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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 59:B659-B673 (2004)
© 2004 The Gerontological Society of America

Hormones and Supplements: Do They Work?

Micronutrient Supplementation in Later Life: Limited Evidence for Benefit

Alan D. Dangour1,, Victoria L. Sibson1 and Astrid E. Fletcher2

1 Nutrition and Public Health Intervention Research Unit
2 Non-communicable Disease Epidemiology Unit, Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, United Kingdom.

Address correspondence to Dr. Alan D. Dangour, Nutrition and Public Health Intervention Research Unit, Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, U.K. E-mail: alan.dangour{at}lshtm.ac.uk


   Abstract
Top
 Abstract
Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
The importance of attaining adequate macronutrient and micronutrient intake throughout the life course is essential for the maintenance of health. Claims have been made for the benefits of micronutrient supplementation in later life, and this review considers the strength of the evidence behind these claims focusing on studies with cardiovascular, cancer, eye health, immune, and cognitive end points. While observational data suggest the presence of a link between dietary micronutrient intake and health outcomes, evidence from large randomized controlled trials does not support the use of antioxidant vitamin or mineral supplements among well-nourished older populations. Moreover, there is evidence of possible adverse affects of micronutrient supplementation. In conclusion, the considerable enthusiasm for the use of micronutrient, especially antioxidant, supplements as anti-aging treatments or as treatments for specific diseases of later life is not supported by the currently available scientific literature.

AT the recent 2nd World Assembly on Ageing, a range of policy initiatives were proposed to promote active and healthy aging (1). Emphasis was placed, among other things, on adequate nutrition throughout the life course, national food policies designed to recognize older people as potentially vulnerable, and the development of culturally relevant healthy eating guidelines. Such proposals aim to increase healthy life-years in older people, and thereby decrease not only the number of years but also the proportion of an older person's lifetime spent in poor health.

The importance of attaining an adequate and balanced diet among older people for the maintenance of health has long been stressed. However, for a variety of physiological, psychological, and social reasons, older people are nutritionally vulnerable (2) and, as a consequence, consume diets that are poor in both quality and quantity (3,4). Further complications in attaining adequate nutrition arise from the well-documented changes in behavior and body composition in later life, which result in decreased energy intake. As a consequence of the relationship between the energy and micronutrient sufficiency of diets, older people with long-term low-energy intake may consume micronutrients at considerably below the required levels. Furthermore, requirements in later life for some micronutrients, such as calcium and vitamin D, may well be greater than previously thought (5), and in certain circumstances (e.g., vitamin B12) may not be achievable through normal dietary means (6). As a consequence, micronutrient supplementation may seem an easier and better way of enhancing micronutrient levels than improving diets.

Many claims have been made for the benefits of micronutrient supplementation, unfortunately most without the supporting evidence from the scientific literature. In this article, we review the available evidence to assess whether micronutrient supplementation has any effect on cardiovascular disease, cancer, age-related eye disease, cognitive function, and immune function in older people. We focus on these five factors, as they are leading causes of loss of healthy life-years and as such have major impacts on the health of older people worldwide. In each case, we summarize the available observational evidence linking micronutrients to the disease, and then we assess the strength of the data emerging from randomized controlled trials (RCTs), concentrating mostly, although not exclusively, on the antioxidant nutrients, since the overwhelming majority of RCT data is from trials of antioxidant supplements. We then discuss some apparent contradictions from these two sources of data, and finally highlight possible adverse effects of micronutrient supplementation.


   CARDIOVASCULAR DISEASE
Top
 Abstract
 Cardiovascular Disease
Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
Vitamin E, vitamin C, and ß-carotene have been frequent foci of studies investigating nutritional influences on cardiovascular health because of their potent free radical-quenching properties. Moreover, a number of animal studies have shown a benefit of antioxidant supplementation, for example by reduced progression of atherosclerosis with vitamin E supplementation (7). A large number of observational epidemiological studies in humans, conducted predominantly in middle-aged populations, have shown associations between high levels of antioxidant vitamins and decreased all-cause or cardiovascular mortality (8). Vitamin levels in these studies have been assessed in a variety of ways: reported dietary intakes, reported vitamin supplement consumption, and analysis of blood samples. These encouraging results have led to the implementation of a number of randomized trials testing the effects of vitamin supplementation (either of single vitamins or multivitamins) on cardiovascular end points in different population groups. The design, intervention, and results from the largest and most powerful of these trials are shown in Table 1.


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  		Table 1. Randomized Trials of Micronutrient Supplements in Cardiovascular Disease.

 
The majority of trials evaluated vitamin E or ß-carotene, either administered alone or together (as in the factorial trials), or as a combined multivitamin supplement with vitamin C. Other interventions included in factorial designs included aspirin or statins, and one trial (the GISSI [Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico] trial) evaluated the effect of n-3 long-chain polyunsaturated fatty acids (n-3 LCPs) along with vitamin E (9). Trial participants have been predominantly male and middle-aged, but a few trials have included a small proportion of older people in their seventh or eight decades. Some trials included people with no history of coronary heart disease (CHD) or stroke (primary prevention trials) while other studies selected participants on the basis of already having cardiovascular disease (secondary prevention). Primary prevention trials with cardiovascular end points need to have large sample sizes, and one of the largest trials, the Women's Health Study (WHS), included nearly 40,000 women [to date, only the results from the ß-carotene arm of this trial have been published (10)]. The Heart Protection Study (HPS) included individuals at high risk of CHD either on the basis of their risk factor profile or previous disease history (11). Two further studies, the Alpha Tocopherol Beta Carotene trial (ATBC) and the ß-Carotene Retinol Efficacy Trial (CARET) (12,13), were designed to evaluate the effects of supplementation on lung cancer, and included mainly smokers or, as in the CARET trial, those who had been exposed to asbestos.

Almost without exception, the trials of antioxidant vitamins found no evidence to support a protective effect of vitamin supplementation on the risk of mortality or cardiovascular events. There was no evidence for a differential effect according to whether people with no history of cardiovascular disease were included, or whether they were at high risk (e.g., smokers, diabetics), or for men compared to women, or by type of supplementation. In the two trials in smokers, there was a small but significant increase in mortality attributed to ß-carotene. In other trials of ß-carotene in the general population or in those at risk of CHD, no increase in mortality was observed, although both the Physicians Heart Study (PHS) (14) and the WHS (10) found small but nonsignificant increases in cardiovascular mortality.

Only one study, the CHAOS (Cambridge Heart Antioxidant Study) trial reported different findings (15). This was the smallest of the trials reviewed; it included patients with angiographically documented artery disease and, after a relatively short period of follow-up, a 47% reduction in the risk of cardiovascular disease (CVD) death or nonfatal myocardial infarction (MI) was observed in the group randomized to vitamin E supplementation. This effect was mainly due to a very large reduction in the risk of nonfatal MI. Surprisingly, there was a small (although not significant) increase in total mortality. However, no other trials have replicated these findings.

