Clinica Chimica Acta 347 (2004) 139 – 144
www.elsevier.com/locate/clinchim
Age-related changes in plasma coenzyme Q10 concentrations and
redox state in apparently healthy children and adults
Michael V. Miles a,b,*, Paul S. Horn c, Peter H. Tang a,d, John A. Morrison e, Lili Miles a,d,
Ton DeGrauw b, Amadeo J. Pesce d
a
Divisions of Pathology and Laboratory Medicine, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and
University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
b
Divisions of Child Neurology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and
University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
c
Department of Mathematical Sciences, University of Cincinnati, Psychiatry Service Veteran’s Affairs Medical Center,
Cincinnati, OH 45221, USA
d
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center Cincinnati, OH 45267-0559, USA
e
Divisions of Cardiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center and
University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
Received 21 February 2004; received in revised form 13 April 2004; accepted 14 April 2004
Abstract
Background: Coenzyme Q10 (CoQ) is an endogenous enzyme cofactor, which may provide protective benefits as an
antioxidant. Because age-related CoQ changes and deficiency states have been described, there is a need to establish normal
ranges in healthy children. The objectives of this study are to determine if age-related differences in reduced CoQ (ubiquinol),
oxidized CoQ (ubiquinone), and CoQ redox state exist in childhood, and to establish reference intervals for these analytes in
healthy children. Methods: Apparently healthy children (n = 68) were selected from individuals with no history of current acute
illness, medically diagnosed disease, or current medication treatment. Self-reported healthy adults (n = 106) were selected from
the ongoing Princeton Follow-up Study in greater Cincinnati. Participants were assessed for lipid profiles, ubiquinol
concentration, ubiquinone concentration, total CoQ concentration, and CoQ redox ratio. Results: Mean total CoQ and ubiquinol
concentrations are similar in younger children (0.2 – 7.6 years) and adults (29 – 78 years); however, lipid-adjusted total CoQ
concentrations are significantly increased in younger children. Also CoQ redox ratio is significantly increased in younger and
older children compared with adults. Conclusions: Elevated CoQ and redox ratios in children may be an indication of oxidative
stress effects, which are associated with early development of coronary heart disease.
D 2004 Elsevier B.V. All rights reserved.
Keywords: Coenzyme Q(10); Ubiquinone; Ubiquinol; Child; Aging; Redox; Reference interval; Antioxidant
Abbreviations: CoQ, coenzyme Q10; HDL, high density lipoprotein; HPLC, high-performance liquid chromatography; LDL, low density
lipoprotein; TC, total cholesterol; TG, triglyceride.
* Corresponding author. Cincinnati Children’s Hospital Medical Center, OSB-Rm. 5449, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Tel.: +1-513-636-7871; fax: +1-513-636-1888.
E-mail address: [email protected] (M.V. Miles).
0009-8981/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.cccn.2004.04.003
140
M.V. Miles et al. / Clinica Chimica Acta 347 (2004) 139–144
1. Introduction
Coenzyme Q10 (CoQ) is an endogenous enzyme
cofactor that is produced in most living cells in
humans, is distributed in cellular membranes, is an
essential component of the mitochondrial respiratory
chain, and may provide protective benefits as an
antioxidant [1,2]. Coenzyme Q10 is a redox molecule
(2,3-dimethoxy, 5-methyl, 6-decaprenyl benzoquinone), which exists in biochemically reduced CoQ
(ubiquinol) and oxidized CoQ (ubiquinone) forms in
biological tissues [1]. Because of its important role in
mitochondrial and membrane functions, the redox
state of CoQ (ubiquinol/ubiquinone ratio) has been
suggested to be a useful biomarker of oxidative stress
[3,4].
The development of mitochondrial abnormalities,
increased production of free radicals, and the cumulative effects of oxidative stress upon the body have
been proposed as the mitochondrial theory of aging
[5]. The hypothesis that mitochondria are both a
source and a target of cellular free radicals and the
knowledge of the important role of CoQ in mitochondrial function have led others to propose that
CoQ may be linked with aging mechanisms [6]. The
common assumption has been that CoQ levels
generally decline with aging [7], but data supporting
this postulate are limited. Interestingly, Hara et al.
[8] reported low ubiquinol concentrations, redox
ratio, and total CoQ plasma concentrations in apparently healthy neonates during the first 5 days
after birth.
CoQ reference ranges are needed to support CoQ
research and clinical monitoring in pediatric populations. The objectives of this study are twofold: to
determine if age-related changes in ubiquinol, ubiquinone, and CoQ redox state (ubiquinol/ubiquinone
ratio) occur in healthy individuals between childhood
and old age; and to establish reference intervals for
these analytes in healthy children.
