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Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts 02111
3To whom correspondence should be addressed. E-mail: >blumberg@hnrc.tufts.edu" locator-type="email">locator-type="email">blumberg@hnrc.tufts.edu locator="" locator-type="email">
 |
ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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8 µmol/L received either a multivitamin/mineral supplement or
placebo for 56 d while consuming their usual diet. After the 8-wk
treatment, subjects taking the supplement had significantly higher
B-vitamin status and lower homocysteine concentration than controls
(P < 0.01). Plasma folate, pyridoxal phosphate
(PLP) and vitamin B-12 concentrations were increased 41.6, 36.5 and
13.8%, respectively, in the supplemented group, whereas no
changes were observed in the placebo group. The mean homocysteine
concentration decreased 9.6% in the supplemented group (P
< 0.001) and was unaffected in the placebo group. There were no
significant changes in dietary intake during the intervention.
Multivitamin/mineral supplementation can improve B-vitamin status
and reduce plasma homocysteine concentration in older adults already
consuming a folate-fortified diet.
KEY WORDS: • homocysteine • multivitamin • aging • humans • folic acid • supplements
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, Boushey et al. 1995
,
Selhub et al. 1995
, Stampfer et al. 1992
). The B-vitamins folate, B-12 and B-6 function as
essential cofactors and coenzymes in regulating the remethylation and
trans-sulfuration pathways of homocysteine metabolism. An inverse
correlation between homocysteine and the dietary intake and nutrient
status of these B-vitamins has been established (Selhub 1993
). Although multivitamin use has also been associated with
low homocysteine concentrations in several observational studies
(Brattstrom et al. 1994
, Giles et al. 1999
, Koehler et al. 1996
, Malinow et al. 1997
, Osganian et al. 1999
, Ridker et al. 1999
, Shimakawa et al. 1997
, Tucker et al. 1996
), no clinical trials using typical
multivitamin/mineral supplements to lower homocysteine have been
conducted.
Clinical trials that examined the effects of B-vitamin
supplementation on homocysteine have been described
(Homocysteine Lowering Trialists’ Collaboration 1998
).
Supplement intervention studies conducted on patients with
hyperhomocysteinemia not due to genetic abnormalities, typically heart
and kidney patients, have demonstrated that >800 µg folate/d
administered in combination with vitamins B-12 and B-6 can reduce
homocysteine and, potentially, the associated morbidity and mortality
rates (Bostom et al. 1996
, den Heijer et al. 1998
, Glueck et al. 1995
, Lindgren et al. 1995
, Ubbink et al. 1994
). More recent
supplement intervention studies have demonstrated the
homocysteine-lowering effect of these B-vitamins at low doses
(Recommended Dietary Allowance levels) in
normohomocysteinemic (range 4.4–13.1 µmol/L) adults. Ward et al. (1997)
demonstrated the efficacy of 200 and 400 µg of
folic acid in lowering homocysteine in healthy men 34–65 y.
Nonpregnant, healthy, young women responded similarly to 250–500 µg
folic acid alone (Brouwer et al. 1999
), 400 µg folic
acid with either 6 or 400 µg vitamin B-12 (Bronstrup et al. 1998
) and 400 µg folic acid with 2 mg vitamin B-6
(Dierkes et al. 1997
). Bronstrup et al. (1999)
later demonstrated the efficacy of the three
B-vitamins combined [400 µg folic acid, 1.65 mg pyridoxine and 3
µg cyanocobalamin] in men and women 60 y old. However, all of
these low dose supplement studies were conducted either outside of the
United States in countries without extensive food fortification
programs or before implementation of the mandatory fortification of the
U.S. food supply with folic acid.
The U.S. Food and Drug Administration issued a regulation in 1996
requiring that all enriched grain products, including flour, rice,
pasta and cornmeal, be fortified with folic acid at 140 µg/100 g of
grain product. Although compliance with this regulation was to be
effective in January 1998, the process was begun in 1996 and
essentially complete by mid-1997. The purpose of the folate
fortification mandate was to reduce the risk of neural tube defects in
newborns by increasing the intake of folate in women of childbearing
age. However, as a consequence of fortification, the prevalence of low
folate concentrations and high homocysteine concentrations in
middle-aged and older adults decreased from 22.0 to 1.7% and from
18.7 to 9.8%, respectively (Jacques et al. 1999b
).
