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journal orf in.n err.3du.3-e : R-:ese-arch
,,Oluine ., issue 5 - la.3rch 2.1'.Ls
C-Reactive Protein as a Biomarker for Aging
Rizvian Kalani and Christiaan Leeuvienburgh
ABSTRACT
Purpose
Inflammation has shown to be involved with the aging process and many age-related pathologies.
Persistent, unwarranted immunological episodes and other pivotal inflammatory agents have the ability to
reduce antioxidant levels. The two most prevalent life-prolonging strategies, life-long wheel running and life-
long caloric restriction (CR), have been shown to increase mean and maximum life span, respectively, but
the mechanisms by which the interventions work remain unclear. Hence, we evaluated the effects of age on
plasma inflammatory markers, C-reactive protein (CRP), interleukin-6 (IL-6), and total antioxidant capacity
(TAC); and we determined the ability of short-term CR, long-term CR and life-long exercise to
attenuate inflammation and restore total antioxidant potential.
Methods
Stored plasma samples were used for these studies. For the caloric restriction study, we used 6-month-old ad
libitum fed (6AL, young; n=8), 26-month-old ad libitum fed (26AL, old; n=8), 6-month-old calorie restricted
(6CR, young CR; n=8), and 26-month-old calorie restricted (26CR, old CR; n=8) male Fisher-344 rats. For the
wheel running study, we used 24-month-old sedentary ad libitum fed (ad libitum; n=8), 24-month-old sedentary
8% food restricted (sedentary; n=8), and 24-month-old wheel running 8% food restricted (runners; n=8)
male Fisher-344 rats.
Results
Short-term CR dramatically reduced CRP levels (61%), but had no significant effect on IL-6 or total
plasma antioxidant status. Plasma CRP levels increased dramatically (357%) in the old 26-month old
animals compared to the young 6-month old rats, whereas 26-month old life-long caloric restricted rats only
showed a 42% increase compared to 6-month old animals. Antioxidant status was significantly decreased in the
26-month old animals and tended to be higher in the 26CR rats compared to the 26-month old animals. Circulating
IL-6 levels, on the other hand, did not show significant changes with age or life-long calorie restriction. Life-
long exercise (and 8% CR) showed a marked decrease in CRP levels (38%) compared to the 8% CR
sedentary control rats and an even greater reduction (53%) compared to the ad libitum fed rats. In contrast,
plasma antioxidant levels were the highest in the life-long exercising 8% CR group compared to either the 8% CR
or ad libitum fed animals. Again, no changes were found in IL-6 levels between any of these treatment groups.
Conclusions
CR and wheel running, the two most prevalent life-prolonging strategies, significantly attenuate chronic
inflammation that is shown to increase with age. These studies show that CRP levels may be useful as a
biomarker for longevity studies, but surprisingly IL-6 levels remained unchanged with all interventions. In
addition, the heightened levels of inflammation were clearly associated with a reduced level of total
plasma antioxidant status.
INTRODUCTION
An increase in chronic inflammation has been shown to play a vital role in numerous disease states and has
been linked with the aging process. 2-4 It has been implicated in a diverse range of diseases including
arthritis, cancer, diabetes and Alzheimer's disease. 6, 20, 23, 27 Moreover, inflammation has been recognized
as playing a major, deleterious role in arteriosclerosis and as an integral component in the pathogenesis of
other cardiovascular disease. 1, 8, 28 C-reactive protein (CRP), an inflammatory biomarker, is increasingly
receiving more attention due to its potential in predicting cardiovascular disease. 7 It is a non-glycosylated protein
of the pentraxin family involved in the acute phase reaction, a non-specific physiological response to tissue
injury, infection, inflammation, and disease activity, which is characterized by an increase in certain cytokines
and hormones. CRP primarily functions to recognize and eliminate pathogens and damaged cells by activating
the complement system and phagocytic cells.40 Moreover, interleukin-6 (IL-6), an acute phase cytokine, has
also been implicated in enhancing the inflammatory response persistent in cardiovascular disease. 36 The
production of circulating CRP levels is primaly modulated by interleukin-6 (IL-6) in hepatocytes, although
trace amounts of mRNA for CRP have been found in lymphocytes and kidney. 22,29 In addition, monokines IL-1
and TNF-_ and interferons are other pro-inflammatory stimulus associated with increased production of CRP.
