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American Journal of Clinical Nutrition, Vol. 71, No. 6, 1665S-1668s, June 2000
© 2000 American Society for Clinical Nutrition

Article

Effect of functional food ingredients: vitamin E modulation of cardiovascular diseases and immune status in the elderly1,2,3,4,5

Mohsen Meydani

1 From the Vascular Biology Program, Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston.

2 Presented at the 17th Ross Research Conference on Medical Issues, held in San Diego, February 22–24, 1998.

3 The contents of this publication do not necessarily reflect the views or policies of the US Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.

4 Supported in part by the US Department of Agriculture, Agricultural Research Service, under contract number 53-K06-01.

5 Address reprint requests to M Meydani, Vascular Biology Program, USDA HNRC on Aging at Tufts University, 711 Washington Street, Boston MA 02111. E-mail: mmeydani{at}hnrc.tufts.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 AGING AND NUTRITION
 VITAMIN E AND CVD
 VITAMIN E AND IMMUNE...
 REFERENCES
 
Increased accumulation of free radicals over time reduces the effectiveness of antioxidant defense mechanisms and heightens the vulnerability of older individuals to a variety of oxidative insults and associated pathologic conditions. Both nutritive and nonnutritive components of foods may slow declines in certain body functions. Ingestion of vitamin E, an antioxidant nutrient, in amounts above current recommendations may reduce the risk of cardiovascular disease, enhance immune status, and otherwise modulate important degenerative conditions associated with aging. Early adoption of proper dietary habits helps adults to maintain quality of life as they age. Increased intake of vitamin E through selection of foods with large amounts of that vitamin and daily consumption of 5–8 servings of fruit and vegetables may reduce risk for cardiovascular disease and improve immune function in later life.

Key Words: Functional food • aging • free radicals • vitamin E • antioxidants


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
AGING AND NUTRITION
 VITAMIN E AND CVD
 VITAMIN E AND IMMUNE...
 REFERENCES
 
Aging in humans is associated with changes in physical characteristics and the decline of many physiologic functions. Although phenomena associated with aging have been described in detail, the basic nature of the aging process is not well understood. Observations accumulated in recent years have provided the basis for a modern concept of aging—the free-radical theory, which relies on a time-dependent shift in the oxidant-antioxidant balance in the body that leads to increased oxidative stress, dysregulation of cellular function, and aging as manifested by phenotypic changes and functional deterioration in later life. Genetic, environmental, and lifestyle factors play important roles in the rate of change in this balance and, thus, in the rate of aging and the development of age-associated diseases.

Lifelong production of free radicals through normal function of mitochondria and other cellular constituents is the major intrinsic source of oxidative stress in the body. According to Ames et al (1), the DNA in each cell of a normal rat produces {approx}100000 oxidative lesions per day. These are constantly being removed by DNA repair enzymes, but with age the balance shifts toward a higher rate of damage than repair, leading to accumulation of DNA lesions, cell dysfunction, and, in rats, death within 2–3 y. Human cells, in contrast, produce about one-tenth as many oxidative lesions as rat cells and excrete fewer damaged DNA products. Thus, they have a relatively better repair process and antioxidant defense mechanism, which is consistent with the longer life span of humans (2).

In addition to endogenous oxidative stress, exposure to free radicals and oxidants in the environment, such as ultraviolet sunlight, ozone, cigarette smoke, smog, and other pollutants, can contribute substantially to the rate of change in the body's oxidant:antioxidant balance (3–6). The presence of complex, intrinsic defense mechanisms that scavenge free radicals and reduce oxidative stress in most aerobic organisms provides convincing evidence linking free radical accumulation with the aging process. Food components as well can modulate maintenance of the oxidant:antioxidant balance and may thereby influence the rate of aging. In short, other than genetic endowment, the major determinants of the aging process and the development of age-related diseases are thought to be factors associated with the environment and with lifestyle, particularly diet. A shift in the oxidant:antioxidant balance because of increased production of free radicals may contribute to the decline of cardiovascular, neuronal, muscular, visual, and immune functions over time. In addition, a high level of oxidative stress and free radicals has been implicated in an ever-widening array of age-related diseases (Table 1Go) (7).


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  		TABLE 1. Degenerative conditions implicated in free radical damage
 

   AGING AND NUTRITION
TOP
 ABSTRACT
 INTRODUCTION
 AGING AND NUTRITION
VITAMIN E AND CVD
 VITAMIN E AND IMMUNE...
 REFERENCES
 
Demographic data show that a major health advance of the 20th century is the increased life expectancy of most of the world's population, which is predicted to continue well into the next millennium. This increase is more apparent in developed than in developing nations, but it is evident throughout most of the world. It can be attributed primarily to increased survival of infants and young children because of substantial advances in sanitation, nutrition, medicine, vaccination, and drug development. Those over the age of 65 y constitute one of the fastest- growing segments of the US population. It is estimated that by the year 2010, people over the age of 65 y will constitute 14% of the US population, or 39 million people (8). This growth of the elderly population requires a great deal of attention, specifically, more emphasis on research on all aspects of geriatric care, including nutrition.

