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Understanding Diet, Health, and Disease Relationships 7 Classic nutrition, which focuses primarily on nutrient cleficiencies, produced breakthroughs of great medical and public health significance, including the prevention anti treatment of rickets, pellagra, beriberi, iron- deficiency anemia, and scurvy throughout most of the world. Advances in understanding the metabolic role of nutrients and the successful imple- mentation of that knowledge by clinicians, public health practitioners, and food technologists led nutrition scientists to focus more attention on the role of diet in achieving and maintaining health by maximizing physiologi- cal functions and reducing the risk of chronic diseases (what some refer to as "optimal" health and development). Fortunately, clinical nutrition in- vestigators are finding the tools, technologies, and opportunities to ex- plore fundamental relationships between diet and long-term health to be increasingly accessible. We define clinical nutrition, the focus of this chapter, broadly to include concepts of health promotion as well as those pertain- ing to the dietary treatment of diseases and metabolic disorders that is, disease prevention as well as therapeutics. A person's age, sex, and stage of growth have a direct impact on his or her nutritional requirements; in turn, nutritional state may influence the rate of growth, development, and aging. However, until recently it was difficult to study the application of these concepts to well-being. Current research shows that undernutrition during the first three years of life is associated with a smaller body size and fat-free mass in later life, support- ing the view that malnutrition during critical periods in early development 143

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144 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES has later consequences. These studies reaffirm the importance of good maternal nutrition during pregnancy and lactation and during childhood by identifying specific developmental outcomes that are affected by nutri- ent intakes during critical periods. The aging process is also an exciting target of investigation. Animal studies show that aging is delayed by restricting food intake, though com- parable studies in humans have not been done. Malnutrition may exacer- bate or potentiate age-related chronic diseases that, in turn, accelerate aging. Malnutrition in later adult life also compromises function, with measurable consequences on morbidity, mortality, and quality of life. Advances in the basic sciences challenge traditional paradigms of rela- tionships between nutrients and their functions. In the case of vitamin D, for example, rickets and osteomalacia are the classic disease markers for insufficient intake. However, this nutrient appears to do more than simply facilitate calcium transport in the intestine. Several studies suggest that the active form of vitamin D has a direct effect on bone, helps regulate cell growth, and may affect immune function and cellular lipid metabo- lism. Vitamin D also affects vascular tissue; it enhances vasoconstriction, for example. These new findings call into question whether the amount of calcium in bone is the best indicator of vitamin D status for any indi- vidual. Nutrients affect the central nervous system and immunological pro- cesses, but which nutrients are important and how they work requires further study. Individual nucleotides, amino acids, zinc, and several other nutrients seem to participate actively in immunological responses. Food intakes can be related directly to neurotransmitter function in the brain. This arises from studies of the function of neuropeptides and amino acids as neurotransmitters and their role in neurodegenerative dis- ease and from an increasing understanding of neurotransmitter receptors and the manner in which they are modulated by ions, free radicals, and the simultaneous action of other transmitters. Information about how the body controls food intake is quite limited. We do not know all the signals that may arise in the intestine, whether and to what extent the liver and other organs are involved, whether and to what extent they may be under genetic control, or how various signals are integrated and processed in the brain and periphery. Furthermore, little is known about which potential regulatory molecules cross the blood-brain barrier, how they do so, where they exert their effects, or how they regu- late function. Signals capable of affecting food intake also may arise from energy reserves in the form of glycogen or fat. These and other comparable opportunities challenge us to examine broader relationships between nutrition and lifestyle. For example, nutri- tion scientists must ask how vitamin D adequacy can be defined in a

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UNDERSTANDING DIET, HEALTH, AND DZSEASE RELATIONSHZPS 145 context that includes an individual's dietary patterns, physical activity, and overall calcium status in order to promote optimal development and main- tenance of the skeletal system, thereby preventing osteoporosis in late adult life. Other relationships between nutrients and serious clinical prob- lems have been proposed, such as those between vitamin A and cancer, antioxidants and atherosclerosis and cataracts, and folio acid and neural tube defects. Sodium's role in hypertension may have been overestimated, while the role of other nutrients (e.g., calcium, magnesium, and potas- sium) may have been underestimated. Furthermore, these four nutrients are likely to interact. How this affects the risk of hypertension requires further study. The complexity of relationships among food components and disease is demonstrated by the unfolding story of lipids and atherosclerotic heart disease. Early investigations discovered links between dietary cholesterol and saturated fats and atherosclerosis. Later, the role of polyunsaturates was explored. Those studies were followed by others exploring the role of monounsaturates, fish oils, and bans fatty acids. Most recently, levels of iron and ferritin in the body have been correlated with atherosclerotic heart disease. Clearly the picture is not complete, as there are conflicting data on the role of specific fats, other nutrients, food components, and dietary patterns and insufficient basic information on how atherosclerotic lesions evolve. Studies of relationships linking diet and heart disease show that sex, and perhaps racial and ethnic background, affect nutrient-out- come relationships and illustrate the need for more attention to these potentially important interactions. Personal behaviors also influence the risk of heart disease. For example, epidemiological studies demonstrate that even modest physical activity is protective. Much more investigation is needed before the relationship of diet and other variables to heart disease is fully explained. The nutrition and food sciences have advanced to the point where we are able to investigate how dietary patterns particularly the amounts and interactions of macro- and micronutrients consumed can either promote health, increase the risk of disease, or increase disease severity. Under- stan(ling the mechanisms linking diet to disease and their dose-response relationships will lead to better dietary advice for individuals and popula- tions. This chapter describes several opportunities for maximizing human function and reducing the risk of diet-related chronic diseases. Our ex- amples were selected to represent major needs and promising opportuni- ties and challenges for nutrition-related research. The past successes of the nutrition and food sciences have enabled us to eradicate or signifi- cantly reduce the incidence of straightforward nutrient deficiencies, un- cover links between diet and chronic diseases, and begin to identify how dietary choices affect development throughout life. Today's science pro