11 Expression is regulated through activation of transcription factors C/EBP_ and C/EBP_ from the C/EBP
family, STAT3, and Rel proteins such as NF-_B. 11 Hence, the primary objectives of these studies were to
determine the relationship between CRP and IL-6 with age and life-long prolonging interventions.
The two most prevalent life-prolonging strategies, life-long caloric restriction and life-long wheel running
exercise, have not been investigated extensively regarding their ability to attenuate chronic systemic
inflammation. Life-long caloric restriction has shown to increase both the mean and maximum life span in rats,
while chronic exercise only increases mean life span. 15, 39, 41 The mechanisms by which these interventions
extend life span remain unclear. Here, these studies were designed to investigate the effect of age, short-term
(40%) and long-term (8% and 40%) caloric restriction as well as life-long wheel running on plasma cytokine levels
of CRP and IL-6 as well as total antioxidant status. These studies provide further insight into how long-term
caloric restriction and exercise affect inflammatory response, in addition to establishing a relationship between IL-
6 and CRP levels in the plasma.
MATERIALS AND METHODS
Subjects
Stored plasma samples were used for these studies. For the caloric restriction study, we used 6-month-old ad
libitum fed (6AL, young; n=8), 26-month-old ad libitum fed (26AL, old; n=8), 6-month-old calorie restricted
(6CR, young CR; n=8), and 26-month-old calorie restricted (26CR, old CR; n=8) male Fisher-344 rats
(National Institutes of Aging Colony, Harlan Sprague Dawley, Indianapolis, IN). For the wheel running study, we
used 24-month-old sedentary ad libitum fed (ad libitum; n=8), 24-month-old sedentary 8% food
restricted (sedentary; n=8), and 24-month-old wheel running 8% food restricted (runners; n=8) male Fisher-
344 rats (National Institutes of Aging Colony, Harlan Sprague Dawley, Indianapolis, IN). The rats were
euthanized with isoflurane, in accordance with the Guiding Principles for Research involving Animals with
all experimental procedures approved by the University of Florida's Institute on Animal Care and Use
Committee. Blood was removed by cardiac puncture, drawn into tubes containing ethylene diamine tetra-acetic
acid and heparin. The aliquots of blood were centrifuged at 40C at 1500 x g for ten minutes and plasma stored at
-806C until use.
Plasma levels of C-reactive protein
C-Reactive protein was measured using a solid-phase sandwich enzyme-linked immunosorbent assay (ELISA)
(BD Biosciences, San Diego, CA) with a minimum detectable CRP concentration of 0.35 ng/ml and inter-
assay coefficient of variation <10%. Sample absorbencies were read in triplicate at 450 nm, with
wavelength correction at 630 nm of a standard curve and expressed in _g/ml. CRP concentrations were normalized
to total protein content, measured by the Bradford method.
Plasma levels of IL-6
IL-6 concentrations were measured using an ELISA (Endogen, Rockford, IL). Sample absorbencies were read
in triplicate at 450 nm, with wavelength correction at 550 nm of a standard curve and expressed in pg/ml.
The sensitivity was < Ipg/ml and inter-assay coefficient of variation <10%. IL-6 concentrations were normalized
to total protein content, measured by the Bradford method.
Total antioxidant status
Total Antioxidant Potential was assayed using a commercially available kit (Calbiochem, La Jolla, CA). The rationale
to use the total antioxidant potential capacity was to determine the totality of all low molecular weight
antioxidants, such as vitamin C, glutathione (GSH), and Uric acid in the plasma. This temperature-
dependent, spectrophotometric assay relies on the ability of the sample antioxidants to inhibit the oxidation of
ABTS (2,2'-Azino-di-[3-ethylbenzthiazoline sulphonate]) to ABTSI+. The amount of ABTSI+ produced
was monitored by reading the absorbance at 600 nm. The degree of suppression of the absorbance at 600 nm by
the antioxidants in the sample is proportional to their concentration.