The most recent trial and one of the largest was the HPS in the United Kingdom, which included over 20,000 middle-aged and older people (11). The trial employed a factorial design with randomization to a statin or a multivitamin supplement (600 mg vitamin E, 250 mg vitamin C, 20 mg ß-carotene) or both, in comparison with a placebo. Substantial benefits were seen in those allocated to statin in reduced risks of cardiovascular outcomes (primarily fatal and nonfatal CHD and stroke), and there was therefore no doubt about the ability of the design and implementation of the trial to demonstrate benefit with an effective intervention. Across a wide range of cardiovascular endpoints and different subpopulations, there was no evidence of a benefit from the multivitamin supplement over the 5 years of the intervention. Compliance with the multivitamin supplement was very high, and plasma levels significantly increased compared to placebo (twofold for vitamin E, fourfold for ß-carotene, and one third for vitamin C). There was also no evidence of a greater benefit of statins for those additionally taking multivitamins.

In contrast to the trials of antioxidant vitamins, the one large trial that tested the benefit of n-3 LCPs found significant reductions in mortality (20% reduction) including cardiovascular deaths (30% reduction) and sudden death (45% reduction) (9). In the same trial, there were no significant benefits in the group taking vitamin E alone. This was a large trial (over 11,000 participants) in patients who had recently experienced an MI. The study design was open and, although care was taken to minimize the effects of this (for example by using an end-point committee unaware of the treatment allocation), the strength of evidence had to be judged lower than for a double-blind trial. One further smaller trial undertaken in Norway showed no benefit of daily supplementation with 4 g n-3 LCPs in 300 adults with acute MI (16). Subsequent analysis of these data has suggested that the null finding was possibly because baseline fish intake in the study sample was already quite high, and that supplementation with n-3 LCPs therefore had no additional benefit for cardiovascular health (17).

In summary, a decade of well-conducted randomized trials involving some 150,000 participants has demonstrated quite conclusively that the vitamin supplements tested in those trials had no benefit on cardiovascular outcomes including mortality. The strongest evidence for this lack of effect is for vitamin E and ß-carotene, as these were the most commonly used supplements. Vitamin C was only used in one trial as part of a multivitamin supplement, but it is also likely that vitamin C in that trial had little impact, as even small benefits were not observed. A recent meta-analysis that carried out formal statistical pooling of the randomized trials (including some trials in other patient groups) reported that, for vitamin E trials, the overall mortality results were 11.3% on vitamin E compared to 11.1% on placebo while cardiovascular deaths were distributed identically (18). For ß-carotene trials, there was a small but significantly increased risk of all-cause mortality (7.4% vs 7.0%) and cardiovascular death (3.4% vs 3.1%). These latter results were however heavily influenced by the two trials in smokers.

A number of other large trials of vitamin supplementation are still running, but on the basis of the evidence to date, we conclude that there is no benefit on cardiovascular disease from supplementation with vitamin E or ß-carotene and probably no benefit from vitamin C. The evidence for n-3 LCP supplements is positive (19) but limited and needs to be confirmed in other trials. Only the main vitamin supplements used in randomized trials have been considered, but there are a number of other supplements available containing nutrients such as lycopene or lutein whose efficacy has not been tested in randomized trials.


   CANCER
Top
 Abstract
 Cardiovascular Disease
 Cancer
Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
There is an increasing awareness of the importance of modifiable environmental risk factors including diet in the etiology of cancer (20). It has been proposed that, in Western societies, 30% of cancer cases may be preventable by a change in dietary patterns, while the corresponding figure for the developing world is 20% (21). The early discovery of an inverse association between fruit and vegetable intake and risk of epithelial cancers has been extremely influential in this field (22), and the potential of dietary "magic bullets" has spurred the search for the specific chemoprotective factors in these foods. Both the free radical and immune function hypotheses of aging have generated a focus on the antioxidant micronutrients (23) including vitamins A, E, and C, and selenium. However, since the 1980s, there have been only a few large-scale clinical trials of micronutrients using cancer as an end point (Table 2).


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  		Table 2. Randomized Trials of Micronutrient Supplements in Cancer.

 
Observational evidence suggests that diets high in vitamin C may protect against a range of cancers (24). A recent prospective study found low blood ascorbate to be strongly linked to raised all-cause mortality among older people (aged 75–84 years) (25), and in a male American cohort, risk of dying from any cause and from cancer were increased 57% and 62%, respectively, among those in the lowest compared to the highest quartile of blood ascorbate (26). In a large cohort study among participants aged 67–105 years, reported use of a combination of both vitamin E and vitamin C supplements was associated with a 42% decreased risk of all-cause mortality; the reported use of vitamin C alone had no effect on mortality (27).

Several randomized trials have been conducted using supplements containing a combination of micronutrients. After 5 years of treatment with ß-carotene, vitamin E, and selenium, a 9% decrease in total mortality was observed among 29,584 poorly nourished residents of Linxian in north central China, encompassing a 13% decrease in overall cancer rates, largely of the esophagus and stomach. However, retinol and zinc, riboflavin and niacin, and vitamin C and molybdenum combinations had no effect on cancer rates (28). More recently, among those randomized to receive ß-carotene and vitamins C and E in the U.K. HPS of 40–80 year olds, there were no significant changes in any causes of mortality, including total and site-specific cancers (11). Combination antioxidant supplements have also been shown to have no effect on the recurrence of precancerous lesions (29,30).

The major carotenoid, ß-carotene, has received considerable attention with regard to its potential for altering cancer risk. The ATBC and CARET studies enrolled a total of approximately 50,000 male smokers aged 40–69 years. Unexpectedly, both trials observed large increases in lung cancer incidence: 16% in the ß-carotene arm of the ATBC trial and 28% in the combination supplement in the CARET trial (12,13,31). However, ß-carotene supplementation had a null effect in two later primary prevention trials among healthy men and women aged over 40 years (10,14) and also in a secondary prevention trial in adults with a history of skin cancer (29).

Within the PHS cohort, prostate cancer risk was reduced in supplement recipients in the lowest quartile of baseline plasma ß-carotene or in the highest body mass index (BMI) quartile, and total cancer risk was reduced in those aged older than 70 years, daily alcohol drinkers, and those in the highest BMI quartile (32,33). Although colon cancer risk was reduced in daily drinkers in this and in the ATBC study (33,34), this finding was not replicated in any of the other large-scale trials. In one further trial conducted in Colombia, precancerous lesion regression was increased with either vitamin C or ß-carotene supplementation alone (35). In sum, these findings suggest that certain subgroups may stand to benefit more than others from supplementation; however, the evidence is inconsistent.

