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*
Department of Nutrition, Koshien University, 10-1 Momijigaoka, Takarazuka, Hyogo 665-0006, Japan
Field of Regeneration Control, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8397, Japan/AFF>
**
Department of Aging Angiology, Research Center on Aging and Adaptation, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
2To whom correspondence should be addressed.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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KEY WORDS: • senescence-accelerated mouse (SAM) • 
-linoleic acid • linoleic acid • serum lipids • longevity
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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). The association between low
serum cholesterol levels and a definite benefit on total mortality is
still unclear.
A murine model of accelerated senescence was developed by our group
(Takeda et al. 1991
): senescence-accelerated mouse
(SAM)3
strains (SAMP1, P2, P3, P6, P7, P8, P9 and P10), and control SAMR
mouse strains (SAMR1, R4 and R5) with normal aging characteristics.
SAMP strains show earlier onset and irreversible advancement of
senescence manifested by clinical signs and gross lesions following a
normal process of development, and each SAMP strain has a
strain-specific age-associated disorder. These mice have been used
as models to investigate the aging process, including senile
amyloidosis (Higuchi et al. 1983
), degenerative joint
disease (Chen et al. 1989
), senile osteoporosis
(Matushita et al. 1986
), deficits in learning and memory
(Yagi et al. 1988
) and senile cataract (Hosokawa et al. 1988
). Senile amyloidosis is one of the most
characteristic age-associated disorders in the SAMP strains. The
three molecular types (type A, B and C) of apolipoprotein A-II
(apoA-II), with different amino acid substitutions at four positions,
correlated with the susceptibility of each strain to senile amyloidosis
(Higuchi et al. 1991
). The strains (SAMP1,P2, etc.) with
a high incidence and severe senile amyloidosis have type C apoA-II,
whereas the strains with a low incidence and slight or mild amyloidosis
have type A apoA-II (SAMP8 and P3) or type B apoA-II (SAMR1, R4
and P6). Mice are typical "HDL-animals" in that HDL is a major
lipoprotein class and the serum cholesterol level is low
(Chapman 1986
). The total cholesterol levels in the type
C or type A apoA-II strains, such as SAMP1 and SAMP8, are
one-third the levels in humans. We utilized the SAMP8 strain mice
as the experimental animal in this study due to the accelerated
senescence, with a low incidence of amyloidosis and an
age-associated decrease in the serum cholesterol concentrations.
(Higuchi et al. 1991
and Higuchi et al. 1993
). An age-associated or diet-induced further
decrease in the serum levels of cholesterol in SAMP8 strains may affect
senescence and life span. However, this is yet to be clarified.
Dietary triglycerides (TG) composed either of (n-6) PUFA or (n-3) PUFA
differ in their effects on serum lipid levels. (n-6) PUFA lower
cholesterol but not TG levels (Balasubrmaniam et al. 1985
, Leaf and Weber 1988
), while (n-3) PUFA
lower serum cholesterol, especially VLDL cholesterol, and TG in rats
(Ventura et al. 1989
) and humans (Phillipson et al. 1985
, Saynor et al. 1984
). Additionally,
dietary PUFA can affect disease pathogenesis and every cell of the
immune system via regulation of the levels of eicosanoids
(Hardardottir et al. 1992
), cytokines (Meydani et al. 1991
) and cell-activation enzymes (May et al. 1993
).
This study was undertaken to investigate the effects of a high (n-3) PUFA and a high (n-6) PUFA diet on serum lipid levels and longevity using SAMP8 strain mice. The two different vegetable oils, perilla and safflower, used in this study have very different (n-3)/(n-6) ratios, but similar proportions of saturated and monoenoic fatty acids.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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SAMP8 mice were bred and raised in our laboratory under conventional
conditions. Male mice at 6 wk of age were fed diets containing 9 g/100
g -linolenate-rich perillaseed oil [18:3(n-3)/18:2(n-6) = 4.09] or 9 g/100 g linoleate-rich safflower seed oil
[18:3(n-3)/18:2(n-6) = < 0.01]. The validity of using these
oils was assessed by examining the reproductive physiology and growth
rates of offspring (Naito et al. 1990
). The major fatty
acids in the diets are shown in Table 1.