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46 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES vices exciting challenges to the nutrition and food sciences for those com- mitted to increasing healthy lifespans and who acquire the knowledge and tools to do so. NEW OPPORTUNITIES: MAXIMIZING FUNCTION Reproduction Our understanding of nutrient function during various stages of the life cycle has advanced markedly during the past decade. It is now recog- nized that a woman's nutritional status at the time she conceives influ- ences several aspects of her physiological response to pregnancy, relation- ships between her weight gain and the infant's birthweight, and the infant's anatomical development. Research now shows that, during lactation, mothers are generally able to produce milk of sufficient quantity and quality to support normal infant growth rates for at least the first three months of life, even when the mother's dietary supply of nutrients is limited, and for four to six months under the desirable conditions common in industrially developed countries. Breastteeding confers several health benefits on the infant. It reduces the incidence and severity of certain infectious gas- trointestinal and respiratory diseases and may lessen the infant's risk of immunologically related chronic diseases of later childhood and, in pre- mature infants, may improve cognitive development. Research Opportunities Develop strategies that will enable women to gain appropriate amounts of weight during pregnancy Weight gains during pregnancy may be either too small or too large. In the last few years, recommendations for weight gain during pregnancy have increased significantly, based on new research and a review of existing data. The recommended weight gain for women of normal pre-pregnancy weight is 25 to 35 pouncls; for women of low pre-pregnancy weight, 28 to 40 pounds; for extremely obese women, at least 15 pounds; and for women carrying twins, 35 to 45 pounds. This weight should be gained gradually, through a nutritionally adequate diet. At a time when many women feel social pressure to be slender, more research is needed to develop strategies that succeed in encouraging women to try to achieve recommended weight gains during their pregnancy. It is also important to identify the number of women who gain excess weight during pregnancy and who do not lose it postpartum. Special treatments should be developed for these women. Physicians and nurses must be educated and trained to enhance their management skills related to gesta- tional weight gain. Research on weight gain during pregnancy must also address the question

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UNDERS'TANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 147 of the significance of the composition of this weight gain. Why do women in some industrially developed countries such as the United States and Sweden have higher fat gains than average? Is the gain in fat linked to food habits, the source of dietary energy, the amount of vitamins and minerals in the diet, or the result of weight fluctuations; What are the long- term consequences of high fat gains during pregnancy? Is there an optimal fat gain for pregnant women? These are all researchable questions. Determine the effects of nutrition on embryogenesis There may be im- portant nutritional influences on embryogenesis, and disturbances of a nutritional-metabolic nature may lead to congenital malformations and limit behavioral development. For example, there is compelling evidence anal giving vitamins, especially toiate, to women around the time of con- ception decreases the risk of their babies developing neural tube defects. Others have related more subtle limits in cognitive performance to other micronutrient deficiencies and general undernutrition. Another example is the suggestive evidence that glucose concentrations in extracellular fluid are linked to the development of various fetal malformations. Several studies, though indirect or not o~timallv designed. imolv that rigid ~Ivcemic con . 1 . - - - . - . .. . . . . a 1 J ~ 4~-) ~ 1 1 - 1 . - . . 1 . . ~ . . ~ 1 ~ . trot In diabetic women at the time of conception lowers the otherwise elevated incidence of fetal malformations. The changes in women's hor- mone production, and the resulting changes in metabolism annetite food tolerance, and dietary intake, need further study. The primary research opportunity in this area is to define the molecu- lar basis of these phenomena and how these mechanisms are influenced by overall dietary intake and food choices. This research bears directly on the issue of teratogenesis (the development of physical defects in utero), but it also will help in determining the benefits of dietary supplements during pregnancy. Explore the relationship between calcium intake and risk of hypertensive disorders of pregnancy There is an association between the status of calcium in the body and the development of acute hypertensive disorders of pregnancy, collectively known as preeclampsia. For example, epidemio- logical studies show an inverse relationship between calcium intake and the incidence of preeclampsia. Calcium supplements lower mean blood pressure in some people. In addition, preliminary clinical trials in which pregnant women were given calcium supplements suggest a lowered fre- quency of preeclampsia. If this relationship between calcium and preeclampsia exists, its mechanism is obscure. Identifying it would raise the hope of reducing the incidence of a disorder that accounts for a substantial proportion of morbidity and mortality among pregnant women and their fetuses.

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148 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES Identify the relationship between lactation and calcium loss in the mother Approximately 280 milligrams (mg) of calcium are secreted in breast milk each day, resulting in significant stress on the mother's calcium stores. If there is no adaptation to conserve calcium by the mother, then this loss could lead to changes in calcium balance, resulting in bone demineraliza- tion and increasing her future risk of osteoporosis. A primary physiologi- cal adaptation to lactation appears to be a decrease in calcium excretion by the kidneys. Whether this decrease is a result of changes in calcitropic hormones (such as parathyroid hormone) during lactation is not known. In fact, an increase in bone mineral content after the baby is weaned has been observed and appears to compensate, in part, for the loss that oc- curred during lactation. The extent to which the significant hormonal changes that occur during lactation and weaning are involved in adapting to the calcium loss imposed by lactation and the increase in bone mineral during weaning needs to be clarified. Once the mechanisms behind these alterations are known, it may be possible to preserve, or even increase, bone mineral content during these periods. Calcium kinetics can now be studied using stable isotopes, and these should show how calcium compartments change during lactation and weaning. More accurate methods of determining calcium status (in- cluding dietary intake) are being developed, and studies of the role of calcitropic hormones, as well as estrogen and progesterone, in bone me- tabolism are proceeding. In addition, advances in technologies to measure bone density are enabling investigators to study regional changes in both trabecular and cortical bone. The radiation doses used in these technolo- gies are now low enough to permit safe long-term studies of bone mineral changes. Develop a better understanding of the role of nutrition in the etiology of various other pregnancy-related outcomes and conditions Low-birthweight infants, delayed onset of milk production, and maternal health problems such as gestational diabetes are still prevalent in the United States. Fur- thermore, the etiologies of these problems are largely unexplained. What maternal dietary and health behaviors are associated with these unfavor- able outcomes? Does maternal dieting, both short- and long-term, influ- ence the onset of these problems? What is the role of overall diet quality, physical activity, occupation, stress, and quality of life? Are vitamin-min- eral supplements beneficial during pregnancy and lactation and prefer- able to fostering improved nutrient intake through diet'? If so, which ones are beneficial and when? How much is needed? Are there any potential health consequences from the long-term use of vitamin and mineral supple- ments, especially those containing iron? Are pregnant women more likely

