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8—
Protein

Proteins account for about three-fourths of the dry matter in most human tissues other than bone and adipose tissue. They are macromolecules with molecular weights ranging from a few thousand to many millions, and they are required for practically every essential function in the body. From the standpoint of nutrition, the human body does not require dietary protein per se. Rather, it requires the nine essential amino acids that are present in dietary proteins. Dietary sources of utilizable carbon, usually from carbohydrates, and nitrogen are required for the synthesis of nonessential amino acids.

The nine essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. They are deemed essential because they cannot be synthesized by mammals, at least in the amounts needed, and are therefore essential constituents of an adequate diet for humans. The earlier classification of amino acids as either indispensable or dispensable (Rose and Wixom, 1955) now requires refinement, since in some conditions (e.g., premature births and liver damage) the so-called dispensable amino acids (e.g., cystine and tyrosine) may be important components of the diet and should be considered to be conditionally dispensable (Horowitz et al., 1981).

It has long been known that proteins differ in their growth-promoting ability. These differences in nutritional or biologic value are often expressed in terms of high-quality reference proteins (i.e., foods such as eggs, cow's milk, meat, and fish, which contain all the essential amino acids in relatively high concentrations). Because amino acid requirements change with growth and development (FAO/WHO/UNU, 1985), it is now accepted that the biologic or nutritional value is not an unchanging attribute of a protein but can vary with the age of the consumer. However, the degree to which the mixed proteins in typical diets differ in their nutritional value for younger children through adulthood seems rather small (FAO/WHO/UNU, 1985), especially when the usual diet contains a mixture of good protein sources (e.g., milk, eggs, meat, fish, legumes, and nuts) whose amino acid content complements that of such staple foods as cereals and potatoes (Bressani, 1977).

Patterns of Intake in the U.S. Diet

Protein available in the U.S. food supply has amounted to about 100 g/person/day, or 11% of total energy, since 1909 when the U.S. Department of Agriculture (USDA) began to report food supply data (see Figure 3-3 and Table 3-3 in Chapter 3). A major change since 1909 has been a marked increase (from 52 to 68%) in the proportion of total protein from animal sources and a concomitant decrease in protein  from  plant sources. Food supply data indicate only the amount



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Page 259 8— Protein Proteins account for about three-fourths of the dry matter in most human tissues other than bone and adipose tissue. They are macromolecules with molecular weights ranging from a few thousand to many millions, and they are required for practically every essential function in the body. From the standpoint of nutrition, the human body does not require dietary protein per se. Rather, it requires the nine essential amino acids that are present in dietary proteins. Dietary sources of utilizable carbon, usually from carbohydrates, and nitrogen are required for the synthesis of nonessential amino acids. The nine essential amino acids are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. They are deemed essential because they cannot be synthesized by mammals, at least in the amounts needed, and are therefore essential constituents of an adequate diet for humans. The earlier classification of amino acids as either indispensable or dispensable (Rose and Wixom, 1955) now requires refinement, since in some conditions (e.g., premature births and liver damage) the so-called dispensable amino acids (e.g., cystine and tyrosine) may be important components of the diet and should be considered to be conditionally dispensable (Horowitz et al., 1981). It has long been known that proteins differ in their growth-promoting ability. These differences in nutritional or biologic value are often expressed in terms of high-quality reference proteins (i.e., foods such as eggs, cow's milk, meat, and fish, which contain all the essential amino acids in relatively high concentrations). Because amino acid requirements change with growth and development (FAO/WHO/UNU, 1985), it is now accepted that the biologic or nutritional value is not