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Experimental Gerontology xxx (2014) xxxxxx

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Experimental Gerontology
journal homepage: www.elsevier.com/locate/expgero

High corn oil dietary intake improves health and longevity of aging mice

2Q3

Hongwei Si a,, Longyun Zhang a, Siqin Liu a, Tanya LeRoith b, Carlos Virgous c

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a r t i c l e

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Article history:
Received 15 July 2014
Received in revised form 29 August 2014
Accepted 2 September 2014
Available online xxxx

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Keywords:
Corn oil
Aging mice
Longevity
Health

i n f o

R
O

Department of Family and Consumer Sciences, Tennessee State University, Nashville, TN 37209, United States
Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, United States
Animal Care Facility, Meharry Medical College, Nashville, TN 37208, United States

a b s t r a c t

Corn oil has been recommended as a replacement for saturated fats because of its high levels of poly- and monounsaturated fatty acids. In the present study, we tested whether very high levels of corn oil (58.6% fat-derived calories, FDC) intake improve health and longevity of aging mice. Twelve month old male C57BL/6 mice were fed a
normal diet (10% FDC of corn oil, N) or a high fat diet (58.6% FDC of corn oil, HF) for 1315 months. Our results
show that a HF diet signicantly increased the longevity of the aged mice (at 25 months of age, 53.8% of mice died
in the N group, whereas the mortality rate was only 23.2% in the HF group). High corn oil also reversed agingincreased blood lipids including triglyceride, total cholesterol and LDL. Similarly, high corn oil intake overturned
aging-raised pro-inammatory markers including IL-1, IL-6, and monocyte chemotactic protein-1 (MCP-1) in
the blood. In addition, corn oil intake reversed aging-damaged rotarod performance and liver function. Interestingly, the HF group was signicantly heavier than the N group (53.6 g/mouse vs. 41.3 g/mouse); however, both
HF and N groups had the same calorie intake (12.48 kcal/d/mouse vs. 12.24 kcal/d/mouse). Although, the HF
group's food consumption was lower than that of the N group (2.4 g/d/mouse vs. 3.4 g/d/mouse). These results
suggest that if total calorie consumption stays in the normal range, very high levels of corn oil intake improve
health and longevity of aging mice.
2014 Published by Elsevier Inc.

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1. Introduction

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High saturated fat diets are well associated with obesity prevalence
and the increased risk of cardiovascular disease, diabetes and cancer.
Reducing saturated fats from the diet is recommended to eliminate
Western diet-induced health problems. The common alternatives of
animal (saturated) fats for humans are plant oil, including soybean oil,
peanut oil and corn oil because of the high percentage of unsaturated
fat acids.
Corn oil is composed mainly (99% of the rened or 96% of the crude
oil) of acylglycerols (mono-, di- and primarily tri-), and has 59% polyunsaturated (PUFA), 24% monounsaturated (MUFA) and 13% saturated
fatty acid (SFA). The PUFA to SFA ratio (P/S) is about 4.6. Corn oil has one
of the highest PUFA levels after sunower, safower, walnut and wheat
germ oil (Landers and Rathmann, 1981). The primary PUFA is linoleic
acid (C18:2n 6), with a small amount of linolenic acid (C18:3n 3)

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N
C
O

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Section Editor: Holly M Brown-Borg

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Abbreviations: BW, body weight; EFAs, essential fatty acids; FDC, fat-derived calories;
GSR, glutathione-disulde reductase; GSH, glutathione; H&E, hematoxylin and eosin;
HDL, high-density lipoprotein; HF, high corn oil diet; IFN-, interferon gamma; IL, interleukin; KC, keratinocyte chemoattractant; LDL, low-density lipoprotein; MCP-1, macrophage
chemoattractant protein-1; MUFA, monounsaturated fatty acid; N, normal diet; PUFA, polyunsaturatedfatty acid; ROS,reactive oxygen species; SFA,saturatedfatty acid; SOD,superoxide dismutase; TNF, tumor necrosis factor-; YC, youth control.
Corresponding author.
E-mail address: hsi@tnstate.edu (H. Si).

