Is cholesterol our friend or enemy? (Part 2)
Zhores MEDVEDEV, "Science and Life" No. 2-2008
Ending. For the beginning, see the article “Is Cholesterol our friend or enemy? (Part 1)”
CHOLESTEROL DISEASESThe 1985 Nobel Prize in Medicine was awarded to two American scientists, Michael Brown and Joseph Goldstein, “For discovering the nature of regulating cholesterol metabolism in humans.”
These scientists, who worked at the University of Texas at Dallas, studied the genetic control of cholesterol intake into cells by endocytosis (the process of absorption by the cell) and discovered the existence of receptor proteins on the surface of cells to which lipoprotein particles (or lipoproteins, both terms are correct. — ed.) containing cholesterol. There is a very rare hereditary disease in which a person has defective genes that regulate the synthesis of cholesterol receptors. If a newborn has two such defective genes in the genome, one from the mother, the other from the father, that is, homozygosity for this anomaly, then the tissues of the body of such a child can almost not absorb cholesterol formed in the liver. This disease is fatal, a person dies before reaching the age of 20, partly from cholesterol deposits in various organs and arteries and partly from functional disorders. Cases of heterozygosity of this cholesterol anomaly are much more common, when a child receives a normal gene from one of the parents, and a defective one from the other. In this case, there are not enough receptors in human cells to bind and draw into the cells all those cholesterol lipoprotein particles that are formed in the liver. There is an excess of cholesterol in the bloodstream, and excess cholesterol, which is part of low-density lipoproteins (LDL) in fat, leads to early obesity, atherosclerosis, heart disease and other abnormalities. This genetic disease is called hypercholesterolemia. It is currently diagnosed in 0.2% of residents of Western countries, that is, one person for every 500 residents. But the fear of cholesterol arose long before the genetic nature of this relatively rare anomaly was discovered. With such a disease, the use of medications to actively reduce cholesterol levels is certainly necessary. However, until the mid-1990s, most anticholesterol drugs were ineffective, as they were developed to delay the absorption of dietary cholesterol from the intestine. At the same time, a broad campaign was launched to introduce low-cholesterol diets.
CHOLESTEROL IN THE DIET AND CHOLESTEROL IN THE BLOOD. LACK OF DIRECT COMMUNICATIONIn the 1970s and 1980s, many books were published with diets that, according to the authors, provided a reduction in cholesterol levels in the blood.
There is no need to discuss them here. We can only mention Robert Kowalski's American bestseller “8-week cholesterol treatment. How to reduce cholesterol in the blood by 40% without medication.” The author himself suffered from hypercholesterolemia and by the age of 40 had already suffered two heart attacks and surgery on the arteries. Not being a doctor, he developed for himself and recommended to all others the most severe low-cholesterol diet, which excluded eggs, butter, cheese and many other valuable products. Bacon, he said, “should be avoided as poison,” and only protein should be used in eggs. However, Kowalski's claims that he reduced his cholesterol from 284 mg per deciliter of blood to 169 mg only due to diet were incorrect. Simultaneously with the diet, he also took a large amount of nicotinic acid, or niacin — vitamin B3, a deficiency of which leads to pellagra. In large doses, niacin inhibits the synthesis of cholesterol in the liver and therefore leads to a decrease in its concentration in the blood. However, in these doses, niacin also acts on the metabolism of other lipids and can be toxic. In other widely advertised diets, not only meat and dairy products were limited, but also fish products. Sardines, herring, mackerel, shrimp and oysters contain about 100 mg of cholesterol per 100 grams, in some diets it was almost a daily minimum. (In international recommendations — from 200 to 300 mg / day. — ed.)