an unchanging attribute of a protein but can vary with the age of the consumer. However, the degree to which the mixed proteins in typical diets differ in their nutritional value for younger children through adulthood seems rather small (FAO/WHO/UNU, 1985), especially when the usual diet contains a mixture of good protein sources (e.g., milk, eggs, meat, fish, legumes, and nuts) whose amino acid content complements that of such staple foods as cereals and potatoes (Bressani, 1977). Patterns of Intake in the U.S. Diet Protein available in the U.S. food supply has amounted to about 100 g/person/day, or 11% of total energy, since 1909 when the U.S. Department of Agriculture (USDA) began to report food supply data (see Figure 3-3 and Table 3-3 in Chapter 3). A major change since 1909 has been a marked increase (from 52 to 68%) in the proportion of total protein from animal sources and a concomitant decrease in protein  from  plant sources. Food supply data indicate only the amount

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Page 260 of protein available for consumption in wholesale and retail markets, however, and not the amounts actually consumed. According to USDA's Nationwide Food Consumption Survey (NFCS) of 1977-1978, the mean protein intake for all respondents (infancy to over 75 years of age) was 74 g/day or 16.5% of total calories and exceeded the RDA for all 22 age-sex groups (USDA, 1984). In later USDA surveys, conducted in 1985 and 1986, protein intake averaged 15 to 16% of calories for children 1 to 5 years, 16% of calories for women 19 to 50 years, and 16.5% for men 19 to 50 years, regardless of income (USDA, 1986, 1987a,b). There was little variation in intake with race or urbanization. The 1977-1978 NFCS indicated that meats, poultry, and fish contributed approximately 49%, dairy products 18%, eggs 4%, legumes 3%, cereal products 18%, and fruits and vegetables 7 to 8% of the protein in the U.S. diet (USDA, 1983). Evidence Associating Protein with Chronic Diseases Several considerations must be borne in mind in reviewing studies on dietary protein and chronic diseases: · Because intakes of animal protein and saturated fat tend to be highly correlated, it is not possible in most epidemiologic studies to separate their independent effects. · Many epidemiologic studies rely on evidence from vegetarians (e.g., complete vegetarians and lacto-ovovegetarians) that should be evaluated carefully for several reasons: The total protein intake of vegetarians is not much lower than that of omnivores; however, the lifestyles of vegetarians are likely to differ from those of omnivores in many ways that may confound the association between vegetable or animal protein intake and health. In addition, there is a lack of consistency among and within some studies regarding the length of time that subjects have followed a vegetarian diet. · Laboratory animal studies are often conducted with large, nonphysiologic doses of protein. Thus, the applicability of their findings to human populations may be severely limited. Coronary Heart Disease Epidemiologic Studies The epidemiologic literature on the etiology of coronary heart disease (CHD) emphasizes the role of dietary fats, particularly saturated fat, rather than dietary protein (see Chapter 7). Because animal protein and saturated fat intake tend to be highly correlated, however, it is not surprising that animal protein intake is positively correlated with CHD mortality as are intakes of total and saturated fats. This is so whether one compares populations among different countries, within countries, or migrant populations, or whether one examines secular trends (Aravanis and Loannidis, 1984; Berkson and Stamler, 1981; Kritchevsky, 1976; Toshima et al., 1984). Findings from the major cohort studies of heart disease have generally failed to demonstrate an independent effect for total dietary protein. For example, Keys et al. (1986) found no association between 15-year mortality from CHD and dietary protein intake (as a percentage of total calories) in an ecological correlation analysis of 15 male cohorts in seven countries. Similarly, Gordon et al. (1981) found no relationship between age-adjusted mean daily protein intake (based on 24-hour dietary recalls) and the occurrence of CHD over periods as long as 6 years in three prospective cohorts of men (in Framingham, Honolulu, and Puerto Rico). A more recent analysis of the Honolulu cohort confirmed the finding; however, because total caloric intake was lower for CHD cases than for the noncases (reflecting a