Multivitamin use and telomere length in women

Article (PDF Available)inAmerican Journal of Clinical Nutrition 89(6):1857-63 · April 2009with17 Reads
DOI: 10.3945/ajcn.2008.26986 · Source: PubMed
Abstract
Telomere length may be a marker of biological aging. Multivitamin supplements represent a major source of micronutrients, which may affect telomere length by modulating oxidative stress and chronic inflammation. The objective was to examine whether multivitamin use is associated with longer telomeres in women. We performed a cross-sectional analysis of data from 586 early participants (age 35-74 y) in the Sister Study. Multivitamin use and nutrient intakes were assessed with a 146-item food-frequency questionnaire, and relative telomere length of leukocyte DNA was measured by quantitative polymerase chain reaction. After age and other potential confounders were adjusted for, multivitamin use was associated with longer telomeres. Compared with nonusers, the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users (P for trend = 0.002). In the analysis of micronutrients, higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Furthermore, intakes of both nutrients were associated with telomere length among women who did not take multivitamins. This study provides the first epidemiologic evidence that multivitamin use is associated with longer telomere length among women.

Figures

See corresponding editorial on page 1721.
Multivitamin use and telomere length in women
1–3
Qun Xu, Christine G Parks, Lisa A DeRoo, Richard M Cawthon, Dale P Sandler, and Honglei Chen
ABSTRACT
Background: Telomere length may be a marker of biological aging.
Multivitamin supplements represent a major source of micronu-
trients, which may affect telomere length by modulating oxidative
stress and chronic inflammation.
Objective: The objective was to examine whether multivitamin use
is associated with longer telomeres in women.
Design: We performed a cross-sectional analysis of data from 586
early participants (age 35–74 y) in the Sister Study. Multivitamin
use and nutrient intakes were assessed with a 146-item food-frequency
questionnaire, and relative telomere length of leukocyte DNA was
measured by quantitative polymerase chain reaction.
Results: After age and other potential confounders were adjusted
for, multivitamin use was associated with longer telomeres. Com-
pared with nonusers, the relative telomere length of leukocyte DNA
was on average 5.1% longer among daily multivitamin users (P for
trend ¼ 0.002). In the analysis of micronutrients, higher intakes of
vitamins C and E from foods were each associated with longer
telomeres, even after adjustment for multivitamin use. Furthermore,
intakes of both nutrients were associated with telomere length
among women who did not take multivitamins.
Conclusion: This study provides the first epidemiologic evidence
that multivitamin use is associated with longer telomere length
among women. Am J Clin Nutr 2009;89:1857–63.
INTRODUCTION
Telomeres, the TTAGGG tandem repeat sequence, and their
binding proteins at the ends of chromosomes prevent chromo-
somes from detrimental recombination and degradation (1). In
somatic cells, the length of telomeres decreases with each cell
division, which may eventually lead to cell senescence or apo-
ptosis. Therefore, telomere length has been proposed as a marker
of ‘biological ageing’ (2). Consistent with this hypothesis, pre-
liminary epidemiologic studies have related shorter telomeres to
higher mortality (3) and higher risk of some age-related chronic
diseases (4–10). Experimental evidence suggests that oxidative
stress and chronic inflammation contribute to the attrition of
telomeres (2, 11). Several micronutrients, such as antioxidant
vitamins and minerals, can modulate the states of oxidative
stress and chronic inflammation and therefore may affect telo-
mere length (12–15). Multivitamin supplements contain large
amounts of many vitamins and minerals and therefore represent
a major source of micronutrient intake (16). We therefore ex-
amined whether multivitamin use was associated with longer
telomeres among 586 women from the Sister Study.
SUBJECTS AND METHODS
Study population
The Sister Study (http://www.sisterstudy.org/) is an ongoing
risk-enriched prospective cohort of healthy sisters (age 35–74 y)
of breast cancer patients (17). Recruitment began in 2004 and is
expected to be completed in 2009. The enrollment includes
a home visit for blood and urine collection, a 90-min computer-
assisted telephone interview, and several self-administered ques-
tionnaires, including a detailed food-frequency questionnaire
(FFQ). Details of this telomere project and sampling procedures
were described elsewhere (18). Briefly, a total of 740 women
were selected for telomere measurement from the first 2086
Sister Study participants by oversampling smokers, nonwhite
women, and women with high perceived stress and by randomly
sampling the rest. Exclusion criteria included missing or in-
eligible biological specimens, missing race or smoking data,
major dental procedure or surgery in the past week, working on
rotating shifts, recent chemotherapy or radiation treatment of
cancer, or a diagnosis of breast cancer before the first annual
follow-up. The sample selection criteria and sample size reflect
the requirements for a US Department of Defense–funded study
on stress and telomere length. We limited our analyses to 586
women with valid dietary information and duplicate laboratory
assays on telomere length. The Sister Study was approved by the
Institutional Review Board of the National Institute of Envi-
ronmental Health Science, National Institutes of Health.
Telomere length measurement
A whole blood sample was collected at enrollment and stored
at 280°C until DNA extraction. Total leukocyte DNA was then
used as a template for polymerase chain reaction (PCR)–based
1
From the Epidemiology Branch, National Institute for Environmental
Health Sciences, National Institutes of Health, Research Triangle Park, NC
(QX, CGP, LAD, DPS, and HC), and the Department of Human Genetics,
University of Utah, Salt Lake City, UT (RMC).