giving a n 6/n3 ratio of 83. Corn oil contains a signicant amount


of ubiquinone and high amounts of gamma-tocopherols (vitamin
E) (Dupont et al., 1990). These high contents of PUFA and vitamin E
may contribute to the health benets of corn oil consumption.
The benecial effects of PUFA have been extensively investigated,
however, there are very few studies investigating the effects on human
health with long-term corn oil consumption, particularly on the older
population. This is very important because corn oil is the second leading
vegetable oil consumed in the United States (USDA, 2014). Since U.S.
adults age 65 and older heavily consume this high fat oil, their population
is rapidly increasing and is projected to reach 71 million by 2030. The objectives of the present study are to investigate the long-term health effect
of high volume of corn oil consumption in aging mice and to understand
the relevant mechanisms.

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2. Methods and Materials

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2.1. Experimental Animals and Diets

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Twelve-month old male C57BL/6 mice were purchased from the


National Cancer Institute (Bethesda, MD). Mice were housed in an
environmentally-controlled (23 2 C; 12-h light: dark cycle) animal
facility and they were given ad libitum access to food and water. To
test the health effect of high corn oil intake, mice were randomly divided into two groups (n = 31) and given either a normal diet (N) or a high

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http://dx.doi.org/10.1016/j.exger.2014.09.001
0531-5565/ 2014 Published by Elsevier Inc.

Please cite this article as: Si, H., et al., High corn oil dietary intake improves health and longevity of aging mice, Exp. Gerontol. (2014), http://
dx.doi.org/10.1016/j.exger.2014.09.001

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2.3. Pathological Analysis

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Fresh livers were xed in 10% phosphate buffered neutral formalin,


embedded in parafn, cut at thicknesses of 5 m, and then stained
with hematoxylin and eosin (H&E) for histological examination of
hepatic lesions. Three sections from each mouse were examined. The

t1:1
t1:2

Table 1
Diet composition and energy distribution.

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t1:3

105
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97

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2.5. Statistical Analysis

Ingredient

t1:4

Casein

t1:5
t1:6
t1:7
t1:8
t1:9
t1:10
t1:11
t1:12
t1:13
t1:14

L-Cystine

Sucrose
Corn starch
Dyetrose
Corn oil
Cellulose
Mineral mix #210050
Vitamin mix #310025
Choline bitartrate
Total

Normal diet (N)

High fat diet (HF)

g/kg

g/kg

kcal/kg

kcal/kg

140
1.8

501.2
7.2

226.8
3

811.9
12.0

100
465.7
155
40
50
35
10
2.5
1000.00

400
1676.52
589
360
0
29.4
38.7
0
3602.02

100
75.7
155
340
50
35
10
2.5
1000.00

400
272.52
589
3060
0
30.8
38.7
0
5214.96

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The longevity curves were plotted using the KaplanMeier method


including all available mice at each time point (Baur et al., 2006), and
the Logrank test was applied to compare the distributions of the different groups. The results from the pathological analysis of the liver were
analyzed using the KruskalWallis test, and signicant differences
between treatment groups were further analyzed using the Mann
Whitney-U test. All other data were analyzed with one-way ANOVA
and signicant differences between treatment groups were further
analyzed using the t-test. P-values less than 0.05 were considered to
be statistically signicant (*, P b 0.05; **, P b 0.01).

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3. Results

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3.1. Longevity

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At 25 months of age, 53.8% of mice had died in the N group, whereas


the mortality rate was only 23.2% in the HF group (P = 0.02, Fig. 1). The
median for the HF group was reached two months later at 27 months of
age. While the sample size (n = 31/group) was relatively small for a
typical longevity study, we think that the observed effects of high corn
oil on the longevity of aging mice is a real action of this compound because such a large difference between the two groups was unlikely
due to random variation.

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3.2. Similar Energy Intake

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Although the average BW in the HF group was signicantly higher 156


than that in the N group as shown in Fig. 2A, the food consumption 157
in the HF group was signicantly lower than that in the N group 158

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Rotarod assay, a simple and accurate approach to examining agerelated changes in balance and motor coordination (Baur et al., 2006),
was performed using the rotarod apparatus (Med Associates, St. Albans
VT) at 14 and 25 month old mice to examine their ability to remain on
an revolving rod (Coyle et al., 2008). Briey, a mouse was briey placed
in a separate lane of a rotarod with an accelerating speed (220 rpm)
until the mouse fell off the rod. The length of time and speed of the
mouse which stayed on the rod were recorded.

