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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.
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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 (Pfor
trend ¼0.002). 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 Environmental 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.
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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 individual sup-
plements of vitamins or minerals. For each supplement, participants
were asked the frequency of use (ranging from ‘‘did not take’’ to
‘‘every day’’) and, for users, the duration of use (ranging from ‘‘less
than 1 year’’ to ‘‘101years’’). 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
level, self-reported health status, adult-onset diabetes, and cardio-
vascular diseases (ie, heart attack, bypass surgery, angioplasty,
congestive 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 ttest
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 a¼0.05.
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 (Pfor
trend ¼0.002). 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
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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% difference; Pfor
trend ¼0.009). 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
(Pfor trend ¼0.09) and 8% for antioxidant combination type (P
for trend ¼0.02). 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 (n¼586) Nonusers (n¼203) Users (n¼378) Pvalue
3
Age (y) 53.6 69.6
4
51.6 69.1 54.6 69.7 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 66.2 28.2 66.6 27.2 65.9 0.09
Physical activity (MET hours) 47.2 630.0 44.2 627.4 48.6 631.0 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 6535 1590 6597 1594 6501 0.9
1
MET, metabolic equivalent task.
2
Five women were missing data on multivitamin use.
3
A Student’s ttest was used for continuous variables, and a chi-square test was used for categorical variables.
4
Mean 6SD (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.
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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 (n¼52) had a longer telomere length than did
nonusers (n¼518): 5850 6159 compared with 5505 689 bp
(5.9% difference; P¼0.03), and iron users (n¼41) had
a shorter telomere length than nonusers (n¼527): 5121 6183
compared with 5583 687 bp (29.0% difference; P¼0.007).
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. Micronutrient intake from foods was gener-
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 telomere length in a dose-response
manner even after multivitamin use was adjusted for. Among
women who did not use multivitamins (n¼203), 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-asignificantly 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 Pfor trend
2
Pfor interaction
3
Age 0.6
,53 y
No. of subjects 122 27 35 99
Lsmean 6SE 5586 6141 5429 6233 5893 6213 5824 6146 0.05
53 y
No. of subjects 81 22 15 180
Lsmean 6SE 5168 6138 5291 6237 5373 6286 5494 6126 0.02
BMI 0.5
,30 kg/m
2
No. of subjects 137 34 37 190
Lsmean 6SE 5434 6126 5483 6194 5705 6197 5624 6122 0.08
30 kg/m
2
No. of subjects 66 15 13 89
Lsmean 6SE 5230 6162 5009 6314 5618 6336 5708 6158 0.008
Smoking 0.6
Never
No. of subjects 87 24 26 139
Lsmean 6SE 5483 6139 5307 6234 5717 6233 5628 6123 0.2
Ever
No. of subjects 116 25 24 140
Lsmean 6SE 5368 6131 5450 6230 5765 6230 5788 6135 0.002
Diabetes or cardiovascular disease 0.4
No
No. of subjects 166 39 47 218
Lsmean 6SE 5587 6104 5508 6180 5817 6168 5796 6103 0.03
Yes
No. of subjects 37 10 3 61
Lsmean 6SE 4908 6219 4966 6390 5813 6667 5590 6187 0.004
1
Least-squares mean (Lsmean) 6SE 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.
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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
(n¼586) Model 2
3
(n¼581)
Nutrient Quartile 1
4
Quartile 4
4
Pfor trend
5
Quartile 1
4
Quartile 4
4
Pfor trend
5
Vitamin A (IU) 4953
6
17,547 4927 17,547
Lsmean 6SE 5293 6106 5633 6108 0.02 5356 6124 5571 6124 0.3
b-carotene (lg) 1621 7226 1613 7206
Lsmean 6SE 5336 6107 5649 6106 0.03 5409 6120 5605 6120 0.2
Vitamin C (mg) 63 785 63 794
Lsmean 6SE 5289 6107 5670 6106 0.02 5318 6132 5620 6121 0.2
Vitamin E (a-TE) 7.6 328 7.6 328
Lsmean 6SE 5324 6104 5640 6111 0.1 5346 6158 5590 6127 0.5
Vitamin B-6 (mg) 1.2 4.9 1.2 4.9
Lsmean 6SE 5424 6107 5737 6107 0.005 5604 6149 5619 6140 0.5
Vitamin B-12 (lg) 2.3 17 2.3 17
Lsmean 6SE 5355 6104 5737 6106 0.002 5442 6142 5641 6127 0.1
Folate (lg) 236 867 236 867
Lsmean 6SE 5336 6108 5689 6107 0.01 5452 6146 5516 6146 0.8
Vitamin D (IU) 75 639 75 637
Lsmean 6SE 5393 6103 5564 6108 0.009 5430 6134 5500 6142 0.7
Calcium (mg) 444 1906 445 1906
Lsmean 6SE 5407 6106 5578 6111 0.04 5454 6120 5501 6126 0.4
Selenium (lg) 61 113 61 113
Lsmean 6SE 5369 6103 5663 6106 0.02 5446 6115 5602 6123 0.3
Iron (mg) 8.5 33 8.5 33
Lsmean 6SE 5391 6107 5568 6110 0.03 5459 6131 5459 6135 0.97
Magnesium (mg) 184 419 184 419
Lsmean 6SE 5314 6105 5659 6109 0.007 5364 6126 5589 6129 0.3
Zinc (mg) 7.1 31 7.1 30
Lsmean 6SE 5332 6102 5630 6106 0.008 5350 6134 5560 6132 0.4
1
Least-squares mean (Lsmean) 6SE 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).