Statistical analysis
Two-tailed, unpaired t tests were used to determine significant differences between groups. Significance was set
at p<0.05.
RESULTS
Effect of short-term calorie restriction on CRP, IL-6, and total plasma antioxidant levels
First, we determined the effects of 2-month calorie restriction (40% less compared to ad libitum fed animals)
on cytokine levels (Fig. 1; Table 1). Short-term CR dramatically reduced CRP levels (Fig. 1A; 61 %), but had
no significant effect on IL-6 concentrations (Table 1). Moreover, inflammation is linked to an increase production
of oxidant, which may have affected the consumption of total plasma antioxidant levels. Total plasma
antioxidant status tended to decrease but changes were not significant (Fig. 1B; p=0.12).
125-
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0)
. 0.75-
E 050-
025-
0.00-
e-
0
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E
E
B
4ko
Figure 1. Effects of short-term calorie restriction on plasma concentration of C-reactive protein (CRP)
and total antioxidant capacity in young (6-months) and age-matched calorie restricted (CR) Fisher-
344 male rats. CR was started at 4 months of age at 40% compared to ad libitum fed animals
(See Methods). Values are means � SEM. E denotes significant ( p<0.0001) difference from
young animals. Young rats, n = 8 for CR group n= 8.
Table 1
Effects of short-term calorie restriction on plasma concentration of Interleukin-6 (IL-6) in
young (6-months) and age-matched calorie restricted (CR) Fisher-344 male rats
Protein 6-month 6-month CR
Interleukin-6
1.78 � 0.23 1.40 �0.18
(pg / mg protein)
Values are means � SEM. For all groups of rats, n = 8.
Long-term calorie restriction
Circulating levels of C-reactive protein are shown to increase with age (Fig. 2A) as the old 26AD rats
had substantially higher plasma levels of CRP compared to the young 6AD group. In contrast, the old 26CR rats
had significantly lower levels of CRP compared to the 26AD group. Plasma levels of Interleukin-6 did not
change significantly with age or life-long calorie restriction (Table 2). Total plasma antioxidant levels
were significantly decreased in the old animals compared to the young (Fig. 2B), whereas the old CR group
tended to show an increase compared to old animals (p= 0.074). Taken together, life-long calorie restriction is
a potent intervention to halt inflammation and to attenuate the age associated decrease in antioxidant potential.
4-
A
- 0 3
o -
0.
S2-
O- B
E ii
O-
Figure 2. Effects of long-term calorie restriction on plasma concentration of C-reactive protein (CRP)
and total antioxidant capacity in young (6-months) and old (26-months) and old (26-month)
age-matched calorie restricted Fisher-344 male rats. CR was started at 4 months of age at
40% compared to ad libitum fed animals (See Methods). Values are means � SEM. For CRP, E
denotes significant (p<0.0001) differences from young animals; _ denotes significant
(p<0.0001) differences from old animals. For total antioxidant capacity, E denotes significant
(p=0.0113) difference from young animals. Total antioxidant capacity was not different (p= 0.1472
NS) between old CR and old rats. For all groups of rats, n = 8.
Table 2
Effects of long-term calorie restriction on plasma concentration of Interleukin-6 (IL-6) in
young (6-months), old (26-months), and old (26-month) age-matched calorie restricted (CR)
Fisher-344 male rats
Protein 6-month 26-month 26-month CR
Interleukin-6
0.70 �0.034 0.74 � 0.045 0.73 � 0.056
(pg / mg protein)
Values are means � SEM. For all groups of rats, n = 8.
