Is cholesterol our friend or enemy? (Part 1)
Zhores Medvedev
"Science and Life" No. 1-2008
An article came to the editorial office from London by mail. The author is a well–known biochemist, writer J.A. Medvedev. Zhores Alexandrovich has been engaged in gerontology for the last decades – the medicine of an aging organism. The article is part of a future book, and, as the author writes, it is the most polemical of the other materials. And the topic is very important. "Science and Life" has addressed the question of the role of cholesterol in the development of cardiovascular diseases many times. But here you have a completely new look, summarizing many of the discoveries of recent years.
When are statins needed?In England, a local polyclinic makes a complete blood test every year for elderly people, the results of which are sent to the attending physician for many indicators.
Every citizen has an attending physician, a "general practitioner". In case of any problems, he sends his patient to the hospital or prescribes prescriptions himself if the disease is trivial enough: hypertension, insomnia or simply arthritis.
My annual blood tests have remained without consequences for many years, and therefore I was somewhat surprised when I received a letter from the polyclinic. I give it here in translation:
"February 16, 2005
Dear Mr. Medvedev,
a recent blood test showed that your cholesterol level is really very high, 7.6 millimoles, and your PSA is also elevated. I would be grateful if you would come to the appointment and we will discuss treatment measures.
Dr. S. Thwaites".
PSA is an indicator of the concentration of protein released into the blood by the prostate gland. Its increase may indicate an increase in the size of this gland, a tumor, and even cancer. Only an additional examination, including tomography and biopsy, taking tissue samples, which is already carried out in a special clinic, can determine the cause more accurately. This examination was quickly done and found, to my relief, only an increase in the size of the gland, which is a common age-related change and does not require treatment. The cholesterol index was really high; the norm in England is 4.5 millimoles, or 200 mg per 100 ml of blood. In my case, the cholesterol content in the blood was 334 mg per deciliter, and I received a prescription for a drug called "lipitor" or "atorvastatin", 20 mg tablets for daily intake. The detailed instructions indicated that lipitor reduces cholesterol in the blood and, consequently, the risk of cardiovascular diseases. Numerous side effects have also been mentioned, but the mechanism of action of this statin has not been explained. I already knew that statins, a new series of very popular drugs, are inhibitors of liver enzymes that synthesize cholesterol and form lipoprotein complexes, in the form of which cholesterol enters the blood and spreads through tissues, performing various functions.
As a professional gerontologist, I do not take medications without first reviewing the scientific literature on their effectiveness for people of my age. Most clinical trials of drugs, including statins, are conducted on middle-aged people who most often have certain "risk factors": hypertension, atherosclerosis, heart disease, etc. Evaluating the effectiveness of a drug in such a case requires from 5 to 10 years and is determined for people with high cholesterol by the number of strokes or heart attacks in the experimental and control groups. In the control groups, people receive a so-called placebo, the same pill, but without the active substance. (In many cases, a drug for the same disease, but with proven efficacy, is used as a comparison drug. – Editor's note) A clinical trial, in which thousands of volunteers often participate, should be "blind": no one, neither the patients, nor the doctor or nurses themselves, knows which of the participants receives a placebo, and who is the actual medicine. This is known only by the computer, which analyzes the results after the end of the test. Since such tests have been going on for many years, people over the age of 70 are usually not accepted as volunteers. They have a lot of other problems without cholesterol. But academic research studies the effects of various drugs on people of all ages. In gerontological studies, of course, they study the effect of drugs on people of the oldest age.
As the results of relatively recent studies have shown, attempts to reduce the level of cholesterol in the blood with statins in middle-aged people really reduce the risk of cardiovascular diseases. On the contrary, an attempt to reduce cholesterol in the blood in the same way, but in people aged 75-85 years, leads to an increase in their mortality. At the next appointment, I brought my doctor several articles from gerontological journals, emphasizing the authors' conclusions about the results of comparative studies:
"Cholesterol metabolism in old people over the age of 75 has been little studied... the earlier a patient of this group begins to reduce the concentration of cholesterol in the blood, the higher the risk of death." In another paper published in 2004, the conclusion is even clearer: "It was shown that in older patients, aged 70-82 years, statin therapy did not reduce, but increased the frequency of fatal and non-fatal heart attacks and strokes." In a fairly large group of old people, residents of Italy, who were examined by the authors of the article for several years, high mortality correlated with low, not high cholesterol.
Doctors, as you know, do not like it when their patients argue with them. But my doctor knew that she was dealing with a gerontologist, and did not insist on treatment. The healthcare budget only benefited from this, since the patient in the UK receives medicines for free according to prescriptions. The logic of gerontology in this case is simple. If a person has lived for 80 years without complaints about the heart and arteries, it is better not to interfere with the usual balance of functions. Only specific diseases should be treated.