Historically, diet and nutrition have been recognized as important for well-being and the prevention of diseases in humans. In recent decades, the possible health benefits of several nutrients, beyond their roles in the prevention of deficiency diseases, have been explored. Observations that supplemental intakes of some nutrients may counteract, decrease, or retard age-related changes in bodily functions and disease pathogenesis suggest such effects. Epidemiologic data strongly suggest that high intakes of fruit and vegetables are associated with a reduced risk of degenerative diseases such as cancer and cardiovascular disease (CVD). In relation to this, components of fruit and vegetables, such as vitamins C and E, as well as carotenoids and flavonoids, have received a great deal of attention for their potential health benefits (9–13). This attention has focused mainly on oxidative stress (ie, the potential involvement of free radicals in the development of disease and in the aging process) and the capacity of these food components to scavenge free radicals and reduce oxidative stress. Among the nutrients and other components of foods that have been studied, vitamins E and C and the carotenoids have been investigated most extensively for their antioxidant activity and their potential roles in disease prevention.


   VITAMIN E AND CVD
TOP
 ABSTRACT
 INTRODUCTION
 AGING AND NUTRITION
 VITAMIN E AND CVD
VITAMIN E AND IMMUNE...
 REFERENCES
 
Current approaches to reducing morbidity and mortality associated with CVD rely largely on reducing dietary fat and sodium intake. Although these practices are effective, the disease remains the leading cause of mortality in the United States and most other Western societies, and thus alternative approaches must be tried as well.

During the past decade, the health benefits of vitamin E have been examined in several epidemiologic studies, with a clear reduction in risk of CVD being shown in many of them (Table 2Go) (14–23). Clinical trials have also shown certain benefits of supplemental intake of vitamin E. Hodis et al (16) reported a significantly retarded progression in coronary lesions among men who had previously undergone coronary artery bypass graft surgery and were supplemented with vitamin E. In a prospective clinical trial (the Cambridge Heart Antioxidant Study, or CHAOS) specifically designed to test the effect of vitamin E supplementation on the incidence of heart attacks in men, vitamin E supplementation was associated with a 77% reduction in the risk of nonfatal heart attacks (15). In that study, supplementation of subjects who had preexisting heart disease with 400 or 800 IU vitamin E for 18 mo modestly affected the severity of atherosclerosis (15). Vitamin E might be responsible for changes in the lipid composition of atherosclerotic plaques, thereby reducing oxidation. The most recent study to confirm earlier reports of a reduced risk of CVD with supplemental vitamin E was conducted with >11000 elderly subjects who were monitored for up to 9 y (18).


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  		TABLE 2. Vitamin E and cardiovascular disease
 
Atherosclerosis is the underlying cause of most of the morbidity and mortality associated with CVD. This disorder is a chronic local inflammatory response of the vessel wall in which dietary factors play a significant role (24). The adhesive interaction of immune and inflammatory cells with the endothelium and their subsequent migration into the subendothelium together with the oxidation of LDL and its accumulation in macrophages are among the events that contribute to the development of atherosclerosis. These events are mediated by localized production of chemokines, cytokines, lipid mediators, and growth factors as well as by expression of adhesion molecules on the surface of endothelial and immune cells, which leads to the stimulation, proliferation, and migration of smooth muscle cells from the media to the intima, where they proliferate, accumulate lipids, and elaborate the extracellular matrix of atheromatous plaque (25).

Several lines of evidence support the epidemiologic and clinical findings on the efficacy of vitamin E intake above currently recommended amounts [the recommended dietary allowance (RDA) is 8–10 mg {alpha}-tocopherol equivalents ({alpha}-TE)/d (26)]. A high intake of vitamin E from foods or supplements may modulate atherogenesis through a variety of mechanisms, including inhibition of LDL oxidation, cytokine release, platelet reactivity, smooth muscle cell proliferation, and control of vascular tone, as well as reduction of the interaction of the endothelium with immune and inflammatory cells (27–30).

Modulation by vitamin E of the interaction of endothelial and immune cells, which we and other investigators (31–33) showed, is an emerging mechanism of action for this vitamin. In brief, vitamin E modulates genes for the expression of adhesion molecules on endothelial cells and also influences the expression of integrins (adhesion ligands) on the surface of leukocytes. Increased intake of vitamin E by diet or supplementation increases concentrations of this vitamin in the immune cells, vessel walls, and other tissues (33–35). We found that vitamin E supplementation reduced LDL- and interleukin (IL) 1ß–induced adhesion of monocytes to human aortic endothelial cells (HAEC) (31). This reduction was mediated by vitamin E suppression of adhesion molecule expression by HAEC, including expression of intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin and a decrease in the release of sICAM-1 (soluble form) (31, 36). Interestingly, recent reports have indicated that lower concentrations of plasma sICAM-1 are associated with reduced risk of myocardial infarction (37). Thus, it is plausible that components of food such as vitamin E, with its capacity to reduce production of sICAM-1, may contribute to lowering the risk of myocardial infarction.