The diets contained by weight: 25% soybean protein isolate, 0.3%
DL-methionine, 32.7% corn starch, 25% sucrose, 2%
cellulose powder, 5% mineral mixture (Umezawa et al. 1990
), 1% vitamin mixture (Umezawa et al. 1990
)
and 9% oil. Diets with peroxide values below 30 meq/kg were routinely
used. This study consisted of two experiments. The groups fed perilla
oil included 21 (Experiment 1) and 12 (Experiment 2) mice, and the mice
in the groups fed safflower oil included 20 (Experiment 1) and 14
(Experiment 2). In addition, 8 SAMP8 male mice at 10-mo-old fed
commercial diet (CD) (CE-2; NIHON Clear, Tokyo, Japan) from 4 wk of age
were used in Experiment 2. The CD contained 25.2% crude protein,
50.2% carbohydrate, 4.4% fat, 4.4% fiber and 7.0% ash (collected works of Nihon CLEA, 1997). Mice were housed at about five per cage,
allowed free access to diet and tap water and were maintained in a
temperature-controlled room (24 ± 2°C) with a 12-h
light/dark cycle, throughout their lives in Experiment 1 and until they
were 5-mo- or 10-mo-old in Experiment 2. All mice were maintained
according to the policies and recommendations of The Kyoto University
Animal Care and Use Committee.
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Experiment 1 |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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Grading score of senescence.
This system was designed to represent changes in the behavior and
appearance of the mice that were considered to be associated with the
aging process (Hosokawa et al. 1984
). Briefly,
the 11 categories measured included reactivity, passivity, glossiness
and coarseness of coat, hair loss, ulcers, periophthalmic lesions,
cataracts, corneal ulcers, corneal opacity and lordokyphosis. Each
category has five grades of intensity of characteristics or changes.
Each mouse was examined by inspection and palpation every 2 to 3 mo,
and the sum of the scores of the 11 categories was recorded.
Histological examination.
The age at death of each mouse was recorded, and the abdominal skin, liver, kidneys, spleen, heart, lungs, stomach, thyroid, adrenals, gonads and aorta were fixed in 10% (v/v) neutral buffered formalin, embedded in paraffin, cut into 4-µm sections and stained with hematoxylin and eosin.
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Experiment 2 |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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Serum lipids and lipoprotein quantitation.
Serum total cholesterol levels were determined using an enzymatic procedure (Cholesterol C test; Wako Pure Chemical Industries, Osaka, Japan). HDL cholesterol was measured according to a modified heparin-manganese precipitation procedure (HDL cholesterol C test; Wako). TG levels were measured spectrophotometrically using acetylacetone (Triglyceride-test; Wako). Phospholipid (PL) levels were measured using a calorimetric kit (Phospholipid-test; Wako).
There are two major proteins, apolipoprotein A-I (ApoA-I) and
ApoA-II in HDL. The levels of ApoA-I and ApoA-II in serum
were determined using an immunoblotting method as described previously
(Higuchi et al. 1995
). Serum (50 nL) was applied
to a 15 to 20% gradient sodium dodecyl sulfate-polyacrylamide mini
gel, 84 mm wide x90 mm high, and electrophoresis was carried out at 15
mA for 2.5 h. After electrophoresis, samples were electroblotted
onto polyvinyliden difluoride membranes (Bio Rad Laboratories,
Richmond, CA) using a semidry apparatus (Nihon Eido, Tokyo, Japan) at
150 mA for 2 h. ApoA-I and ApoA-II were detected after
incubation of the membranes with monospecific rabbit anti-mouse
ApoA-I and ApoA-II antiserum (diluted 1:4,000) by the
avidin-biotinylated horseradish peroxidase complex method, using
3-3'-diaminobenzidine tetrahydrochloride as a substrate. The amounts of
ApoA-I and ApoA-II were determined by comparing the intensity
of bands with that of bands of the internal control, purified mouse
ApoA-I and ApoA-II protein, using a Densitoron (Jookoo, Tokyo,
Japan).
Nondenaturing gradient polyacrylamide gel electrophoresis.