Interest has recently been focused on other carotenoids, and prospective cohort studies have linked low serum levels of ß-cryptoxanthin, lutein, and zeaxanthin with all-cause mortality (36), and {alpha}-carotene and lycopene with decreased cancer risk (37,38). Clinical trials of these carotenoids have not yet been conducted.

Epidemiological evidence suggesting a possible protective effect of vitamin E against a range of cancers is weak and largely limited to smokers. However, a reduction of 32% in prostate cancer incidence was observed early on among those receiving vitamin E in the ATBC trial, contributing to a 41% decrease in prostate cancer mortality (39); the association was strongest in those with the lowest baseline dietary intakes of the vitamin (40). These findings are also supported by the Health Professionals' Follow-up Study among male smokers aged 40–75 years (41).

Finally, the lowered plasma levels of the glutathione peroxidase cofactor selenium, observed in older people, suggests a link between selenium deficiency and cancer risk. Although one randomized trial supports this hypothesis, additional evidence is inconsistent. The small selenium supplementation trial among patients with a history of skin cancer demonstrated a 63% reduction in prostate cancer incidence as well as reductions in the incidence of lung and colorectal cancer. There was, however, no effect on the primary outcome measure, incidence of basal and squamous cell carcinomas of the skin (42). In support, two large cohort studies have found significant inverse associations between toenail selenium quintile and prostate cancer incidence (43,44). However, the ATBC and CARET trials found no associations between baseline selenium intake and prostate cancer risk, or baseline selenium serum levels and prostate or lung cancer risk, respectively (40,45).

To date, the specific chemoprotective micronutrients have yet to be conclusively identified, mainly because of methodological inaccuracy in observational studies and a paucity of evidence from randomized trials, particularly among older people. While some micronutrient supplementation trials have indicated possible benefit, particularly among those with a deficiency, many have shown a null or adverse effect in terms of cancer incidence or mortality. Moreover, the inconsistency of observational and experimental evidence suggests that other dietary constituents may confound the observed relationships.


   AGE-RELATED EYE DISEASE
Top
 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
Cataract and age-related macular degeneration (AMD) account for over 90% of the visual disability in older people in Western populations. Between 30% and 50% of people aged older than 70 years in European populations have cataracts, with women being more frequently affected than men. Although cataracts are eminently treatable by surgery, the enormous numbers of individuals requiring surgery is a substantial burden on health care costs. Age-related macular degeneration is less common than cataract but its consequences are more severe, and in Western adult populations, AMD is the leading cause of blindness and visual impairment. Age-related macular degeneration is not curable, and such treatment that is available is limited to a small proportion of the population and, at best, only halts the progression of the disease. Early forms of macular degeneration (age-related maculopathy [ARM]) are more common among older people, occurring in one in five of those aged 65 to 74 years, and a third of those aged 75 to 84 years. There is increasing evidence that early ARM progresses to AMD. Similarly, opacification of the lens of the eye starts in middle age and becomes both more prevalent and more severe with advancing age, to the point where visual loss occurs and surgery is required.

Both these age-related eye diseases are thought to have a nutritional etiology. There is some evidence from observational studies that low dietary intakes of vitamin C, vitamin E, and carotenoids increase cataract risk, and that the reported use of vitamin C, vitamin E, and multivitamin supplements is protective (46). The limited evidence for AMD suggests that high plasma and dietary carotenoid levels, in particular lutein, are protective (46).

Because of the progressive nature of these age-related conditions, a distinction has frequently been drawn between randomized trials that evaluate the effects of an antioxidant supplement on prevention, either of early or late disease, and those trials that evaluate the effect of supplementation on progression of the disease in people with clinical manifestations of disease at baseline. However, in some trials, the data collected do not permit such distinctions to be made.

Age-Related Macular Degeneration
A few small trials of short duration are not considered here because of the limitations of their study design, however, two systematic reviews have been published that include full details of these smaller trials (47,48). Of the large studies, only the Age-Related Eye Disease Study (AREDS) (49) was specifically designed to investigate the effects of vitamin supplementation on AMD (Table 3). The Vitamin E, Cataract and Age-related maculopathy Trial (VECAT) was powered on cataract outcomes, although data on AMD were also collected (50). One other large study investigating the effects of vitamin supplements on cancer (the ATBC trial) also collected data on the occurrence of AMD (51).


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  		Table 3. Randomized Trials of Micronutrient Supplements in Age-Related Eye Disease.

 
The AREDS trial recruited 4757 participants aged 55 to 80 years, who were assigned into one of four categories: no or minimal ARM signs (23%), minor ARM signs (22%), intermediate ARM (34%), and advanced AMD (20%). Over the 7 years of follow-up, the number of participants in the first two categories at baseline who progressed to intermediate ARM or advanced AMD was small and those participants were therefore excluded from analysis. The results of the trial were based on 2577 participants (median age 69 years) with intermediate ARM or late AMD at baseline, and demonstrated that supplementation with either antioxidants or zinc or both resulted in a significant reduction in the rate of progression to AMD. The effect was slightly greater for the combination therapy. There were also benefits on outcomes likely to be noticed by patients (loss of lines of sight). The VECAT trial was smaller in size, and participants tended to have minimal or no signs of early ARM. There was no evidence of a benefit from supplementation, but the number of cases progressing was small. In the ATBC trial, a subsample of those aged older than 65 years underwent an eye examination at the end of the follow-up to ascertain whether they had signs of ARM or AMD. No effect of supplementation was observed.

Cataracts
Only two trials to date have been specifically designed to evaluate the effects of supplementation on cataracts. Participants in the AREDS trial who had no history of cataract extraction were also assessed for the development and progression of lens opacities over the follow-up period. No benefit was observed for antioxidant supplements in these outcomes or by type of lens opacity (52). The VECAT trial has not yet reported its results. Three of the other large supplementation trials designed for cancer or cardiovascular outcomes also examined cataracts and found no differences between those taking supplements or those taking placebo. A subgroup analysis in the PHS found a 26% reduced risk of cataract in smokers taking ß-carotene, but no effect in nonsmokers (53). This may have been a chance finding, as it was not observed in the ATBC trial, which specifically recruited smokers (54). The HPS also reported no differences in the prevalence of self-reported cataract extractions (11).