Preenrichment of HAEC with vitamin E was also effective in significantly reducing HAEC production of IL-8, a chemokine, and IL-6, a proinflammatory cytokine. We also found that HAEC production of prostaglandin (PG) I2, which has vasodilatory and antiaggregatory properties, was also enhanced when cells were enriched with vitamin E (36). Thus, vitamin E modulation of immune and inflammatory cell interactions with endothelial cells, together with accumulated evidence on the modulation of cytokines and inhibition of platelet aggregation, smooth muscle cell proliferation, and LDL oxidation, provides evidence of a mechanistic link for the beneficial role of vitamin E on atherosclerosis, which has been observed in human, animal, and epidemiologic studies. Thus, there is a rational basis for including food containing high amounts of vitamin E in the daily diet and generous amounts of supplemental vitamin E in designing functional foods for reducing the risk of heart disease.


   VITAMIN E AND IMMUNE STATUS
TOP
 ABSTRACT
 INTRODUCTION
 AGING AND NUTRITION
 VITAMIN E AND CVD
 VITAMIN E AND IMMUNE...
REFERENCES
 
Aging is associated with a decline in immune status and reduced immunologic vigor, which increase the vulnerability of older individuals to infections, cancers, and other chronic diseases. An increase in free radical burden with age is responsible, in part, for the decline of the immune system with aging. Therefore, the amounts of dietary antioxidants, such as vitamin E, required for the normal function of the immune system in the elderly are probably higher than the current RDA of 8 mg {alpha}-TE for women and 10 mg {alpha}-TE for men (26).

Vitamin E supplementation improves some aspects of the age-related decline in immune function in laboratory animals (38). Increasing the amount of vitamin E in the diet of old mice from 30 to 500 ppm significantly increases delayed-type hypersensitivity (DTH) response, lymphocyte proliferation in response to mitogen, and production of IL-2; these effects of vitamin E are also associated with decreased PGE2 production (38). Enhancement of immunity after supplementation with vitamin E has also been shown in elderly human populations. Institutionalized elderly women taking 200 mg vitamin E/d had increased serum globulin concentrations (39). In a double-blind, placebo-controlled study, Meydani et al (34) showed that vitamin E enhances cell-mediated immunity. Healthy subjects aged >60 y were given 800 IU vitamin E for 1 mo. Vitamin E supplementation was associated with increases in plasma vitamin E concentrations, DTH score, mitogenic response to concanavalin A, and IL-2 production. Vitamin E also effectively reduced production of PGE2 by the activated peripheral blood mononuclear cells as well as plasma lipid peroxide concentrations. IL-1 production was not affected by vitamin E supplementation.

In a dose-response study, Meydani et al (40) investigated the long-term effect of vitamin E supplementation in healthy older adults. In a double-blind, randomized design, subjects aged >=65 y received vitamin E supplements at doses of 60, 200, or 800 IU for 235 d. All 3 doses increased DTH responses, with subjects supplemented with 200 IU showing the greatest response. A significant increase in antibody response to hepatitis B was observed in subjects supplemented with 200 and 800 IU/d. However, those subjects supplemented with 200 IU/d also had a significant increase in antibody response to tetanus toxoid vaccine. Even though the dose of 60 IU/d was effective in increasing DTH, it was not adequate to exert a significant effect on antibody titer against hepatitis B or tetanus toxoid in the elderly subjects. It appears that 200 IU/d is an optimal amount of vitamin E to increase immunity in elderly individuals. Because >40% of older Americans have a vitamin E intake below the RDA, this population in particular may benefit from supplemental vitamin E to increase their immune response, thereby improving resistance to disease (41, 42). Interestingly, vitamin E–supplemented subjects in the study by Meydani et al (40) had a 30% lower incidence of self-reported infections than did placebo-treated control subjects, indicating that the immunostimulatory effect of vitamin E might have clinical significance for the elderly.

Through careful selection and incorporation of ingredients containing high amounts of vitamin E into daily meals, one can increase dietary intake of vitamin E to 60 IU/d; however, an intake of 200 IU/d is attainable only by supplementation. Inclusion of 200 IU vitamin E along with 5–8 servings of fruit and vegetables in the daily diet potentially reduces the risk of CVD and improves immune function in later life.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 AGING AND NUTRITION
 VITAMIN E AND CVD
 VITAMIN E AND IMMUNE...
 REFERENCES
 

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