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Serum total cholesterol, HDL-cholesterol, and triglycerides in mice


were measured using a PTS CardioChek Blood Analysis Meter (Maria
Stein, OH) according to the manufacturer's instructions and our previous report (Si et al., 2011). LDL-cholesterol was calculated using the formula from the manual of the analysis meter: LDL-cholesterol = total
cholesterol HDL-cholesterol triglyceride / 5. Serum cytokines
and chemokines including interleukin (IL)-6, IL-1, IL-10, tumor necrosis factor- (TNF), keratinocyte chemoattractant (KC), monocyte chemotactic protein 1(MCP-1) and interferon gamma (IFN-) were tested
by a Luminex mouse cytokine array assay (Capital Biosciences, MD) as
previously described (Si et al., 2011; Veenbergen et al., 2010). The activity of glutathione-disulde reductase (GSR) in the liver was measured
as we previously described (Si et al., 2011).

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2.4. Rotarod Test

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O

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2.2. Measurements of Serum Biological Markers and Hepatic Antioxidants

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pathological alterations in the liver were scored according to the levels


of vacuolar changes (hydropic degeneration or lipidosis) in hepatocytes
(1 = 010%, 2 = 1030%, 3 = 3050%, and 4 50% of hepatocytes
affected).

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corn oil diet (HF). Both diets are based on the AIN-93 produced by Dyets
Inc. (Bethlehem, PA) with two exceptions: 1) soybean oil was replaced
with corn oil and 2) the percentage of corn oil in each diet. The normal
diet has 10% fat derived calories (FDC) and the HF diet has 58% fat derived calories (FDC) (Reeves et al., 1993). This dose of corn oil (58%
FDC) was calculated based on previous studies using high fat diet (60%
FDC, 6% from soybean oil and 54% from lard) (Sung et al., 2014). Detailed
compositions of the diets are listed in Table 1. To ensure the stability of
the corn oil, diets were stored at 4 C and were kept away from light. The
diets were replaced every week. Body weight (BW) and food consumption were monitored weekly. The general health and well-being of the
mice were monitored daily. If a mouse was reported as or marked as
sick, the criteria for euthanizing mice were independently assessed by
a veterinarian adhering to the Institutional Animal Care and Use Committee guidelines. Mice with a BW less than 30% of their original BW
and other critical conditions including severe ulcerative dermatitis, urinary obstruction and abdominal masses were euthanized by inhalation
of CO2 and censored. When the median for the control group was
reached, the remaining 14 mice from the control group and 12 mice
from the HF group were fasted overnight and euthanized using CO2,
and their blood and tissues were collected for biochemical and physiological analysis. The HF group continued until the median was reached.
We also collected blood and tissues from youth control mice (12-month
old, 12 mice, YC) to compare the changes of biochemical and physiological analysis with the other two groups. The animal protocol was
approved by the Institutional Animal Care and Use Committee at
Meharry Medical College.

Survival Rate (%)

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H. Si et al. / Experimental Gerontology xxx (2014) xxxxxx

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40

N
HF

20
0
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Age: month
Fig. 1. Longevity curve in normal diet (N) and high corn oil diet (HF) mice for 1315 months.
There initially was 31 mice/group. *P b 0.05.
Q1

Please cite this article as: Si, H., et al., High corn oil dietary intake improves health and longevity of aging mice, Exp. Gerontol. (2014), http://
dx.doi.org/10.1016/j.exger.2014.09.001

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Food intake (g/mouse/d)

H. Si et al. / Experimental Gerontology xxx (2014) xxxxxx

Body weight (g)

50
40
30
N
HF

20
10
0

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

4.0

3.0
2.0
1.0
0.0

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

F
O

R
O

8.0

N
HF

4.0

12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

Energy intake (Kcal/mouse/d)