Statins were introduced into widespread practice and prescribed to millions of patients after 5-7 years of clinical trials in the period 1985-1995 on very large groups, mainly 50-60 years of age, since this age accounts for the main risk of cardiovascular diseases. However, now, 10-12 years after these trials, when former patients who continue to take statins become pensioners of 70-80 years of age, it is found that such long-term statin therapy weakens memory, increases the risk of Parkinson's disease and increases the incidence of Alzheimer's disease. This result cannot be considered unexpected, since cholesterol is primarily important for the functions of the brain and nervous system. Reducing the risk of diseases of the elderly, the hasty introduction of mass chemical therapy, fueled by commercial advertising, increased the risk of chronic and incurable diseases of later age.
Physiologically and biochemically, the human body is such a precisely and finely coordinated system that prolonged intervention in one or another natural life process cannot remain without various, often unexpected consequences. Statins act on the liver by inhibiting certain enzymes of cholesterol metabolism. From this, the blood vessels of people with a sedentary lifestyle and moderate to severe obesity benefit for some time. But in the end, this interference with the physiological system, becoming permanent, disrupts the much more complex mental abilities of people at a later age. But this no longer worries those pharmaceutical companies that produce and sell statins: the world trade in them in 2007 exceeded $ 40 billion.
The physiological role of cholesterolCholesterol appeared in evolution together with animal cells hundreds of millions of years ago.
Plant cells are covered with two shells: one is a delicate lipid–protein, the other is a strong cellulose. Animal tissue cells have only one shell, but the strength of the lipid-protein membrane was not enough, especially for tissues with mechanical functions and for "wandering" cells, such as lymphocytes and erythrocytes. It is cholesterol molecules that give the necessary strength to the cell membranes of animals. The structure of their molecules is such that they can be embedded between the hydrocarbon chains of fatty acids of cell membranes and "cement" the lipoprotein film. Among the different mammalian cells, the most durable are the non–renewable shells of erythrocytes. These cells have the shape of a concave disk, which ensures their maximum surface relative to the mass. Red blood cells are pushed under pressure through the thinnest capillaries, colliding with their walls in narrow places. In the arteries, they constantly collide with each other, being subjected to pressure from contractions of the heart muscle. This goes on for many weeks, since the synthesis of new molecules in red blood cells does not occur, they are deprived of the nucleus and other cellular organelles and are filled only with hemoglobin. It is for the strength of the erythrocyte shells that they contain 23% cholesterol, which is more than the shells of other cells need. In the membranes of liver cells, the cholesterol content is about 17%. In the membranes of intracellular structures, for example, mitochondria, the cholesterol content does not exceed 3%. The myelin multilayer coating of nerve fibers, which performs insulating functions, consists of 22% cholesterol. The white matter of the brain contains 14% cholesterol, and the gray matter of the brain contains 6%. Bile acid salts are formed from cholesterol in the liver, without which it is impossible to digest fats. In the sex glands, cholesterol is converted into steroid hormones, testosterone and progesterone, which have a structure of molecules similar to cholesterol. In the adrenal glands, the derivative of cholesterol is the hormone cortisol. In the female ovaries, estradiol is formed from cholesterol. Cholesterol is important for kidney cells, spleen and for bone marrow functions. Vitamin D is formed from cholesterol in the skin under the influence of light, which saves people from rickets.
Cholesterol and atherosclerosisMost people know about cholesterol from popular literature only that it supposedly causes atherosclerosis.
In fact, atherosclerosis is a very complex disease and has many different forms. The appearance of cholesterol in atherosclerotic plaques is a secondary process. The cholesterol theory of atherosclerosis is not shared by many biochemists, physiologists and gerontologists. Atherosclerosis under a variety of conditions can occur with a low cholesterol content in the blood and, conversely, may be absent in people with a high cholesterol content.
In the annual reports of the UN World Health Organization (WHO) on the health status of the population in all countries of the world, among the numerous mass risk factors such as smoking, drugs, alcohol, pollution of water sources, immunodeficiency and hepatitis B viruses, hunger, vitamin deficiency and others, cholesterol is also mentioned, a completely normal component of our body, necessary for the functions of many organs, and an unavoidable component of a daily diet. According to one of the latest WHO reports, "cholesterol is a key component in the development of atherosclerosis... an increase in cholesterol in the blood accounts for 18% of all cases of cardiovascular diseases and is the direct cause of 4.4 million deaths annually ..." The WHO associates annual mortality with smoking at the same level, and with alcoholism - only 1.8 million deaths. This "demonization" of cholesterol is completely wrong. No biologist can agree that cholesterol, an important component of the normal physiological activity of all animals, from the lowest to the highest, turned out to be such a dangerous substance for humans.
The cholesterol theory of atherosclerosis was first expressed by Nikolai Anichkov, then a young 26-year-old pathophysiologist, at a meeting of the Society of Russian Doctors in St. Petersburg on October 25, 1912. The author reported that when a solution of cholesterol in oil is injected into the digestive tract of rabbits for a long time, changes in the form of cholesterol deposition in the arteries and in some internal organs characteristic of the initial stages of atherosclerosis can be detected. This effect was, however, reversible when the rabbits returned to their usual plant food. The results of experiments that have been reproduced many times cannot be directly transferred to humans. Rabbits, as purely herbivorous animals, do not have systems for processing dietary cholesterol. Their cholesterol metabolism is fully provided by their own synthesis of cholesterol in the liver. Atherosclerosis in rabbits is also not a typical age-related pathology. The results obtained on rabbits could not be reproduced in experiments on dogs.