2
Supported by the Intramural Research Program of the NIH, National In-
stitute of En vironmental Health Sciences (Z01ES044005 AND Z01ES101986),
and the Department of Defense Breast Cancer Research Concept Award
(BC045286).
3
Address reprint requests and correspondence to H Chen, Epidemiology
Branch, National Institute of Environmental Health Sciences, 111 TW Al-
exander Drive, PO Box 12233, Mail drop A3-05, Research Triangle Park,
NC 27709. E-mail: chenh2@niehs.nih.gov.
Received September 18, 2008. Accepted for publication February 8, 2009.
First published online March 11, 2009; doi: 10.3945/ajcn.2008.26986.
Am J Clin Nutr 2009;89:1857–63. Printed in USA. Ó 2009 American Society for Nutrition 1857
by guest on October 13, 2011www.ajcn.orgDownloaded from
86.DC1.html
http://www.ajcn.org/content/suppl/2010/12/08/ajcn.2008.269
Supplemental Material can be found at:
measurement of relative telomere length according to previously
published protocols (19). The assay used 100–200 ng template
DNA in 1-lL aliquots for triplicate PCR amplifications per sample
per plate. Cycle threshold was transformed into nanograms DNA
based on a standard curve. The quantitative assay determines the
amount of telomeric DNA (T) relative to the amount of single-
copy control gene (human b-globin) DNA (S) and then calculates
a T/S ratio. This PCR-based telomere assay was found to be highly
correlated with Southern blot analysis (19). We further estimated
the relative length of telomeres in base pairs (bp) by multiplying
the T/S ratio with a constant of 4270 (19). Whereas this constant
was derived and validated in another study, the assays here were
performed in the same laboratory by using the same genetic
controls. Of the 740 specimens submitted for telomere assays, 647
were run on duplicate plates including 3 internal controls (one
each at a high, medium, and low T/S ratio) to further account for
variation over time and plates. The CV across averaged adjusted
replicates was 8.5%. These average plate-adjusted values were
used for the present analyses.
Exposure assessment
The Sister Study dietary survey was based on a modified Block
1998 FFQ with additional questions and changes (20, 21). The
FFQ asked for the portion size and frequency of consumption of
146 food items in the past 12 mo. Intake of individual nutrients
was then calculated with software from the Block Dietary Data
Systems (Berkeley, CA). Participants were asked whether they
had taken any vitamins or minerals regularly (at least once per
month) during the past 12 mo. For those who answered ‘yes,
the FFQ further elicited details about the use of 3 types of
multivitamins [regular once-a-day, Centrum (Wyeth Consumer
Healthcare, Madison, NJ), or Thera type; stress-tabs or B-complex
type; and antioxidant combination type] and 16 indiv idual sup-
plements of vitamins or minerals. For each supplement, participants
were asked the frequency of use (ranging from ‘did not take’ to
‘ev ery day’’) and, for users, the duration of use (ranging from ‘less
than 1 year’ to ‘101 years’’). We further calculated an overall
frequency variable for multivitamin use by combining the use of all
3 types of multivitamins. The Sister Study also collected in-
formation on age, race, education, smoking status, perceived stress
lev el, self-reported health status, adult-onset diabetes, and cardio-
vascular diseases (ie, heart attack, bypass surgery, angioplasty ,
congestiv e heart failure, cardiac arrhythmic, medicated angina, and
stroke/transient ischemic attack). Body weight and height were
measured during a home visit for blood collection, and body mass
index (BMI) was calculated by dividing weight in kilograms by
height squared in meters.
Statistical analyses
For multivitamins, the frequency and duration of use were
defined categorically. The use of most individual vitamin and
mineral supplements was infrequent; therefore, the participants
were classified as users or nonusers. We compared the population
characteristics by multivitamin use status using Student’s t test
for continuous variables and a chi-square test for categorical
variables. Dietary intake of micronutrients was categorized into
quartiles (25% of the participants in each quartile) after ad-
justment for energy intake with the residual method (22). The
least-square means and SEM of relative telomere length for each
exposure category were calculated with generalized linear re-
gression models, adjusted for age (continuous), race (non-Hispanic
white and others), BMI (continuous), education (high school,
some college, associate degree/technical training, college grad-
uate, and graduate degrees), cigarette smoking (never, former,
and current smokers), presence of diabetes or cardiovascular
diseases (yes, no), energy intake (continuous), perceived stress
level (very low, low, moderate, high, and very high), self-reported
health status (excellent, very good, good, and fair or poor), and
physical activity (metabolic equivalent hours in quartiles). The
statistical significance of a linear trend was tested by including
the median of each category as a continuous variable in the
regression model and interactions by including a multiplicative
term between supplement use frequency and the stratifying
variable.
To further explore the relation between multivitamin use and
telomere length, we conducted stratified analyses according to
median age (median: , and 53 y), smoking status (never and
ever), BMI (, and 30), and the presence of diabetes or car-
diovascular diseases (yes and no). In addition, we conducted
a sensitivity analysis by excluding women who reported ‘fair or
poor’ health status.
Finally, we examined whether intakes of any important mi-
cronutrients that were commonly found in multivitamins were
related to telomere length in the study population. Among
multivitamin users, a substantial proportion of the micronutrient
intake was from multivitamins. This was particularly true for
vitamins C, D, and E and most B vitamins. We therefore fit the
regression models with and without adjusting for multivitamin
use and conducted an analysis among women who did not take
multivitamins to evaluate the independent relation between di-
etary micronutrient intake and telomere length. All statistical
analyses were conducted by using SAS software (version 9.1;
SAS Institute, Cary, NC), and the significance tests were 2-tailed
with a ¼ 0.05.