Before folate fortification, low folate intake and high homocysteine
levels were prevalent among older adults. The original cohort of the
Framingham Heart Study (aged 67–96 y) showed a 29% prevalence of
hyperhomocysteinemia, attributable largely to low folate, vitamin B-12
and vitamin B-6 concentrations (Selhub 1993
). Data from
the 1997 CSFII (U.S. Department of Agriculture 1997
)
confirms that a substantial number of adults 50 y old were not
meeting current dietary recommendations for folate (33–45%) and
vitamin B-6 (52–66%). Data from NHANES III (Wright et al. 1998
) show the prevalence of low serum vitamin B-12
concentration (<185 pmol/L) increasing from 9% in 50- to 59-y-olds to
13% in persons 70 y old. The increased prevalence of hypochlorhydria
in this population (Saltzman and Russell 1998
) adds to
the problem by reducing the bioavailability of these B-vitamins for
many individuals, thereby predisposing them to an increased risk for
elevated homocysteine concentrations.
To compensate for perceived dietary deficiencies, 31–56% of older
Americans take dietary supplements (Ervin et al. 1999
).
In the United States, the use of dietary supplements by adults
increases with age and, with the exception of pregnant and lactating
females, is most prevalent among non-Hispanic white men and women
50 y old (Block 1988
, Ervin et al. 1999
, Mares-Perlman 1993
). Multivitamins,
typically formulated at 
100% Daily Value
(DV)4for most vitamins and selected minerals, are the most commonly used
supplement (Neuhouser et al. 1999
). Previous clinical
trials with multivitamins have indicated a beneficial effect on
nutrient status (Preziosi et al. 1998
), antioxidant
defenses (Girodon et al. 1997
), immune response
(Bogden et al. 1994
, Chandra 1992
),
hypertension (Mark et al. 1996
), cerebrovascular disease
mortality rates (Mark et al. 1996
), proliferation in
esophageal dysplasia (Taylor et al. 1995
) and fertility
(Czeizel et al. 1996
). We determined whether a
multivitamin/mineral supplement formulated at 100% DV will further
lower homocysteine concentrations and improve B-vitamin status in
healthy older adults already consuming a diet fortified with folic
acid.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Healthy, free living adults 50 y old residing in the greater Boston
area were recruited via newspaper advertisements, direct mailings and
clinic postings. Volunteers were excluded if they were smokers; used
dietary supplements regularly for 3 mo before screening; were taking
medications known to interfere with folate metabolism; had established
diseases of the gastrointestinal tract, liver or kidney; or had any
disability that would impede full participation in the study. On the
basis of these criteria, 272 men and women were recruited for an
initial blood screening for homocysteine status between October 1997
and January 1999 (Fig. 1
). Ninety-two subjects with a total plasma homocysteine
concentration of 8 µmol/L at this initial screening visit were
invited to participate in the clinical trial. Subjects began the study
within 1–12 mo of their initial screening visit and were enrolled
regardless of their baseline homocysteine concentration at d -7 and 0.
During the study, six subjects had clinical chemistry values outside
standard reference ranges, three developed medical conditions
undetected during the initial screening visit, one was no longer
interested in participating, one was unwilling to refrain from dietary
supplements and one had gastrointestinal complaints, leaving a total of
80 subjects who completed the study. All except one of the subjects who
withdrew did so within the placebo "run-in" period, i.e., between d
-7 and 0. The remaining subject withdrew on d 7. The age range of
study subjects was 50–87 y (mean age 66.5 ± 8.6 y).
|
Experimental design.
A double-blind, placebo-controlled clinical trial was conducted of
an effervescent multivitamin/mineral preparation formulated at 100%
DV for most nutrients (Table 1
). After gender stratification, subjects were randomly assigned to
receive either supplement or placebo before study entry. The placebo
was composed of the same non-nutritive, base ingredients found in
the supplement, i.e., citric acid, sodium bicarbonate, sweeteners,
flavoring and coloring agent. During the 7 d before the
intervention, all subjects were given placebo to test their ability to
comply with the protocol and were required to provide two overnight
fasting blood samples (on d -7 and 0) to determine baseline values for
homocysteine concentrations and selected micronutrients. Blood samples
were again collected from fasting subjects on d 49 and 56.