2. Materials and methods
This study was approved by the Institutional
Review Board of the Cincinnati Children’s Hospital
Medical Center (CCHMC), Cincinnati, OH. Informed consent was obtained from all subjects or
their parents. Adult participants in the study were
drawn from the ongoing Princeton Follow-up Study,
a 28-year follow-up of former students and their
parents from the Princeton Lipid Research Clinics
(LRC) Study. The Princeton LRC Study has been
described previously [9 – 11]. Adults provided a
medical history/health status questionnaire during
their study visit, and had blood collected after an
overnight fast. Pediatric participants were screened in
the CCHMC phlebotomy laboratory. Parents or caregivers provided medical history/health status information about their child. Children were having blood
collected for presurgical screening or physical examinations required for school or athletic activities.
Children who had not fasted for at least 4 h were
excluded. Anyone, who had a history of current
acute illness or medically diagnosed disease, was
receiving concurrent medication treatment, had a
current smoking history, or was taking CoQ supplementation, was excluded.
Blood specimens were obtained from participants
seen between March 1, 2000 and August 31, 2001,
and were collected from the antecubital vein into glass
vacuum tubes containing sodium heparin. The blood
processing procedure, which is essential for accurate
measurement of ubiquinol and ubiquinone, was described earlier [12]. Briefly, blood was immediately
placed on wet ice and centrifuged at 2000 g ( + 5
jC) for 10 min within 1 –3 h after collection. Plasma
specimens were immediately transferred to prelabeled
1.5 ml screw-capped polypropylene tubes and stored
at 80 jC until analysis.
Plasma samples were analyzed for ubiquinone,
ubiquinol, and total CoQ concentrations in the
CCHMC Clinical Neuropharmacology Laboratory using a previously validated high-performance liquid
chromatography (HPLC) procedure with electrochemical detection [12]. Lipid profiles were tested in the
CCHMC Clinical Laboratory by standard clinical
laboratory methods.
The Wilcoxon rank – sum test was conducted on
the differences between the overall levels of continuous variables. The Fisher’s Exact test was conducted
on the categorical variables sex and race. In addition,
separate 95% reference intervals are reported for
younger children ( < 8 years), older children (10 – 18
years), and adults for CoQ measurements (absolute
range is not given). The procedure used to derive the
M.V. Miles et al. / Clinica Chimica Acta 347 (2004) 139–144
141
Table 1
Summary of demographic and lipid profile data of apparently healthy younger children (n = 50), older children (n = 18), and adults (n = 106);
mean F S.D. [range]
Younger children
Age (years)
Females (%)
Black/White race (%)
BMI (kg/m2)
Total cholesterol (mmol/l)
HDL (mmol/l)
LDL (mmol/l)
Triglyceride (TG; mmol/l)
3.3 F 2.1 (0.2 – 7.6)
22 (44)
25 (50)/25 (50)
17.2 F 4.6 (11.3 – 42.8)
3.8 F 0.8 (2.2 – 5.4)
1.1 F 0.3 (0.5 – 1.9)
2.2 F 0.7 (0.7 – 3.7)
1.1 F 0.4 (0.3 – 2.1)
P-valuea
Older children
c
13.8 F 2.4 (10.4 – 17.4)
11 (61)
4 (22)/14 (78)
22.8 F 5.4 (14.1 – 34.8)
4.4 F 1.1 (2.9 – 7.3)
1.2 F 0.3 (0.7 – 1.8)
2.5 F 0.7 (1.1 – 3.9)
1.0 F 0.4 (0.6 – 2.0)
< 0.001
< 0.275d
< 0.054d
< 0.001c
< 0.056c
< 0.240c
< 0.169c
0.436c
Adults
P-valueb
43.7 F 11.5 (29 – 78)
72 (68)
36 (34)/70 (66)
26.9 F 5.9 (18.7 – 57.7)
5.1 F 0.8 (3.3 – 6.9)
1.4 F 0.3 (0.6 – 2.4)
3.2 F 0.8 (1.5 – 5.0)
1.0 F 0.6 (0.4 – 4.5)
< 0.001c
< 0.005d
< 0.078d
< 0.001c
< 0.001c
< 0.001c
< 0.001c
0.135c
a
Younger vs. older children.
Younger children vs. adults.
c
Wilcoxon rank – sum test.
d
Fisher’s Exact test.
b
reference intervals is that of Horn et al. [13]. This
procedure screens for outliers prior to computing
robust estimates of the endpoints of the reference
interval. The robust estimates of the endpoints of the
reference interval use a function that smoothly downweights observations the further they are from the
center of the sample. Thus, central values will be
weighted more heavily than those at the extremes of
the sample. Summary statistics for continuous variables are expressed as the mean F S.D. The level of
significance was set at the 0.05 level.
