241

ORIGINAL
Effect of olive oil consumption on aging in asenescence-accelerated mice-prone 8 (SAMP8) model
Masahiro Bando1, Saeko Masumoto1, Masashi Kuroda1, Rie Tsutsumi1, and Hiroshi Sakaue1
1

Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

Abstract : Background : Mediterranean diets have been linked to a reduced risk of cancer, vascular illnesses,
Parkinson’s and Alzheimer’s disease. Olive oil is the primary fat source in the Mediterranean diet ; however,
only a few studies have investigated the effect of olive oil on aging. In the present study, we aimed to determine whether consumption of olive oil significantly influences aging and memory in senescence-accelerated
mouse-prone 8 (SAMP8). Methods : SAMP8 and senescence-accelerated mouse resistant 1 (SAMR1) mice were fed
either 7% soy oil or 1% olive oil and 6% soy oil during a six-month study period. Reduction in memory in passive
avoidance learning was examined after two months from the initiation of the experiment. Results : The weightof organs including the liver, kidney, spleen, and fat tissue changed significantly and memory performance was
reduced in SAMP8 than in SAMR1 mice. There were no significant differences in SAMP8 and SAMR1 mice; however, blood triglyceride level decreased significantly in SAMP8 mice fed on olive oil. Conclusions : These results
suggest that consuming olive oil may not have a protective role in aging and memory recall, but beneficial effects
may be related to improvement in lipid metabolism. J. Med. Invest. 66 : 241-247, August, 2019
Keywords : Mediterranean diet, olive oil, MUFA, SAMP8, aging

INTRODUCTION
The consumption of a Mediterranean diet has extensively
been reported to be associated with favorable health and an
improved quality of life, and recently, an increased interest ina possible relationship between diet and cognitive health has
also been noted. Intake of a Mediterranean diet has been linked
with the reduced risk of developing cancer and vascular illnesses
and also with decreased incidences of chronic diseases, such as
Parkinson’s disease (1, 2, 3, 4). Several studies have revealed
the protective effects of this dietary pattern against numerous
diseases, including neurodegenerative disorders like Alzheimer’s
disease (5). Recent research suggests that the intake of Mediterranean diets enriched with coconut oil improves cognitive function in patients presenting with Alzheimer’s disease (6). Thus,
the benefits Mediterranean diets have on the health of both the
body and the mind are evident.
The Senescence-Accelerated Mouse-Prone 8 (SAMP8) is agood model for studying the effects of aging. The SAMP8 mousestrain is a mouse model exhibiting accelerated aging, phenotypically selected from the AKR/J strain by Dr. Takeda’s lab at Kyoto
University (7). These SAMP8 mice are also used to study brain
aging and neurodegeneration (8). While these mice are an accepted model to investigate the aging process, most phenotypes
in the SAMP8 mice are not fully explained by genetic factors(9). In contrast, the Senescent-Accelerated Mouse-Resistant 1(SAMR1) model, with a similar genetic background to SAMP8
mice, has been used as an appropriate control model displaying
normal aging characteristics.
These SAMP strains have been used widely in research focusing on the effects of feeding and various food constituents on
Received for publication February 13, 2019 ; accepted February 20,
2019.
Address correspondence and reprint requests to Hiroshi Sakaue,
Department of Nutrition and Metabolism, Tokushima University
Graduate School, 3-18-15, Kuramoto, Tokushima, Tokushima, 7708503, Japan. and Fax : +81-88-633-7113.