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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
(n¼581) Multivitamin nonusers
3
(n¼203)
Quartile 1
4
Quartile 4
4
Pfor trend
5
Quartile 1
4
Quartile 4
4
Pfor trend
5
Vitamin A (IU) 3845
6
13,160 3508 11,273
Lsmean 6SE 5399 6115 5527 6117 0.3 5230 6171 5674 6167 0.008
b-carotene (lg) 1168 5323 1052 4708
Lsmean 6SE 5463 6115 5549 6117 0.4 5120 6174 5484 6164 0.045
Vitamin C (mg) 42 153 38 134
Lsmean 6SE 5340 6115 5683 6113 0.03 4945 6173 5701 6153 0.002
Vitamin E (a-TE) 6.1 12 5.7 12
Lsmean 6SE 5311 6115 5672 6118 0.004 5134 6161 5533 6173 0.03
Vitamin B-6 (mg) 1.0 1.8 0.9 1.7
Lsmean 6SE 5434 6112 5625 6117 0.3 5308 6159 5300 6164 0.8
Vitamin B-12 (lg) 1.8 4.6 1.7 4.6
Lsmean 6SE 5574 6108 5611 6116 0.8 5317 6159 5414 6171 0.6
Folate (lg) 201 401 181 388
Lsmean 6SE 5371 6115 5530 6117 0.4 5091 6175 5586 6162 0.02
Vitamin D (IU) 50 250 42 215
Lsmean 6SE 5606 6110 5591 6114 0.8 5389 6157 5537 6164 0.3
Calcium (mg) 366 931 331 824
Lsmean 6SE 5549 6110 5520 6116 0.9 5187 6165 5583 6163 0.06
Selenium (lg) 54 92 51 90
Lsmean 6SE 5518 6110 5574 6116 0.8 5264 6163 5563 6163 0.1
Iron (mg) 7.6 14 6.9 14
Lsmean 6SE 5511 6111 5605 6119 0.7 5365 6176 5367 6162 0.9
Magnesium (mg) 165 304 154 273
Lsmean 6SE 5382 6113 5572 6118 0.1 5183 6167 5603 6172 0.04
Zinc (mg) 6.4 12 5.7 12
Lsmean 6SE 5504 6114 5576 6116 0.6 5292 6162 5480 6168 0.2
1
Least-squares mean (Lsmean) 6SE 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 ATaylor 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.
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... In vitro and in vivo studies showed that long-term exposure to magnesium deficiency led to telomere shortening 51,52 . In a cross-sectional analysis of the Sister Study, instead, reported a positive association between magnesium intake and telomere length of leukocyte DNA from women who did not use multivitamin supplements 53 . From a biological point of view, magnesium is an important cofactor for the catalytic activity of enzymes implicated in DNA replication and repair [54][55][56][57] , and in RNA synthesis 54 . ...
... studies were conducted during the periconceptional period. Regarding iron, results from the Sister Study did not demonstrate an association between its dietary intake and telomere length 53 , however, it has been suggested a negative effect of iron supplementation 53,60 . Indeed, iron is a prooxidant and its supplementation might increase the production of free radicals 61 , thus fostering an oxidative environment 60 . ...
... Indeed, iron is a prooxidant and its supplementation might increase the production of free radicals 61 , thus fostering an oxidative environment 60 . By contrast, the supplementations with multivitamins, which contained less iron than specific supplements, did not produce a negative effect 53 . The lack of any solid evidence in this field of research, therefore, encourages further efforts to understand the influence of maternal dietary factors on biological aging, as determined by telomere length. ...