To ascertain whether dietary oils affected the size distribution of
HDL, nondenaturing polyacrylamide gradient gel electrophoresis was used
(Higuchi et al. 1993
). Gels containing a 2–15% linear
polyacrylamide gradient were electrophoresed in 25 mmol/L of Tris and
192 mmol/L of glutamic acid. Prior to electrophoresis, serum samples (3
µL) were stained for lipid by incubation at 4°C overnight with 2.5
µL of freshly prepared Sudan Black B dye solution (5 parts 10 g/L of
Sudan Black B in ethylene glycol-3 parts 400 g/L of sucrose).
Electrophoresis was carried out at 25 mA for 2 h. The amounts of
the HDL species were determined by comparing the intensity of bands
with that of bands of the HDL3 level in the safflower oil
group, using a Densitoron.
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Statistical analysis |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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), and a
comparison of the curves was carried out by Log-Rank test analysis
using the Statistical Analysis System (SAS Institute, Cary, NC). The
significance of the differences with respect to the pathological
findings due to age within each dietary oil group was analyzed using
Fisher’s Exact Test (Steel and Torrie 1980
).
Statistical significance was established when P < 0.05. |
RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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Growth and grading score of senescence. Food consumption did not differ in the two vegetable oil-fed groups of SAMP8 (2–10-mo-old) mice (3.5 ± 0.1 g/d in mice fed safflower oil; 3.4 ± 0.2 g/d in those fed perilla oil). Body weight gains from 6 wk to 15 mo did not differ (not shown).
Grading scores that reflect senescence are shown in Figure 1.
Increasing senescence scores with aging were found in both groups. The
grading scores of mice fed perilla oil were significantly lower than
those fed safflower oil after 7 mo of age (P < 0.05).
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).The mean life span of the perilla oil group (357 ± 21 d) was
significantly (P < 0.05, 17%) shorter than that of
the safflower oil group (426 ± 24 d) (P < 0.05).
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).Abscess and overall inflammatory changes were significantly greater in
6–20-mo-old mice in the perilla oil group (abscess:7, pneumonia:5,
ulcer:2) than in mice of the same age in the safflower oil group
(abscess:2, ulcer:2, pneumonia:1) (P < 0.01). However,
in the perilla oil group, inflammatory changes were directly related to
death for only 6 of 16 mice that exhibited them. Almost all the mice in
the safflower oil group died as a result of tumors, amyloidosis and
contracted kidneys, and the number of mice that had tumors was
significantly higher than that in the perilla oil group (P
< 0.05). The mice in the safflower oil group exhibited thymic
lymphoblastic lymphomas (n = 6), nonthymic
lymphoblastic lymphomas (n = 1) and squamous cell
carcinoma (n = 1). Two of those in the perilla oil
group had developed thymic lymphoblastic lymphomas. Severely contracted
kidneys were observed in seven mice in the safflower oil group, and
there were amyloid protein deposits in the kidneys. Others in the
safflower oil group exhibited myocardial infarction (n
= 1), coagulative necrosis of the liver (n = 1),
congestion and edema of the lung (n = 1) and volvulus
(n = 2). The direct causes of death of 6 of 15 perilla
oil-fed mice that died after 10-mo-old could not be identified.
Reasons for all deaths could be determined in the mice fed safflower
oil.
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Serum lipids and cholesterol.
Serum concentrations of total cholesterol, HDL cholesterol, TG and
phospholipids (PL) in mice fed two dietary oils at both 5- and
10-mo-old were significantly lower in the perilla oil group than in the
safflower oil group (P < 0.01) (Table 3
).The concentrations of total cholesterol and PL in both diet groups did
not significantly differ between 5- and 10-mo-old mice. However, the
serum HDL cholesterol concentrations were significantly lower in
10-mo-old mice than in 5-mo-old mice in both diet groups (P
< 0.01). The ratio of HDL cholesterol to total cholesterol in the
perilla oil group was 55% lower at 10-mo-old compared with at 5 mo,
while those in the safflower oil group was 33% lower at 10 mo than at
5 mo (P < 0.01). The serum TG level in the safflower
oil group only was significantly lower at 10-mo-old compared with 5 mo
(P < 0.01). Lipid concentrations at 10 mo in the CD
group generally were between the safflower and perilla oil groups.