lower intake of carbohydrates and alcohol), protein as a percentage of total calories was significantly higher for the CHD cases (McGee et al., 1984). Clinical Studies The importance of the source of the protein as a factor in CHD  risk is supported indirectly by studies of the effects of different dietary proteins on serum cholesterol—a well-established risk factor for CHD (see Chapter 7). Soy protein-based diets have been shown to have a substantial serum cholesterol-lowering effect in hypercholesterolemic subjects, and the major decrease is in low-density liproprotein (LDL) cholesterol (Descovich et al., 1980; Gaddi et al., 1987; Goldberg et al., 1982; Sirtori et al., 1979, 1985; Verillo et al., 1985; Widhalm, 1986; Wolfe et al., 1981). The effect of soy-based protein diets on people with normal serum cholesterol is less consistent. For example, Wolfe et al. (1986) and Carroll et al. (1978b) reported that the substitution of vegetable protein (primarily soy) for meat and dairy protein resulted in a substantial lowering of mean serum cholesterol in healthy adults of both sexes. Van Raaij et al. (1981) reported that substitution of

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Page 261 65% soy protein for casein in diets containing 13% of total calories from protein resulted in a marked decline in LDL cholesterol and a weaker but still significant increase in high-density liproprotein (HDL) cholesterol. In other studies, however, no cholesterol-lowering effect of different dietary proteins (e.g., soy protein) was found in subjects with normal serum cholesterol (Bodwell et al., 1980; Terpstra et al., 1983b; van Raaij et al., 1979). The variability in these findings for subjects with normal cholesterol may reflect such factors as interindividual differences in lipid metabolism, differences among studies in the preparation and type of protein sources, and the failure in some studies to exclude animal protein completely from the experimental diets. Animal Studies Early animal studies suggesting an effect of protein on atherosclerosis (Ignatovski, 1908) were largely discounted because the diets also contained cholesterol, which is known to be atherogenic. Subsequent studies (Meeker and Kesten, 1940, 1941), however, showed that rabbits fed a cholesterol-free casein diet developed hypercholesterolemia and atherosclerosis in contrast to rabbits fed a similar diet containing soy protein. Again, these findings were largely discounted for nearly two decades (Carroll, 1978; Kritchevsky et al., 1987). In the late 1950s, workers in two different laboratories reported that rabbits became hypercholesterolemic  and developed atherosclerosis when fed cholesterol-free, semipurified diets and that the effect persisted over time (Lambert et al., 1958; Malmros and Wigand, 1959). Subsequent experiments implicated casein as the causative agent (Carroll et al., 1979; Hamilton and Carroll, 1976). The effects of casein were found to be dose related (Huff et al., 1977; Terpstra et al., 1981) and appeared to be associated with enhanced intestinal absorption of cholesterol, decreased fecal excretion of cholesterol and bile acids, slower rate of turnover of plasma cholesterol, reduction in apolipoprotein B/E receptor activity in liver, and inhibition of hepatic cholesterol biosynthesis (Chao et al., 1982; Huff and Carroll, 1980a; Nagata et al., 1982; Sirtori et al., 1984). Most animal proteins produce some degree of hypercholesterolemia independent of body weight, whereas plant proteins uniformly produce low levels of plasma cholesterol. The hypercholesterolemic effects of animal proteins vary according to the type of protein (e.g., mixtures or single animal proteins) and the animal model used (Beynen and West, 1987; Hermus et al., 1983; Jacques et al., 1986; Kim et al., 1983; Kritchevsky et al., 1983; Van der Meer and Beynen, 1987), as well as to the type and amount of other dietary constituents. For example, high levels (20% of total calories) of certain polyunsaturated fats such as corn oil and sunflower oil (Lambert et al., 1958; Malmros and Wigand, 1959), fiber-rich foods such as alfalfa (Hamilton and Carroll, 1976; Kritchevsky et al., 1977), dietary carbohydrates such as potato starch (Carroll et al., 1978a; Hamilton and Carroll, 1976), and calcium and zinc (Samman and Roberts, 1987) have all been reported to attenuate the hypercholesterolemic effect of semipurified cholesterol-free diets. The different effects of animal and plant proteins on serum cholesterol and lipoprotein levels in rabbits (Huff and Carroll, 1980b; Huff