In Europe, with its long-established culinary traditions, all these diets were not successful, but in the USA they were taken more seriously. Recommendations here on diets were decided at the level of government commissions. So, in 1985, the American National Institute of Health, together with the American Association for the Treatment of Heart Disease, adopted strict dietary guidelines for Americans. They included the consumption of only skimmed milk, low-fat cheeses and reducing the consumption of eggs to two per week. At the same time, the reduction in fat consumption extended to children from the age of two. All these recommendations were supported by the results of 33 extensive clinical trials conducted over 20 years (involving tens of thousands of people). However, volunteers for such tests were selected not from “average” Americans, but from risk groups, most often from among those middle-aged citizens who had already had heart disease or suffered a heart attack or stroke. Following the recommendations in these risk groups prolonged life by 2-3 years. But the council of experts decided that since the benefits of the recommendations were noticeable in the risk groups, the rest of the population would also benefit if they followed the same restrictions. The argument was simple: if therapeutic nutrition is useful for patients, then it is also useful for healthy people with high cholesterol. In fact, this argument is controversial and has been criticized many times.
As a rule, in the West, national recommendations, popularized by the general press, are quickly reflected in the spheres of production and trade, which change their policies according to the demand of the population. In many Western countries, the production of eggs and animal fats decreased from 1982 to 1992.
The campaign launched by American medicine against cholesterol-rich products failed after in 1991, on March 28, the most authoritative American medical journal “The New England Journal of Medicine”, published in Boston and intended for a wide range of practitioners, published an article by Professor Fred Kern, an authoritative specialist in the USA in gastroenterology. The unusual title of the article — “Normal cholesterol level in the blood plasma of an 88-year—old man who eats 25 eggs a day” - immediately attracted attention. A summary of this article quickly appeared in many newspapers, as medical reporters of news agencies do not miss such unusual incidents. Professor Fred Kern was the head of the department at the University of Colorado. In 1990, he was informed about a man who, after the death of his wife, lived in a nursing home in Denver. Nurses bought him 20-30 eggs every day. He boiled them soft-boiled and ate them all day in addition to the rest of the food. According to his personal doctor, he followed this practice for at least 15 years, and according to friends — even longer. He was an intelligent and well-educated man. His height was 187 cm, weight 82 kg, and his overall physical condition was assessed as “excellent". The kidneys, heart and arteries had no abnormalities. The medical record showed numerous measurements of cholesterol, and all of them were within the normal range, from 3.88 to 5.18 millimoles per liter of blood or from 150 to 200 mg per deciliter — below the average American level. There were no genetic reasons for longevity, the egg lover's father died at 40, his mother at 76. An average-sized egg provides the body with 75 calories. 25 eggs gave 1,900 calories. In the USA, the “average American” in 1990 consumed about 3,600 calories per day. Each yolk contains 250-300 mg of cholesterol. The man to whom the article was dedicated consumed, thus, from 6250 to 7500 mg of cholesterol per day, 20 times more than the recommended maximum. Apparently, it even did him good.
Researchers were interested in: where does all the excess cholesterol go? The patient agreed to become a “guinea pig” for a while, and for two months small amounts of cholesterol labeled with radioactive carbon C-14 and radioactive hydrogen — tritium were added to his food. Together with the egg lover, 11 volunteers aged 30 to 60 years joined the experiment, who, however, agreed to consume no more than five eggs a day for 18 days. This gave them about 1,000 mg of extra cholesterol over the norm. There was also a control group that received a standard diet. The study took into account all fractions of cholesterol in low and high density lipoproteins.
The results of the experiments showed that neither an 88-year-old man who ate 25 eggs a day, nor those who ate 5 eggs a day, had an increase in the concentration of cholesterol fractions in the blood. According to the distribution of “labeled" cholesterol, it was found that excess dietary cholesterol reduced cholesterol synthesis in the liver by 20%. Basically, excess cholesterol was processed in the liver into bile acids and excreted through the gallbladder into the intestine. In the main patient who absorbed too much excess cholesterol, more than half of it was simply not absorbed in the intestine and was removed from the body along with the remains of undigested food. Since cholesterol is insoluble in water, its absorption in the intestine is a complex process. The digestive system could not cope with the assimilation of such surpluses, and cholesterol passed through it in transit, just like, for example, cellulose, or the fiber of mushrooms. Large excess fats, as is known, do not have time to be digested by the human digestive system.