Serum total protein (g/L) at 10 mo in the two oil groups did not differ
(77.3 ± 5.6, perilla oil group; 76.8 ± 7.5, safflower oil
group).
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). The serum levels of ApoA-II were significantly lower in
10-mo-old mice than in 5-mo-old mice in both dietary oil groups
(P < 0.05): 50% lower in the perilla oil group and
29% lower in the safflower oil group. The ratio of ApoA-I to
ApoA-II was significantly higher at 10 mo of age compared with 5 mo
in both diet groups, and at 10 mo of age those in the perilla oil group
were significantly higher than those in the safflower oil group
(P < 0.05). The serum levels of ApoA-I, ApoA-II
and the ratio of ApoA-I to ApoA-II at 10 mo in the CD group
were comparable to those of the perilla oil group.
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The predominant form observed in both dietary oil groups was
HDL3, whereas HDL1 was present at very low
levels. Densitometric gel scanning of the peaks representing the three
major species of HDL yielded the findings shown in Figure 3B
. As observed with the serum levels of HDL cholesterol,
the SAMP8 mice had a 55% lower HDL lipid stain intensity in response
to the perilla oil diet compared with the intensity observed for the
safflower oil diet group. However, there were clear differences between
the dietary oil groups on the different HDL species. The perilla oil
group exhibited 58, 48 and 54% lower levels of HDL3,
HDL2 and HDL1, respectively, compared with the
levels observed for the safflower oil group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSExperiment 1Experiment 2Statistical analysisRESULTSDISCUSSIONREFERENCES |
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Routine postmortem examinations of the SAMP8 strain fed CD showed that
amyloidosis was the most common autopsy finding with an incidence of
39.1%, while tumors were second (32.6%), and the third was abscess
(26.1%)(Takeda et al. 1997
). All SAMP8 mice fed
safflower oil developed tumors (42.1%), amyloidosis (31.5%) and/or
contracted kidneys (36.8%), and these were directly related to death.
However, it was found that replacing safflower oil with perilla oil in
the diet suppressed the appearance of amyloidosis (18.8%) and tumors
(12.5%) in SAMP8 mice; the inflammatory changes including abscess,
pneumonia and ulcer were directly related to death in 37% of the mice
fed perilla oil, although almost all mice fed perilla oil exhibited
these findings (87.5%). The benefits of (n-3) PUFA in cancer
(Dajani 1993
) and kidney disorders (DeCaterina et al. 1993
), as well as in cardiovascular disease (Schmidt and Dyerberg 1994
), have been demonstrated. A diet supplemented
with perilla oil suppressed tumor metastasis (Hori et al. 1987
) and tumorigenesis (Okuyama et al. 1987
),
and reduced hypertension and apoplexy (Shimokawa et al. 1988
), thrombosis (Watanabe et al. 1989
) and
allergic response (Hashimoto et al. 1988
). Additionally,
it was reported that rats fed perilla oil had extended mean survival
times compared to that of those fed safflower oil (Yamamoto et al. 1991
). The beneficial effects of perilla oil were evident
in SAMP8 mice fed perilla oil, but it did not affect life span, and for
44% of the mice fed perilla oil, the direct cause of death could not
be identified.
It has been reported that the type A ApoA-II gene is responsible
for lower plasma cholesterol concentrations and smaller HDL size
(Doolittle et al. 1990
). In 10-mo-old male SAM mice fed
CD, the SAMP8 mice with type A ApoA-II showed lower serum levels of
total cholesterol (about two-thirds) and even lower levels of HDL
cholesterol (about one-third) compared to those of SAMR1 mice with type
B ApoA-II (Higuchi et al. 1995
). In this study,
10-mo-old SAMP8 mice fed perilla oil had lower serum levels of total
cholesterol (about half) and even HDL cholesterol (about one-quarter)
than SAMR1 mice fed CD. This hypolipidemic effect of perilla oil may be
due to inhibition of lipogenic enzymes in the liver (Iritani et al. 1980
) and decreased formation of both chylomicrons in the
intestine and VLDL in the liver (Nestel et al. 1984
).