et al., 1977) and baboons (Wolfe and Grace, 1987) are largely due to their amino acid composition, although the specific amino acids, or combinations of amino acids, responsible for these observed effects are not known (Huff and Carroll, 1980b). The ratio of lysine to arginine (Kritchevsky, 1979; Kritchevsky et al., 1983, 1987) and the absolute amounts of methionine and glycine (Terpstra et al., 1983a) in the diet have been reported to influence serum cholesterol levels. These findings have not been uniformly replicated (Carroll, 1981), however, and their interpretation is complicated because such studies may not mimic the feeding of intact proteins, which are acted upon by the digestive process (Woodward and Carroll, 1985). Hypertension Epidemiologic Studies Many of the data on the effect of protein on blood pressure are derived from studies of people with chronic protein malnutrition. Many chronically malnourished people have low blood pressure (Viart, 1977); however, the relative contribution of protein deficiency to this condition cannot be readily determined since many such people also suffer from caloric and other nutrient deficiencies as well as other illnesses. Malhotra (1970) found no association of animal protein intake with blood pressure in a study of two omnivorous populations in India. In a large prospective study of omnivorous Japanese men in Hawaii with threefold higher protein intakes, Reed et al. (1983) found significant inverse associations between protein, calcium, potassium, and milk intake (determined from 24-hour diet recalls) and

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Page 262 both systolic and diastolic blood pressure levels, although it was not possible to determine whether any of these dietary components had an independent effect on blood pressure. A similar inverse association between dietary protein intake and systolic blood pressure was found in a group of male college students in the United States (Pellum and Medeiros, 1983). Most epidemiologic studies of protein and blood pressure involve comparisons of groups of vegetarians with other populations that include meat and fish in their diets. These studies consistently reported lower blood pressures among the vegetarians independent of age, weight, and pulse, but it was not possible to determine whether these findings resulted from decreased animal protein intake or from some other dietary components or nondietary factors that differed among the comparison groups (Armstrong et al., 1977; Donaldson, 1926; Ophir et al., 1983; Rouse and Beilin, 1984; Sacks et al., 1974). Nevertheless, these studies suggest that some component of animal products in the diet, possibly animal protein or fat, may influence blood pressure in well-nourished populations. Clinical Studies In a randomized trial of 59 omnivorous volunteers, Rouse et al. (1983) found a lowering of both systolic and diastolic blood pressures in those placed on a lacto-ovovegetarian diet as compared to controls on an omnivorous diet. The specific components of the lacto-ovovegetarian diet responsible for this effect were not determined. In a randomized trial of 69 normotensive subjects in Holland, Brussaard et al. (1981) found that blood pressure was not affected differently by the various types of protein in the diet (e.g., vegetable or animal). Yamori et al. (1984) suggested that deficiencies of certain amino acids, specifically tyrosine and possibly tryptophan, may influence blood pressure in hypertensives either at the vascular level or through the neuronal control of the cardiovascular system. In contrast, Wurtman and Milner (1985) found no convincing evidence that plasma amino acids in general, or tyrosine or tryptophan specifically, are involved in the pathogenesis of human hypertension. Animal Studies Most studies of animals with experimentally induced hypertension suggest that dietary protein restriction alone does not lower blood pressure. In rats that have undergone extensive ablation of renal tissue, protein restriction severe enough to limit body growth does not lower blood pressure (Madden and Zimmerman, 1983; Meyer et al., 1983), nor does protein restriction lower blood pressure in the uninephrectomized spontaneously hypertensive rat (Dworkin and Feiner, 1986). However, protein restriction coupled with alterations in other dietary factors (e.g., added dietary salt) accelerates the development of severe hypertension in the spontaneously hypertensive rat (Kimura, 1977; Yamori, 1980). Different effects by type of protein have also been noted. For