3. Results
Demographic characteristics and lipid profiles of
population samples are summarized in Table 1.
Age-related increases in BMI, total cholesterol
(TC), high density lipoprotein (HDL), and low
density lipoprotein (LDL) are evident (Table 1).
No significant differences in total plasma CoQ or
ubiquinol concentrations are found between younger
children and adults (Table 2). Younger children
have increased mean lipid-adjusted total CoQ con-
Table 2
Comparison of mean CoQ measurements ( F S.D.) in apparently healthy younger children (n = 50), older children (n = 18), and adults (n= 106),
and associated 95% reference intervals
Younger
children
Ubiquinone (Amol/l)
Ubiquinol (Amol/l)
Total CoQ (Amol/l)
Total CoQ/TC
(Amol/mmol)
Total CoQ/LDL
(Amol/mmol)
Total Q10/TC + TG
(Amol/mmol)
Ubiquinol/
ubiquinone ratio
a
Older
children
Adults
P-valuea 95% Reference intervals
0.038 F 0.032 0.027 F 0.019 0.041 F 0.018
0.012
1.02 F 0.31
0.85 F 0.25
1.00 F 0.32
0.669
1.06 F 0.32
0.88 F 0.26
1.04 F 0.33
0.703
0.29 F 0.10
0.20 F 0.05
0.20 F 0.05 < 0.001
Younger children
Older childrenb
Adults
Lower
limit
Lower
limit
Lower Upper
limit
limit
Upper
limit
Upper
limit
0
0.45
0.48
0.15
0.12
1.59
1.80
0.48
0
0.37
0.37
0.12
0.08
1.48
1.54
0.32
0.01
0.48
0.50
0.11
0.08
1.71
1.77
0.33
0.56 F 0.36
0.37 F 0.09
0.33 F 0.10
< 0.001
0.23
1.52
0.21
0.58
0.17
0.53
0.22 F 0.08
0.17 F 0.04
0.17 F 0.04
< 0.001
0.12
0.35
0.10
0.27
0.10
0.27
49.4 F 42.3
47.2 F 35.2
27.3 F 9.6
0.005
9.6
161.6
11.3
147.0
11.9
50.3
Younger children vs. adults; Wilcoxon rank – sum test.
As a result of the small sample size (n = 18), reference interval endpoints based on nonparametric methods are not appropriate. Thus, the
lower limit of the reference interval for younger children is based on a transformed version of the robust reference interval estimate [31]. All
other reference interval endpoints are based on the robust (upper endpoint) and nonparametric (lower endpoint) methods described by Horn et al.
[13,31].
b
142
M.V. Miles et al. / Clinica Chimica Acta 347 (2004) 139–144
centrations compared with adults (Table 2). CoQ
redox ratios are significantly increased in both
pediatric groups compared with adults (Table 2).
Reference ranges for pediatric and adult groups are
also reported in Table 2.
4. Discussion
CoQ deficiency states have been associated with
many diseases and conditions in pediatric and adult
populations [14 – 25]; however, in a recent study,
age-related CoQ changes were not evident in
healthy adults ranging from 28 to 80 years [26].
In this study, comparison of CoQ measures in
younger adults (29 – 50 years) vs. older adults
(53 – 78 years) also shows no significant age-related
differences (data not shown). Review of previous
studies, which measured ubiquinol and ubiquinone
concentrations in healthy adults, also indicated relatively consistent CoQ concentrations across a broad
age range (Table 3). On the basis of these findings,
all adults in this study were included in the analysis
of data.
Often, the healthy control populations in CoQ
studies are small, poorly matched, or inadequately
described making it difficult to assess the significance of disease- or age-related CoQ differences.
While CoQ references intervals have been delineated
for self-reported healthy adults [26], to our knowl-
edge only a preliminary (letter) report has described
reference intervals for healthy children [27]. Artuch
et al. [27] compared total serum CoQ concentrations
in 62 healthy younger children (1 month– 7 years)
with 40 older children (8 – 18 years). Their results
suggested that after adjusting for total cholesterol,
median serum total CoQ concentration was decreased in older children [27]. Adjustment of CoQ
concentrations to lipid concentrations has been recommended because virtually all CoQ in plasma is
associated with lipoproteins [28]. The current results
agree with their findings, in that lipid-adjusted total
CoQ concentrations tend to be lower in older children than in younger children (Table 2). The previous study is limited however because CoQ
concentrations were not compared between children
and adults, and ubiquinol concentrations were not
determined [27].