Age:month

12

0.0

N
HF

Age:month
16

Age:month

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3.3. Maintained Rotarod Performance

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Physical activity and locomotor function continuously diminishing


with aging (Baur et al., 2006; Yankner et al., 2008) and although corn
oil increased longevity, it is important to know whether the quality of
life was maintained. We evaluated the ability to perform on a rotarod,
a classic method of testing balance and motor coordination. While the
time on the rod was signicantly decreased as mice aged in the N
group (decreased from 115 s at month 14 to 80 s at month 25), the

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E
R

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120

N
C
O

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170

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168

Time on rod(s)

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(Fig. 2B). This may be a result of the texture of the HF diet, which has the
consistency of paste. Some days an oily liquid would form on the top of
the rodent feeding jars, while the N diets were typical pellets. Interestingly, there was no signicant difference in energy intake between
these two groups (Fig. 2C).

Fig. 2. Curves of body weight (A), food intake (B) and energy intake (C) in normal diet (N) and high corn oil diet (HF) mice for 1315 months. There initially was 31 mice/group. *P b 0.05.

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30
0

N
HF
Mo: 14

N
HF
Mo: 25

Fig. 3. Corn oil maintained rotarod performance in both normal diet (N) and high corn oil
diet (HF) mice at 14 and 25 months of age. Data are means SE, n = 12 mice/group.
*P b 0.05.

HF group maintained their motor skills until they were 25 months of 172
age (Fig. 3).
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3.4. Improved Hepatic Pathology

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Histological examination of liver sections stained with hematoxylin


and eosin revealed a loss of cellular integrity and the accumulation of
large lipid droplets in the livers of the N group, but the HF group reduced
the size of intracytoplasmic lipid vacuoles. Blinded scoring of the liver
sections for overall pathology on a scale of 04 (with 4 being the most
severe) gave mean values of 2.5 for the N group, 1.8 for the HF group
and 0.8 for the YC group (Fig. 4).

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3.5. Lowered Serum Lipids

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Circulating lipid abnormalities are increasingly recognized as


playing an important role in the aging process and age-related disorders such as diabetes and vascular dysfunction (Labinskyy et al.,
2006). Compared to the YC group, serum triglyceride, total cholesterol
and LDL-cholesterol were signicantly increased in the N group; however,
all these three serum lipids were reversed in the HF group as shown in
Table 2.

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3.6. Decreased Serum Inammatory Cytokines

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Consistent with observations of the pathological alterations in the


liver and remarkably shortened lifespan of mice in the N group, circulating levels of cytokines including IL-1, IL-6, IFN- and MCP-1 were signicantly elevated in the N group compared to those in the YC group
(Table 3). However, dietary consumption of corn oil signicantly reduced these pro-inammatory markers (Table 3), indicating that corn
oil may suppress chronic inammation caused by aging. In addition,
GSR activity in the livers of the N group was signicantly decreased

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Please cite this article as: Si, H., et al., High corn oil dietary intake improves health and longevity of aging mice, Exp. Gerontol. (2014), http://
dx.doi.org/10.1016/j.exger.2014.09.001

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1.0
0

YC

HF

Fig. 4. Corn oil improved hepatic pathology in aging mice. Hematoxylin and eosin stained slides of liver (three sections from each mouse) from young control (YC), normal diet (N) and
high corn oil diet (HF) mice were scored and the number of mice at relevant categories based on the levels of vacuolar change (hydropic degeneration or lipidosis for the liver) was
reported. A set of representative images and bar graphs (means SE, n = 1214/group) were shown. The arrows point to intracytoplasmic lipid vacuoles. 200 magnication. Scale
bar = 50 um. *P b 0.05.

Q2

R
O

2.0

3.0

4.0

HF

Pathological alterations
of liver ( arbitrary unit)

YC

compared to that in the YC group, whereas the activity of this enzyme


was reversed in the HF group (data no shown).