example, consumption of diets rich in milk protein (either casein or whey) limits the development of severe hypertension in stroke-prone spontaneously hypertensive rats (Ikeda et al., 1987). Stroke Epidemiologic Studies There are few epidemiologic studies on dietary protein and stroke. Kagan et al. (1985) found weak evidence of a positive association between consumption of a low-fat, low animal-protein diet and the incidence of stroke in a cohort of Japanese men in Hawaii. The finding for animal protein persisted in a further analysis of these data (Lee et al., 1988) and was supported by the results of an autopsy study of cerebral atherosclerosis in the same study population (Reed et al., 1988). In intercountry comparisons, per capita intake of plant proteins (except those from  cereals) was also inversely correlated with cerebrovascular mortality rates (Seely, 1982). However, these data are insufficient to reach any conclusion about the effect of dietary protein on the risk of stroke in humans. Animal Studies Very high-protein diets (@50% of total calories) limit the development of severe hypertension and reduce the incidence of stroke in various strains of spontaneously hypertensive rats (Lovenberg and Yamori, 1984; Wang et al., 1984; Yamori et al., 1978, 1984), whereas diets with a moderately low protein content (approximately 10% protein but with 1% added saline) have the opposite effect (Wexler, 1983a). The type of protein may influence the outcome; for example, diets low in fish protein cause more rapid increases in blood pressure in stroke-prone, spontaneously hypertensive rats than do diets low in animal protein (Wexler, 1983b), and in the same animal model, diets rich in milk protein restrict the development of severe hypertension and extend lifespan (Ikeda et al., 1987).

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Page 263 Specific Cancer Sites Epidemiogic Studies A direct effect of dietary protein on cancer risk has been difficult to assess in epidemiologic studies because of the very high correlation between fat and protein intake in the Western diet (Armstrong and Doll, 1975; Carroll and Khor, 1975; Jain et al., 1980; Kolonel et al., 1981). Thus, the effects of these two macronutrients cannot easily be separated. Research has focused more on fat than on protein, and where both have been examined together, associations have generally been stronger for fat (NRC, 1982). Most of the evidence on protein pertains to cancers of the large bowel and the breast, but other sites have been implicated as well. Large-bowel cancer Ecological correlations of protein consumption with large-bowel cancer rates are not consistent. In international comparisons, large-bowel cancer incidence and mortality were positively correlated with per-capita total protein, and especially animal protein intake, particularly in developing countries (Armstrong and Doll, 1975; Gregor et al., 1969; Thind, 1986). In contrast, more rigorous dietary assessments in less extensive comparisons, e.g., between two Scandinavian populations or among regional populations in Britain, did not suggest any associations of large-bowel cancer with dietary protein intake (Bingham et al., 1979; IARC-IMG, 1977; Jensen et al., 1982). In four recent case-control studies, investigators assessed protein intake in relation to risk for large-bowel cancer. In two of these (Jain et al., 1980; Potter and McMichael, 1986), protein consumption was associated with cancers of both the colon and the rectum in both sexes after adjustment for other risk factors. However, this association with protein could not be clearly separated from a similar association with dietary fat in the former study and with total energy intake in the latter. In the other two reports (Kune et al., 1987; Macquart-Moulin et al., 1986), no associations with protein were found in more detailed analyses of the data. Two prospective cohort studies do not support an association between dietary protein and colon cancer risk. Neither Garland et al. (1985) nor Stemmermann et al. (1984) found any differences in intakes of animal or vegetable protein between colon cancer cases and noncases. In several epidemiologic studies, both correlation and case-control, positive associations were found between meat consumption (an important source of protein and saturated fat in Western diets) and colon cancer risk, whereas no association was found in many other studies (Kolonel, 1987). Thus, taken together, these findings do not provide added support for a role of dietary protein in the etiology of