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Blood analyses and questionnaires.
Blood samples were collected from fasting subjects in
EDTA-containing evacuated tubes. Blood samples for homocysteine
analysis were centrifuged within 15 min of blood draw (3000 x g, 15 min, 4°C) with an SUR-Sep cap (Organon
Teknika, Durham, NC), and the plasma stored in a 5-mL NUNC tube
(Vanguard Cryotubes, Neptune, NJ) at -80°C. Samples for
B-vitamin analyses were centrifuged within 1 h of blood draw,
and both plasma and red blood cells were stored at -80°C for up to
12 mo (most at 4–6 mo). All samples for each subject were analyzed
within the same run for every assay performed. Total plasma
homocysteine concentration was determined by HPLC with fluorescence
detection according to the method of Araki and Sako (1987)
. Plasma folate and vitamin B-12 concentrations were
measured by radioimmunoassay (catalogue no. 1911040,Quantaphase II
B-12/Folate Radioassay Kit;BioRad Laboratories,Hercules,CA). Plasma
PLP was measured according to the tyrosine apodecarboxylase method
described by Camp et al. (1983)
, and vitamin B-6 status
was determined according to the aspartic transaminase activity
coefficient (AC) assay described by Williams (1976)
.
The Willett food frequency questionnaire (Rimm et al. 1992
) was administered by a trained dietician on d -7 and 56.
On d -7, subjects were asked to estimate their usual dietary intake
for the previous year, whereas on d 56, subjects were asked about their
intake during the previous 2 mo. The nutrient database used for the
questionnaire (U.S. Department of Agriculture 1996
) had
not yet been modified to reflect recent changes in food folate content
due to fortification, so folate intake from food is consistently
underestimated.
Statistical analyses.
All statistical analyses were performed with the software package SPSS v8.0 (SPSS, Chicago, IL). Before formal analysis, a logarithmic transformation was applied to homocysteine and all B-vitamin concentrations to achieve homogeneity of variance and linearity of regressions. However, untransformed values were used to construct tables and graphs of summary statistics. Tests of repeated measures analysis of variance were used to determine statistically significant changes in plasma nutrient and homocysteine values. Student’s t test was used to compare baseline characteristics between the placebo and supplemented groups. Multivariate regression and Pearson’s correlation matrix were used to determine and describe the relationship between B-vitamin concentration changes and their effect on homocysteine. The Wilcoxon-Mann-Whitney test was used to determine whether nutrient and homocysteine concentration changes from suboptimal to optimal categories were different in placebo and supplemented groups.
Baseline values of micronutrient and homocysteine status were calculated as the mean of values determined on d -7 and 0, whereas values at the end of the intervention were calculated as the mean of values determined on d 49 and 56. Values are expressed as means ± SD, and two-sided observed significance levels (P-values) of <0.05 were considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Eighty-nine percent of subjects were white, 10% were black and
1% were Hispanic. No significant differences were observed between the
groups with respect to age, gender and body mass index. Baseline plasma
concentrations of homocysteine, folate, PLP and vitamin B-6 status (AC)
also did not differ significantly between groups (Table 3
). Plasma vitamin B-12 was lower in the placebo group than in the
supplemented group (P = 0.02), although data from the
food frequency questionnaire suggested a higher vitamin B-12 intake in
the placebo group (P = 0.23).
|
|
, although
the reported intakes of folate (P = 0.37), vitamin B-6
(P = 0.78), coffee (P = 0.56) and
alcohol (P = 0.21) were all higher in the supplemented
group.
Baseline homocysteine concentrations did not change significantly
within either group between -7 and 0 d, the placebo run-in
period (Table 4
). Similarly, no changes were detected within groups between 49 and
56 d. The range of baseline homocysteine concentrations was
5.7–16.4 µmol/L (median 9.0 µmol/L) in the placebo group and
5.4–14.8 µmol/L (median 9.2 µmol/L) in the supplemented group.
|
. Plasma folate, PLP and vitamin B-12 concentrations were
increased 41.6, 36.5 and 13.8%, respectively, in the supplemented
group (P < 0.01). The mean homocysteine concentration
decreased 9.6% in the supplemented group (P < 0.01)
(Fig. 2
). Homocysteine concentration was unaffected in the placebo group.