The experiment led to simple conclusions: there are effective compensatory mechanisms in the body. Cholesterol, as we said, enters the blood in the form of complex lipoprotein particles. The rate of their formation is regulated at a certain level, which does not depend on the level of cholesterol in food. The intake of cholesterol to the tissue cells is in an optimal mode, regardless of our diet. In the USA, egg production increased by one million tons per year from 1991 to 2001. Whether it was related to Fred Kern's research or not is very difficult to determine. I tried to follow the subsequent research of this, of course, a major scientist. Unfortunately, he retired in 1993 and died in 1997 at the age of 78. But even one of his recent works discussed here has had a great impact on research on the role of cholesterol. In the next ten years, it was shown that cholesterol in the diet has no direct connection with the mortality of the country's population from cardiovascular diseases.
LONGEVITY AND CHOLESTEROL. GERONTOLOGICAL ADVICEAtherosclerosis is not a universal disease, and genetic factors play a role in its development.
A considerable number of centenarians demonstrate the absence of this disease. If there are no genetic prerequisites for cardiovascular diseases, elevated cholesterol levels are not a risk factor, especially since the level of cholesterol in the blood can vary quite widely depending not only on age, but also on gender and ethnic and racial differences. There are many studies in this direction, but I will touch here on only two works in which the objects of observation were really very old people.
Dutch gerontologists, who chose the whole city of Leiden as an object of observation in 1986, found that out of 105,000 residents of the city, 1,258 people, or 1.2%, were 85 years old or older. The average age of this group of centenarians was 89 years. For 10 years, from 1986 to 1996, blood tests for cholesterol were taken from each of the centenarians who remained alive. Patients were divided into three groups: with normal cholesterol, that is, less than 5 millimoles per liter of blood; with moderately elevated, from 5 to 6.4 millimoles, and with high, from 6.5 to 10.0 millimoles per liter. Since at the beginning of the experiment the average age of centenarians was 89 years old, in the next decade a little more than half lived to the age of 99. The rest died of cancer, cardiovascular diseases, infections and other causes. Mortality from cardiovascular diseases, expressed as a percentage, was the same in all three groups, high cholesterol did not affect it. However, mortality from cancer and infections is noticeably lower in groups with a high cholesterol content and decreased to a minimum in people with the highest cholesterol content. It was this group that had the greatest chance of living to 99 years. The researchers conclude that the level of cholesterol in the blood of old people is not a risk factor and that “the benefits of using drugs to lower cholesterol in old people can be questioned.” Elevated cholesterol, as it turned out, activates the immune system, which in turn increases resistance to infections and reduces the likelihood of carcinogenic processes.
In a second study conducted in France, a group of elderly women who lived in nursing homes were selected to determine correlations between blood cholesterol levels and mortality. The average age of the patients at the beginning of the experiment was 82.2 years, and their cholesterol concentration ranged from 4.0 to 8.8 millimoles per liter of blood. The observations were carried out over five years, during which 53 out of 92 women died. Mortality was maximal in patients with low cholesterol and minimal in women with a relatively high cholesterol content in the blood, which was 7 millimoles per liter. The authors suggest that an increase in cholesterol in the blood of old people contributes to the stabilization of the physical and chemical characteristics of cell membranes. The use of drugs to reduce cholesterol can only have a negative effect in this case.
The concentration of cholesterol in the blood, in the fractions of lipoproteins with both low and high density, is not stable and changes with age. Since longevity, in addition to many reasons, is inherited in family lines, that is, it is controlled genetically, it is worth mentioning the study of a group of Austrian and German gerontologists who tried to find a correlation between hereditary “family” longevity and the level of different fractions of cholesterol in the blood. In one of these family groups, life expectancy was low, about 70 years, in the other — 91 years and reached 98 years. No correlation was found between longevity and the level of cholesterol fractions in the blood. Both in the first and in the second group (in one there were 109, in the other 103 people) very wide variations of all fractions of cholesterol were observed.