colon cancer. Breast cancer Several studies demonstrate a strong ecological correlation between dietary protein, particularly animal protein, and breast cancer incidence or mortality (Armstrong and Doll, 1975; Carroll and Khor, 1975; Gaskill et al., 1979; Gray et al., 1979; Hems, 1978; Knox, 1977; Kolonel et al., 1981). In the study by Armstrong and Doll (1975) and in a further analysis by Hems (1980), the association of breast cancer with dietary fat was stronger than with protein. Furthermore, in the analysis by Gaskill et al. (1979), no association with protein was observed after controlling for age at first marriage. Several case-control studies have looked at dietary protein in relation to breast cancer risk. In most of these studies (Hirohata et al., 1985, 1987; Miller et al., 1978; Phillips, 1975), no convincing evidence of an effect of protein was found. On the other hand, J. Lubin et al. (1981) found a positive association between breast cancer risk and level of consumption of animal protein (estimated from only eight food items on a questionnaire). F. Lubin et al. (1986) addressed the problem of intercorrelation among dietary variables (fat, animal protein, and fiber) by stratifying their study sample by four consumption levels in a conditional logistic regression analysis. They showed increased risks associated with animal protein, but not a clear dose-response trend, and concluded that the combination of a high-fat, high-animal-protein, low-fiber diet increased the risk for breast cancer in their population. Meat consumption was positively associated with breast cancer mortality in a cohort of women in Japan (Hirayama, 1986), but not in a cohort of omnivorous  Seventh-Day  Adventists in  the United States (Mills et al., 1986; Phillips and Snowdon, 1983). Other cancers Pancreatic cancer has been associated with dietary protein intake in several geographic correlation analyses (Armstrong and Doll, 1975; Böing et al., 1985; Lea, 1967). High frequency of meat consumption has also been associated with risk for

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Page 264 this cancer in some analytic studies (Hirayama, 1981; Ishii et al., 1968; Mack et al., 1986) but not in others (Gold et al., 1985; Norell et al., 1986). Prostate cancer was positively correlated with protein intake (animal as well as total) in several ecological analyses (Armstrong and Doll, 1975; Böing et al., 1985; Kolonel et al., 1981). In one case-control study, Heshmat et al. (1985) found a nonsignificant increase in protein intake by cases. In another, Graham et al. (1983) did not examine protein but found a statistically significant trend in risk associated with higher frequency of consumption of meats and fish in men 70 years or older. The relationship of dietary protein to other cancer sites has received little attention. Positive associations with endometrial and stomach cancers (Jedrychowski et al., 1986; Kolonel et al., 1981), and a lack of association with renal and ovarian cancers (Armstrong et al., 1976; Byers et al., 1983), have been reported. Animal Studies The evidence associating protein intake with incidence of spontaneous tumors in rodents is inconsistent. Some studies have shown negative associations (Slonaker, 1931), others have been positive (Ross et al., 1970; White and Andervont, 1943; White and White, 1944), whereas still others have shown no association (Tannenbaum and Silverstone, 1949). Studies have been conducted in rodents to investigate how proteins influence transplanted tumors and tumors induced by such chemicals as aflatoxins, N-acetyl-2-aminofluorene, dimethylbenz(a)anthracene (DMBA), methylcholanthrene, and dimethylhydrazine. Their results indicate that diets with protein at approximately 5% of calories (i.e., below the requirement for optimum growth) generally suppress the development of tumors as well as their subsequent growth and development (Clinton et al., 1984, 1986; Elson, 1958; Engel and Copeland, 1951; Madhavan and Gopalan, 1968; Morris et al., 1948; Temcharoen et al., 1978; Topping and Visek, 1976; Visek, 1985; Walters and Roe, 1964; Wells et al., 1976). The only apparent exception is the increase in DMBA-induced tumor yield in rats fed a low protein diet (Clinton et al., 1979; Elson, 1958; Miller et al., 1941; Silverstone, 1948). Increasing dietary protein to 20 or 25% of total calories generally enhances tumorigenesis. Further increases have little effect or, in many cases, even inhibit tumorigenesis (Appleton and Campbell, 1982; Engel and Copeland, 1952; Ross and Bras, 1973; Ross