RESULTS
Study sample characteristics are presented in Table 1. Com-
pared with women who did not take multivitamins, regular users
were older, more likely to be non-Hispanic white and never
smokers, and had higher education level. However, multivitamin
users and nonusers were not significantly based on other pop-
ulation characteristics.
Sixty-five percent of the women used multivitamins at least
once per month, and most users (74%) took multivitamins on
a daily basis. About 89% of the users took once-a-day type
multivitamins, 21% took antioxidant combination, and 17% took
stress-tabs or B-complex vitamins. Among users, multivitamins
represented a major source of total vitamin and mineral intakes,
contributing .50% of the total intake for vitamins C, E, D, B-6,
B-12, folate, iron, and zinc and 30–50% for vitamin A, b-carotene,
and calcium.
In general, the use of multivitamin supplements was associated
with longer telomere length (Figure 1). Compared with non-
users, daily users had on average 5.1% longer telomeres (P for
trend ¼ 0.002). This difference (273 bp) corresponds to 9.8 y
of age-related telomere loss since each year of age was associated
with a 28-bp shorter telomere in our sample. Significant
1858 XU ET AL
by guest on October 13, 2011www.ajcn.orgDownloaded from
associations were also obtained for the once-a-day or the anti-
oxidant combination type, but not for the stress-tab or B-complex
type. Excluding women who reported fair or poor health did not
change the results: the relative telomere length was 5398 bp for
nonusers and 5645 bp for daily users (4.6% dif ference; P for
trend ¼ 0.009). Analysis of the duration of individual multivi-
tamin use showed similar results. Compared with nonusers, the
adjusted telomere length of those who took multivitamins
for .5 y was 3% longer for once-a-day type multivitamins
(P for trend ¼ 0.09) and 8% for antioxidant combination type (P
for trend ¼ 0.02). The duration of stress-tabs or B complex use
was not related to telomere length. Multivitamin use was also
TABLE 1
Characteristics of the study participants
1
Multivitamin supplement
2
All (n ¼ 586) Nonusers (n ¼ 203) Users (n ¼ 378) P value
3
Age (y) 53.6 6 9.6
4
51.6 6 9.1 54.6 6 9.7 0.0005
Non-Hispanic whites [n(%)] 493 (84.1) 162 (79.8) 327 (86.5) 0.03
Education [n(%)] 0.005
High school 90 (15.4) 40 (19.7) 49 (13.0)
Some college 152 (25.9) 63 (31.0) 88 (23.3)
Associate degrees/technical training 84 (14.3) 31 (15.3) 53 (14.0)
College graduate 148 (25.3) 37 (18.2) 110 (29.1)
Graduate degree 112 (19.1) 32 (15.8) 78 (20.6)
Smoking [n(%)] 0.009
Former 173 (29.5) 54 (26.6) 116 (30.7)
Current 136 (23.2) 62 (30.5) 73 (19.3)
BMI (kg/m
2
) 27.5 6 6.2 28.2 6 6.6 27.2 6 5.9 0.09
Physical activity (MET hours) 47.2 6 30.0 44.2 6 27.4 48.6 6 31.0 0.07
Self-reported health [n(%)] 0.5
Excellent 185 (31.6) 62 (30.5) 121 (32.0)
Very good 211 (36.0) 67 (33.0) 142 (37.6)
Good 145 (24.7) 56 (27.6) 88 (23.3)
Fair or poor 45 (7.7) 18 (8.9) 27 (7.1)
Perceived stress level [n(%)] 0.08
Very low 109 (18.6) 35 (17.2) 74 (19.6)
Low 144 (24.6) 43 (21.2) 99 (26.2)
Moderate 108 (18.4) 44 (21.7) 63 (16.7)
High 128 (21.8) 39 (19.2) 89 (23.5)
Very high 97 (16.6) 42 (20.7) 53 (14.0)
Self-reported diabetes or cardiovascular
diseases [n(%)]
112 (19.1) 37 (18.2) 74 (19.6) 0.7
Total energy (kcal) 1590 6 535 1590 6 597 1594 6 501 0.9
1
MET, metabolic equivalent task.
2
Five women were missing data on multivitamin use.
3
A Student’s t test was used for continuous variables, and a chi-square test was used for categorical variables.
4
Mean 6 SD (all such values).
FIGURE 1. Least-squares mean (6SE) telomere length according to the frequency of multivitamin use. Generalized linear models were used in the
analysis, adjusted for age, race, BMI, education, cigarette smoking, presence of diabetes or cardiovascular diseases, energy intake, perceived stress level, self-
reported health status, and physical activity. Numbers within the bars represents the sample size for each exposure group.
MULTIVITAMIN USE AND TELOMERE LENGTH 1859
by guest on October 13, 2011www.ajcn.orgDownloaded from
associated with longer telomere length in most of the subgroup
analyses by age, sex, and smoking status (Table 2), although not
all associations were significant. Use of individual micronutrient
supplements was less common in this study sample, and, in
general, they were not associated with telomere length after
multivitamin use was accounted for (data not shown). The only
exceptions were vitamin B-12 and iron: vitamin B-12 supple-
ment users (n ¼ 52) had a longer telomere length than did
nonusers (n ¼ 518): 5850 6 159 compared with 5505 6 89 bp
(5.9% difference; P ¼ 0.03), and iron users (n ¼ 41) had
a shorter telomere length than nonusers (n ¼ 527): 5121 6 183
compared with 5583 6 87 bp (29.0% difference; P ¼ 0.007).