Long-term exercise
Life-long exercise (and 8% CR) showed a marked decrease (38%) in CRP levels compared to the 8% CR
sedentary control rats and an even greater reduction (53%) was observed when compared with the ad libitum
fed rats (Fig. 3A). In contrast, plasma antioxidant levels were the highest (p <0.001) in the life-long exercising
8% CR group compared to 8% CR and ad libitum fed animals (Fig. 3B). No changes were found in IL-6
levels between these treatment groups (Table 3). In summary, life-long 8% calorie restriction has already
a remarkable ability to reduce CRP levels, and this group shows increases in total antioxidant status compared to
old animals. Exercise has an additional beneficial effect in reducing inflammation (CRP) and shows the highest
total plasma antioxidant status of all three groups.
41 A
o 6
0 C L
CE
'C -
r E25
Figure 3. Effects of long-term calorie restriction combined with exercise on plasma concentration of
C-reactive protein (CRP) and total antioxidant capacity in old (24-months) ad libitum fed, old (24-
month) calorie restricted (CR O/8%) as well as old (24-month) life-long wheel running calorie
restricted (8%) Fisher-344 male rats. CR was started at 4 months of age at 8% compared to ad
libitum fed animals (See Methods). Values are means � SEM. For CRP, E denotes significant
(p=0.0010) differences from old animals; _ denotes significant (p<0.0001) differences from old 8%/
CR rats. For total antioxidant capacity, E denotes significant (p= 0.0276) differences from old animals;
_ denotes significant (p= 0.0004) differences from old 8% CR rats. For all groups of rats, n = 8.
Table 3
Effects of long-term calorie restriction and exercise on plasma concentration of interleukin-6
(IL-6) in old (24-months) ad libitum fed, old (24-month) calorie restricted (CR 8%), and old (24-
month) life-long wheel running calorie restricted (8%) Fisher-344 male rats
Protein 24-month 24-month 8% CR 26-month 8% CR Excercise
Interleukin-6
1.31 � 0.14 1.41 � 0.12 1.39 � 0.09
(pg / mg protein)
Values are means � SEM. For all groups of rats, n = 8.
DISCUSSION
The objective of these studies was to examine the effects of caloric restriction and chronic exercise on the
circulating levels of CRP and IL-6 and the effect on total antioxidant potential. We found that short-term CR
(2-months) was highly effective in reducing plasma CRP levels by 61%. Life-long 40% CR and 8% CR showed
also significantly lower levels of plasma CRP compared to age-matched ad libitum fed control animals (reductions
of 60% and 25%, respectively). Moreover, life-long exercise (and 8% CR) reduced the levels of CRP by
38% compared to the 8% CR sedentary controls and by 53% compared to ad libitum fed rats. In contrast,
circulating IL-6 levels were not affected by age, diet, or exercise. Taken together, interventions known to
extend maximum and mean life span in rodent studies were effective in reducing a general systemic biomarker
of inflammation (CRP) but had no effect on the cytokine IL-6.
An elevated inflammatory milieu are among the physiological changes deemed synonymous with the aging
process and have been cited as significant indicators of mortality in older populations. 10, 24, 28, 38 Given the
social and economic impact of inflammation and cardiovascular heart disease and subclinical inflammation with
age, 28, 38 our research attempted to elucidate some potential mechanisms driving these outcomes. A
recently emerging and potentially important area of aging research closely associated with inflammation is
biological redox status. The presence of an aging effect on systemic levels of inflammation was confirmed
by increased levels of the CRP in the plasma of old animals, which significantly reduced plasma total
antioxidant redox status. Plasma contains several key cellular thiols (i.e., GSH), vitamin C and uric acid, which
are important in maintaining the plasma redox potential and largely reflect to total antioxidant capacity. Hence,
the reduction of antioxidant potential could reflect an increased consumption of antioxidants by oxidants or
a decreased synthesis of low molecular antioxidants. Further studies should explore the numerous
potential antioxidants which were affected, but it is clear from these studies that inflammation level can
significantly affect the total antioxidant potential in the plasma.
