decades and are known to protect against some cardiovascular events. Vitamin E strongly inhibits the oxidation of LDL particles.118,119
Alpha tocopherol is the best known form of vitamin E and is found in the largest quantities in blood and tissue. It is critical, however, for anyone supplementing with vitamin E to make sure they are also getting adequate gamma tocopherol each day. The key benefit is gamma tocopherol’s ability to dramatically reduce inflammatory threats, a major cause of virtually all degenerative diseases. One of the most important benefits of gamma tocopherol is its ability to improve endothelial functionby increasing nitric oxide synthase, the enzyme responsible for producing vessel-relaxing nitric oxide.120 One major way it produces this effect is by sponging up destructive reactive nitrogen species, such as peroxynitrite.121 In fact, gamma tocopherol is able to “trap” a variety of reactive nitrogen species and halt their negative effects on a host of cellular processes.122
Supplementation in humans with 100 mg per day of gamma tocopherol showed resulted in a reduction in several risk factors for vascular disease such as platelet aggregation and LDL cholesterol levels.123
Pomegranate is now widely viewed as a superfruit with a myriad of health benefits, and rightfully so; dozens of placebo controlled clinical trials have been carried out on pomegranate juice, or pomegranate extract. With respect to lipid management, the efficacy of pomegranate is rivaled by very few natural compounds. The high concentration of polyphenols (particularly punicalagins) in pomegranate make it an ideal ingredient for suppressing LDL oxidation.124,125
Consumption of pomegranate polyphenols significantly lowered total and LDL cholesterol concentrations while maintaining HDL levels in subjects with elevated cholesterol profiles.126 Pomegranate also suppresses immunoreactivity against oxidized LDL, a mechanisms which would be expected to limit plaque formation in the intimia.127 In fact, this is exactly what was shown in a long-term study of pomegranate consumption. Subjects received either pomegranate juice or placebo for three years; in the group receiving the placebo, carotid intima media thickness (cIMT; a measure of atherosclerosis) increased by 9% one year after study initiation, while in the group receiving pomegranate, cIMT was reduced by an astonishing 30%. Moreover, pomegranate significantly reduced oxidized LDL concentrations, and increased serum antioxidant activity, compared to placebo, while simultaneously lowering blood pressure. This study also showed that pomegranate nearly doubled the activity of paraoxonase-1 (PON-1), an antiatherogenic enzyme that optimizes the function of HDL and protects lipids from oxidative damage.128 Both groups in this study continued on standard therapy that may have included statins, anti-hypertensives, etc.
Polyphenols are a diverse set of phytonutrients that are ubiquitous in the diet. Polyphenol intake has been associate with lower risk of cardiovascular mortality, and may partially explain the health benefits of several common foods (tea, fruits, vegetables, wine, chocolate).129 Flavonoids, the largest and best studied class of polyphenols, include catechins from green tea and chocolate, theaflavins from black tea, soy isoflavones, flavan-3-ol polymers from red wine, and anthocyanidins from grapes and berries. A systematic analysis of over 130 human studies of flavonoids revealed significant improvements in endothelial function (cocoa and black tea polyphenols) and blood pressure (anthocyanidins, isoflavones, cocoa); however, only green tea catechins exhibited significant cholesterol (LDL-C) lowering in this analysis (averaging about 9 mg/dL over 4 studies).130 Subsequently, a study of black tea extract in 47 mildly hypercholesterolemic Japanese men and women demonstrated an 8% reduction in total cholesterol and 13% drop in LDL-C after 3 months.131
Other polyphenolic compounds with significant lipid modification potential based on human studies include methylated citrus flavonoids (polymethoxyflavones), which were shown to lower total-cholesterol, LDL-C, and triglycerides by 27%, 25%, and 31%, respectively when combined with tocotrienols in a small pilot trial.132 Additionally, the red wine polyphenol resveratrol was shown to incorporate into the LDL particles of human volunteers following ingestion of a high-resveratrol wine, potentially acting as a resident antioxidant.133 This is consistent with resveratrol’s role in the prevention of LDL oxidation observed in humans.134
Curcumin has a variety of protective roles in CVD, potentially reducing oxidative stress, inflammation, and the proliferations of smooth muscle cells and monocytes. 95 Small human trials studies have revealed the effects of curcumin on reducing in lipid peroxidation135,136 and plasma fibrinogen,137 both factors in the progression of atherosclerosis.138 Curcumin may also reduce serum cholesterol by increasing the production of the LDL receptor,139,140 but despite successes in animal models, human data on the antihypercholesterolemic effects of curcumin is conflicting. A small study of 10 healthy volunteers revealed significant decreases in lipid oxidation products (-33%) and total cholesterol (-12%), with a concomitant increase in HDL-C (29%) when using 500 mg curcumin daily for 7 days.141 In two subsequent studies, low-dose curcumin showed a non-significant trend toward lowering total- and LDL-C in acute coronary patients,142 while high dose-curcumin (1-4 g/day) exhibited non-significant increases in total-, LDL-, and HDL cholesterol.143
Enhancing Cholesterol Elimination