To date, no trial has been able to investigate whether vitamin supplementation can prevent the onset of age-related eye disease. Such trials require very large numbers of participants and a long period of follow-up because of the relatively slow development and progression of age-related eye diseases. A limitation of the cancer and cardiovascular trials that also collected end-of-trial data on eye disease is that they had no baseline measures, and it is therefore not possible to ascertain whether there were any differences in the rate of progression. The only trial that recruited sufficient people with intermediate ARM or advanced AMD at baseline did demonstrate a reduction in the rate of progression with a multivitamin and zinc supplement. Unlike the other trials that found no effect of supplementation with vitamin E or ß-carotene, the AREDS trial used zinc and a high dose of vitamin C (nearly 10 times the Recommended Daily Allowance [RDA]). There was, however, no effect on cataracts of this supplement although the observational evidence for an association with vitamin C is, if anything, more persuasive for cataract than AMD. A number of trials in cancer and CVD that are ongoing are also collecting data on these eye diseases.


   IMMUNE FUNCTION
Top
 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
There is a considerable body of evidence that aging is associated with alterations of immune function (55). These effects are thought to be the result of dysregulation of the immune system leading to lower effectiveness of cell-mediated immunity and less suitable antibody responses (56). This dysregulation has been linked to the increased incidence of infectious and inflammatory diseases observed in older people (57). It is important to note, however, that age-linked alterations to immune response are not observed in all individuals, and indeed the immune response of self-sufficient healthy older participants appears to remain comparable to that found in younger adults (58).

It is well known that, in older people with protein-energy malnutrition, immune responses are decreased. Given the prevalence of subclinical micronutrient deficiencies among older people, it has been suggested that part of the effect of macronutrient undernutrition on immune function is the result of lowered micronutrient status. The relative effects of macronutrient and micronutrient status are hard to tease apart, and in refeeding experiments, for example, it is not always clear whether the improvement in protein-energy nutrition or the concomitant increase in micronutrient status has caused the enhanced immune function (59).

There are, however, several candidate micronutrients that have been suggested to have important impacts on immune function, including ß-carotene (60), vitamin E (61), and zinc (62), and numerous clinical trials investigating the effects of micronutrient supplementation on immunological markers have been carried out. Interpretation of the results is complicated by several factors such as the dose of micronutrient given (from physiological to mega-doses), the marker of immune function used (such as natural killer cell activity and delayed-type hypersensitivity), and the micronutrient status of the study participants at baseline. However, in his review, High (63) concluded that there was strong evidence that micronutrients play a role in maintaining immune competence in later life and that micronutrient supplementation may reverse some of the changes associated with impaired immunity in older people.

What is less clear, however, is whether the changes in markers of immune function respond to changes in clinical end points such as the incidence, duration, or severity of infection. Only very few studies are available to answer this important question (Table 4).


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  		Table 4. Randomized Trials of Micronutrient Supplements in Immune Function-Related Clinical End Points.

 
Chandra (64) carried out a 12-month placebo-controlled trial on 96 noninstitutionalized older people aged 65 years and older in Canada. Approximately 10% of the sample had low micronutrient status at baseline. The supplement contained a large range of micronutrients at concentrations of up to 200% of the RDA. Following 12 months of supplementation, the intervention group showed significant improvements in serum micronutrient status, and over the course of the trial, there were significantly fewer days with infection-related illnesses in the intervention group than in the placebo group (23 vs 48 days). This trial was recently repeated with essentially the same protocol among 44 individuals aged 50–65 years (65) and among 36 individuals aged 51–78 (66). In both these latter studies, there was again a significant reduction in the total number of days of infection experienced by participants in the experimental compared with the control arm of the trial (11 vs 24 days and 14 vs 29 days, respectively). The size of the benefit was considerable, that is, a halving of the number of days ill, and interestingly appeared to be of the same order of magnitude irrespective of the age of the patients. However, these potentially important results have not been replicated in any other trials.

An RCT of 218 noninstitutionalized older people aged 60 years and older in central France was carried out by Chavance and colleagues (67). The 4-month trial assessed the impact of a daily multivitamin supplementation at doses of up to 200% of the RDA on the incidence of infection. No information is presented on micronutrient deficiencies at baseline, but supplementation with micronutrients was reported to result in significant increases in serum micronutrient status in the intervention arm. There was no difference in the incidence of infection between the two study groups over the 4 months of the trial.

Following positive results obtained in a pilot study (68), a large trial was conducted on 725 institutionalized older people aged 65 years and older in France (69). A factorial design was employed with supplementation over 2 years with trace elements (zinc and selenium) and/or vitamins (C, E, and ß-carotene) at doses of up to 200% of the RDA. No information is presented on the prevalence of micronutrient deficiency in the study sample, although at baseline in the intervention arms, approximately 80% of the participants were deficient in selenium, suggesting that deficiency rates may have been relatively high. Specific nutrient deficiencies within participants were resolved after 6 months of supplementation. Supplementation with trace elements (either alone or in combination with vitamins) appeared to result in an increased number of patients without respiratory tract infections (although the effect was statistically borderline). No difference between the four study groups was seen on the incidence of urogenital infections or survival.

Most recently, an RCT of 652 noninstitutionalized older people aged 60 years and older was conducted in the Netherlands (70), in which the baseline levels of micronutrient deficiencies were very low. A factorial design was used to determine the effects of daily supplementation for 15 months with a range of multivitamins at concentrations from 25%–50% of RDA and/or vitamin E at approximately 17–20 times the RDA. No effect of supplementation was seen on the incidence of infection. However, comparing the vitamin E groups with the no-vitamin-E groups suggested that supplementation with vitamin E significantly increased several markers of illness severity, namely illness duration, number of symptoms, presence of fever, and restriction of activity.

In summary, the results of micronutrient supplementation trials on clinically relevant disease end points are currently equivocal. While a few studies based on a small number of participants have found very large effects of micronutrient supplementation, other researchers have not replicated these findings and indeed have suggested that supplementation with large doses may be deleterious. It seems likely that any effect that may be present will be modulated by the micronutrient status of the participants at baseline, with the largest effect seen in individuals who present with micronutrient deficiencies.


   COGNITIVE FUNCTION
Top
 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 
The proportion and absolute number of individuals with age-related cognitive impairment is rising (71). The rate of increase is outpacing the rise in the population of older people, suggesting that environmental factors may affect the onset of cognitive decline. There is considerable interest in the hypothesis that improving the diet of older people may delay the initiation, or slow the progression, of cognitive decline. Until recently, studies assessing the association between diet and cognitive function in older people concentrated on the B and antioxidant vitamins. Interest was initially aroused by a cross-sectional survey carried out in 1979 among 260 free-living older people (72), which demonstrated an association between blood levels of vitamins C and B12 and tests of cognitive ability.

The evidence from cross-sectional studies is indeed quite suggestive of a link between B vitamin status and cognitive function in older people [as reviewed by Selhub and colleagues (73)]. However, assigning causality in the relationship is problematic with possible mechanisms suggested in both directions. Moreover, B vitamin status is a crucial modulator of plasma homocysteine concentration (74), a known risk factor for vascular disease (75,76), which may result in brain ischemia and subsequent cognitive decline.