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 149 VON GIERKE'S DISEASE: A REVOLUTION IN TREATMENT Nutritional therapy has had a very important impact on the lives of people with certain genetic diseases known as inborn errors of metabo- lism. One of the more common and most important of the inborn errors of metabolism affecting glycogen storage is glycogenosis type 1. First de- scribed by Von Gierke in 1929, it is caused by a deficiency of glucose-6- phosphatase activity in the liver and kidneys. Affected children are unable to produce glucose from liver glycogen normally, and they consequently suffer from recurrent hypoglycemia. Their growth is stunted, and they have a host of secondary abnormalities, including serious clinical prob- lems such as metabolic acidosis and recurrent nose bleeds. In the past, these children frequently died before puberty, and those who did survive almost invariably developed complications including multiple adenomas of the liver that could become malignant. It has been well understood for some time that the continual provi- sion of carbohydrate to children with this disorder by frequent feedings could ameliorate the biochemical abnormalities, such as lactic acidosis and high blood concentrations of uric acid and lipids. However, the intro- duction of nocturnal nasogastric feeding of a high-glucose formula in 1976 dramatically changed the outlook for children with Von Gierke's disease, so that most of them now live into adult life with markedly improved health and amelioration of all the consequences of sustained hypoglyce- mia. This form of treatment was largely superseded in 1984 when investi- gators reported that feeding affected individuals uncooked starch in a suspension of water maintained their blood glucose levels for up to six hours, because of the slow degradation of this form of starch by pancre- atic amylase. Thus, the difficult nasogastric regimen that required intuba- tion each night was replaced by a much simpler one that is virtually as effective. Phenylketonuria was the first inborn error of metabolism treated successfully by nutritional means (by a diet low in phenylalanine). The dietary treatment of Von Gierke's disease is an equally impressive exam- ple of nutritional therapy based upon knowledge of metabolic pathways. to adopt healthful behaviors? At what point after pregnancy and lactation is it best to initiate weight management? Growth and Development Growth and development are uncler genetic control, but they are modified by diet and the environment. Each developmental step is contingent upon

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150 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES the preceding one. This process probably accounts for the normal varia- tion in maturation and likely influences the development of chronic dis- eases throughout life. Not well described are the mechanisms relating specific phenotypes to a person's genetic endowment (except in the case of certain inborn errors of metabolism), nutritional intake, and environ- ment and the importance of specific dietary variables in determining indi- vidual risk of chronic disease. Research Opportunities Identify behavioral consequences of ingesting breast milk during infancy Only now are the nonnutritive effects of milk ingestion and their underlying mechanisms being discovered. Milk, through its fat moiety, calms infants. Moreover, it reduces gross motor activity, reduces tachycardia, and doubles the pain threshold. These responses appear to be mediated by central opioid and cholecystokinin (CCK) receptors. One intriguing speculation is that these responses may influence long-term motivational systems. One challenging opportunity is to identify the mechanism of how milk, within the context of its delivery by parent or caretaker, quiets the infant and thereby conserves energy while concomitantly providing energy. This may help us to treat low-birthweight infants with increased energy needs and provide an understanding of fundamental issues related to energy conservation and growth. Meeting this research challenge should reveal the earliest mechanisms that determine food intake en cl its affective con- sequences, including food selection, feeding disorders, and the develop- ment of obesity. Develop a better understanding of the tong-term consequences of nutri- tional insults on early development The hypothesis that growth failure in early childhood predicts functional impairment at later ages has been sub- stantiated recently in the follow-up to a supplementary feeding study conducted in Guatemala between 1969 and 1977. Length at age three was found to be independent of linear growth from age three to adulthood, indicating that individuals were unable to compensate for growth retarda- tion incurred in early childhood. The degree of stunting at age three was related to measures of intellectual achievement such as literacy and high- est grade completed. The relationships among early growth, diet, and later functional abilities remain to be elucidated. Especially important is the role of micronutrients in development; for example, recent investiga- tions have related iron nutriture to cognitive development and subclinical vitamin A deficiency to mortality. A number of questions illustrate the challenge presented by this op- portunity. What are the vulnerable periods of development in humans? What type and degree of malnutrition affects development during specific

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 151 periods of maturation? Is there a generational carryover in malnutrition? Does early malnutrition limit economic productivity in adults? What is the role of early overnutrition versus undernutrition on long-term function? Is exercise balanced with an increased energy intake essential to healthy development and normal function in chiTclren? What is the nature of pa- rental influences on infants who fail to thrive? Explore the relationship between early diets and metabolic "imprinting'' Changes in diet during the prenatal, sucking, and weaning periods may have a lasting impact on metabolic development. The activi- ties of the rate-limiting enzymes of cholesterol and bile acid syntheses appear to be affected by diet during these periods of development. Simi- larly, studies of spontaneously hypertensive and salt-sensitive strains of rats also suggest that maternal diets during gestation and preweaning diets modulate blood pressure responses. Also, diets in early infancy can affect whether insulin-dependent diabetes develops in rat strains genetically pre- disposed to the abnormality. Unfortunately, neither the mechanisms responsible for the apparent "imprinting'' of metabolic responses by early diet nor the bases for the susceptibility to dietary influences during specific stages of development are known. Similarly, it is not clear whether we should extrapolate the results of animal studies of metabolic imprinting to humans. For example, while breastfee(ling has been suggested to prevent or ameliorate atopic conditions, insulin-dependent diabetes, and some forms of childhood can- cers, the evidence is not conclusive. Identify the role of nutrition in prolonging the span of healthy lives Overall health and function among the elderly are not linked to chronological age. Environmental and genetic factors also play an important role in the aging process. What factors contribute to variation in the aging process? How can we distinguish the pathologic from physiologic accompaniments of aging, such as changes in blood pressure and glucose tolerance? What long-term eating behaviors and lifestyles are associated with attaining a healthy old age? Undernutrition in animals slows the aging process. Will low intakes of specific nutrients also slow aging in humans? If so, at what cost to other functions? Does nutritional status influence the onset of menopause? If so, why? What is the role of antioxidants in aging? Do they exert an effect independent of their known physiological function and their role in the prevention of chronic disease? What effect does aging per se have on circulating concentrations of key metabolites used to assess health (e.g., cholesterol in the blood)? These and related questions illus- trate important issues that will gain increasing attention as the population ages.