et al., 1970; Saxton et al., 1948; Tannenbaum and Silverstone, 1949; Topping and Visek, 1976; Wells et al., 1976). It is not clear whether the general inhibition or the absence of effect on tumorigenesis at very high levels of dietary protein is due to a reduced intake of food and total calories, or whether it is due to other adverse effects, e.g., renal toxicity due to high levels of protein (NRC, 1982). However, tumor enhancement by dietary protein occurs only when there is amino acid balance, suggesting that the effect is not due to specific amino acids or to amino acid imbalance (NRC, 1982). Osteoporosis Epidemiologic and Clinical Studies High dietary protein taken as a purified isolated nutrient increases urinary excretion of calcium (Allen et al., 1979; Anand and Linkswiler, 1974; Chu et al., 1975; Hegsted and Linkswiler, 1981; Hegsted et al., 1981; Johnson et al., 1970; Kim and Linkswiler, 1979; Margen et al., 1974; McCance and Widdowson, 1942; Schwartz et al., 1973; Walker and Linkswiler, 1972). There is little evidence, however, that natural diets high in protein increase osteoporosis risk. In the U.S. Ten-State Nutrition Survey, a very low, nonsignificant correlation was found between average daily protein intake and metacarpal cortical bone area in elderly adults (Garn et al., 1981). However, these intakes were based on 24-hour dietary recalls, which are poor measures of intake for individuals (see Chapter 2). Furthermore, because bone mass at older ages is determined primarily by the mass achieved at maturity (Draper and Scythes, 1981; Matkovic et al., 1979), correlations of bone density with contemporaneous dietary intake in the elderly may be misleading. Bone mineral mass appears to be lower in omnivorous women than in lacto-ovovegetarian women (Marsh et al., 1980; Sanchez et al., 1980) and lower in North Alaskan Eskimos consuming an extremely high animal-protein diet than in North American Caucasians (Mazess and Mather, 1974). It has not been shown, however, that either the type or the amount of protein in the diet is responsible for these differences. In a 4-year clinical trial of postmenopausal women who did not take calcium supplements, Freudenheim et al. (1986) observed a positive correlation between protein intake and changes in bone mineral content of the radius. However, although such short-term studies in the elderly

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Page 265 suggest that high-protein diets produce an increase in urinary calcium excretion and often a worsening in calcium balance (Licata et al., 1981; Lutz and Linkswiler, 1981), the long-term effects of such diets, particularly on bone mass, are unknown. In addition, urinary calcium excretion increases with increased protein intake only if phosphorus intake is held constant (see Chapter 13). If phosphorus intake rises with protein intake as it does in typical U.S. diets, the effect of protein is minimized (Hegsted et al., 1981; Schuett and Linkswiler, 1982). Thus, although it has been suggested that a habitual high intake of protein may contribute to an increased risk of osteoporosis, this is not supported by current evidence. Chronic Renal Disease Epidemiologic and Clinical Studies Brenner et al. (1982) hypothesized that glomerular capillary hypertension (which is associated with an increase in glomerular filtration rate and capillary blood flow) results from unrestricted intake of protein-rich foods and leads to glomerular sclerosis, thus accounting for the progressive decrease in renal function observed with age. However, although both glomerular filtration rate and capillary blood flow increase in response to a high protein intake (Bosch et al., 1983; Pullman et al., 1954), thus far there are no epidemiologic or clinical data to support this hypothesis. Animal Studies In animals, as in humans, glomerular sclerosis increases with age (Couser and Stilmant, 1975; Guttman and Andersen, 1968). In rats fed ad libitum standard chows containing about 20 to 25% protein, most glomeruli showed signs of sclerosis by 2 years of age (Coleman et al., 1977). However, development of glomerular sclerosis in rats can be delayed either by decreasing the amount of standard chow by one-half to two-thirds that consumed by animals fed ad libitum (Berg and Simms, 1960; Tucker et al., 1976; Yu et al., 1982) or by decreasing the amount of protein in the chow to 6% of total calories (Meyer et al., 1983). Conversely, increasing dietary animal protein to 31% or more of total calories has been shown to accelerate development of glomerular