One recent study is noteworthy in this regard, as participants were part of a birth cohort that had been cognitively assessed in childhood at age 11 years (77). This study demonstrated that, among 183 subjects aged 78 years, there were significant positive correlations between current plasma folate and vitamin B12 concentrations and cognitive ability, and significant negative correlations between current homocysteine concentration and cognitive ability. Of particular interest was the finding that, while approximately 50% of the variance in cognitive test score at age 78 could be explained by cognitive ability at age 11 years, plasma homocysteine concentration at age 78 years accounted for an extra 7%–8% of the variance.

Knowledge in this area has recently been importantly strengthened by the results from the Rotterdam Scan study (78), which has collected magnetic resonance images on 1077 individuals aged 60–90 years. This study demonstrated that the risk of having silent brain infarcts increased significantly with increasing total homocysteine levels independent of other cardiovascular risk factors. Furthermore, a recent 5-year follow-up study of 1015 of these participants demonstrated an association between silent brain infarcts and cognitive decline (79).

These results therefore allow a direct link to be postulated between B vitamin status and cognitive health, but disappointingly, this has not been corroborated by the results of the few clinical trials on B vitamins and cognitive function in older people. Two recent Cochrane reviews of all available clinical trials suggest that neither folate (80) nor vitamin B6 (81) supplementation has any effect on cognitive function in later life.

The link between brain aging and oxidative stress has led many researchers to investigate the possible role of antioxidants in cognitive function. For example, the Basel study (82) demonstrated a positive relationship, in 452 participants aged 65 years and older, between plasma vitamin C and ß-carotene and cognitive ability. Interestingly, in this study, the associations were significant if plasma antioxidant levels collected either at the same time as cognitive ability or 20 years earlier were used in the analysis. Other research showing similar findings include the Rotterdam study (83), the SENECA-EURONUT (Survey Europe on Nutrition in the Elderly: A Concerted Action–European Community Concerted Action on Nutrition and Health) investigation (84), and the NHANES III (National Health and Nutrition Examination Survey) (85).

In contrast to the large number of cross-sectional surveys assessing the link between antioxidant status and cognitive function, very few studies have looked at the longitudinal association between antioxidant status and cognitive decline. Of particular note is a recent study among 2889 free-living adults aged 65 years and older (86). This study showed a 36% reduction in the rate of cognitive decline over 3 years between those in the highest and lowest quintiles of total vitamin E intake.

Interpretation of the very few randomized controlled trials in this field is complicated and controversial. Some small studies suggest benefits (87–89), while results from the large HPS, which additionally included a measure of cognitive function, showed no benefit (11,90). A recent Cochrane review concluded that there was insufficient evidence of efficacy of antioxidants in the treatment of people with Alzheimer's disease (91) and that further trials were under way.

The B vitamins and antioxidants have been the focus of most research to date, and far less attention has been paid to other dietary factors plausibly related to cognitive health, such as n-3 LCPs. The brain is particularly rich in n-3 LCPs such as docosahexaenoic acid (DHA), and n-3 LCPs have repeatedly been shown to be crucial to brain development (92). A decrease in n-3 LCP level in total brain lipids has been reported in aging humans, and this decline appears to be correlated in part with age-related deterioration of functions of the central nervous system. Intervention studies on aged animals suggest that n-3 LCPs have a role in maintaining and improving cognitive functions (93,94). In these studies, modifications in brain fatty-acid composition, particularly an increase in DHA level, were detected subsequent to the ingestion of modified diets.

Two cross-sectional surveys in humans have shown that a high intake of fish in the diet, where the main active compound is DHA, is inversely associated with cognitive impairment (95,96). Moreover, a recent prospective study demonstrated that reported consumption of one or more portions of fish a week was associated with a 60% reduction in the risk of the incidence of Alzheimer's disease over an average 3.9 years of follow-up (97).

The mechanisms behind the role of n-3 LCPs in improving vascular health outcome (9,98) are now beginning to be relatively well understood, and include the ability of n-3 LCPs to inhibit hepatic triglyceride synthesis and, by modifying eicosanoid function to cause vascular relaxation, a diminished inflammatory process and decreased platelet aggregation (99). In addition, DHA is known to protect in vitro-cultured hippocampal neurons from apoptotic death induced by serum deprivation (100). These actions may also be of particular importance in ensuring vascular health in the aging brain and may have beneficial effects on two factors that are increasingly being recognized as major contributors to age-associated cognitive impairment, namely vascular integrity and microthrombotic obstruction (101). It is therefore possible that n-3 LCP supplementation may act to prevent or reduce the occurrence of microvascular events in the brain and thereby have a significant effect on the rate of cognitive decline in older people.


   WHY DO CLINICAL TRIALS FREQUENTLY NOT CONFIRM THE RESULTS OF OBSERVATIONAL EPIDEMIOLOGICAL STUDIES?
Top
 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
Adverse Effects
 Conclusions
 References
 
There are a number of arguments that have been put forward to explain the discrepancy in results between observational studies and clinical trials, and the lack of effect of supplementation in clinical trials. These are summarized below.

There Is Unexplained Confounding in the Observational Studies
People who report the use of vitamin supplements or eat diets rich in antioxidants, for example, are generally more health conscious and tend to have healthier lifestyles. Although these so-called "confounding" factors are adjusted for in analyses of observational studies, there always remains the strong possibility of unexplained confounding because of other unmeasured factors for which adjustment cannot be made. In randomized trials, confounding factors (whether known or unknown) are distributed randomly across the arms of the trial, and therefore the results are unlikely to be confounded. The larger the trial, the less likely it is that random imbalance between trial groups will have occurred.

The Trials Are Not of Sufficient Duration
Most clinical trials have tested the effects of daily micronutrient supplementation for a period of between 1 and 6 years. It can be argued that a much longer intervention period is required to observe a benefit. However, even the longest trial to date, the PHS, which lasted 12 years, did not find any significant effect of supplementation on CVD (14).

The Trials Are Not Large Enough to Demonstrate Small Effects
Given the importance of many of the diseases reviewed in this article as major causes of death and disability worldwide, any reduction in disease rate at a population level, however small, would entail substantial public health benefits. Many trials have included very large numbers of participants, and such large trials are powered to detect very small effects. For example, the HPS trial of more than 20,000 participants was able to exclude, with a high degree of certainty, proportional differences of as small as 10% in the occurrence of vascular events between placebo and multivitamin arms (11).