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Pregnancy represents a crucial period in which several exposures—and especially maternal diet—might shape children’s health. Thus, identifying how maternal dietary intakes early affect biological aging in children represents a public health mission. We aimed to assess the relationship between maternal intake of nutrients in early pregnancy and telomere length of cell-free circulating DNA (cfDNA) from amniotic fluid. We used data and samples from the ongoing prospective “Mamma & Bambino” study, which recruits mother–child pairs from Catania at the first prenatal visit. Maternal nutrient intakes were assessed using a Food Frequency Questionnaire, while relative telomere length of cfDNA was assessed by real-time polymerase chain reaction. Our analysis included 174 mother–child pairs. The intakes of iron, vitamin B1, and magnesium were positively correlated with relative telomere length (p-values < 0.05). However, only the intake of magnesium was positively associated with relative telomere length, after applying a linear regression model (β = 0.002; SE = 0.001; p = 0.024). Magnesium deficiency was negatively associated with relative telomere length after adjusting for the same covariates (β = −0.467; SE = 0.176; p = 0.009). To our knowledge, this is the first evidence of a positive relationship between maternal nutrient intake and telomere length of cfDNA. Further efforts are needed for deeply investigating the effect of maternal dietary intakes on telomere length, in order to develop effective public health strategies.
... The authors posit that shortened telomeres may not necessarily mean a dysfunctional telomeres, and poor intake of β-carotene may not be extensive enough to induce dysfunctionality [80]. In addition, multivitamin usage of both Vitamin C and Vitamin E had a positive association on TL in women and elderly people too [78,81]. This finding was further extended by another evidence that earlier consumption of Vitamin C, folate as well as potassium had a positive correlation with TL in older Korean adults [82]. ...
... In all these findings, it appears that effects of antioxidant vitamins on TL may be gender, age or population-dependent, as well as limited by different study designs or sample size issues. Lastly, it is paramount to also consider that many supplements often contain more than one type of vitamins, and effects of TL and diseases may be confounded by the interaction of one or more of these organic compounds [81,111]. ...
... This finding is consistent with another group that showed that selenium increased telomerase activity and induced overexpression of c-Myc and p53 to promote apoptosis in rat hepatocytes [114]. High ferric iron intake has a negative association with TL in women as well as adults aged 65 years or older [81,75,115]. Elevated plasma magnesium and calcium levels possess an inverse association with TL in older women. ...
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Telomeres play a critical role in maintaining cellular fate through tight regulation of cell division and DNA damage or repair. Over the years, it is established that biological ageing is defined by a gradual derangement in functionality, productivity, and robustness of biological processes. The link between telomeres and ageing is highlighted when derangement in telomere biology often leads to premature ageing and concomitant accompaniment of numerous age-associated diseases. Unfortunately, given that ageing is a biologically complicated intricacy, measures to reduce morbidity and improve longevity are still largely in the infancy stage. Recently, it was discovered that dietary habits and interventions might play a role in promoting successful healthy ageing. The intricate relationship between dietary components and its potential to protect the integrity of telomeres may provide unprecedented health benefits and protection against age-related pathologies. This review aims to summarise recent findings that investigate the roles of nutrition on telomere biology and provide enough evidence for further studies to consider the topic of nutrigenomics and its contributions toward healthy ageing and concomitant strategy against age-associated diseases.
... All of these studies and applications (1,11) seem to confirm a potential link between vitamin C and telomere length, but the mechanism of action is still unclear. Some previous studies have investigated the association between blood vitamin C concentrations and telomere length (12), as well as the effect of vitamin use on telomere length in women (13), but these studies had small sample sizes and did not fully investigate the possible influencing factors of the association between dietary vitamin C intake and telomere length. Therefore, this study will use data from National Health and Nutrition Examination Surveys (NHANES) to perform statistical studies to complement current research on the association between dietary vitamin C intake and telomere length. ...
... Previous studies have examined the association between multivitamin use and telomere length in women (13), as well as the effect of high concentrations of nutrients such as lutein on telomere length (12). These studies reached similar conclusions to this one, the first of which used only 586 participants from the sister study, although they were recently screened and adjusted for confounding factors. ...
