103 HOW TO LIVE LONGER AND FEEL BETTER
Chapter 10
Biochemical Individuality
The genetic mutation that deleted the capacity to manufacture vitamin C in the primate line presents one vivid example of the countless genetic variations from which natural selection produced the diversity of biological organisms we know in the world today. Such biochemical insight permits us to see evolution, as it were, from the inside. It gives a quantitative measure of the wealth of differences among individuals within a single species upon which natural selection acts in choosing the "fittest." It shows each of us human beings to possess a biochemical individuality that is scarcely expressed in (but only partly accounts for) the differences we observe in one another.
Let us consider some genetic characteristic, such as the weight of the liver relative to the total weight of the human being or the concentration of a certain enzyme in the red cells of the blood. It is found that, when a sample of a hundred human beings is studied, this characteristic varies over a wide range. The variation often is approximately that given by the standard, bell-shaped probability function. It is customary to say that the "normal" range of values of the characteristic is that range within which 95 percent of the values lie and that the remaining 5 percent of the values, representing the extremes, are abnormal. If we assume that five hundred characteristics are independently inherited, then we can calculate that there is only a small chance, 3 percent, that one person in the whole population of the world would be normal with respect to each of these five hundred characteristics.
It is estimated, however, that a human being has a complement of one hundred thousand genes, each of which serves some function, such as controlling the synthesis of an enzyme. The number of characteristics that can be variable, because of a difference in the nature of a particular gene, is presumably somewhere near one hundred thousand rather than only five hundred: and accordingly we reach the conclusion that no single human being on earth is normal (within the range that includes 95 percent of all human beings) with respect to all characteristics. This calculation is, of course, oversimplified. It helps emphasize, however, that human beings differ from one another and that each human being must be treated as an individual, biologically as well as morally.
The species Homo sapiens is more heterogeneous, with respect to genetic character, than most other animal species. Nevertheless, heterogeneity has been found also for laboratory animals such as guinea pigs. It was recognized long ago that guinea pigs fed the same scurvy-producing diet, containing less than 5 milligrams (mg) of ascorbic acid per day per kilogram of body weight, differed in the severity of the scurvy that they developed and in the rapidity with which they developed it. A striking experiment was carried out in 1967 by Williams and Deason. These investigators obtained some male weanling guinea pigs from an animal dealer. After a week of observation during which the guinea pigs were on a good diet, including fresh vegetables, they were placed on a diet free of ascorbic acid or with known amounts added. They were divided into eight groups, each of ten to fifteen guinea pies, with one of the groups receiving no ascorbic acid and the other groups receiving varying amounts through a pipette into the mouth. About 8O percent of the animals receiving no ascorbic acid or only 0.5 mg per kilogram per day developed signs of scurvy, whereas only about 25 percent of those receiving between 1 mg and 4 mg per kilogram per day, and none of those receiving 8 mg per day or more, developed these signs. These results agree with the customary statement that about 5 mg per kilogram per day of ascorbic acid is required to prevent scurvy in guinea pigs.
It was observed, however, on the one hand, that two animals receiving only 1 mg per kilogram per day remained healthy and gained weight over the entire period of the experiment (eight weeks). One of them showed a total gain in weight larger than that for any animal receiving two, four, eight, or sixteen times as much ascorbic acid.
On the other hand, seven of the guinea pigs receiving 8, 16, or 32 mg per kilogram per day were unhealthy and showed very small growth during the first ten days on the diet. They were then provided with a larger amount of the vitamin, five of them with 64 mg per kilogram per day and two of them with 128 mg per kilogram per day. These animals showed a remarkable response: whereas they had grown only 12 grams (g), on the average, in a period of ten days on the smaller amounts of ascorbic acid, their growth during the ten-day period after beginning to receive the larger amounts was, on the average, 72 g. The indicated conclusion is that these animals, seven of the thirty that were given between 8 mg and 32 mg per kilogram per day, required more vitamin C for good health than the others. Williams and Deason (1967) reached the conclusion that there is at least a twentyfold range in the vitamin-C needs of individual guinea pigs in a population of a hundred. They pointed out that the population of human beings is presumably not more uniform than that of the guinea pigs used in their experiments and that accordingly the individual variation in the vitamin-C needs of humans is probably just as great.
I have accepted their conclusion, and similar conclusions reached by other investigators, in suggesting that the optimum rate of intake of ascorbic acid by human beings may extend over a wide range, perhaps the eightyfold range from 250 mg per day to 20 g per day or an even wider range.