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4. Discussion

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Aging is well-known as an inevitable process that is physiologically


characterized as a progressive, generalized systematic dysfunction of
almost or all organs, giving rise to the escalated vulnerability to environmental challenges and resulting in increased risks of disease and death.
Indeed, aging is associated with a greatly increased metabolic and oxidative stress, elevated chronic, low-grade inammation, and accumulated DNA mutations as well as increased levels of its DNA damages
(Frisard and Ravussin, 2006; Heininger, 2000a,b). It is established that
calorie restriction delays age-associated organ disorders and increases
longevity as well as improves inammation and oxidative stress in a
wide range of species, suggesting that targeting nutrient-sensing and
energy metabolism pathways may be an effective approach to delay
the aging process and age-related diseases. In the present study, we
found that high level of corn oil (58.6% FDC) intake improved health
and longevity of aging mice, which may be associated with reversing
aging-increased blood lipids and pro-inammatory makers as well as
aging-damaged rotarod performance test and liver function. To our

t2:1
t2:2

Table 2
Blood lipid levels (mg/dL).

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t2:3

Group

Triglyceride

Total cholesterol

LDL

HDL

t2:4
t2:5
t2:6

YC
N
HF

115 9
142 15
124 12

197 19
314 26
171 15

135 22
240 23
113 11

39 1
52 7
40 3

t2:7
t2:8

Values are means SE (n = 1214 per group).


P b 0.05.

knowledge, the present study is the rst study that shows that if total
calorie intake is kept in the normal range, long-term very high level of
corn oil intake can improve health and increase longevity of aging mice.
A large body of evidence indicates that increased generation of reactive oxygen species (ROS) which are chemically reactive molecules with
most of them containing oxygen and unpaired electrons is one of the
major triggers of aging. There is a strong correlation between chronological age and the levels of ROS generation and oxidative damage of
tissues. ROS are primarily produced by mitochondria during energy production (about 2% of total oxygen consumption was funneled to ROS)
(Chance et al., 1979). Extra amounts of ROS induces oxidation of fatty
acids and proteins and causes oxidative damage of DNA that may lead
to cellular senescence, functional alterations, and pathological conditions (Harman, 1972; Linnane et al., 1989). This extra amount of ROS
is deactivated to water and oxygen by endogenous enzymes including
superoxide dismutase (SOD), catalase or glutathione peroxidases
(Chang et al., 2004). Endogenous antioxidant glutathione (GSH) and exogenous antioxidants including vitamins C and E are also important ROS
scavengers. Reducing ROS is proposed as a leading strategy to delay
aging and related degenerative diseases. Corn oil is one of the highest
natural sources of vitamin E (62.01 mg/100 g oil) and is just a little
less than cottonseed oil (62.37 mg/100 g oil). This high content of vitamin E may prevent aging-increased ROS and extend the lifespan of
aging mice. This is supported by our results showing that a decreased
GSR activity, a critical endogenous antioxidant enzyme, was reversed
by corn oil intake (data not shown).
Aging-induced ROS also contributes to low-grade chronic inammation (Brod, 2000), a crucial player of the process of aging and agerelated diseases in older adults. Indeed, chronic pro-inammatory
markers including IL-6, MCP-1 and TNF- are consistently elevated
with age in the absence of acute infection or other physiological stress
(Ferrucci et al., 2005). Consequently, the sustained increases of these

Please cite this article as: Si, H., et al., High corn oil dietary intake improves health and longevity of aging mice, Exp. Gerontol. (2014), http://
dx.doi.org/10.1016/j.exger.2014.09.001

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H. Si et al. / Experimental Gerontology xxx (2014) xxxxxx