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.52 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES NUTRITION AND VISION-RELATED DISORDERS OF AGING The lens of the eye is designed to focus images on the retina. Aging compromises the function of both lens and retina. Age-related macular (i.e., retinal) degeneration (AMD) and age-related cataract are the major causes of blindness among the elderly. There are two forms of AM D. The more common is the "dry" form, characterized by a slow, insidious atro- phy of the photoreceptors, retinal pigment epithelium (RPE), and chorio- capillaries (the rich capillary bed that serves the photoreceptors, outer plexiform layer, and RPE). This atrophy severely compromises normal visual tasks such as reading, facial recognition, and depth perception. The atrophied area expands with time but rarely leads to total blindness. At present, there is no prevention or treatment for this condition. "Wet," or exudative, AMD is characterized by subretinal neovascularization, an aggressive growth of blood vessels from the choriocapillaris up through the retina that causes hemorrhage and scarring in the retina. Almost 90 percent of severe visual loss in AMD occurs in the 10 percent of cases with wet AMD. Dysfunction of the lens caused by partial or complete opacification is called cataract. Research Opportunities Explore the relationships between AMD and antioxidants AMD affects al- most 30 percent of people in the United States over age 65, and the proportion of affected persons increases with age. AMD is also the pri- mary cause of new blindness in persons over age 65. Clinicians estimate that by the year 2011, over 8 million Americans will experience some loss of vision due to AMD. Although careful monitoring and laser ablation slow the course of the exudative disease, this treatment may cause some immediate loss of vision, and it usually does not prevent the ultimate loss of central vision. Although the pathogenesis of AMD has not been elucidated, it is believed widely that the primary lesion lies within the RPE cells and that excessive exposure to light and active forms of oxygen are involved. This is because the photoreceptors and RPE cells reside in a highly oxygenated environment subject to bright illumination. As with cataract, oxidation appears to play a role in the etiology of AM D. Elevated concentrations of carotenoids, vitamin A, vitamin E, zinc, or all of these have been associated with diminished risk or progression of AMD in several preliminary reports. It is essential to examine the relationship between AMD and antioxidants for the prevention of AMD and to determine what concentrations of these antioxidants may be helpful.

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 153 Develop an improved understanding of the ability of antioxidants to prevent cataract formation Approximately 50 million persons in the world are blind from cataracts. More than 700,000 cataract extractions are per- formed annually in the United States. In fact, cataract extraction is the most frequently performed surgery among the elderly. In this country, the prevalence of senile cataract sufficiently severe to reduce vision is approximately 4.5 percent, 18 percent, and 45 percent among people age 52 to 64, 65 to 74, and 75 to 85, respectively. If cataracts cou Id be delayed by only 10 years, the need for cataract extraction would be diminished by half. This would lead to considerable financial benefit, gains in productivity, and enhanced quality of life among the elderly. Although an awesome problem in the industrially developed nations, the situation is worse in the developing countries because (1) there is a dearth of ophthalmologists to perform the lens extractions and replacements, (2) cataracts are three to four times as common, and (3) cataracts develop earlier in life. About 98 percent of the solid mass of the lens is protein. Lens proteins are extremely long-lived, therefore it is not surprising that in the aged lens the vast majority of protein matter may be damaged extensive- ly. Much of the damage involves oxidation. The altered proteins accumu- late, aggregate, and precipitate. Recent studies indicate that consumption of dietary antioxidants (vitamins C, E, and carotenoids) is associated with delay of cataract, but clinical trials must be completed. Body Composition Understanding the determinants of body composition is central to the nutritional sciences. In few other areas is the interplay between genetic endowment and the environment as evident as it is in the phenotypic expressions of diverse body compositions. Opportunities in the area of body composition assessment encompass a wide range of challenges in human physiology coupled with biophysics and bioengineering. Research Opportunities Explore relationships between lean body mass and selected functional in- dicators In [ate adult life Cross-sectional data show that loss of lean body mass (LBM) occurs with advancing age. The Baltimore Longitudinal Study on Aging showed an approximately 12 percent loss of LBM, determined anthropometrically, in men age 75 to 84 compared to men age 25 to 34. Using total body potassium as an indirect measure of LBM, one sees even more dramatic differences. Thus, it seems clear that erosion of LBM ac . . companies aging.