The Dose of Supplements Given Are Not High Enough
Supplement doses in clinical trials have ranged from 25% to 500% or more of the RDA. The trials are normally conducted in well-nourished groups, and participants drawn from free-living populations have generally not been at risk of vitamin deficiency. In most trials, high levels of compliance with the supplements were achieved even over several years. This is reflected by the increased plasma levels of micronutrients reported in the intervention arms in most trials. However, in, for example, the HPS trial, achieving high plasma levels did not result in any benefit on CVD. There also has been discussion over whether it is preferable to use natural or synthetic forms of micronutrients, which may have altered bioavailability. However, here again, the evidence is contradictory, with the two trials in the cardiovascular literature that have used natural vitamin E (CHAOS and HOPE [Heart Outcomes and Prevention Evaluation study]) (15,102) providing conflicting results.

The Supplements Are Ineffective Because They Do Not Represent Dietary Sources Adequately
The micronutrients tested in clinical trials were chosen on the basis of scientific evidence, not only from the observational studies but also from animal and in vitro laboratory research. However, it can be argued that supplementation with a few antioxidants, for example, cannot substitute for the richness and variety of antioxidants present in dietary sources. Antioxidants act in synergy and appear to act in cascades of free-radical-quenching reactions. Moreover, only a small proportion of potentially beneficial micronutrients can be measured in observational studies either because of the lack of appropriate laboratory assays, or because current food composition tables are inadequate. It seems likely, therefore, that supplementation with only a limited range of micronutrients will not be able to achieve the expected results.


   ADVERSE EFFECTS
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 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
Conclusions
 References
 
Concern regarding the use of dietary supplements has been raised by findings from clinical trials such as the ATBC trial and CARET, which showed increased risk of lung cancer in at-risk participants supplemented with ß-carotene. In order to provide guidance on safe micronutrient intakes, the U.K. Food Standards Agency recently published comprehensive recommendations, based on all available nutrition and toxicological evidence, on the safe upper levels of vitamin and mineral intake (103). The report provides guidance on 30 of the most important micronutrients and highlights several for which there is evidence of harmful effects of high-dose supplement use over extended time periods.

The setting of safe upper limits for micronutrient intake is, however, becoming ever more complicated by the increased awareness of the influence of genetic factors on individual micronutrient requirements (104). It is likely that interpopulation and intrapopulation genetic variability may become an important determinant of micronutrient requirements, which will, in the future, need to be taken into account in the design of micronutrient recommendations.


   CONCLUSIONS
Top
 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
References
 
The importance of attaining adequate macronutient and micronutrient intake throughout the life course to maintain health is indisputable and forms the basis of all consensual statements on diet and health. In the current article, the literature relating to micronutrient intake and CVD, cancer, eye health, immune function, and cognitive function has been reviewed with a particular focus on supplementation and on antioxidants. Survey data suggest that there is a link between dietary micronutrient intake or blood micronutrient levels and health outcomes. However, the evidence from randomized controlled trials does not support the use of antioxidant vitamin or mineral supplements among healthy, well-nourished older populations. The evidence for no benefit from supplementation on CVD and cancer derives from large well-conducted randomized trials. In contrast, the evidence base for areas such as age-related eye disease, immune function, and cognitive function is much weaker. Furthermore, while certain at-risk population groups who may have subclinical micronutrient deficiencies, such as institutionalized older people, may benefit from supplements, the evidence is again weak. There has been considerable enthusiasm for the use of micronutrient, especially antioxidant, supplements as anti-aging treatments or as treatments for specific diseases of later life; this is, however, not supported by the currently available scientific literature.

This review is necessarily incomplete, as there are several trials currently under way testing more subtle outcomes such as change in cognitive function. Moreover, trials using other nutrients such as n-3 LCPs, which have recently been suggested to be essential nutrients in the modern diet (105), are also under way. In the meantime, the best advice must remain that older people should endeavor to consume a diverse and healthy diet, preferably in the company of others (6).


   Footnotes
 
Decision Editor: James R. Smith, PhD

Received January 21, 2004


   References
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 Abstract
 Cardiovascular Disease
 Cancer
 Age-Related Eye Disease
 Immune Function
 Cognitive Function
 Why Do Clinical Trials...
 Adverse Effects
 Conclusions
 References
 