Table 3
Serum inammatory cytokines (pg/ml).
IL-1

IL-6

IL-10

IFN

TNF

KC

MCP-1

26.3 10.8
43.4 15.9
26.2 8.4

17.5 6.7
57.7 11.6
20.2 9.6

1.9 0.0
4.9 1.0
13.1 4.0

43.9 10.2
110.0 28.5
99.0 24.7

9.1 3.9
6.8 2.2
6.4 2.0

42.2 16.2
43.5 6.6
55.3 3.3

62.2 15.2
310.0 27.5
198.0 18.3

pro-inammatory molecules impair the function and integrity of various tissues and organs and thus accelerate aging and aging-related
chronic diseases, although this increase is still in the sub-acute range
(Chung et al., 2006). Interestingly, calorie restriction signicantly
attenuates the increase of these pro-inammatory markers while extending the lifespan (Chung et al., 2006; Zou et al., 2004), suggesting
that anti-inammatory agents may have the potential to extend a
healthy lifespan. Results from the present study show that dietary intake of corn oil signicantly reversed the increase of circulating proinammatory markers including IL-1, IL-6, IFN- and MCP-1 in aging
mice and therefore increased longevity.
Elevated LDL-cholesterol is well known as one of the major risks of
cardiovascular disease and reducing blood LDL is recommended to
lower cardiovascular disease as well as other aging-related chronic diseases (NCEP, 2002). Corn oil has been found to be highly effective in
lowering blood cholesterol, particularly LDL-cholesterol (Ahrens et al.,
1957; Hill et al., 1979). Our results are in line with these previous studies
that corn oil lowers LDL-cholesterol, total cholesterol and triglyceride. This effect may be due to the high PUFA, which is supported by
evidence that corn oil is more effective than olive oil in lowering
LDL-cholesterol because corn oil has higher PUFA (58.7 g/100 g oil)
than olive oil (8.4 g/100 g oil) (Dupont et al., 1990; Howell et al.,
1998). Corn oil has a plant sterol content of 128 mg/1000 kcal vs.
66 mg/1000 kcal for olive oil, and these plant sterols can reduce cholesterol absorption from the gut which in turn lowers body pools and
enhances synthesis rate through de-suppression of cellular hydroxymethylglutaryl-CoA reductase activity (Howell et al., 1998).
A lower ratio of omega-6/omega-3 fatty acids (n6/n3) is recommended to reduce the risk of many highly prevalent chronic diseases in
Western societies (ratio of n6/n3 in Western diets is 15/116.7/1
(Simopoulos, 2002). Mammalian cells cannot convert omega-6 to
omega-3 fatty acids because they lack the converting enzyme, omega3 desaturase. These two classes of essential fatty acids (EFAs) are not
interconvertible, are metabolically and functionally distinct and have
opposing physiological functions. Therefore, too much omega-6 may
be detrimental for cells. Corn oil is not a good source for EFAs because
the ratio of omega-6/omega-3 fatty acids from corn oil is 83, which is
much higher than the recommended ratio (1/1 to 4/1) (Simopoulos,
2002). However, the present study and other studies show that high
corn oil intake improves health and longevity in mice and rats
(10 mg/kg/d by oral gavage) (NTP, 1994). One explanation is that majority of omega-6 PUFA from corn oil is used for energy, and is not
used to produce thrombi and atheromas, which are required for cardiovascular disease development. Moreover, high levels of vitamin E (majorly -tocopherol) (Elmadfa and Park, 1999) and plant sterols (0.77% by
weight) (Ostlund et al., 2002) may counter the bad effects of omega-6
PUFA of corn oil. For example, -tocopherol, the major form of vitamin
E in the corn oil, and its metabolite have more anti-inammatory properties than -tocopherol, the predominant form of vitamin E in the tissues
and most supplements (Jiang and Ames, 2003).
Taken together, if total calorie intake is kept in a normal range,
long-term very high intake of corn oil (58.6% FDC) reverses agingincreased blood lipids and circulating pro-inammatory cytokines as
well as aging-damaged rotarod performance test and liver function,
and thus increases longevity of aging mice. These health benets of
corn oil may result from the combinations of the high levels of PUFA,

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N
C
O

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vitamin E and plant sterols. Therefore, corn oil, even at a high energy 307
percentage (58%), is a favorable replacement of animal fats in the 308
human diet if the total energy intake is controlled.
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Conict of Interest

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Values are means SE (n = 1214 per group).


P b 0.05.

The authors declare that there are no conicts of interest associated 311
with this manuscript.
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Acknowledgments

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We are grateful for the support of the National Institute of Food and 314
Agriculture of USDA, Evans-Allen program (TENX-1103-FS, to H. Si) for 315
this work.
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t3:7
t3:8

R
O

YC
N
HF

t3:4
t3:5
t3:6

t3:3

References

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