In the following years and decades, thousands of studies have been conducted on the possible connection of cholesterol levels in food with cholesterol levels in the blood. The results were extremely contradictory and did not lead to dietary recommendations. A more hostile attitude towards dietary cholesterol began to appear in the late 1960s due to the fact that in Western countries, along with an increase in animal products in the diet and an increase in life expectancy, there was an increase in the relative proportion of cardiovascular diseases in the overall mortality statistics. In the USA in 1983, 413 people died of cardiovascular diseases for every 100 thousand people, in the UK - 579, in West Germany – 585. Although there are a lot of reasons for cardiovascular diseases and in addition to cholesterol, the official explanations for the increase in mortality from cardiovascular diseases were mainly reduced to diets. It was during this period that recommendations were made about increasing carbohydrate components in diets. For 10 years in the USA and in the UK, the proportion of "meat" calories in the diet decreased from 20 to 14%, while the proportion of "cereal" calories increased from 18 to 22%. Fat calories were still at a very high level – 40%, but they shifted almost half towards vegetable fats. These dietary changes have led to some reduction in mortality from cardiovascular diseases, but not too significant. In the UK in 1999, 501 cases of cardiovascular mortality were registered for every 100 thousand people, in the USA – 350. The bulk of this decline was, of course, due to the progress of medicine, and not to diets. In France, where there was no reduction in the proportion of animal products in the diet during this period, the incidence of cardiovascular diseases decreased by 30%.
Such an indirect approach to assessing the increase or decrease in mortality from cardiovascular diseases and an attempt to explain the observed changes by diets are anti-scientific. In the same decade, from 1989 to 1999, in all the republics of the former USSR and in all the countries of Eastern Europe, there was a significant reduction in the proportions of high-quality animal products in the diet of the population and, accordingly, a decrease in cholesterol consumption. In the Russian Federation, egg production has decreased by 20% over the decade, milk by 35%, and meat by 40%. Meanwhile, mortality from cardiovascular diseases in the same period increased from 560 to 749 cases for every 100 thousand people. Ukrainians in 1999 consumed two times less cholesterol with food than residents of Germany. But in terms of cardiovascular diseases, they were also twice ahead of the Germans. In terms of consumption of animal products, Bulgaria was in last place in Europe in 1999. However, in terms of mortality from cardiovascular diseases, it was Bulgaria that held the European record during this period. These examples show that atherosclerosis, with the whole complex of diseases associated with it, is not so much a "cholesterol" disease as a socially stressful disease. By 2003, the incidence of atherosclerosis in Europe was highest in Romania and Moldova. This epidemic of atherosclerosis in Eastern Europe is associated with socio-economic, not dietary factors.
Cholesterol metabolism and ageCholesterol molecules, substances with the general formula C27H46O, can be synthesized by almost all cells from simpler organic components.
However, for complex structural functions, such as nerve tissue or bone marrow, cholesterol is formed in the liver and delivered to different body tissues through the circulatory system. Cholesterol is insoluble in water and is therefore transported through the circulatory system as part of spherical lipoprotein particles – chylomicrons. Cholesterol molecules are located inside such a micro-ball in a fat solution. There are special receptor proteins on the cell surface, which, interacting with a large chylomicron protein molecule, include a special process of chylomicron absorption by the cell – endocytosis. All such processes occur dynamically as self-updating. The chylomicrons formed in the liver are delivered to the cells, but other chylomicrons formed inside the cell are removed from it by the processes of exocytosis (release of substances by the cell), are delivered to the liver, where they are included in the process of formation of bile acids, and are eventually removed from the body. In animal organisms, the removal of waste, but water–soluble products occurs mainly through the kidneys, and insoluble in water - through the intestines. Lipoprotein particles, which are formed in the liver and delivered through the blood to the tissues, are relatively large; they come in two sizes – from 425 to 444 angstroms and from 208 to 237 angstroms. They are often referred to as "very low and low density lipoproteins". Very small chylomicrons with a diameter of 106 to 124 angstroms are transported from cells and tissues back to the liver. Since their surface-to-volume ratio is much higher, they are designated as high-density lipoproteins. These three types of cholesterol particles are known in popular literature as "bad" cholesterol, which goes from the liver to the tissues, and as "good" cholesterol, which is removed from the tissues. In fact, there are not three, but many more forms and varieties of lipoprotein particles circulating in the blood. Different tissues have their own specific features in cholesterol metabolism. In medical research, the determination of total cholesterol in the blood and separate measurements of cholesterol from lipoprotein particles with very low (VLDL), low (LDL) and high (HDL) density are accepted. These analyses are not simple and require many procedures. A total survey of the population for the level of cholesterol fractions, and starting from the age of 20, is carried out only in the USA.
(To be continued.)Portal "Eternal youth" www.vechnayamolodost.ru