Artichoke has traditional usage as a liver protectant and choleretic (compound that stimulates bile flow). In stimulating bile flow, artichoke may aid the body in the disposal of excess cholesterol. In vitro studies suggest its anti-atherosclerotic effects may also be linked to an antioxidant capacity that reduces LDL oxidation, or the ability of one of its constituents, luteolin, to indirectly inhibit HMG-CoA reductase.144
In addition to several uncontrolled human studies and case reports145, two randomized, controlled trials support the ability of artichoke extracts to lower total- and/or LDL-cholesterol. In the first trial, artichoke extract (1800 mg/day) for 6 weeks reduced total cholesterol (-9.9%) and LDL-C (-16.6%) in 71 hypercholesterolemic patients, with no differences in HDL-C or triglycerides.146 In the second, also in hypercholesterolemic patients, 1280 mg artichoke extract/day for 12 weeks reduced total cholesterol by 6.1%, when compared to a control group. Changes in LDL-C, HDL-C, and triglycerides were insignificant.147 Artichoke extract also improved parameters of endothelial function in a small human trial.148
Optimizing the Lipid Profile
Niacin/Nicotinic acid (vitamin B3) is an essential nutrient with roles throughout human metabolism. At dosages substantially above the recommended daily intake (RDI), prescription niacin treatments can significantly raise HDL-C (by 30-35% in some cases, at dosages averaging 2.25 grams/day).149,150 Niacin can also change the distribution of LDL by increasing the amount of large buoyant LDL and reducing the amount of small dense LDL.151 Niacin can also reduce the susceptibility of LDL to oxidation.152
In 2010, the results of seven published studies on the effects of niacin therapy were combined to examine the overall effect. This meta-analysis is considered more powerful than an individual study because it increases the sample size. The results showed that patients taking niacin (compared with a placebo) had significant reductions in nonfatal myocardial infarction and and transient ischemic attack.153
On May 26, 2011, the National Institutes of Health stopped a clinical trial of a prescription-strength level of niacin one year prior to its projected completion. The participants were 3400 patients with stable heart disease, well-controlled LDL, and elevated triglycerides. They added high dose, extended release niacin to their statin therapy. The level of niacin used in the study was much higher than that contained in dietary supplements. As shown in previous studies, the niacin drug successfully elevated HDL and lowered triglycerides, but failed to reduce the risk for heart attack or stroke. The findings of this trial highlight the multifactorial pathology of cardiovascular disease; Life Extension believes that had these patients been receiving antioxidants like CoQ10 to reduce LDL oxidation, pomegranate to improve endothelial function, and fish oil to regulate triglyceride levels there would have been a strong reduction in risk. Mainstream media outlets have used this study as a basis for headlines suggesting that niacin is ineffective for promoting cardiovascular health. However, the lesson that should be taken from these findings is that optimal cardiovascular protection requires a multi-modal approach, and should not be limited to one or two interventions.
Fish Oil, is a source of omega-3 fatty acids (eicosapentaenoic acid — EPA, and docosahexaenoic acid — DHA), which cannot be synthesized by humans but are nonetheless essential for several metabolic processes. Aside from reductions in the risk of cardiovascular mortality and non-fatal cardiovascular events (supported by studies of tens of thousands of moderate and high risk patients)154, fish oil fatty acids significantly reduce serum triglycerides. Forty-seven studies, comprising over 15,000 patients, have confirmed an average triglyceride reduction of 30 mg/dL, at an average intake of 3.35g EPA+DHA over 24 weeks.155 Triglycerides were reduced in a dose-dependent manner, and were dependent on baseline levels (reductions of greater than 40% were observed in patients with the highest starting triglyceride levels). Slight increases in LDL-C and HDL-C were also observed in these studies, although other large analyses failed to detect any significant effects of fish oil on cholesterol.156 The mechanism by which EPA + DHA lowers triglycerides thought to be by slowing the release of VLDL particles into the plasma, or increasing lipid degradation and clearance of triglyceride-rich lipoproteins from the blood.157Lowering triglyceride levels is a known strategy for increasing the amount of large buoyant LDL and reducing the amount of small dense LDL.
Prescription fish oil uses a highly concentrated EPA+DHA fish oil ester that provides a dosage of 3.36 g of omega-3 in 4 capsules; its degree of triglyceride reduction (up to 45%) is similar to non-prescription fish oil at a similar dose (usually requiring several more capsules.)157 Non-prescription fish oil supplements sell at a fraction of the price of prescription fish oil and usually require one or more additional capsules to be taken daily to obtain the same amount of EPA/DHA.
Life Extension Suggestions
Those with vascular disorders often manifesting as coronary artery disease should consider using a wide range of supplements, hormones and drugs to suppress the multiple risk factors involved in atherosclerosis progression. Healthy individuals should carefully follow blood test results to ascertain which nutrients are more important.
Inhibiting Cholesterol Synthesis
Inhibiting Absorption of Dietary Cholesterol
Enhancing Cholesterol Elimination
Inhibiting Oxidation and Glycation of LDL
Optimizing the Lipid Profile
Improving reverse cholesterol transport
In addition, the following blood testing resources may be helpful:
Disclaimer and Safety Information
This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.
The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.