Several studies revealed that reduction of HDL cholesterol levels
accompanied by increased VLDL + LDL cholesterol levels in a diet
result in susceptibility to diet-induced atherosclerosis. Though
the findings were not published, 5-mo-old mice fed perilla oil had
higher proportions of LDL cholesterol to total cholesterol and lower
proportions of VLDL cholesterol to total cholesterol. Lower formation
of VLDL-triacylglycerol (Harris et al. 1984
) and
VLDL ApoB (Nestel et al. 1984
) by (n-3) PUFA was shown.
However, the serum HDL cholesterol levels of SAMP8 mice fed safflower
oil were twice those of SAMP8 mice fed CD, while their total
cholesterol levels were nearly the same levels as those of SAMR1 mice
fed CD, which were 1.4 times higher than those of SAMP8 mice fed CD.
HDL consists of two major proteins, ApoA-I and A-II.
Interestingly, the levels of ApoA-I in mice fed perilla oil or
safflower oil did not change between 5- and 10-mo-old, despite the HDL
cholesterol levels being clearly lower at 10 mo than at 5 mo. However,
both dietary oil groups at 10 mo had low levels of serum ApoA-II
that were associated with HDL cholesterol levels. Transgenic mice with
ApoA-II revealed that increased ApoA-II expression results in
an elevated HDL cholesterol concentration and a greater proportion of
larger HDL particles (Hedrick et al. 1993
). Lower HDL
cholesterol concentrations in congenic mouse strains have been reported
to be caused by lower ApoA-II concentrations (Wang et al. 1997
). In SAM mice fed CD, the serum ApoA-II concentrations
of SAMP8 mice with type A ApoA-II were about 0.30 g/L, those of
SAMP1 mice with type C ApoA-II were about 0.20 g/L, and those of
SAMR1 mice with type B ApoA-II were about 0.60 g/L (Higuchi et al. 1983
, Higuchi et al. 1991
).
The serum ApoA-II concentrations in 10-mo-old SAMP8 mice fed the
perilla oil or CD were comparable, while those in the safflower oil
group were close to those observed in SAMR1 mice with normal aging
characteristics. Generally, at higher ratio of ApoA-I/ApoA-II, HDL
function more efficiently in reverse cholesterol transport
(Mehrabian and Lusis 1992
). In this study, perilla oil
lowered HDL cholesterol levels but increased the ratio of
ApoA-I/ApoA-II compared with the safflower oil.
An important factor influencing HDL size is the ratio of ApoA-I/ApoA-II
in plasma, and the higher ApoA-II content of the larger HDL species
which contain more lipids than smaller HDL (Doolittle et al. 1990
). Dietary saturated fats resulted in an increase in
HDL1 in baboons and a decrease in the amount of large HDL
and an increase in small HDL in monkeys (Babiak et al. 1988
). A soybean oil diet resulted in a larger proportion of
small HDL in hamsters (Ahn et al. 1994
). In human
studies, heart disease is associated with low concentrations of
HDL2 and HDL3 (Miller 1987
).
Consistent with these data, both HDL2 and HDL3
size classes were reduced by high fat diets in a mouse strain
susceptible to diet-induced atherosclerosis (LeBoeuf et al. 1990
). The consumption of perilla or safflower oil by
SAMP8 mice resulted in a larger proportion of small HDL, and the
proportions of smaller HDL subclasses did not differ significantly
between the two dietary oil groups.
In humans, most guidelines recommend reducing plasma levels of
cholesterol to decrease risks for coronary heart disease. On the other
hand, in men receiving dietary and/or pharmacological treatments to
lower cholesterol concentrations, mortality for coronary heart disease
tended to be lower, but total mortality was not affected by the
treatments and deaths not related to illness, accident, suicide or
violence, increased (Muldoon et al. 1990
, LaRosa et al. 1990
). SAMP8 mice have a genetic characteristic of low
serum cholesterol levels, and the supplied dietary oils modified their
serum lipid metabolism, causing their serum cholesterol concentrations
to become still lower or higher. Those differences between the two diet
groups may influence both the cause of death and mean life span. The
relationship between serum lipids and longevity requires further study.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: Apo, apolipoprotein; CD, commercial diet; PL, phospholipid; SAM, senescence-accelerated mouse; TG, triglyceride.
Manuscript received April 23, 1999. Initial review completed June 9, 1999. Revision accepted October 14, 1999.
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