aging. For instance, SAMP8 mice were used to investigate theprotective effect that Antarctic Krill Oil, rich in polyunsaturated fatty acids (PUFA), has on memory (10). Similarly, dietary
resveratrol was shown to decrease the progressive accumulationof extracellular brain β -amyloid (Aβ) aggregates in Alzheimer’s
disease and prolonged survival in SAMP8 mice (11). Sesaminol,
a component of sesame oil, reduced brain Aβ accumulation anddecreased serum 8-hydroxydeoxyguanosine, an indicator of oxidative stress in the same model (12).
A Mediterranean diet is characterized by high olive oil content.
Olive oils are predominantly composed of mono-unsaturated
fatty acids (MUFA) (13). Diets rich in MUFAs are associatedwith a reduction in the risk of developing diabetes and cardiovascular diseases (14). For instance, a Mediterranean diet supplemented with either olive oil or mixed nuts for approximately five
years, reduced the incidence of cardiovascular diseases in older
individuals (15). Recent research shows that dietary MUFAs, but
not PUFAs, extends lifespan of Caenorhabditis elegans (16). Other
studies have focused on identifying a possible link between the
consumption of fish oil containing PUFAs and dementia (17, 18).
However, only a few studies have investigated the effect of olive
oil on cognitive function. As such, in this study, we investigatedthe effect of olive oil on aging and memory in SAMP8 mice.
We first investigated the characteristic aging differences
between SAMR1 and SAMP8 models that were either provided a diet consisting of soy oil (saturated fatty acids) or olive oil(MUFA) for a period of six months. Memory performance wasinvestigated through passive avoidance tests at two months fromthe start of feeding. At the end of the feeding period, body andorgan weight were taken

METHODS

Animals and experimental design
Ten-week old SAMR1 and SAMP8 male mice were purchasedfrom Japan SLC Inc. In terms of the process of senescence,
SAMR1 mice exhibited normal development and maturation,

The Journal of Medical Investigation Vol. 66 2019

M. Bando, et al. Effects of olive oil in SAMP8 mice242

while SAMP8 mice spontaneously develop accelerated senescence (19, 20). Mice were maintained under a 12-h light/darkcycle with food and water available ad libitum. From 11 weeks old
and throughout the 24 week study period, SAMR1 and SAMP8
mice were fed either a Control diet, Western diet D10012GM(Table 1)-adjusted Calories Diet (Research Diets, Inc., NJ) oran Olive Oil diet, Western diet D17052602px (Table 1) supplemented with 1% olive oil (Nippon Suisan Kaisha, Tokyo, Japan).
Body weight and food intake were recorded twice per week. All
experimental procedures conformed to the guidelines for animal
experimentation of Tokushima University.
Table 1. Composition of the experimental diets for SAMR1 and

SAMP8 mice.

a mouse was released into the bright box and tended to migrate
to the dark box through the central door opening. When themouse entered the dark box, the central door was closed, andthe mouse was exposed to a 0.5 mA electric shock. On the secondday, the mouse was released into the bright box again, and the
choice made by the mouse whether or not to enter the dark box
was recorded each day (maximum assay time is 180 s). A longer
interval or the lack of entry on the second day indicates a memory response, as described previously (24).

Grading score of senescence
The grading score of the senescence system (20, 25) represents
the senescent status according to the animals’ appearance
and behavioral changes with regard to 11 items (reactivity,
passive flight reaction, skin glossiness, coarseness, hair loss,
ulcer, catarrhal change in the periophthalmic lesions, corneal
opacity, corneal ulcer, cataract, and kyphosis). Each item wasgraded with a score between 0 and 4 according to the intensity ofchanges (grade 0 represented no particular change and grade 4
represents the most severe changes). In this study, we used six
items, reactivity, passivity, glossiness, coarseness, hair loss, andcatarrhal change in the periophthalmic lesions.