ANTICHOLESTEROL THERAPYBy the end of the 1990s, the simplified cholesterol theory of mortality from cardiovascular diseases was no longer shared by most gerontologists and experimental cardiologists.
But it was by this time that many large pharmaceutical companies finally developed effective drugs from the group of statins that inhibited the key enzyme of cholesterol synthesis. The development of such drugs requires at least ten years, the cost of hundreds of millions of dollars and dozens of clinical trials with thousands and even tens of thousands of people. The pharmaceutical industry was ready to treat millions of people. Meanwhile, scientific data indicated that active treatment is necessary only for a limited contingent of patients with hypercholesterolemia, and the identification of potential patients required additional genetic family analyses. But a powerful statin industry has already been launched. Pfizer Lipitor was the first to appear on the market, and by 2002, its prescription sales revenues exceeded $10 billion in the United States alone. Almost simultaneously, the Merck, Sharp and Dome (MSD) Zokor went on sale, it was sold for $ 9 billion. The AstraZeneca company started producing Crestor with some delay, but by this time there were stable signs of adverse reactions from the effects of these drugs, and their mass release to the medical market slowed down somewhat. In 15% of patients who regularly take Zocor, muscle pain appeared, accompanied in some cases by their atrophy. Statins were banned for pregnant women, as they sometimes led to abnormalities of embryonic development. A sharp decrease in cholesterol in the blood led to a weakening of memory and the appearance of aggressiveness. The use of statins weakened immune functions. The enzyme, which was inhibited by statins, turned out to be necessary not only for the synthesis of cholesterol, but also for many other functions. The control figures of the normal level established by WHO did not take into account possible national differences. Norwegian doctors were the first to rebel against these standards. In this country, which had the best population health indicators in Europe, according to the instructions of the World Health Organization and the European Union (WHO and the EU), 90% of the entire population over 45 years old was enrolled in the risk group for high cholesterol. Taking fairly expensive statins by almost half of the population of Norway, which has free healthcare, was beyond the power of this petrodollar-rich country. Even among Norwegians under the age of 20, 40% were at risk for cardiovascular diseases. In the United States, statin treatment was supposed to be extended to 36 million people this year.
CHOLESTEROL AND LONGEVITYIn December 2006, quite recently, there was a new “cholesterol” sensation that threatens the multibillion-dollar statin business.
Created earlier “The Longevity Genes Project decided to study the ”cholesterol profile" of centenarians — people who have lived for more than 100 years. This project, initiated by the Albert Einstein College Institute of Aging in the USA, surveyed 158 people in Europe, mostly Jews, the genetically most homogeneous ethnic group, aged 95 to 105 years. As it turned out, all these centenarians had an increased content of “bad” cholesterol, localized in very large cholesterol particles, chylomicrons. Additional studies of European Jews aged 75 to 85 years found a clear correlation between the content of large lipoprotein particles in the blood and the preservation of intellectual abilities in old age. The results of the research, published in the journal “Neurology” of the American Federation of Neuropathologists on December 26, 2006, caused a sensation in many newspapers and television reports. Some medications designed specifically to selectively reduce this previously considered “bad" fraction of cholesterol are in development. Pfizer, which intended to release a new drug, is delaying its production for the time being. A company representative explained this decision as follows: “People want to preserve their intelligence in old age and prevent Alzheimer's disease, even if it is associated with a slight increase in risk to the heart.”
The synthesis of this large lipoprotein particle was controlled by a special gene, which was called the SETR code, and in print — the longevity gene.
In this case, the large pharmaceutical business faced common sense. In the USA in 2003, the cost of drug consumption exceeded the cost of food consumption. Mass medical psychosis, which began with cholesterol phobia, can only be cured by time.
Specialist's commentIT'S ALL ABOUT THE CLASSES OF LIPOPROTEINS
Professor N. PEROVA (Federal State University “State Research Center for Preventive Medicine of Rosmedtechnology").