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 169 vasorelaxation is dependent on calcium. From the clinical arena, reports recently have noted that salt sensitivity is only evident in populations on low-calcium and low-potassium diets. Research is needed to identify the mechanisms whereby these elec- trolytes interact. Given the critical role that electrolytes play in signal transduction, enzyme activation, and control of gene expression, we need basic investigations to identify the mechanisms whereby specific concen- trations of electrolytes reduce overall cardiovascular risk. For example, calcium intake in experimental models of hypertension can be manipu- lated to produce the optimal amount of calmoduTin, a ubiquitous calcium- binding protein. Given the essential role of this protein in all cells, further exploration of the mechanisms whereby ingestion of dietary calcium re- sults in increased cell production of calmodulin will enhance our uncJer- stancling of how it and possibly other electrolytes influence regulation of blood pressure. We need to find out whether sodium sensitivity could be eliminated completely if people simply maintain an adequate intake of these other electrolytes, and, perhaps most important, we must determine whether the protective action of calcium, magnesium, and potassium is somehow sodium-dependent. Studies of both humans and animals suggest that the ability of calcium and potassium, and possibly magnesium, to Tower blood pressure may require an intake of 150 milliequivalents (mEq) of sodium per day. Studies to define this carefully may be of immediate value. identify the role of lipids anc] carbohydrates in tile deve70pment of hypertension Other dietary components also influence blood pressure. While there is little doubt that omega-3 fatty acids improve regulation of blood pressure, monounsaturated fatty acids, as well as saturated fatty acids, neec! to be investigated. The contribution of phenylated proteins, the metabolic offspring of the cholesterol pathway, also merits explora- tion. The influence of dietary fats on G proteins is postulated to be critical to the regulation of function of vascular smooth muscle. The 80 percent concordance of essential hypertension and carbohy- drate intolerance has been confirmed repeatedly. While much of the fo- cus has been on insulin's potential for affecting regulation of blood pres- sure (primarily through sodium reabsorption in the kidneys), more recent investigations suggest that insulin may link abnormal carbohydrate me- tabolism and blood pressure directly. Careful examination of the impact of glucose itself and of general cellular metabolism is needed to delineate the role of carbohydrates in the control of blood pressure. In addition, the effects of various types of carbohydrates and their respective influences on tone of vascular smooth muscle and sympathetic muscle require fur- ther exploration.

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170 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES Cardiovascular Disease and Arteriosclerosis Strong correlations among the amounts and types of fat consumed by various populations and their rates of coronary heart disease (CHD) have directed attention to diet as a potentially important cause. Research has . ~ implicated numerous constituents of diet such as saturated, monounsaturated, and polyunsaturated fatty acids; trans-unsaturate] fatty acids; antioxidants; and various minerals and water-soluble vitamins. This research under scores the role of nutrition and the challenges to the field. Further, popu- lations migrating from areas with a low incidence of CHD to high-inci- dence regions also experience substantial increases in CHD, emphasizing the importance of lifestyle over genetic factors in explaining many geo- graphical differences. Research Opportunities Improve our understc~nding of the biological mechanisms linking CHD to the consumption of dietary fats The intake of saturated fatty acids (satu- rated fat) has received the greatest attention as a potential cause of CHD because of its particularly strong geographical correlation with incidence rates. Although the ecological correlations are notably susceptible to con- founding by other (lietary and nondietary lifestyle factors, major support for the saturated-fat hypothesis derives from metabolic feeding studies indicating that saturated fats increase total and low-density lipoprotein (LDL) cholesterol, combined with firm epidemiological data relating these serum lipids to the risk of CHD. Nevertheless, the relation of saturated- fat intake to CHD risk appears more complex than previously thought. There are several reasons for this. For example, the chain lengths of satu- rated fatty acids influence their response to lipids in the blood. Some saturated fatty acids do not appear deleterious, indicating the need to reevaluate individual fatty acids in relation to specific lipid fractions. Since coronary thrombosis is a common precipitating event in the development of CHD, the Diverse effect of any dietary factor on development of CEID need not be limited to its effect on serum cholesterol concentrations. Indeed, some investigators have suggested that saturated fats may pro- mote coronary thrombosis. Unfortunately, remarkably few studies have ~ , , evaluated this important question, and several ot them have serious meth- odological limitations. Furthermore, randomized trials of dietary interven- tions for the prevention of CHD have often been complicated by simulta- neous modification of multiple factors and have not provided any clear evidence of reducing saturated fat. Accumulated evidence of several types suggests that saturated fat intake plays a more complex role in the etiology of CHD than has often been assumed. Analogous issues relate to the

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UNDERSTANDING DIET, HEALTH, AND DZSEASE RELATIONSHZPS 171 study of the mechanisms linking CHD to the consumption of other fats, such as the n-3 fatty acids. Define the role of linoleic acid in CHD prevention A small quantity of linoleic acid (about ~ g per day) is required for human health. In one prospective study conducted in the l950s to 1960s, when the average intake by the U.S. population was far lower than today, an inverse relation between linoleic acid intake and risk of CEID was observed. Similar re- sults have been reported recently. When linoleic acid is substituted for saturated fatty acids in the diet, concentrations of cholesterol in the blood fall. The significance of its effect on specific lipid components is less clear. For example, linoleic acid can lower concentrations of high-density lipoproteins (lIDL) as well as LDL. The previously stated goal of increas- ing polyunsaturated fat to 10 percent of total calories in the U.S. diet is being reconsidered, in part because of theoretical concerns regarding the long-term effects of such a diet on other health risks (e.g., possible in- creased risk for cancer and suppression of the immune system). Explore the role of monounsaturated fatty acids in lipoprotein regu- [ation Monounsaturated fats have been considered neutral; they were thought neither to raise nor to lower serum cholesterol. In more recent studies, substituting monounsaturated for saturated fat decreased LDL cholesterol without decreasing HDL cholesterol, whereas substituting car- bohyclrates for saturated fats decreased both LDL and ElDL. Further- more, LDL particles rich in monounsaturated fatty acids appear to be snore resistant to oxidation, which may make them less atherogenic, at least compared to LDL enriched in polyunsaturated fatty acids. These recent metabolic findings are consistent with the geographical association between high intakes of monounsaturated fat in the southern Mediterra- nean countries and low rates of CEID. Assess the role of processed fats (e.g., trans-unsaturated fatty acids) in CHD Trans-unsaturated fatty acids are formed by the partial hydrogena- tion of polyunsaturated liquid vegetable oils during the production of margarine and vegetable shortening. These products have the advantage of being devoid of dietary cholesterol and being generally low in cholesterol-rais- ing saturated fatty acids. Although no consistent effect of bans isomers on total serum cholesterol was observed in several earlier studies, in more recent feeding studies, bans isomers of unsaturated fatty acids increased LDL and reduced lIDL. These findings have caused concern about the ingestion of bans isomers, which today contribute about 3 percent of total calories to the U.S. diet.