The total intake of most micronutrients was positively asso-
ciated with telomere length (Table 3); however, these associa-
tions became statistically nonsignificant after multivitamin use
was adjusted for. Micronutr ient intake from foods was g ener-
ally not related to telomere length, except for vitamins C and E
(Table 4). Higher dietary intake of these 2 antioxidants was
associated with longer te lomere length i n a dose-response
man ner even aft er multivitamin use was adjusted for. Among
women who did not use multivitamins ( n ¼ 203), higher di-
etary intakes of b-carotene, folate, magnesium, and vitamins C,
E, and A were each associated with longer telomere length
(Table 4).
DISCUSSION
In this cross-sectional analysis, multivitamin use was related to
longer telomere length in women aged 35–74 y. Nutrient analysis
suggests that one or more dietary antioxidant vitamins may
contribute to this relation.
Telomeres typically shorten by a few dozen to a couple
hundred bps per cell division (23); therefore, telomere length has
been proposed as a marker of biological aging. Furthermore,
because telomere attrition may eventually lead to chromosomal
instability and cell death, excessive telomere shortening may
play an important role in the development of some chronic
diseases (1, 23). In recent epidemiologic studies, shorter leu-
kocyte telomeres have been linked to higher mortality (3–5),
accelerated aging (1), and higher risk of a variety of chronic
diseases (4, 5, 24).
Telomere attrition in human somatic cells is likely the result of
multiple forces, including the ‘end-replication’ problem and low
telomerase activity (2). Compared with these factors, oxidative
stress is probably a more important contributor to telomere at-
trition (2). Telomeres are particularly vulnerable to oxidative
damages, which often cannot be efficiently repaired (23). Fur-
thermore, inflammatory reactions induce oxidative stress, and
tumor necrosis factor-a significantly decreases telomerase ac-
tivity and reduces telomere length in leukemic cells (25).
TABLE 2
Average telomere length according to frequency of multivitamin use in subgroups
1
Users
Nonusers ,3 d/wk 4–6 d/wk Daily P for trend
2
P for interaction
3
Age 0.6
,53 y
No. of subjects 122 27 35 99
Lsmean 6 SE 5586 6 141 5429 6 233 5893 6 213 5824 6 146 0.05
53 y
No. of subjects 81 22 15 180
Lsmean 6 SE 5168 6 138 5291 6 237 5373 6 286 5494 6 126 0.02
BMI 0.5
,30 kg/m
2
No. of subjects 137 34 37 190
Lsmean 6 SE 5434 6 126 5483 6 194 5705 6 197 5624 6 122 0.08
30 kg/m
2
No. of subjects 66 15 13 89
Lsmean 6 SE 5230 6 162 5009 6 314 5618 6 336 5708 6 158 0.008
Smoking 0.6
Never
No. of subjects 87 24 26 139
Lsmean 6 SE 5483 6 139 5307 6 234 5717 6 233 5628 6 123 0.2
Ever
No. of subjects 116 25 24 140
Lsmean 6 SE 5368 6 131 5450 6 230 5765 6 230 5788 6 135 0.002
Diabetes or cardiovascular disease 0.4
No
No. of subjects 166 39 47 218
Lsmean 6 SE 5587 6 104 5508 6 180 5817 6 168 5796 6 103 0.03
Yes
No. of subjects 37 10 3 61
Lsmean 6 SE 4908 6 219 4966 6 390 5813 6 667 5590 6 187 0.004
1
Least-squares mean (Lsmean) 6 SE values were derived from generalized linear regression models, adjusted for age, race, BMI, education level,
cigarette smoking, presence of diabetes or cardiovascular diseases, energy intake, perceived stress level, self-reported health status, and physical activity.
Stratified variables were also adjusted for in the subgroup analysis when possible.
2
Tested by including the median of each category as a continuous variable in the regression model.
3
Tested by including a multiplicative term in the regression model.
1860 XU ET AL
by guest on October 13, 2011www.ajcn.orgDownloaded from
Therefore, oxidative stress and chronic inflammation may be
among the major mechanisms of telomere attrition. On the other
hand, many micronutrients, such as dietary antioxidants, B-vi-
tamins, and certain minerals, can modulate oxidative stress and
inflammatory reactions (26–28) and therefore can contribute to
the maintenance or attrition of telomeres. Few studies to date
have investigated the role of these micronutrients in telomere
maintenance. Earlier in vitro experiments showed that ascorbic
acid or its derivatives (12, 29, 30) or a-tocopherol (13) slowed
telomere shortening and increased the life span of certain so-
matic cells. In rats, iron overload significantly increased telo-
merase activity in liver cells but caused no change in telomere
length (31). Recently, 2 population-based cross-sectional anal-
yses examined dietary biomarkers in relation to telomere length
(14, 15). In the first study, higher plasma vitamin D was asso-
ciated with longer leukocyte telomere length among women,
probably via antiinflammatory actions of vitamin D (14). In the
other study, higher plasma homocysteine was associated with
shorter telomere length, whereas higher folate was related to
longer telomeres (15).
Containing most key vitamins and minerals 100% of the
recommended daily intake, multivitamins are major sources of
micronutrients in the US diet. According to the recent National
Health and Nutrition Examination Survey, 35% of US adults took
one or more types of multivitamins, the majority of whom were
elderly white women (16). To our knowledge, this was the first
epidemiologic study of multivitamin use and telomere length.