Vitamin C has been under investigation, reported in thousands of scientific papers, ever since it was discovered fifty years ago. The reader of this book might well be justified in asking first, why the range of values of the optimum intake of this important substance was not reliably determined long ago and, second, why no one can tell him or her what amount to take to be in the best of health. Part of the answer to the first question is that only a very small amount of the vitamin, perhaps 10 mg per day, is enough to keep most people from developing scurvy, and physicians and nutritionists accepted the idea that no larger amount is needed. Even though some physicians had observed forty or fifty years ago that amounts a hundred or a thousand times larger have value in controlling various diseases, as described elsewhere in this book, the medical profession and most scientists ignored the evidence.
Another part of the answer to this first question is that studies that would yield the answer can be carried out only with great effort and at great expense. It is much easier to investigate some powerful drug that has an immediate beneficial effect on the patient (although it is harder to check the possible long-term damage that the powerful drug may do to some fraction of the people for whom it is prescribed). Several excellently planned and executed epidemiological studies involving nutritional and other factors in relation to the incidence of disease and the chance of death at various ages has been carried out. In sonic of these studies the nature of the ingested food has been tabulated, and the amounts of vitamin C and other vitamins in the diet have been calculated using tables giving the vitamin contents of various foods. Some of these studies show that the incidence of disease and the chance of death at each age are less for people with a larger intake of vitamin C (and also for some other vitamins) than for those with a smaller intake. In these studies, however, the intakes of vitamin C are small; usually, for example, mg to 50 mg per day for the low-intake group and between 50 mg and 100 mg for the high-intake group.
In their San Mateo County, California, study, Lester Breslow and his colleagues in 1948 interviewed 577 randomly selected residents of the county who were fifty years old or older. They obtained much information about their state of health and about environmental, behavioral, and nutritional factors that might affect it. After seven years they examined the death records and compared the age-corrected death rates for the subpopulations related to the different factors. Of all of these factors, the intake of vitamin C was found to have the greatest correlation with the age-corrected death rate, even greater than that for cigarette smoking (Chope and Breslow, 1955).
Whereas cigarette smokers have at each age twice the chance of dying that a nonsmoker has, the persons with a lower intake of vitamin C (calculated from the content of vitamin C in the food that they ate) had a chance of dying 2.5 times greater than the persons with a higher intake of the vitamin. The amount of illness was also correspondingly greater. This difference means that the length of the period of good health and of life was ten years greater for the persons with the higher intake than for those with the lower intake of vitamin C. The dividing line was 50 mg per day, approximately equal to the recommended dietary allowance. The average intake of the low-intake group was 24 mg per day and that of the high-intake group was 127 mg per day.* [*These averages are calculated on the assumption that the distribution of intakes for each of the two groups is the same as that for the corresponding groups (age over sixty) in the First Health and Nutrition Examination Survey. 1971-72 (Abraham. Lowenstein. and Johnson, 1976)] It is interesting that drinking a large glass of orange juice each day (about 90 mg of ascorbic acid in 6 ounces of juice) or taking a 100-mg tablet each day would put a person in the high-intake group.
Part of the improvement in health in the high-intake group may be attributed to other substances in the foods that provided the extra vitamin C. There is no doubt that orange juice, lettuce and other vegetables, and fruits contain important nutrients in addition to vitamin C. But the effect of a higher intake of vitamin A in improving the health was found in the San Mateo study to be only half as great as that of vitamin C, and the effect of niacin, one of the B vitamins, was only one-quarter as great. The foods with a high content of vitamin A and niacin, although they have value in improving the health, are not so valuable as those with a high content of vitamin C.
When vitamin C is taken by mouth, most of it is absorbed into the blood through mucous membranes of the mouth and the upper part of the small intestine. If the amount taken is rather small, up to 250 mg, about 80 percent is absorbed into the blood. With larger doses the amount absorbed is less, about 50 percent for a dose of 2 g and still smaller for larger doses (Kubler and Gehler, 1970). Accordingly it is more economical to ingest vitamin C in smaller doses, such as 1 g every three hours, than to take a single, much larger dose once a day. Also, a quantity of sodium ascorbate injected into the bloodstream is more effective in the treatment of disease than the same amount taken by mouth.
For a small daily intake of ascorbic acid, up to about 150 mg, the concentration in the blood plasma is nearly proportional to the intake: this concentration is about 5 mg per liter for a daily intake of 50 mg, 10 mg per liter for 100 mg, and 15 mg per liter for 150 mg. Above an intake of 150 mg per day the concentration in the blood increases much less with increasing intake, reaching about 30 mg per liter for an intake of 10 g per day (ascorbic acid plus dehydroascorbic acid: Harris, Robinson, and Pauling, 1973).