sclerosis (Newburgh and Curtis, 1928). These findings suggest that dietary protein influences renal blood flow, glomerular filtration rate, and, ultimately, progression of age-related glomerular sclerosis in the healthy animal. Summary Animal proteins in the diet have not been linked specifically to CHD risk in humans, although high levels induce hypercholesterolemia and atherosclerosis in laboratory animals. Substitution of soybean protein for animal protein in the diet reduces the level of serum cholesterol in humans, particularly in hypercholesterolemic subjects, and there is evidence that groups eating vegetarian diets have lower average blood cholesterol levels than the general population. The data linking elevated intakes of animal protein to increased risk of hypertension are weak. Some epidemiologic studies suggest that higher intakes of animal protein may be associated with increased risk of cancer at certain sites, although the data are not entirely consistent. However, because of the strong positive correlation between dietary protein and fat over the range of normal intakes in most Western populations, it is not clear whether dietary protein exerts an independent effect on cancer. In laboratory experiments, the relationship of dietary protein to carcinogenesis appears to depend upon protein level. Chemically induced carcinogenesis is enhanced as protein intake is increased up to 2 or 3 times the normal requirement. Higher levels produce no further enhancement and, in many cases, may inhibit tumorigenesis. Although high dietary protein taken as a purified isolated nutrient increases urinary excretion of calcium, there is little evidence that natural diets high in protein increase osteoporosis risk. High intakes of animal protein are hypothesized to lead to progressive glomerular sclerosis and deterioration of renal function by promoting sustained increases in renal blood flow and glomerular filtration rates. Although both human and animal studies indicate that a high-protein intake can increase glomerular filtration rate and age-related progression of renal disease, the effect of high dietary protein on the risk of chronic renal disease in humans needs further investigation. Directions for Research · The relative effects of different levels of total protein and different types of protein (animal or vegetable) in chronic disease etiology and their mechanisms of action (e.g., in CHD, hypertension, specific cancers, osteoporosis, chronic renal disease, and stroke).

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Page 266 · The long-term effects of protein intake above nutritional requirements on renal function in humans and the relationship of dietary protein to increased risk of end-stage renal disease. · The role of specific amino acids or combinations of amino acids in augmenting chronic disease risk. · The optimal range of protein intake (animal or vegetable) for reducing chronic disease risk. · The effect of the kind and amount of protein upon various stages and mechanisms of neoplastic development. References Allen, L.H., E.A. Oddoye, and S. Margen. 1979. Protein-induced hypercalciuria: a longer term study. Am. J. Clin. Nutr. 32:741-749. Anand, C.H., and H.M. Linkswiler. 1974. Effect of protein intake on calcium balance of young men given 500 mg calcium daily. J. Nutr. 104:695-700. Appleton, B.S., and T.C. Campbell. 1982. Inhibition of aflatoxin-initiated preneoplastic liver lesions by low dietary protein. Nutr. Cancer 3:200-206. Aravanis, C., and P.J. Loannidis. 1984. Nutritional factors and cardiovascular diseases in the Greek Islands Heart Study. Pp. 125-135 in W. Lovenberg and Y. Yamori, eds. Nutritional Prevention of Cardiovascular Disease. Academic Press, Orlando, Fla. Armstrong, B., and R. Doll. 1975. Environmental factors and cancer incidence and mortality in different countries, with specific reference to dietary practices. Int. J. Cancer 15:617-631. Armstrong, B., A. Garrod, and R. Doll. 1976. A retrospective study of renal cancer with special reference to coffee and animal protein consumption. Br. J. Cancer 33:127-136. Armstrong, B., A.J. Van Merwyk, and H. Coates. 1977. Blood pressure in Seventh-Day Adventist vegetarians. Am. J. Epidemiol. 105:444-449. Berg, B.N., and H.S. Simms. 1960. Nutrition and longevity in the rat. II. Longevity and onset of disease with different levels of food intake. J. Nutr. 71:255-263. Berkson, D.M., and J. Stamler. 1981. Epidemiology of the killer chronic diseases. Pp. 17-55 in M. Winick, ed. 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