Regular multivitamin users tend to follow a healthy lifestyle and
have a higher intake of micronutrients, which sometimes makes
it difficult to interpret epidemiologic observations on multivi-
tamin use (16). In this study, we took extra caution in the data
analyses by adjusting for and stratifying by important factors
that may affect telomere length, including age, smoking status,
and BMI (32, 33). Furthermore, we controlled for several in-
dicators of socioeconomic status or lifestyle choice in all anal-
yses. Women with less optimal health or chronic diseases may
be more likely to use vitamin supplements; however, the ex-
clusion of these women from the analysis did not alter the re-
sults. Previous epidemiologic results on multivitamin use and
risk of chronic diseases vary, depending on the nutrient
TABLE 3
Average telomere length according to total intake of selected micronutrients with and without adjustment for
multivitamin use
1
Model 1
2
(n ¼ 586) Model 2
3
(n ¼ 581)
Nutrient Quartile 1
4
Quartile 4
4
P for trend
5
Quartile 1
4
Quartile 4
4
P for trend
5
Vitamin A (IU) 4953
6
17,547 4927 17,547
Lsmean 6 SE 5293 6 106 5633 6 108 0.02 5356 6 124 5571 6 124 0.3
b-carotene (lg) 1621 7226 1613 7206
Lsmean 6 SE 5336 6 107 5649 6 106 0.03 5409 6 120 5605 6 120 0.2
Vitamin C (mg) 63 785 63 794
Lsmean 6 SE 5289 6 107 5670 6 106 0.02 5318 6 132 5620 6 121 0.2
Vitamin E (a-TE) 7.6 328 7.6 328
Lsmean 6 SE 5324 6 104 5640 6 111 0.1 5346 6 158 5590 6 127 0.5
Vitamin B-6 (mg) 1.2 4.9 1.2 4.9
Lsmean 6 SE 5424 6 107 5737 6 107 0.005 5604 6 149 5619 6 140 0.5
Vitamin B-12 (lg) 2.3 17 2.3 17
Lsmean 6 SE 5355 6 104 5737 6 106 0.002 5442 6 142 5641 6 127 0.1
Folate (lg) 236 867 236 867
Lsmean 6 SE 5336 6 108 5689 6 107 0.01 5452 6 146 5516 6 146 0.8
Vitamin D (IU) 75 639 75 637
Lsmean 6 SE 5393 6 103 5564 6 108 0.009 5430
6 134
5500 6 142 0.7
Calcium (mg) 444 1906 445 1906
Lsmean 6 SE 5407 6 106 5578 6 111 0.04 5454 6 120 5501 6 126 0.4
Selenium (lg) 61 113 61 113
Lsmean 6 SE 5369 6 103 5663 6 106 0.02 5446 6 115 5602 6 123 0.3
Iron (mg) 8.5 33 8.5 33
Lsmean 6 SE 5391 6 107 5568 6 110 0.03 5459 6 131 5459 6 135 0.97
Magnesium (mg) 184 419 184 419
Lsmean 6 SE 5314 6 105 5659 6 109 0.007 5364 6 126 5589 6 129 0.3
Zinc (mg) 7.1 31 7.1 30
Lsmean 6 SE 5332 6 102 5630 6 106 0.008 5350 6 134 5560 6 132 0.4
1
Least-squares mean (Lsmean) 6 SE values were derived from generalized linear regression models. TE, tocopherol
equivalents.
2
Adjusted for age, race, BMI, education level, cigarette smoking, presence of diabetes or cardiovascular diseases,
energy intake, perceived stress level, self-reported health status, and physical activity.
3
Adjusted as for model 1 and for multivitamin use. Five women with missing data on multivitamin use were not
included in model 2.
4
Each quartile represents 25% of the study participants: quartile 1, the lowest 25%, and quartile 4, the highest 25%.
5
Tested by including the median of each category as a continuous variable in the regression model.
6
Median (all such values).
MULTIVITAMIN USE AND TELOMERE LENGTH 1861
by guest on October 13, 2011www.ajcn.orgDownloaded from
composition, the disease type, and the design of the study (34–
36). Further investigations would be needed to understand the
role of multivitamin use and telomere length and its implication
in the etiology of chronic diseases.
Sorting out which micronutrients underlie our findings is
difficult because multivitamins contain various vitamins and
minerals and contribute in large amounts to daily micronutrient
intakes. Nevertheless, higher intakes of the antioxidant vitamins
C and E consistently showed associations with longer telomeres
in different analyses. In multivitamin users, 63% of vitamin C
and 84% of vitamin E were from supplemental sources. Whereas
the evidence is not sufficient to conclude that these 2 dietary
antioxidants mediated the observed relation, the results are
consistent with experimental findings that vitamins C and E
protect telomeres in vitro (12, 13, 29, 30).
This study had several limitations. The quantitative PCR-based
assay measures the average telomere length across all leukocytes
in the peripheral blood. We therefore could not exclude the
possibility that multivitamin use might have shifted the com-
position of leukocyte subpopulations in a way that favored cells
with longer telomeres as an alternative explanation for our
finding. Furthermore, as the first study on this topic, our analysis
was explanatory in nature; this was particularly true for subgroup
analyses that included a smaller number of participants. Finally,
although it is unlikely that telomere length affects multivitamin
use, this analysis was cross-sectional and we were unable to make
a direct causal inference. It is advisable to follow-up these
findings in future large longitudinal studies.