The reason for this change when the intake exceeds about 150 mg per day is that a larger amount of the vitamin then begins to be excreted in the urine. One of the functions of the kidney is to clear the blood of unwanted and harmful molecules, the molecules of toxic substances that have got into the blood through the food or impure air or of waste products such as urea, the compound of nitrogen that is formed when old protein molecules in the body are degraded. Every twenty minutes the entire volume of the blood passes by a set of molecular filters in the two million glomeruli of the kidney. In the glomeruli the capillaries through which the blood is flowing have small holes in them. These holes, the pores of the glomerular filter, are small enough that the protein molecules in the blood, such as the antibodies (globulins) that protect us against disease, cannot pass through them, but water molecules and other small molecules, such as those of blood sugar (glucose) and ascorbic acid, can pass through. The blood pressure operates to push part of the water of the blood, together with its burden of small molecules, through these pores into a surrounding capsule.* [*A seriously ill person or a person in shock may have such low blood pressure that he cannot produce any urine.] The glomerular filtrate, with its dilute urine, is produced in amounts of about 180 liters (1) per day, thirty-six times the volume of the blood itself. We cannot stand to lose so much water, and fortunately there is a mechanism to concentrate the urine to the usual volume of one or two 1 a day. As the glomerular filtrate moves along through tubules toward the vessels that carry the urine to the bladder, molecular pumps in the walls of the tubules transfer most of the water back into the bloodstream.* [*The process of concentrating the unne is regulated by the antidiuretic hormone, which is secreted hv the pituitary gland Some people develop I rather rare illness, diabetes insipidus, involving an insufficient output of this hormone; their unne volume may reach 40 liters per day. requiring them to drink an equal amount of water] The blood sugar is valuable as a fuel for the body, and it would not be good to lose it. Accordingly, there are special tubular pumps to pump the glucose molecules back into the blood. There are also special pumps for other important molecules, including those of vitamin C.
This is fortunate, because if the process of tubular reabsorption of vitamin C did not operate, even a big dose of the vitamin would be nearly completely excreted in an hour or two. In fact, a person who ingests 100 mg per day excretes only about 10 mg in the urine. As discussed in Chapter 7, the necessity of conserving our supply of ascorbic acid arose when our ancestors lost the ability to synthesize it and we were required to depend on what we could obtain in our food. We have developed the mechanism of tubular reabsorption to such an extent that it works nearly perfectly (pumping 99.5 percent of the ascorbate in the glomerular filtrate back into the bloodstream) until it reaches the limit of its pumping capacity. This limit is reached when the concentration in the blood plasma equals about 14 mg per liter, corresponding to a daily intake of about 140 mg.
On the one hand, when the discovery was made that at higher intakes than 140 mg per day a greatly increased amount of vitamin C is excreted in the urine, the idea developed that at 140 mg per day the tissues of the body are saturated with the vitamin and are beginning to reject any additional amount. Although this idea is false, it continues to be advanced in the medical and nutritional literature, and the intake of 140 mg per day, corresponding to the so-called tissue saturation, is considered to be an upper limit to the amount of vitamin C required for 'ordinary good health."
An argument similar to those developed in Chapter 9, on the other hand, leads us to the conclusion that this intake, at which the tubular pumps reach their capacity, is a lower limit to the optimum intake (Pauling, 1974). Let us compare a tubular pump for ascorbic acid that pumps until the concentration of ascorbic acid in the blood is 14 mg per liter with one that operates only until concentration is 13 mg per liter. The second pump is 7 percent smaller than the first and requires 7 percent less energy, which is provided by the food that we burn as fuel, for its operation. The smaller pump would accordingly be less of a burden to us than the larger one. Then why should we have developed the larger pump? The answer surely is that we need the larger pump to conserve the extra 7 percent of vitamin C. Hence the limit to which tubular reabsorption has been developed represents a lower limit to the optimum intake of vitamin C. This lower limit is more than twice the Recommended Daily Allowance (RDA) set by the Food and Nutrition Board.
If a large amount of vitamin C is taken, 62 percent of the amount that enters the bloodstream is excreted in the urine, so that only about 38 percent remains in the body to carry on its valuable functions. It is, however, good to have vitamin C in the urine. It protects against urinary infections and also against cancer of the bladder, as will be shown in Chapter 19.