Folate and vitamin B-6 status were not changed in the placebo group,
whereas vitamin B-12 decreased 4% (P = 0.13). There
were no significant changes in dietary intake during the intervention.
|
) from 15 to 5%, of
suboptimal vitamin B-12 status (<258 pmol/L) (Lindenbaum et al. 1994
) from 42 to 27% and of low PLP status (<20 nmol/L)
(van der Wielen et al. 1996
) from 7 to 0%. The
prevalence of suboptimal vitamin B-12 in the placebo group increased
from 67% to 80% during the intervention. Changes differed between
groups only for vitamin B-12 (P = 0.004). No subjects
presented with subnormal plasma folate concentrations (
9.9 nmol/L)
(Pietrzik 1989
) at baseline. After supplementation, the
number of subjects with homocysteine concentrations of 12 µmol/L
was reduced from 7% to 5%, and the number of subjects of 10
µmol/L was reduced from 37% to 24%. The change in folate
concentration after supplementation ranged from -8 to +25 nmol/L, the
change in PLP concentration ranged from -136.4 to +105.0 nmol/L and
the change in vitamin B-12 concentration ranged from -24 to +141
pmol/L. After supplementation, the change in homocysteine concentration
ranged from -3.0 to +0.7 µmol/L.
Multiple regression analysis indicated that only the change in folate
status was predictive of homocysteine change (P = 0.01)
when folate, PLP, vitamin B-6 AC and vitamin B-12 were included in the
model. Figure 3
shows a significant inverse correlation between the change in total
plasma homocysteine and change in folate status in the supplemented
group. No significant correlations were shown for change in
homocysteine and change in vitamin B-6 AC, PLP and vitamin B-12 after
supplementation. Regression analysis indicated supplemented subjects
would be expected to have an improvement in total plasma homocysteine
concentration of -0.9 µmol/L (P < 0.001).
|
10 µmol/L. Baseline
homocysteine and B-vitamin status of hypertensive and normotensive
subjects did not differ. After supplementation, the change in
homocysteine and B-vitamin status was attenuated for hypertensive
subjects, but this difference was significant only for their response
to PLP (P = 0.02) and vitamin B-12 (P = 0.01). The change in vitamin B-6 AC was -0.07 ± 0.13 in
hypertensive subjects compared with -0.14 ± 0.09 in
normotensives; vitamin B-12 changes were 21 ± 37 versus 54
± 39 pmol/L, respectively. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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100% DV for folic acid, vitamin B-6 and
vitamin B-12 significantly improved plasma concentrations of these
vitamins and reduced total plasma homocysteine concentrations in
free-living older adults already consuming a diet fortified with
folic acid. Dietary intake of folate, vitamins B-6 and B-12 and other
dietary factors known to have an affect on folate and homocysteine
status, i.e., alcohol (Hultberg et al. 1993
) and coffee
(Nygard et al. 1997
, Stolzenberg-Solomon et al. 1999
), did not change during the intervention, and thus they
are not responsible for the observed change in nutrient status.
Regression analysis indicated that only the increase in folate status
was responsible for the homocysteine concentration–lowering effect. The effects of supplementation were greater in subjects who presented with higher homocysteine concentration and lower B-vitamin status at baseline; however, we were unable to show this differential effect was not the result of a regression to the mean. The attenuated effect of supplementation in subjects who reported having hypertension on study entry has not been previously reported and warrants further investigation.
Other low dose (400 µg) folate supplementation studies in healthy
adults showed a somewhat greater magnitude of change in homocysteine
concentration (11–16%) after 4 wk (Bronstrup et al. 1998 and 1999
, Brouwer et al. 1999
, Dierkes et al. 1997
). The range of mean baseline homocysteine concentrations
was higher in the studies of Brouwer et al. (1999)
and
Bronstrup et al. (1999)
(9.7–11.1 µmol/L) and lower
in the studies of Dierkes et al. (1997)
and
Bronstrup et al. (1998)
(7.4–8.2 µmol/L), although
all were within the normohomocysteinemic range. Baseline plasma folate
concentrations in this study were comparable to those reported by
Bronstrup et al. (1999)
(25 nmol/L) and Dierkes et al. (1997)
(21 nmol/L), although the increase in folate
status after supplementation in these studies was higher (12–16.3
nmol/L) than that observed in our subjects. The prevalence of vitamin
B-12 concentrations of <258 pmol/L in our study was higher (53.8%)
than that reported in the Framingham Heart Study cohort (40.5%)
(Lindenbaum et al. 1994
), whereas the prevalence of low
PLP (6%) was less than that reported in the SENECA study of elderly
Europeans (22%) (van der Wielen et al. 1996
).