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1~? OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES Explore the role of micronutrients in CHD In addition to the long-stand- ing hypotheses relating type and amount of dietary fats to CHD, newer hypotheses have emerged in recent years. These do not necessarily con- flict with, and may ultimately complement, relationships with dietary fats. Several dietary antioxidants, particularly vitamins E, C, and beta-caro- tene, may reduce the oxidation of LDL particles and thereby interfere with the development of atherosclerosis. At present, epidemiological data are largely ecological in nature, but they support the hypothesis that high intakes of antioxidants may reduce the risk of CHD. This possibility rep- resents one of the more exciting developments in nutritional research. Rapidly accruing data also indicate that high concentrations of homo- cysteine in the blood are a risk factor for CHD (see box). An excess of this amino acid in plasma may directly damage the arterial wall which can promote atherogenesis. Supplementation with folio acid or vitamin B6, or both, often reduces elevated homocysteine substantially. Whether such supplementation can reduce the risk of CHD remains unclear. Understand the metabolic interrelationship between obesity and concli- tions related to increased CHD The relationship between obesity and CHD is poorly understood. Obesity has several metabolic consequences that increase the risk of CEID, including dyslipi(lemia Higher very-low- clensity lipoproteins (VLDL), higher LDL, and lower HDL concentra- tions], hypertension, and insulin resistance. The more severe the obesity, the more severe the metabolic consequences. Whether obesity enhances the risk of CHD through other mechanisms (e.g., hyperinsutinemia or thrombogenesis) remains to be elucidated, but some authorities speculate that it does. Certainly, additional investigation of the impact of obesity on development of CHD is needed, together with research on the mecha- nisms of this relationship. At least as important as the severity of obesity is the distribution of body fat. Even a modest increase in visceral fat increases all risk factors for CHD. In addition to the overall risk conferred by visceral fat in CEID, it has been implicated in several pathological conditions, such as familial combined hyperlipidemia. These abnormalities, and others related to obe- sity, seem to accelerate the development of atherosclerosis, dyslipidemia Characterized by small VLDL particles, increased intermediate-density lipoproteins (IDL), small-dense LDL, increased total apolipoprotein B. decreased HDL2, and decreased apolipoprotein A-1], hypertension, and hyperuricemia. This aggregate of metabolic abnormalities appears with and without familial predispositions and is frequently associated with pre- mature CHD, peripheral vascular disease, and stroke. Although visceral obesity alone appears to predispose people to these abnormalities, the particular pattern of abnormality that develops (e.g., dyslipidemia or hy

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UNDERS'TANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 1 /3 HOMOCYSTEINE AND VASCULAR DISEASE Abnormal homocysteine metabolism was first described in 1 962 in two siblings with mental retardation who excreted large quantities of homocystine in their urine. Several years later, homocystinuria caused by an inherited defect in hepatic cystathionine beta-synthase was reported. Later, homocystinuria and vascular disease were also associated in pa- tients with inherited defects in either hepatic cystathionine beta-synthase or methylenetetrabydrofolate reductase. When the pathology of these patients was reviewed, a causal association was proposed between arte- riosclerosis and homocysteine elevation in blood. A possible relationship with nutritional cofactors folate, vitamin B12, and vitamin B6 was implicit in these original observations, and a number of early papers demonstrat- ed some amelioration of activity of genetically defective pathways with large doses of these vitam ins. Recently, there has been increased interest in the relationship of moderate homocysteinemia to vitamin status and its association with cardiovascular disease. The serum protein-bound homocysteine concen- tration was related inversely to serum folate. This suggested that pro- longed folate depletion, even at low normal levels, might lead to moder- ate or persistent homocysteinemia and hence to vascular disease. Homocysteinemia has been induced nutritionally in animals made defi- cient in either folate or vitamin B6. High doses of folate or pyridoxine have been used in humans to lower concentrations of homocysteine in the blood. In addition, elevated homocysteine concentrations have been corrected with vitamin B12 therapy when those elevations were related to deficient or borderline concentrations of vitamin B12. Thus, a clear theoretical basis for B 12 regulation of homocysteine in the blood has emerged. Plasma homocysteine concentrations were measured in surviving elderly members of the Framingham Study cohort, along with concentra- tions and dietary intakes of vitamins B12, B6, and folate. Homocysteine concentrations increased with age and lower B-vitamin status. The age association remained strong even after adjustment for B-vitamin concen- trations. This increase in homocysteine with age, independent of B-vita- min status, may result from an age-related decline in cystathionine beta- synthase and possibly other enzymes involved in homocysteine metabolism. We cannot yet conclude that lowering chronically elevated plasma homocysteine or increasing vitamin intake will cause regression of vascu- lar disease. However, a strong case can be made for preventing the marginal or manifest vitamin deficiency states that may contribute sub- stantially to this potentially important risk factor for cardiovascular dis- ease, the largest cause of mortality among the elderly. Efforts to address the best means by which to prevent deficiencies of folate, vitamin B12, and vitamin B6 in the increasing number of our population over age 65 now have added impetus.