  1. WHO. Active Ageing: A Policy Framework. Geneva: World Health Organization; 2002.
  2. Kohrs M, Czajka-Narins D, Nordstrom J. Factors affecting nutritional status of the elderly. In: Munro H, Danford D, eds. Nutrition, Aging and the Elderly. New York: Plenum; 1989:305–333.
  3. de Groot CP, van den Broek T, van Staveren W. Energy intake and micronutrient intake in elderly Europeans: seeking the minimum requirement in the SENECA study. Age Ageing. 1999;28:469-474.[Abstract/Free Full Text]
  4. King JE, Mazariegos M, Valdez C, Castaneda C, Solomons NW. Nutritional status indicators and their interactions in rural Guatemalan elderly: a study in San Pedro Ayampuc. Am J Clin Nutr. 1997;66:795-802.[Abstract/Free Full Text]
  5. Richard MJ, Roussel AM. Micronutrients and ageing: intakes and requirements. Proc Nutr Soc. 1999;58:573-538.[Medline]
  6. WHO/TUFTS. Keep Fit for Life: Meeting the Nutritional Needs of Older Persons. Geneva: World Health Organization; 2002.
  7. Williams RJ, Motteram JM, Sharp CH, Gallagher PJ. Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis. 1992;94:153-159.[Medline]
  8. Ness AR, Powles JW, Khaw KT. Vitamin C and cardiovascular disease: a systematic review. J Cardiovasc Risk. 1996;3:513-521.[Medline]
  9. GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354:447-455.[Medline]
  10. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women's Health Study. J Natl Cancer Inst. 1999;91:2102-2106.[Abstract/Free Full Text]
  11. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:23-33.[Medline]
  12. Alpha-Tocopherol Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029-1035.[Abstract/Free Full Text]
  13. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-1155.[Abstract/Free Full Text]
  14. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334:1145-1149.[Abstract/Free Full Text]
  15. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347:781-786.[Medline]
  16. Nilsen DW, Albrektsen G, Landmark K, Moen S, Aarsland T, Woie L. Effects of a high-dose concentrate of n-3 fatty acids or corn oil introduced early after an acute myocardial infarction on serum triacylglycerol and HDL cholesterol. Am J Clin Nutr. 2001;74:50-56.[Abstract/Free Full Text]
  17. Grundt H, Nilsen DW, Mansoor MA, Nordoy A. Increased lipid peroxidation during long-term intervention with high doses of n-3 fatty acids (PUFAs) following an acute myocardial infarction. Eur J Clin Nutr. 2003;57:793-800.[Medline]
  18. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361:2017-2023.[Medline]
  19. Din JN, Newby DE, Flapan AD. Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment. BMJ. 2004;328:30-35.[Free Full Text]
  20. WHO. Diet, Nutrition and the Prevention of Chronic Diseases: Report of a Joint WHO/FAO Expert Consultation. Geneva: World Health Organization; 2003.
  21. Key TJ, Allen NE, Spencer EA, Travis RC. The effect of diet on risk of cancer. Lancet. 2002;360:861-868.[Medline]
  22. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc. 1996;96:1027-1039.[Medline]
  23. Khaw KT. Healthy aging. BMJ. 1997;315:1090-1096.[Free Full Text]
  24. Fairfield KM, Fletcher RH. Vitamins for chronic disease prevention in adults: scientific review. JAMA. 2002;287:3116-3126.[Abstract/Free Full Text]
  25. Fletcher AE, Breeze E, Shetty PS. Antioxidant vitamins and mortality in older persons: findings from the nutrition add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Am J Clin Nutr. 2003;78:999-1010.[Abstract/Free Full Text]
  26. Loria CM, Klag MJ, Caulfield LE, Whelton PK. Vitamin C status and mortality in US adults. Am J Clin Nutr. 2000;72:139-145.[Abstract/Free Full Text]
  27. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996;64:190-196.[Abstract/Free Full Text]
  28. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483-1492.[Abstract/Free Full Text]
  29. Greenberg ER, Baron JA, Tosteson TD, et al. A clinical trial of antioxidant vitamins to prevent colorectal adenoma. Polyp Prevention Study Group. N Engl J Med. 1994;331:141-147.[Abstract/Free Full Text]
  30. Li JY, Taylor PR, Li B, et al. Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst. 1993;85:1492-1498.[Abstract/Free Full Text]
  31. Virtamo J, Pietinen P, Huttunen JK, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003;290:476-485.[Abstract/Free Full Text]
  32. Cook NR, Stampfer MJ, Ma J, et al. Beta-carotene supplementation for patients with low baseline levels and decreased risks of total and prostate carcinoma. Cancer. 1999;86:1783-1792.[Medline]
  33. Cook NR, Le IM, Manson JE, Buring JE, Hennekens CH. Effects of beta-carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (United States). Cancer Causes Control. 2000;11:617-626.[Medline]
  34. Glynn SA, Albanes D, Pietinen P, et al. Alcohol consumption and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control. 1996;7:214-223.[Medline]
  35. Correa P, Fontham ET, Bravo JC, et al. Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy. J Natl Cancer Inst. 2000;92:1881-1888.[Abstract/Free Full Text]
  36. De Waart FG, Schouten EG, Stalenhoef AF, Kok FJ. Serum carotenoids, alpha-tocopherol and mortality risk in a prospective study among Dutch elderly. Int J Epidemiol. 2001;30:136-143.[Abstract/Free Full Text]
  37. Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res. 1999;59:1225-1230.[Abstract/Free Full Text]
  38. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in. 2 prospective US cohorts. Am J Clin Nutr. 2000;72:990-997.[Abstract/Free Full Text]
  39. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90:440-446.[Abstract/Free Full Text]
  40. Hartman TJ, Albanes D, Pietinen P, et al. The association between baseline vitamin E, selenium, and prostate cancer in the alpha-tocopherol, beta-carotene cancer prevention study. Cancer Epidemiol Biomarkers Prev. 1998;7:335-340.[Abstract]
  41. Chan JM, Stampfer MJ, Ma J, Rimm EB, Willett WC, Giovannucci EL. Supplemental vitamin E intake and prostate cancer risk in a large cohort of men in the United States. Cancer Epidemiol Biomarkers Prev. 1999;8:893-899.[Abstract/Free Full Text]
  42. Clark LC, Combs GF, Jr, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA. 1996;276:1957-1963.[Abstract/Free Full Text]
  43. van den Brandt PA, Zeegers MP, Bode P, Goldbohm RA. Toenail selenium levels and the subsequent risk of prostate cancer: a prospective cohort study. Cancer Epidemiol Biomarkers Prev. 2003;12:866-871.[Abstract/Free Full Text]
  44. Yoshizawa K, Willett WC, Morris SJ, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst. 1998;90:1219-1224.[Abstract/Free Full Text]
  45. Goodman GE, Schaffer S, Bankson DD, Hughes MP, Omenn GS. Predictors of serum selenium in cigarette smokers and the lack of association with lung and prostate cancer risk. Cancer Epidemiol Biomarkers Prev. 2001;10:1069-1076.[Abstract/Free Full Text]
  46. Christen WG, Glynn RJ, Hennekens CH. Antioxidants and age-related eye disease. Current and future perspectives. Ann Epidemiol. 1996;6:60-66.[Medline]
  47. Evans J, Henshaw K. Antioxidant Vitamin and Mineral Supplementation for Preventing Age-Related Macular Degeneration (Cochrane Review) Issue 4. Chichester, UK: John Wiley & Sons; 2003.
  48. Evans J. Antioxidant Vitamin and Mineral Supplements for Age-Related Macular Degeneration (Cochrane Review) Issue 4. Chichester, UK: John Wiley & Sons; 2003.
  49. Age Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:1417-1436.[Abstract/Free Full Text]
  50. Taylor HR, Tikellis G, Robman LD, McCarty CA, McNeil JJ. Vitamin E supplementation and macular degeneration: randomised controlled trial. BMJ. 2002;325:11.[Abstract/Free Full Text]
  51. Teikari JM, Laatikainen L, Virtamo J, et al. Six-year supplementation with alpha-tocopherol and beta-carotene and age-related maculopathy. Acta Ophthalmol Scand. 1998;76:224-229.[Medline]
  52. Age Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119:1439-1452.[Abstract/Free Full Text]