Compared with national data, more women in our population
took multivitamins (16). This may be a characteristic of women
who volunteer for cohort studies and itself does not necessarily
affect the validity of our study. Residual confounding is always
a concern in epidemiologic research on health behaviors, such as
multivitamin use. In this study, we adjusted for and stratified by
a variety of potential confounders and conducted a sensitivity
analysis by excluding women with fair or poor health. Finally,
our dietary data relied on an FFQ, which was subject to mea-
surement errors. However, the Block FFQ is widely used for
dietary surveys and has been consistently updated and validated
in various populations (20, 21, 37).
In summary, our study provides preliminary evidence linking
multivitamin use to longer leukocyte telomeres. This finding
TABLE 4
Average telomere length according to intake of selected micronutrients from foods
1
All women
2
(n ¼ 581) Multivitamin nonusers
3
(n ¼ 203)
Quartile 1
4
Quartile 4
4
P for trend
5
Quartile 1
4
Quartile 4
4
P for trend
5
Vitamin A (IU) 3845
6
13,160 3508 11,273
Lsmean 6 SE 5399 6 115 5527 6 117 0.3 5230 6 171 5674 6 167 0.008
b-carotene (lg) 1168 5323 1052 4708
Lsmean 6 SE 5463 6 115 5549 6 117 0.4 5120 6 174 5484 6 164 0.045
Vitamin C (mg) 42 153 38 134
Lsmean 6 SE 5340 6 115 5683 6 113 0.03 4945 6 173 5701 6 153 0.002
Vitamin E (a-TE) 6.1 12 5.7 12
Lsmean 6 SE 5311 6 115 5672 6 118 0.004 5134 6 161 5533 6 173 0.03
Vitamin B-6 (mg) 1.0 1.8 0.9 1.7
Lsmean 6 SE 5434 6 112 5625 6 117 0.3 5308 6 159 5300 6 164 0.8
Vitamin B-12 (lg) 1.8 4.6 1.7 4.6
Lsmean 6 SE 5574 6 108 5611 6 116 0.8 5317 6 159 5414 6 171 0.6
Folate (lg) 201 401 181 388
Lsmean 6 SE 5371 6 115 5530 6 117 0.4 5091 6 175 5586 6 162 0.02
Vitamin D (IU) 50 250 42 215
Lsmean 6 SE 5606 6 110 5591 6 114 0.8 5389
6 157
5537 6 164 0.3
Calcium (mg) 366 931 331 824
Lsmean 6 SE 5549 6 110 5520 6 116 0.9 5187 6 165 5583 6 163 0.06
Selenium (lg) 54 92 51 90
Lsmean 6 SE 5518 6 110 5574 6 116 0.8 5264 6 163 5563 6 163 0.1
Iron (mg) 7.6 14 6.9 14
Lsmean 6 SE 5511 6 111 5605 6 119 0.7 5365 6 176 5367 6 162 0.9
Magnesium (mg) 165 304 154 273
Lsmean 6 SE 5382 6 113 5572 6 118 0.1 5183 6 167 5603 6 172 0.04
Zinc (mg) 6.4 12 5.7 12
Lsmean 6 SE 5504 6 114 5576 6 116 0.6 5292 6 162 5480 6 168 0.2
1
Least-squares mean (Lsmean) 6 SE values were derived from generalized linear regression models. TE, tocopherol
equivalents.
2
The analysis among all women was adjusted for age, race, BMI, education level, cigarette smoking, presence of
diabetes or cardiovascular diseases, energy intake, perceived stress level, self-reported health status, physical activity, and
multivitamin use.
3
The analysis among multivitamin nonusers was adjusted as for all women, except for multivitamin use.
4
Each quartile represents 25% of the study participants: quartile 1, the lowest 25%, and quartile 4, the highest 25%.
5
Tested by including the median of each category as a continuous variable in the regression model.
6
Median (all such values).
1862 XU ET AL
by guest on October 13, 2011www.ajcn.orgDownloaded from
should be further evaluated in future epidemiologic studies and
its implications concerning aging and the etiology of chronic
diseases should be carefully evaluated.
We thank Jack A Taylor for his helpful comments and Teresa Stepanek in
RM Cawthon’s laboratory for the telomere assay.
The authors’ responsibilities were as follows—QX and LAD: study con-
cept and design, statistical analysis, data interpretation, manuscript prepara-
tion and critical revision; CGP, DPS, and HC: study concept and design, data
collection, statistical analysis, data interpretation, manuscript preparation,
critical revision, and financial support; and RMC: study design, data collec-
tion and interpretation, and critical revision of the manuscript. None of the
authors had a conflict of interest.
REFERENCES
1. Blasco MA. Telomeres and human disease: ageing, cancer and beyond.
Nat Rev Genet 2005;6:611–22.
2. von Zglinicki T, Martin-Ruiz CM. Telomeres as biomarkers for ageing
and age-related diseases. Curr Mol Med 2005;5:197–203.
3. Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. As-
sociation between telomere length in blood and mortality in people aged
60 years or older. Lancet 2003;361:393–5.
4. Martin-Ruiz C, Dickinson HO, Keys B, Rowan E, Kenny RA, Von
Zglinicki T. Telomere length predicts poststroke mortality, dementia,
and cognitive decline. Ann Neurol 2006;60:174–80.