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1~4 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES pertension) may be genetically determined. Modern molecular biological techniques may be especially useful for elucidating the genetic basis of these metabolic abnormalities. Obesity Obesity is one of the most important nutritional problems in this country, affecting over 25 percent of the population. In addition to being a direct risk to health, it increases the risk of chronic diseases such as coronary heart disease, Type II diabetes, hypertension, and several can- cers. A major advance in our understanding of human obesity has been the recent demonstration of the importance of genetic factors in its etiol- ogy. Obesity is a disease whose origins lie in the interaction between genetic predisposition and environmental variables, chief among which are food intake and physical activity. It arises from periods of imbalance between energy intake and energy expenditure. However, we do not un- derstand the causes of these imbalances or, indeed, how energy balance is regulated. Meeting challenges in each of these areas is crucial to unravel- ing the etiologies of this condition. Research Opportunities Enhance our understanding of the socioclemographic determinants of obesity Obesity is increasingly prevalent in the United States and is more common here than in other industrially developed countries. It is particu- larly common in some subgroups, such as black women, in whom the prevalence (50 percent) is twice that in white women, and it is strongly inversely related to socioeconomic status in women of all races. What dietary behaviors predispose individuals to obesity? Does it reflect an increased reliance on fast foods or convenience foods, lack of opportunity or requirement for physical work, or all of these? EIow can obesity be prevented or treated'? Obesity in children and teens can have a devastat- ing effect on their self-esteem. What is the role of food behaviors (e.g., snacking) and limited physical activity in the etiology of obesity among children and teens? How can obesity be treated in this group without increasing the risk of eating disorders? These and related questions re- main central to this area of investigation. Improve our understanding of the control offood intake Research is needed to clarify the controls on neurotransmitters and receptor systems in the central and peripheral nervous systems. Over the past two decades, considerable progress has been made in research on the roles of several peptides involved in the regulation of food intake cholecystokinin and

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATZONSHZPS 175 bombesin-like peptides, glucagon, neuropeptide Y. galanin, endorphins, calcitonin, and neurotensin. However, we have yet to establish the physi- ological relevance of these signals, their mechanisms of action, and their clinical utilities, especially the interactions, if any, among these systems and macronutrient intake to produce satiety. Much remains to be learned about their physiological interrelationships and how they can be affected pharmacologically. Further research in this area will be facilitated greatly by the genetic strains of animals predisposed to obesity now available and the development of others with anomalies in target receptor systems. Re- search is expected to yield pharmacological and dietary strategies for the prevention and treatment of obesity. Develop a better understanding of metabolic strategies for short- and tong- term control offood intake It is likely that homeostatic controls on food intake can be disrupted when the caloric concentrations, sensory qualities, or both of the diet are enhanced. The result may be obesity among geneti- cally vulnerable individuals. Determining the genetic and physiological basis of this vulnerability will improve our understanding of obesity and increase our understanding of the short- and long-term homeostatic con- trols of food intake. Identify the metabolic role of energy reserves in the regulation of body composition and weight A critical area for future research in obesity is regulation of body weight. Food intake in some individuals appears to vary widely over the short term, while body weight remains within narrow limits. What are the mechanisms that maintain body weight within rela- tively narrow limits despite seemingly wide fluctuations in food intake? In such cases, what signals occur and how are they processed? Whether en- ergy reserves produce signals that might regulate intake is unknown. Also, there have been suggestions that circulating concentrations of carbohy- drate, fat, and amino acids, as well as energy production, determine hun- ger and satiety. There is experimental evidence in favor of each of these possibilities, but we still do not understand fully why eating is initiated and terminated or how it is controlled over long periods of time. Apply molecular genetics to decipher the roles of genetics and the environ- ment in the development of human obesities The tools of molecular ge- netics can greatly advance our understanding of obesity. Indeed, studies of obese animals provide the best evidence of interaction between genetic and dietary factors in the expression of obesity. Animal models of obesity slow that the disorder can be caused by a single defective gene or by more than one defective gene. Twin and adoption studies show that ge- netic factors contribute significantly to the etiology of human obesity and

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176 OPPORTUNITIES IN THE NUTRITION AND FOOD SCIENCES suggest that a major gene may be responsible. The characterization of the human genome will help us identify genetic contributions to human obe- sity, particularly as phenotypic expressions of obesity are better under- stood. The ob/ob mouse and the Zucker rat gain excess weight through overeating of any diet, whereas other animals' obesities are promoted by high-fat diets, sucrose solutions, or the so-called cafeteria diet. Diets con- taining high proportions of fat are more efficient in promoting obesity than are low-fat or fat-free regimens. While a portion of excess carbohy- drate calories is lost as heat, fat calories tend to be deposited more effi- ciently as body fat. Elucidating the genetic endowments that predispose people to obesity and the metabolic mechanisms underlying the (distinct characteristics of obesities of apparently diverse etiologies will represent a major advance in obesity research. Explore the role of defects in energy expenditure in human obesities Recent studies have suggested that decreased energy expenditure for a given lean body mass may contribute to the development of obesity in some indi- viduals. Thus, pre-obese individuals may be metabolically more efficient. As a result, more energy is available for storage. These studies show, however, that the calories saved by the increased efficiency are inad- equate to account for the weight gain and that increased energy intake probably plays the more important role. Thus, decreased energy expencli- ture may serve more as a marker of overeating than as the only cause of weight gain. This controversy provides significant challenges to under- standing energy regulation. Longitudinal studies of infants, children, and adults are needed to determine the relative contribution of different risk factors to the clevel- opment of adiposity and obesity. Studies of persons at genetically deter- mined high risk of obesity are particularly necessary; we need to learn the relative contribution of total energy expenditure, resting metabolic rate, and food intake on body composition during growth and development. Learn more about the basic biology of adipose tissue Regulation of li- polysis and lipogenesis is an important area of investigation. While a great deal is known about these processes, little information is available about interindividual differences and how they can affect the induction or main- tenance of obesity. We need to know more about differences among obese and nonobese persons in lipoprotein lipase, hormone receptor number and regulation, glucose transporters, second messengers within the cell, and relevant enzymatic activation and inhibition, all of which may be im- portant in the development of the condition. Our knowledge of differ- ences in adipose cells (e.g., those associated with distinct anatomical loca