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Currently, telomere length is known to reflect the replication potential and longevity of cells, and many studies have reported that telomere length is associated with age-related diseases and biological aging. Studies have also shown that vitamin C acts as an oxidant and free radical scavenger to protect cells from oxidative stress and telomere wear, thus achieving anti-aging effects. At present, there are few and incomplete studies on the relationship between vitamin C and telomere length, so this study aims to explore the relationship between vitamin C and telomere length. This study used cross-sectional data from the National Health and Nutrition Examination Surveys (NHANES) database from 1999 to 2002, a total of 7,094 participants were selected from all races in the United States. Male participants accounted for 48.2% and female participants accounted for 51.8%. The correlation between vitamin C and telomere length was assessed using a multiple linear regression model, and the effect of dietary vitamin C on telomere length was obtained after adjusting for confounding factors such as age, gender, race, body mass index (BMI), and poverty income ratio (PIR). This cross-sectional study showed that vitamin C was positively correlated with telomere length, with greater dietary vitamin C intake associated with longer telomeres (β = 0.03, 95% CI: 0.01–0.05, P = 0.003). This study shows that vitamin C intake is positively correlated with human telomere length, which is of guiding significance for our clinical guidance on people’s health care, but our study need to be confirmed by more in-depth and comprehensive other research results.
... Evidence from human studies suggested that oxidative stress may accelerate telomere shortening in human cells, whereas antioxidants have the potential to retard this process (13,14). Given the fact that the amount of food and nutrient intake of antioxidants (including vitamin C and vitamin E) may help maintain telomere length (15,16), RF intake as part of a normal diet may also support the fight against oxidative stress (2). Therefore, it is natural to hypothesize that increased dietary RF intake is associated with telomere lengthening. ...
... Our findings indicated that dietary RF intake is significantly associated with telomere length prolongation in female (adjusted for age, sex, BMI, smoking, alcohol consumption, vitamin C intake, vitamin B12 intake, selenium intake, zinc intake, copper intake, dietary fiber intake, CHF, CHD, and DM), but not in male. This is consistent with the findings of Xu et al., who found that multivitamin use was associated with longer telomere length in females (16). Increased RF intake were also found in several studies to have a significant sex difference in reducing the risk of DM and cardiovascular disease (38,39), typically higher effect in female than in male. ...
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Background Dietary habits and dietary intake affect telomere length, a reliable marker of biological aging and a predictor of chronic disease. Riboflavin (RF) is known as a water-soluble antioxidant vitamin, but its role in telomere length maintenance has yet to be elucidated. Objective The purpose of this study was to examine the relationship between dietary RF intake and telomere length in a nationally representative sample of adults. Methods Using the NHANES (1999–2002), telomere data of 4,298 participants aged ≥45 years were analyzed in a cross-sectional manner. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary RF intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear regressions were performed to evaluate the association between dietary RF intake and telomere length. Subgroup analyses were performed to further explore this relationship in sex and body mass index (BMI) subgroups. Results Among the 3,788 participants included, the average telomere length was longer in females ( P = 0.014), while they had a lower average RF intake compared to males ( P < 0.001). There was a weak positive correlation between RF intake and telomere length both when unadjusted (β = 0.011; P = 0.037) and adjusted for age, sex, and ethnicity (β = 0.013; P = 0.033). Subgroup analyses showed a positive association between RF intake and the telomere length in female after adjusting for confounding factors (β = 0.029; P = 0.046). In the female subgroup, there were significant positive relationships between telomere length and RF intake in the obese group (β = 0.086, P = 0.022). Conclusion Increased dietary RF intake was significantly associated with longer telomere length in middle-aged and older American females, especially in low RF intake obese female.
... However, studies that evaluated the effects of individual antioxidant or prooxidant exposures on senescence have produced inconsistent results [20,[27][28][29][30][31][32][33][34]. Actually, except for vitamin C [27,35], which is a well-known strength antioxidant, the associations between other dietary components and LTL were always conflicting, such as carotene, vitamin E, selenium, and iron [20,[27][28][29][30]. Similarly, the effects of some lifestyle factors, including drinking [31,32], physical activity [33], and obesity [34], on LTL were also controversial. ...
... However, studies that evaluated the effects of individual antioxidant or prooxidant exposures on senescence have produced inconsistent results [20,[27][28][29][30][31][32][33][34]. Actually, except for vitamin C [27,35], which is a well-known strength antioxidant, the associations between other dietary components and LTL were always conflicting, such as carotene, vitamin E, selenium, and iron [20,[27][28][29][30]. Similarly, the effects of some lifestyle factors, including drinking [31,32], physical activity [33], and obesity [34], on LTL were also controversial. ...