Moreover, that fraction of a large dose of vitamin C taken by mouth that remains in the intestines has value. DeCosse and his coworkers studied the effect of 3 g per day of ascorbic acid in controlling the growth of adenomatous polyps of the rectum in people who have inherited the tendency to develop them (1975). This polyposis is serious because the polyps usually develop into a malignant cancer. In a group of eight patients, the polyps regressed completely in two and partially in three.
The appearance of vitamin C in the urine has been used by nutritional authorities as an argument against a high intake. Dr. Fredrick J. Stare in his book Eating for Good Health (1969) states that 60 mg or 70 mg per day is enough: "An extra amount of the vitamin cannot be stored in the body and is simply excreted. You don't need vitamin-C pills under normal circumstances.'* These statements are repeated by him in his latest book Panic in the Pantry (Whelan and Stare, 1975). The statements are not true.
The observations that have been made on the concentration of ascorbate in the blood plasma corresponding to the capacity of the mechanism of tubular reabsorption in different people give some information about biochemical individuality with respect to vitamin C. In one study, with nineteen subjects, the capacity varied between 10 mg and 20 mg per liter (Friedman, Sherry, and Ralli, 1940). Similar variation has been found by other investigators.
Ascorbic acid is present in the various body fluids and organs, especially the leukocytes and the blood. Its concentration in the brain is also high. When a person with an insufficient supply of ascorbic acid ingests a quantity of it, it moves very rapidly from the blood serum into the leukocytes, other cells, and organs such as the spleen. The amount remaining in the blood serum may be so small, less than the capacity of the mechanism of tubular reabsorption, that very little is eliminated in the urine.
A test was developed long ago (Harris and Ray, 1935) to show the avidity with which the tissues remove ascorbic acid from the blood serum. This test, called a loading test, involves giving the subject a certain amount of vitamin C by mouth or by injection, collecting the urine for the following six hours, and analyzing it for ascorbic acid. If an oral dose of about 1 g is given, most people whose blood serum is not depleted of the vitamin eliminate about 20 to 25 percent of it in the urine in six hours.
A person who eliminates a smaller fraction of the ingested ascorbic acid may do so either because he or she has been living on a diet containing an insufficient quantity of the vitamin, such that the tissues are depleted, or because some biochemical abnormality of his or her body operates to remove ascorbate from the blood serum very rapidly, perhaps by converting it rapidly into other substances. It was reported by VanderKamp in 1966 that patients with chronic schizophrenia required a loading dose of ascorbic acid about ten times greater than that required by other persons to cause the appearance of a certain amount in the urine. This observation was verified by Herjanic and Moss-Herjanic (1967).
The results of another loading test are shown in the illustration on page 114 (Pauling and others, Chapter 2 in Hawkins and Pauling, 1973). In this study forty-four patients recently hospitalized with acute schizophrenia and forty-four other subjects were given 1.76 grams of ascorbic acid by mouth, and the fraction excreted in the urine in six hours was measured. There was a twentyfold individual variation in this fraction, from 2 percent to 40 percent, with the schizophrenic patients excreting only about 60 percent as much as the others. This variation is probably partly nutritional and partly genetic in origin.
The distribution functions suggest that there are three kinds of human beings with respect to their handling of ascorbic acid, the low excretors, the medium excretors, and the high excretors. This idea has not, however, been thoroughly tested as yet.
Some of the subjects in this study were given 1.76 g of ascorbic acid every day for eight days, and the fraction excreted in the six hours after the last dose was determined. Of sixteen low excretors (less than 17 percent excreted), eight had moved out of the low-excretor class, whereas the excretion of the other eight remained low. This observation suggests that these persons have an abnormal way of handling their ingested vitamin C. They might require much larger intake to be in good health.
Several serious genetic diseases, such as phenylketonuria, galactosemia, and methylmalonicaciduria, are discussed in Chapter 11. Of the many such diseases now known, some can be controlled by a large intake of an appropriate vitamin. It is harder to recognize a mild genetic disease than a serious one, but the mild genetic diseases may in the aggregate cause more suffering than the serious ones, because so many more people suffer from them. It is likely that many of the low excretors of ascorbic acid shown in the illustration on page 114 have a genetic defect such that a low intake of vitamin C is more damaging to them than to other people. For them a larger intake of the vitamin may be essential if they are to avoid a short and miserable life. At the present time it is very difficult to determine the nutritional needs of an individual person except by trial of various intakes, but we may hope that reliable clinical tests that show the individual needs will be developed before long.
115