Post–folate fortification homocysteine concentration means in the
Framingham Heart Study cohort (age 67–96 y) among supplement users
(8.5 µmol/L) and nonusers (9.4 µmol/L) were similar to the means of
our supplement group before and after intervention. Although the
Framingham cohort is an observational study and the supplements used
are not well defined, the magnitude of the post–fortification
supplementation effect on homocysteine is consistent with our study.
Folate was the nutrient primarily responsible for the observed
homocysteine concentration–lowering effect, and although the
additional 70–120 µg/d from fortified foods can substantially
improve the homocysteine and folate status of older adults (Food and Drug Administration 1993
), our results suggest that a daily
multivitamin/mineral supplement is capable of enhancing these effects.
Increased homocysteine may accelerate cardiovascular and
cerebrovascular disease risks via various mechanisms, including direct
damage to vascular endothelium, stimulation of smooth muscle cell
proliferation, enhanced LDL peroxidation and interference with
hemostasis. Although standard reference ranges for "healthy"
homocysteine concentrations are not well defined, 98.8% of subjects in
this study were considered normohomocysteinemic (range of all subjects,
5.4–16.4 µmol/L) (Ueland et al. 1993
). Nonetheless,
the multivitamin/mineral supplement was able to further lower
homocysteine concentrations. Potential benefits of lowering plasma
concentrations in normohomocysteinemic people were suggested by
Selhub et al. (1995),
who found an increased risk of
carotid artery stenosis in men and women (aged 67–96 y) with
homocysteine concentrations of 9.2–11.3 and 11.4–14.3 µmol/L,
respectively. Boushey and Beresford (1995) considered 10
µmol/L to be a "healthy" concentration, but lower homocysteine
concentrations have been associated with increased risk for stroke
(Bostom et al. 1999
, Kittner et al. 1999
), atherosclerosis (Malinow et al. 1993
) and
death (Kark et al. 1999
).
Although coronary heart disease risk was reduced among the 80,082 women
(aged 30–55 y) in the Nurse’s Health Study who regularly used
multiple vitamins (relative risk 0.76, 95% confidence interval
0.65–0.90) (Rimm et al. 1998
), the design of the
current study does not allow confirmation of the protective effect of a
multivitamin against heart disease as an end point. Randomized clinical
trials are under way to test whether lowered homocysteine
concentrations reduce the risk of major cardiovascular events
(Eikelboom et al. 1999
).
Moderately elevated plasma homocysteine concentrations are common among
older adults, with vitamin status a primary determinant accounting for
approximately two thirds of all such cases (Jacques et al. 1999a
, Selhub et al. 1999
). Increased folate
intake due to fortification had a positive impact on reducing
homocysteine in an older adult population (Jacques et al. 1999b
). Nonetheless, supplemental folate intake via
multivitamins may provide further benefit in increasing vitamin status
and lowering plasma homocysteine concentrations. Importantly, concerns
regarding the ability of folate to mask vitamin B-12 deficiency are
reduced when multivitamins containing vitamin B-12 are consumed.
Further, the crystalline form of vitamin B-12 found in supplements is
more bioavailable than the protein-bound vitamin B-12 obtained from
food (Baik and Russell 1999
). In conclusion, modest
supplementary vitamin intakes may provide benefit among older adults by
improving B-vitamin status and reducing concentrations of total
plasma homocysteine.
|
ACKNOWLEDGMENTS |
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|
FOOTNOTES |
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2 The contents of this publication do not
necessarily reflect the views or policies of the U.S. Department of
Agriculture nor does mention of trade names, commercial products, or
organizations imply endorsement by the U.S. government.
4 Abbreviations used: AC, activity coefficient;
DV, Daily Value; PLP, pyridoxal phosphate.
Manuscript received May 15, 2000. Initial review completed June 27, 2000. Revision accepted August 31, 2000.
|
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