5. Honig LS, Schupf N, Lee JH, Tang MX, Mayeux R. Shorter telomeres
are associated with mortality in those with APOE epsilon 4 and de-
mentia. Ann Neurol 2006;60:181–7.
6. Fitzpatrick AL, Kronmal RA, Gardner JP, et al. Leukocyte telomere
length and cardiovascular disease in the Cardiovascular Health Study.
Am J Epidemiol 2007;165:14–21.
7. Wu X, Amos CI, Zhu Y, et al. Telomere dysfunction: a potential cancer
predisposition factor. J Natl Cancer Inst 2003;95:1211–8.
8. Shao L, Wood CG, Zhang D, et al. Telomere dysfunction in peripheral
lymphocytes as a potential predisposition factor for renal cancer. J Urol
2007;178:1492–6.
9. Shen J, Terry MB, Gurvich I, Liao Y, Senie RT, Santella RM. Short
telomere length and breast cancer risk: a study in sister sets. Cancer Res
2007;67:5538–44.
10. McGrath M, Wong JY, Michaud D, Hunter DJ, De Vivo I. Telomere
length, cigarette smoking, and bladder cancer risk in men and women.
Cancer Epidemiol Biomarkers Prev 2007;16:815–9.
11. Houben JMJ, Moonen HJJ, van Schooten FJ, Hageman GJ. Telomere
length assessment: biomarker of chronic oxidative stress? Free Radic
Biol Med 2008;44:235–46.
12. Furumoto K, Inoue E, Nagao N, Hiyama E, Miwa N. Age-dependent
telomere shortening is slowed down by enrichment of intracellular vi-
tamin C via suppression of oxidative stress. Life Sci 1998;63:935–48.
13. Tanaka Y, Moritoh Y, Miwa N. Age-dependent telomere-shortening is
repressed by phosphorylated alpha-tocopherol together with cellular
longevity and intracellular oxidative-stress reduction in human brain
microvascular endotheliocytes. J Cell Biochem 2007;102:689–703.
14. Richards JB, Valdes AM, Gardner JP, et al. Higher serum vitamin D
concentrations are associated with longer leukocyte telomere length in
women. Am J Clin Nutr 2007;86:1420–5.
15. Richards JB, Valdes AM, Gardner JP, et al. Homocysteine levels and
leukocyte telomere length. Atherosclerosis 2008;200:271–7.
16. Radimer K, Bindewald B, Hughes J, Ervin B, Swanson C, Picciano MF.
Dietary supplement use by US adults: data from the National Health and
Nutrition Examination Survey, 1999-2000. Am J Epidemiol 2004;160:
339–49.
17. Weinberg CR, Shore DL, Umbach DM, Sandler DP. Using risk-based
sampling to enrich cohorts for endpoints, genes, and exposures. Epi-
demiology 2007;166:447–55.
18. Parks CG, Miller DB, McCanlies EC, et al. Telomere length, current
perceived stress, and urinary stress hormones in women. Cancer Epi-
demiol Biomarkers Prev 2009;18:551–60.
19. Cawthon RM. Telomere measurement by quantitative PCR. Nucleic
Acids Res 2002;30:e47.
20. Boeckner LS, Pullen CH, Walker SN, Abbott GW, Block T. Use and
reliability of the World Wide Web version of the Block Health Habits
and History Questionnaire with older rural women. J Nutr Educ Behav
2002;34(suppl 1):S20–4.
21. Boucher B, Cotterchio M, Kreiger N, Nadalin V, Block T, Block G.
Validity and reliability of the Block98 food-frequency questionnaire in
a sample of Canadian women. Public Health Nutr 2006;9:84–93.
22. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake
in epidemiologic studies. Am J Clin Nutr 1997;65:1220S–8S
(discussion 1229S–31S).
23. Monaghan P, Haussmann MF. Do telomere dynamics link lifestyle and
lifespan? Trends Ecol Evol 2006;21:47–53.
24. Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA.
Monocyte telomere shortening and oxidative DNA damage in type 2
diabetes. Diabetes Care 2006;29:283–9.
25. Beyne-Rauzy O, Recher C, Dastugue N, et al. Tumor necrosis factor
alpha induces senescence and chromosomal instability in human leu-
kemic cells. Oncogene 2004;23:7507–16.
26. Singh U, Devaraj S, Jialal I. Vitamin E, oxidative stress, and in-
flammation. Annu Rev Nutr 2005;25:151–74.
27. Peyrin-Biroulet L, Rodriguez-Gueant R-M, Chamaillard M, et al. Vas-
cular and cellular stress in inflammatory bowel disease. Revisiting the
Role of Homocysteine The Am J Gastroenterol 2007;102:1108–15.
28. Maggini S, Wintergerst ES, Beveridge S, Hornig DH. Selected vitamins
and trace elements support immune function by strengthening epithelial
barriers and cellular and humoral immune responses. Br J Nutr 2007;
98(suppl 1):S29–35.
29. Yokoo S, Furumoto K, Hiyama E, Miwa N. Slow-down of age-
dependent telomere shortening is executed in human skin keratinocytes
by hormesis-like-effects of trace hydrogen peroxide or by anti-oxidative
effects of pro-vitamin C in common concurrently with reduction of in-
tracellular oxidative stress. J Cell Biochem 2004;93:588–97.
30. Kashino G, Kodama S, Nakayama Y, et al. Relief of oxidative stress by
ascorbic acid delays cellular senescence of normal human and Werner
syndrome fibroblast cells. Free Radic Biol Med 2003;35:438–43.