Inflammatory cell types are sensitive to reactive oxygen species and regulate their function based on the presence
of oxidants. 19, 34 In other words, specific pro-inflammatory enzymes induciblee nitric oxide synthase;
iNOS, cyclooxygenase-2; COX 2, and xanthine oxidase; XOD) can be activated by gene regulators (NF-kB
activation) in response to the formation of oxidants. This fact presents the possibility that a pro-inflammatory
state may become more chronic in association with advancing age. Key mediators of inflammatory pathways, such
as tumor necrosis factor-alpha (TNF-a) and nuclear factor-kappa B (NF-kB), have been extensively studies
by laboratories (including ours) with regard to a possible role in aging. 4, 9, 13, 21, 26, 30-32 Moreover,
several laboratories have explored the attenuation of inflammation through use of life-long calorie restriction.
Indeed, an overall chronic inflammation present in rodents was blunted with this intervention. 4, 21 Based on
these studies, researchers formulated the inflammation theory of aging, which complements the free radical
oxidative stress theory of aging and the glycooxidation theory of aging. However, whether IL-6 and CRP are
molded by interplay between oxidative stress and inflammatory mediators has not been investigated in
animal models used for aging.
We assessed CRP and IL-6 levels and antioxidant status in the plasma and observed an age-associated increase
in CRP levels (and reduction in antioxidant status), which calorie restriction (40%) attenuated. Even with short-
term CR at the age of 6 months, there is a 60% decrease in CRP levels compared to the same age rats, which
were fed an ad libitum diet. Surprisingly, 8% CR was also highly effective in reducing circulating CRP levels.
Recent studies showed that long-term calorie restriction is highly effective in reducing the risk for atherosclerosis
in humans, and this finding was strongly associated with a reduction in plasma CRP levels. 10 Hence,
caloric restriction is exceptionally effective in reducing inflammation, which may contribute to the aging process.
Wheel running (combined with 8% CR) was also very effective in modulation CRP concentration in the
plasma compared to 8% CR only. We found that plasma C-reactive protein levels were decreased by
caloric restriction (8%) and were even lower when 8% CR was combined with exercise. Combining both 8%
calorie restriction and chronic exercise decreases the levels of CRP by approximately 53%. Previous studies
have investigated whether exercise can modulate inflammatory responses. 12, 25, 42 It has been shown that
physical activity and exercise decrease levels of inflammatory markers, achieved by a decrease in the
inflammatory response. 5, 33 Exercise can also reduce the risk of numerous chronic diseases including
cardiovascular disease, hypertension, diabetes, metabolic syndrome and several forms of cancer, all of which have
an inflammatory component. 37
In our studies, IL-6 levels in the plasma did not change to a significant degree with age, caloric restriction,
or exercise. We found these data very interesting because CRP levels did increase significantly with age, and
plasma CRP is mainly under the transcriptional control of IL-6 produced by hepatocytes. However, no
quantitative relation between the circulating levels of the two markers was found. This finding implies that
other cytokines may have a more significant role in regulating CRP production with age and CR or that
inflammation may not be the only condition that causes an elevation in CRP levels. Future studies should
to determine if monokines IL-1, TNF-_, and/or interferons are responsible for the changes observed in CRP
levels, because those inflammatory markers are associated with CRP production (especially since TNF-_ has
been shown to increase with age). 31
In summary, since CRP has been shown to be a good clinical marker in predicting cardiovascular disease and
other diseases associated with inflammation, effective strategies in attenuating and maintaining this
inflammation that should be considered are caloric restriction and chronic exercise. 7 Our results imply that
the mechanisms by which caloric restriction and exercise enhance health and life span are involved with
inflammation and inflammatory pathways. Finally, life-long (40%) calorie restriction may always remain the
most robust intervention to extend maximum life span; however, moderate (8%) CR combined with exercise may
be more easily achieved in humans and is worthy of further investigation in human populations for
reducing inflammation and maintaining good health.
ACKNOWLEDGEMENTS
We are very grateful to all current and past members of the Biochemistry of Aging Laboratory for their
technical assistance in this study. This research was supported by grants to Dr. Christiaan Leeuwenburgh from
the National Institute on Aging (R01-AG17994 and AG21042). Rizwan Kalani is a University Scholar and funding
was provided by The University of Florida Scholar's Program.
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