Age-related differences in CoQ concentrations
have also been reported in infants. Hara et al. [8]
found decreased mean plasma total CoQ concentrations in 20 apparently healthy neonates. During the
first 5 days after birth, mean total CoQ values
ranged from 0.28 to 0.39 Amol/l [8]. The nine
youngest participants in this study (0.2 –1.0 year)
have total CoQ concentrations >0.65 Amol/l, and
seven of the youngest nine have total CoQ concentrations over twofold higher than the mean concentrations reported in young neonates [8]. These
findings suggest there is a marked increase in
Table 3
Summary of previous and current study results describing plasma ubiquinol, ubiquinone, total CoQ concentrations, and redox ratio in apparently
healthy children and adults
Study group, n (age)
Ubiquinone (Amol/l)
Ubiquinol (Amol/l)
Total CoQ (Amol/l)
Ubiquinol/ubiquinone ratio
Ref. no.
Healthy pediatric subjects
20 (5 days)
0.11 F 0.04
40 (11 – 22 years)
0.52 F 0.09
50 (0.2 – 7.6 years)
0.038 F 0.032
0.24 F 0.08
0.40 F 0.12
1.02 F 0.31
0.34 F 0.10
0.92 F 0.21
1.06 F 0.32
f 2.2
–
49.4 F 42.3
[8]
[19]
Current study
Healthy adult subjects
148 (28 – 80 years)
81 (19 – 62 years)
31 (mean 22 years)
100 (24 – 62 years)
16 (40 – 83 years)
106 (29 – 78 years)
1.07 F 0.34
1.18 F 0.35
0.70 F 0.27
1.15 F 0.36a
0.78 F 0.26
1.00 F 0.32
1.10 F 0.35
1.23 F 0.36
0.74 F 0.28
–
0.81 F 0.27
1.04 F 0.33
29.3 F 10.7
26.0 F 8.1
23.3
30.2 F 8.8a
–
27.3 F 9.6
[3]
[4]
[8]
[16]
[17]
Current study
0.05 F 0.01
0.05 F 0.02
0.03 F 0.01
0.04 F 0.015a
0.05 F 0.026
0.04 F 0.018
Data are presented as mean F S.D.
a
Serum.
M.V. Miles et al. / Clinica Chimica Acta 347 (2004) 139–144
plasma CoQ during the first few weeks of life. This
CoQ increase may be an important factor in the
development of endogenous antioxidant defenses of
young infants. Further studies are needed to evaluate
these changes.
As mentioned previously, the redox state of CoQ
has been suggested as a useful indicator of oxidant
stress [3,4], although it should be noted that plasma
CoQ redox state may not always agree with CoQ
redox state in tissues [29]. A few studies have
reported decreased plasma CoQ redox ratios in diseases and conditions thought to be associated with
increased oxidative stress (Table 3) [3,4,8,16,17];
however, to our knowledge only one has shown an
age-related change in the ubiquinol/ubiquinone ratio
in apparently healthy individuals. Hara et al. [8]
determined the CoQ redox ratio in 5-day-old healthy
neonates was significantly lower than in 31 healthy
adults. The CoQ redox ratio in infants was f 2.2
(calculated from the reported 31.2% ubiquinone in
total CoQ concentration) [8]. In this study, four of the
nine youngest children (0.2 –1.0 year) have the lowest
redox values, which range from 9.3 to 11.2. It seems
likely that infants may require weeks or even months
to attain a ubiquinol/ubiquinone ratio within the
reference range for children. It should also be noted
that De Luca et al. [19] reported mean ubiquinol and
ubiquinone concentrations were 0.40 and 0.52 Amol/l,
respectively, in 40 healthy children (Table 3). Although they did not report the ubiquinol/ubiquinone
ratio, their mean concentration results are significantly
different than other reports (Table 3). Their results
appear to be inaccurate, perhaps as a result of a
methodological problem in the CoQ assay procedure
[19]. This study’s findings, which suggest a significant age-related decrease in CoQ redox ratio occurs
after 18 years (Table 2) may be related to the early
effects of oxidative stress associated with hyperlipidemia [30] and coronary heart disease [16].
In conclusion, the results of this study indicate that
total CoQ and ubiquinol concentrations are unchanged between early childhood and adults 30 – 80
years old. However, lipid-adjusted total CoQ concentrations are slightly, but significantly, increased in
children. A decrease in CoQ redox status seems to
occur in adults and may be associated with early
effects of oxidative stress. Further studies are needed
to evaluate the effects of aging and diseases on
143
ubiquinol, ubiquinone, and CoQ redox state, particularly in infants, young adults, and in extreme old age
(>80 years).
Acknowledgements
This study was supported in part by NIH grant
HL62394.
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