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 177 tions such as visceral and subcutaneous abdominal sites) that may contrib- ute to obesity is inadequate. The process by which a pre-adipocyte be- comes an adipocyte and the stimulatory factors that promote this process at various sites in the body and at various ages needs to be explored in much more depth. Develop improved treatments for obesity At the present time, over $30 billion is spent each year on programs and products designed to control body weight, and the market is growing. Yet the prevalence of overweight has increased over the past two clecades. The treatment of obesity has improved during the past decade, and it is now possible to safely achieve weight losses of 20 kg (44 lbs) with some consistency. The major problem remaining in the treatment of obesity is maintenance of the weight loss. The major research priority in this area is the development of methods for long-term maintenance of weight control. Diarrhea While not a significant problem in the United States, diarrhea re- mains the most frequent cause of death of young children in the world. In addition to those who die, many more children suffer significantly im- paired health, nutritional status, and development. The increased frequency of evacuation and the high fluid content of the feces that characterize diarrhea are usually caused by pathogens, including parasites, viruses, and bacteria, but they may also result from food intolerance or a variety of other functional, metabolic, or anatomical abnormalities. Research Opportunities Enhance our understanding of how specific nutrients modulate individual responses to diarrheas of specific etiology From a nutritional standpoint, the prevention and optimal management of diarrhea! illness present im- portant challenges. Information is needed regarding the mechanisms that determine nutrient absorption and utilization in diseases caused by spe- cific pathogens. The precise role of micronutrients in immune function or epithelial cell replication is particularly important. Zinc, for example, ap- pears to affect a number of immunological responses. Without adequate zinc, the ability of T cells to release autocrine-stimulating growth factors, such as IL-2, is impaired. Zinc deficiency may adversely affect the normal replacement of epithelial cells in the intestinal tract. Selenium affects the release of humoral immunoglobulins (particularly subclasses of IgG) and influences the production and release of IL-1, an important initial step in

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j73 OffOBTC\~TlES IN T~E \~\ 4~ Fang SC1E\~S the immune response. The role of Lt-soluble vitamins rise merits in- creused scrutiny. Vitamins A and E appear to inOoence the release of interleuLins Mom lymphocytes under mitogenic shmulubon and to modu- lute the leuLotriene prostu~lundin system. An example of more direct ~gniEcunce to industriuDy developed coun- tries is the composition of infant ~rmulus. Then, nucleotides are not provided to infants Ad synthetic Surplus, but recent in~rmudon su~- ges~ that they may brave important shmulutory enacts on immune ~nc- hon, both systemic and gastrointestinal. Other nutrients known to be es- sentiu1 to epithelia1 Unction of the gustrointestinu1 tract, such as glutumine, ado have ~ profound enact on the secretory IgA system. ~f~ fag ~~& 69 ~~66 66~& p~f66~ /~9 4~~ )~ At the interface of Liolo~icu1 and Leh~vioru1 research is the impact of breust~eding on diurrhea1 disease. Breasted infants are ex- posed to Aver ~odhorne pathogens. In uddibon, treast~eding protects infants in other ways, although the mechanisms that underlie these modes of protection are not well understood. For example, the role of immuno- logicu1 agents in human milk has been the subject of numerous invesUga- hons, yet controversy remains us to which is more important: the passive trunsm~sion of protection to the infant Duty lumen or the trunsm~sion of Actors that may induce the intones own immune system to respond more electively to infectious challenges. Simd~rly, there is little consensus re- gurding the role of growth Actors in milk in promoting the maturation of the infant? gustrointestinu1 epithelium (thereby augmenting mucosu1 hur- ders against the penetration of the gustrointestinu1 tract by antigens) ver- sus promoting the renew of inured intesUnu1 mucous. ~/~2 ~ ~fr~f~6 ~r p~~ff~y ~ ~~& ~ fief fn60^ aft {~9 6~7 ~67~ The ussoci~don between nuthtionu1 sta- tus and diarrhea ~ strongly influenced by cultured socials and economic Actors that Tact Ceding practices. The Piloting algorithm iEustrutes the kinds of beh~vioru1 issues that require attention. community? content? Are Hods that are appropriate Far the young child ~v~d~Lle in the Are they avuEuble in the household? Are Rods gored and prepared in ways that m~xim~e nutritive Does the child receive the appropriate floods? Does the child eat the Cods if they are oared To develop interventions that Dig reduce the sickness and death caused

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UNDERSTANDING DIET, HEALTH, AND DISEASE RELATIONSHIPS 179 by diarrhea and other infectious diseases, we must understand the factors involved in the five questions above. For example, anorexia often accom- panies diarrhea! illness, but because the basis for it is poorly understood, the role of caregiver behavior in managing the problem cannot yet be specified. Similarly, interventions to improve the energy and nutrient density of foods given to young children may require reallocation of household resources and maternal time and changes in beliefs about what constitutes appropriate foods and feeding practices for children. Furthermore, to deal effectively with these problems, it also is necessary to develop food-pro- cessing technologies appropriate to specific settings and to provide foods with acceptable storage stability, adequate energy and nutrient density, and appropriate preparation time and fuel-use requirements for cooking and hygiene purposes. CONCLUDING REMARKS ~1 . . 1 1 ~1 _ In this chapter, our examples of opportunities and challenges have focused on the nutritional well-being of individuals. We chose examples in two categories: research targeting ways to maximize functions important to well-being and optimal development (in the areas of reproduction, growth and development, body composition, immune function, central nervous system function, and food-related behavior) and research that focuses on disorders and diseases influenced by diet (cancer, diabetes, hypertension, cardiovascular disease and arteriosclerosis, vision-related disorders of ag- ing, obesity, and diarrhea in infancy and early childhood). These examples suggest important strategies for improving our understanding of food be- havior, diet, health, and disease relationships. The challenges and oppor- tunities demonstrate the value of multidisciplinary research for the future application of new knowledge in the basic sciences. They stress the knowl- edge base and skills needed to assess the relevance of new information to the individual and to make use of it efficaciously. In addition, the chal- lenges and opportunities illustrate the seamless continuity of the impor- tance of diet to health promotion and disease prevention throughout the life cycle. This characteristic is of special relevance because of the marked changes in the age structure of populations throughout the world. While we know how to avoid frank nutrient deficiencies, we cannot achieve maximal function or avoid diet-related diseases effectively without a closer and more sophisticated attention to diet.