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Purpose: Leukocyte telomere length (LTL) is an important biomarker of aging. The oxidative balance score (OBS) is used to assess the oxidative stress-related exposures of diet and lifestyle. This study is aimed at exploring if the OBS was associated with LTL. Methods: 3220 adults were included in this study from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. LTL was assayed from leukocyte DNA. Twenty dietary and lifestyle factors were selected to score the OBS. Survey-based multivariable linear regression was conducted to assess the association between the OBS and log-transformed LTL. Results: The association between the OBS and log-transformed LTL was positive in females but not males. For females, compared with the lowest OBS category as a reference, the multivariable-adjusted beta estimate (95% confidence interval, CI) for the highest OBS category was 0.0701 (0.0205-0.1197) (p for trend < 0.01), and the multivariable-adjusted beta estimate (95% CI) of the continuous OBS was 0.0039 (0.0014-0.0065). There was also the gender difference in the correlations of the dietary OBS and the lifestyle OBS with log-transformed LTL. Conclusion: There was a positive association between the OBS and LTL in females. This result suggested that diet and lifestyle might affect LTL by regulating oxidative balance.
... The report of Kidd [106] showed that astaxanthin slowed age-related functional decline [106], while Weber et al. and co-workers [107] revealed that the prevalence of age-related diseases is significantly reduced with lycopene and alphacarotene. According to Xu et al. [108], a higher dietary intake of β-carotene was associated with longer telomere length. ...
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Carotenoids are isoprenoid-derived natural products produced in plants, algae, fungi, and photosynthetic bacteria. Most animals cannot synthesize carotenoids because the biosynthetic machinery to create carotenoids de novo is absent in animals, except arthropods. Carotenoids are biosynthesized from two C20 geranylgeranyl pyrophosphate (GGPP) molecules made from isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) via the methylerythritol 4-phosphate (MEP) route. Carotenoids can be extracted by a variety of methods, including maceration, Soxhlet extraction, supercritical fluid extraction (SFE), microwave-assisted extraction (MAE), accelerated solvent extraction (ASE), ultrasound-assisted extraction (UAE), pulsed electric field (PEF)-assisted extraction, and enzyme-assisted extraction (EAE). Carotenoids have been reported to exert various biochemical actions, including the inhibition of the Akt/mTOR, Bcl-2, SAPK/JNK, JAK/STAT, MAPK, Nrf2/Keap1, and NF-κB signaling pathways and the ability to increase cholesterol efflux to HDL. Carotenoids are absorbed in the intestine. A handful of carotenoids and carotenoid-based compounds are in clinical trials, while some are currently used as medicines. The application of metabolic engineering techniques for carotenoid production, whole-genome sequencing, and the use of plants as cell factories to produce specialty carotenoids presents a promising future for carotenoid research. In this review, we discussed the biosynthesis and extraction of carotenoids, the roles of carotenoids in human health, the metabolism of carotenoids, and carotenoids as a source of drugs and supplements.
... Patients with MS were found to have relatively low levels of vitamin B-12 (SMD = −0.25) [211], and vitamin B-12 supplement users had ~6% longer LTL than nonusers [212]. Moreover, a significant positive correlation was seen for LTL and intake of vitamin E, which protects against oxidative damage (r 2 = 0.084) [213]. ...
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Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS.
Chapter
Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for “biological aging.” Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.
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Telomeres are repetitive DNA sequences that cap and protect the ends of chromosomes; critically short telomeres may lead to cellular senescence or carcinogenic transformation. Previous findings suggest a link between psychosocial stress, shorter telomeres, and chronic disease risk. This cross-sectional study examined relative telomere length in relation to perceived stress and urinary stress hormones in a sample of participants (n = 647) in the National Institute of Environmental Health Sciences Sister Study, a cohort of women ages 35 to 74 years who have a sister with breast cancer. Average leukocyte telomere length was determined by quantitative PCR. Current stress was assessed using the Perceived Stress Scale and creatinine-adjusted neuroendocrine hormones in first morning urines. Linear regression models estimated differences in telomere length base pairs (bp) associated with stress measures adjusted for age, race, smoking, and obesity. Women with higher perceived stress had somewhat shorter telomeres [adjusted difference of -129bp for being at or above moderate stress levels; 95% confidence interval (CI), -292 to 33], but telomere length did not decrease monotonically with higher stress levels. Shorter telomeres were independently associated with increasing age (-27bp/year), obesity, and current smoking. Significant stress-related differences in telomere length were seen in women ages 55 years and older (-289bp; 95% CI, -519 to -59), those with recent major losses (-420bp; 95% CI, -814 to -27), and those with above-average urinary catecholamines (e.g., epinephrine: -484bp; 95% CI, -709 to -259). Although current perceived stress was only modestly associated with shorter telomeres in this broad sample of women, our findings suggest the effect of stress on telomere length may vary depending on neuroendocrine responsiveness, external stressors, and age.
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