In the article Zh . Medvedev touched upon a number of both the most interesting and controversial issues about the role of cholesterol. Cholesterol is a substance that is vital for a person and at the same time a risk factor for cardiovascular diseases and mortality from them. Those caused by atherosclerotic lesions of the walls of blood vessels, including the heart and brain. This has been proven in many experimental, clinical and epidemiological studies. But they also prove that the amount of cholesterol that is synthesized in the body is quite enough for a person to perform basic functions. Most of it is formed in the liver, and with food it is enough to consume 200-300 mg per day. Cholesterol, as a fat-like substance, is transferred to tissues in aqueous media, primarily in blood plasma, as part of a complex system of lipid—protein complexes — lipoproteins (lipid — fat, protein - protein). Zh. Medvedev in his article calls them chylomicrons, but this name refers only to one class of the largest lipoproteins, which are formed in intestinal cells. They include in their composition dietary cholesterol, absorbed from the intestinal lumen. Chylomicrons are carriers of “exogenous” lipids coming into the body from the outside. In the liver, lipoproteins are formed mainly from lipids synthesized in it, including cholesterol. These are very low density lipoproteins (LDL — VLDL). Low—density lipoproteins (LDL — LDL) are formed in the bloodstream from them after the breakdown of triglyceride fats. They are the most dangerous in terms of the development of atherosclerosis (the most atherogenic).
A healthy person has a harmonious cholesterol metabolism system. But it often fails — the number of lipoproteins of certain classes changes dramatically: there are a lot of low—density lipoproteins (LDL) transporting cholesterol into tissues, in particular into the walls of blood vessels, and the number of high-density lipoproteins (HDL - HDL) carrying cholesterol out of tissues, including blood vessels, decreases. Then cholesterol accumulates inside the vascular wall — one of the components of the atherosclerotic plaque. It is with such disorders, usually accompanied by an increase in the level of total cholesterol in the blood, that it becomes one of the main risk factors for atherosclerotic cardiovascular diseases. Atherogenicity of cholesterol in the blood may have one or more reasons: excessive consumption of animal fatty foods, increased synthesis of cholesterol in the liver, decreased activity of receptor proteins involved in the removal of atherogenic LDL from the bloodstream, a genetically determined or acquired change in the number of protein enzymes involved in its metabolism. For example, cholesterol esters with fatty acids are formed, proteins transferring cholesterol esters between lipoproteins of different classes, say a protein transferring cholesterol esters, mentioned by J. Medvedev as SETR.
Moreover, the level of cholesterol in the blood is only one of many risk factors for the development of atherosclerosis and related cardiovascular diseases. To a greater extent, a combination of several, even moderately pronounced risk factors plays a role: high blood pressure, smoking, the presence of cardiovascular diseases (especially deaths from them) in relatives of the first degree of kinship, obesity, diabetes mellitus and many others.
However, in large, multi-thousandth, multicenter, placebo-controlled, long-term studies (see “Science and Life” No. 11, 2007), it has been proven that it is possible to reduce cholesterol levels in the blood by changing the diet, increasing physical activity, quitting smoking and using medications (mainly statins). This, in fact, is also said by Zh. Medvedev. The effect mainly on LDL cholesterol leads to a decrease in new cases of the disease in still healthy people and acute complications in patients with cardiovascular diseases, to a decrease in mortality from them. This is considered the main victory of medicine of the twentieth century. The results of such programs, deployed in a number of countries at the national level and showing a 50% reduction in mortality from cardiovascular diseases over 30-35 years (Finland, USA, etc.), are particularly indicative.
Indeed, as J. writes. Medvedev, the programs that demonstrated the documented benefits of reducing elevated cholesterol levels in the blood usually included people under 75 years of age. After all, at an older age, many other diseases accumulate (leading to the death of deeply elderly people). And the given Zh . Medvedev's examples of studies on centenarians include small groups or isolated cases, so the question of indications for lowering cholesterol in old age remains unresolved.
Portal "Eternal youth" www.vechnayamolodost.ru
04.05.2008