  53. Christen WG, Manson JE, Glynn RJ, et al. A randomized trial of beta carotene and age-related cataract in US physicians. Arch Ophthalmol. 2003;121:372-378.[Abstract/Free Full Text]
  54. Teikari JM, Rautalahti M, Haukka J, et al. Incidence of cataract operations in Finnish male smokers unaffected by alpha tocopherol or beta carotene supplements. J Epidemiol Community Health. 1998;52:468-472.[Abstract]
  55. Lesourd B, Mazari L. Nutrition and immunity in the elderly. Proc Nutr Soc. 1999;58:685-695.[Medline]
  56. Green-Johnson J WA, Szewczuk MR. The immunobiology of ageing. In: Cooper E, Nisbet-Brown E, eds. Developmental Immunobiology. New York: Oxford University Press; 1993:426–451.
  57. Cohn JR, Hohl CA, Buckley CE, III. The relationship between cutaneous cellular immune responsiveness and mortality in a nursing home population. J Am Geriatr Soc. 1983;31:808-809.[Medline]
  58. Lesourd BM. Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments. Am J Clin Nutr. 1997;66:478S-484S.[Abstract/Free Full Text]
  59. Lesourd B. Protein undernutrition as the major cause of decreased immune function in the elderly: clinical and functional implications. Nutr Rev. 1995;53:S86-S91 discussion S92–S94.[Medline]
  60. Santos MS, Meydani SN, Leka L, et al. Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation. Am J Clin Nutr. 1996;64:772-777.[Abstract/Free Full Text]
  61. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. JAMA. 1997;277:1380-1386.[Abstract/Free Full Text]
  62. Fortes C, Forastiere F, Agabiti N, et al. The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc. 1998;46:19-26.[Medline]
  63. High KP. Micronutrient supplementation and immune function in the elderly. Clin Infect Dis. 1999;28:717-722.[Medline]
  64. Chandra RK. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Lancet. 1992;340:1124-1127.[Medline]
  65. Chandra RK. Influence of multinutrient supplement on immune response and infection-related illness in 50–65 year old individuals. Nutr Res. 2002;22:5-11.
  66. Jain A. Influence of vitamins and trace-elements on the incidence of respiratory infection in the elderly. Nutr Res. 2002;22:85-87.
  67. Chavance M, Herbeth B, Lemoine A, Zhu BP. Does multivitamin supplementation prevent infections in healthy elderly subjects? A controlled trial. Int J Vit Nutr Res. 1993;63:11-16.
  68. Girodon F, Lombard M, Galan P, et al. Effect of micronutrient supplementation on infection in institutionalized elderly subjects: a controlled trial. Ann Nutr Metab. 1997;41:98-107.[Medline]
  69. Girodon F, Galan P, Monget AL, et al. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network. Arch Intern Med. 1999;159:748-754.[Abstract/Free Full Text]
  70. Graat JM, Schouten EG, Kok FJ. Effect of daily vitamin E and multivitamin-mineral supplementation on acute respiratory tract infections in elderly persons: a randomized controlled trial. JAMA. 2002;288:715-721.[Abstract/Free Full Text]
  71. Melzer D, Ely M, Brayne C. Cognitive impairment in elderly people: population based estimate of the future in England, Scotland, and Wales. BMJ. 1997;315:462.[Free Full Text]
  72. Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA. 1983;249:2917-2921.[Abstract/Free Full Text]
  73. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71:614S-620S.
  74. Selhub J, Miller JW. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992;55:131-138.[Abstract/Free Full Text]
  75. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274:1049-1057.[Abstract/Free Full Text]
  76. Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet. 1999;354:407-413.[Medline]
  77. Duthie SJ, Whalley LJ, Collins AR, Leaper S, Berger K, Deary IJ. Homocysteine. B vitamin status, and cognitive function in the elderly. Am J Clin Nutr. 2002;75:908-913.[Abstract/Free Full Text]
  78. Vermeer SE, van Dijk EJ, Koudstaal PJ, et al. Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study. Ann Neurol. 2002;51:285-289.[Medline]
  79. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med. 2003;348:1215-1222.[Abstract/Free Full Text]
  80. Malouf M, Grimley EJ, Areosa SA. Folic acid with or without vitamin B12 for cognition and dementia. Cochrane Database Syst Rev. 2003:CD004514.
  81. Malouf R, Grimley EJ. The effect of vitamin B6 on cognition. Cochrane Database Syst Rev. 2003:CD004393.
  82. Perrig WJ, Perrig P, Stahelin HB. The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc. 1997;45:718-724.[Medline]
  83. Jama JW, Launer LJ, Witteman JC, et al. Dietary antioxidants and cognitive function in a population-based sample of older persons. The Rotterdam Study. Am J Epidemiol. 1996;144:275-280.[Abstract/Free Full Text]
  84. Haller J, Weggemans RM, Ferry M, Guigoz Y. Mental health: mini-mental state examination and geriatric depression score of elderly Europeans in the SENECA study of 1993. Eur J Clin Nutr. 1996;50:(Suppl. 2): S112-S116.
  85. Perkins AJ, Hendrie HC, Callahan CM, et al. Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150:37-44.[Abstract/Free Full Text]
  86. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002;59:1125-1132.[Abstract/Free Full Text]
  87. Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002;132:1345-1356.[Abstract/Free Full Text]
  88. Chandra RK. Effect of vitamin and trace-element supplementation on cognitive function in elderly subjects. Nutrition. 2001;17:709-712.[Medline]
  89. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336:1216-1222.[Abstract/Free Full Text]
  90. Prince M, MacDonald A, Sham P, et al. The development and initial validation of a telephone-administered cognitive test battery (TACT). Int J Meth Psychiatr Res. 1999;8:49-57.
  91. Tabet N, Birks J, Evans JG, Orrel M, Spector A., Vitamin E for Alzheimer's disease (Cochrane Review) Issue 1. Oxford: Update Software; 2003.
  92. Uauy R, Hoffman DR, Peirano P, Birch DG, Birch EE. Essential fatty acids in visual and brain development. Lipids. 2001;36:885-895.[Medline]
  93. Suzuki H, Park SJ, Tamura M, Ando S. Effect of the long-term feeding of dietary lipids on the learning ability, fatty acid composition of brain stem phospholipids and synaptic membrane fluidity in adult mice: a comparison of sardine oil diet with palm oil diet. Mech Ageing Dev. 1998;101:119-128.[Medline]
  94. Lim SY, Suzuki H. Intakes of dietary docosahexaenoic acid ethyl ester and egg phosphatidylcholine improve maze-learning ability in young and old mice. J Nutr. 2000;130:1629-1632.[Abstract/Free Full Text]
  95. Barberger-Gateau P, Letenneur L, Deschamps V, Peres K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002;325:932-933.[Free Full Text]
  96. Kalmijn S, Feskens EJ, Launer LJ, Kromhout D. Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men. Am J Epidemiol. 1997;145:33-41.[Abstract/Free Full Text]
  97. Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60:940-946.[Abstract/Free Full Text]
  98. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med. 2002;346:1113-1118.[Abstract/Free Full Text]
  99. Uauy R, Valenzuela A. Marine oils: the health benefits of n-3 fatty acids. Nutrition. 2000;16:680-684.[Medline]
  100. Kim HY, Akbar M, Lau A, Edsall L. Inhibition of neuronal apoptosis by docosahexaenoic acid (22:6n-3). Role of phosphatidylserine in antiapoptotic effect. J Biol Chem. 2000;275:35215-35223.[Abstract/Free Full Text]
  101. O'Brien JT, Erkinjuntti T, Reisberg B, et al. Vascular cognitive impairment. Lancet Neurol. 2003;2:89-98.[Medline]
  102. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154-160.[Abstract/Free Full Text]
  103. Expert Group on Vitamins and Minerals. Safe Upper Levels of Vitamins and Minerals. London: Food Standards Agency; 2003.
  104. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.[Abstract/Free Full Text]
  105. Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004;134:183-186.[Free Full Text]
  106. de Gaetano G. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet. 2001;357:89-95.[Medline]




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