31. Brown KE, Meleah Mathahs M, Broadhurst KA, et al. Increased hepatic
telomerase activity in a rat model of iron overload: A role for altered
thiol redox state? Free Radic Biol Med 2007;42:228–35.
32. Zannolli R, Mohn A, Buoni S, et al. Telomere length and obesity. Acta
Paediatr 2008;97:952–4.
33. Valdes AM, Andrew T, Gardner J, et al. Obesity, cigarette smoking, and
telomere length in women. Lancet 2005;366:662–4.
34. Huang H-Y, Caballero B, Chang S, et al. multivitamin/mineral supple-
ments and prevention of chronic disease: executive summary. Am J Clin
Nutr 2007;85(suppl):265S–8S.
35. Godfrey JR. Toward optimal health: Meir Stampfer, M.D., Dr.P.H.,
discusses multivitamin and mineral supplementation for women. J
Womens Health 2007;16:959–62.
36. Prentice RL. Clinical trials and observational studies to assess the
chronic disease benefits and risks of multivitamin-multimineral sup-
plements. Am J Clin Nutr 2007;85(suppl):308S–13S.
37. Block G, Wakimoto P, Jensen C, Mandel S, Green RR. Validation of
a food frequency questionnaire for Hispanics. Prev Chronic Dis 2006;3:
A77 (abstr).
MULTIVITAMIN USE AND TELOMERE LENGTH 1863
by guest on October 13, 2011www.ajcn.orgDownloaded from
    • "Higher intake of processed meat, red meat, sweetened carbonated beverages , white bread, short-to medium-chain saturated fatty acids and their sources such as whole milk (and products such as butter and cheese), linoleic acid (n6 fatty acid), and higher sodium intake (in those with high BMI) were all associated with shorter telomeres [58,59,65,67,68,70,71]. Multivitamin use was associated with both shorter and longer telomeres [69,70]. Studies on blood nutrient concentrations showed U-shaped relationships between plasma folate and telomere length [69,75] and a reduction of telomere length is associated with higher homocysteine (a metabolic biomarker of folate and/or vitamin B12 deficiency) in older subjects indicating a rather complex relationship with B vitamins [72À74]. "
    [Show abstract] [Hide abstract] ABSTRACT: Telomeres are TTAGGG repeats at the ends of chromosomes that have been consistently associated with accelerated aging and higher risk of developmental and degenerative diseases when they are too short or dysfunctional. The biology of telomere structure, function, and maintenance is reviewed in the context of aging, genetics, environmental factors, life-style and nutrition. The current evidence regarding which dietary factors are associated positively or negatively with telomere integrity is discussed.
    Full-text · Chapter · Dec 2016 · Genes
    • "Similar observations also showed in the emergency physicians working in rotating shifts [81]. However, some dietary and lifestyle factors such as marine omega-3 fatty acid [82], antioxidants [23], vitamin intake [83], physical activity [72], and healthy lifestyle [84] were reported to decrease rates of LTL shortening. These factors might contribute to reduced reactive oxygen species, inhibit inflammation, increase endothelial nitric oxide synthase (eNOS) activity, and increased telomerase activity. "
    [Show abstract] [Hide abstract] ABSTRACT: Telomeres are tandem repeat DNA sequences present at the ends of each eukaryotic chromosome to stabilize the genome structure integrity. Telomere lengths progressively shorten with each cell division. Inflammation and oxidative stress, which are implicated as major mechanisms underlying cardiovascular diseases, increase the rate of telomere shortening and lead to cellular senescence. In clinical studies, cardiovascular risk factors such as smoking, obesity, sedentary lifestyle, and hypertension have been associated with short leukocyte telomere length. In addition, low telomerase activity and short leukocyte telomere length have been observed in atherosclerotic plaque and associated with plaque instability, thus stroke or acute myocardial infarction. The aging myocardium with telomere shortening and accumulation of senescent cells limits the tissue regenerative capacity, contributing to systolic or diastolic heart failure. In addition, patients with ion-channel defects might have genetic imbalance caused by oxidative stress-related accelerated telomere shortening, which may subsequently cause sudden cardiac death. Telomere length can serve as a marker for the biological status of previous cell divisions and DNA damage with inflammation and oxidative stress. It can be integrated into current risk prediction and stratification models for cardiovascular diseases and can be used in precise personalized treatments. In this review, we summarize the current understanding of telomeres and telomerase in the aging process and their association with cardiovascular diseases. In addition, we discuss therapeutic interventions targeting the telomere system in cardiovascular disease treatments.
    Full-text · Article · Sep 2016
    • "доказали, что статины способны повысить миграционную способность эндотелиальных клеток-предшественниц посредством влияния через TRF2 – белок, входящий в состав шелтерин-комплекс Т-петли теломер [68]. Аналогичные данные имеются в отношении омега-3 полиненасыщенных жирных кислот, витамина В12 [69,70]. Витамин D снижает концентрацию медиаторов системного воспаления, таких как интерлейкин-2 и фактор некроза опухоли-альфа. "
    [Show abstract] [Hide abstract] ABSTRACT: Review of clinical studies showing the pleiotropic effect of vitamin D with a detailed description of pathogenetic ways to implement these effects is presented. Relation of vitamin D with cardiovascular diseases, kidney diseases, disorders of the immune and nervous systems, aging is discussed according to results of current researches.
    Full-text · Article · May 2016
Show more