Ingredient (g/kg)

Control diet

Olive oil diet

Casein200

200

L-Cystine

3

3Corn Starch

397.486

397.486

Maltodextrin 10

132

132

Sucrose100

100

Cellulose, BW200

50

50

Soybean Oil

70

60

olive oil

010t-Butylhydroquinone

0.014

0.014

Mineral Mix S10022G

35

35

Vitamin Mix V10037

10

10Choline Bitartrate

2.5

2.5

Energy content, Kcal/g

4

4Protein, % of energy

20

20

Carbohydrate, % of energy

Organ weight and blood analysis in SAMR1 and SAMP8 mice

64

64

Fat, % of energy

16

16

SAMR1 and SAMP8 mice were fed a diet supplemented with
7% soy oil throughout the 24-week study. At the end of the feeding period, mice of each strain were sacrificed to measure organ
weight and intestinal length. Although there were no significant
differences in body weights between SAMR1 and SAMP8 mice,the liver and spleen weight did increase, and kidney and epididymal fat weight was significantly lower in SAMP8 mice (Table2). The result of blood analysis demonstrated that AST, ALT,and LDL-C were significantly higher and T-CHO, NEFA, and
HDL-C were significantly lower in SAMP8 mice when comparedwith SAMR1 mice. There were no significant differences in TG,
GLU, and PL between the groups (Table 3).

Statistical analysis
For comparison of the two groups, the Student’s t-test for independent samples was applied for categorical data. The results
are presented as mean ± standard error. All statistical analysis
was performed using the 4-Steps Excel Statistic Third Edition(The Publisher OMS Ltd., Tokyo, Japan). A p-value less than
0.05 was considered statistically significant.

Nutritional values

Plasma analysis
The fasting plasma level of aspartate-aminotransferase (AST),
alanine-aminotransferase (ALT), total cholesterol (T-CHO), freecholesterol (F-CHO), cholesterol ester (E-CHO), triglycerides
levels (TG), phospholipids (PL), non-esterified fatty acid (NEFA),
low-density lipoprotein (LDL), high-density lipoprotein (HDL)
and blood glucose level (GLU) were quantified using routine
laboratory methods (Nagahama Life Science Laboratory, Shiga,
Japan). Mice from each group were sacrificed via decapitation,and their blood was collected in heparinized capillary tubes.
Plasma was separated from blood samples by centrifugationand stored in aliquots at -80°C. All experimental procedures
conformed to the guidelines for animal experimentation ofTokushima University.

Passive avoidance test
Passive avoidance tests were performed using the shuttle box
system (Shin Factory Corporation, JAPAN). This test was used
to study memory performance in mice and is carried out over a
period of two days (21, 22, 23, 24). The system consists of the twoboxes centrally divided by a wall with sliding door that can beeither open or closed. One box is a bright compartment without a
top covering (bright box), while the other is a dark compartment
in which all sides enclosed (dark box). The floor of the box was
made of a stainless-steel grid, which in the dark box can produce
a mild electric shock under certain stimuli. On the first day, after

RESULTS

Table 2. Body and organ weight in SAMR1 or SAMP8 mice after 24
weeks of feeding on 7 % soy oil.

SAMR1

SAMP8

P values

Body weight (g)39.57 ± 1.38

39.75 ± 1.51

NS

Liver (g)1.798 ± 0.074

2.033 ± 0.082< 0.05Kidney (g)0.574 ± 0.022

0.475 ± 0.026< 0.05Spleen (g)0.103 ± 0.004

0.156 ± 0.020< 0.05

Mesenteric fat (g)0.786 ± 0.056

0.597 ± 0.079

NS

Perirenal fat (g)0.954 ± 0.093

0.728 ± 0.097

NS

Epididymal fat (g)2.181 ± 0.210

1.170 ± 0.071< 0.001

Intestinal length (cm)6.9 ± 0.2

7.1 ± 0.2

NS

Scores are presented as the mean ± standard error ; NS = nonsignificant.

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The Journal of Medical Investigation Vol. 66 August 2019
Table 3. Result of analyzing the plasma in SAMR1 or SAMP8 mice
after 24 weeks feeding on 7% soy oil.
SAMR1

SAMP8

P values

AST (IU/L)

50.2 ± 4.2

77.1 ± 5.4< 0.001

ALT (IU/L)

44.7 ± 7.5

74.7 ± 11.0

< 0.05

T-CHO (mg/dL)

148.6 ± 3.2

116.4 ± 8.1< 0.01

F-CHO (mg/dL)

38.5 ± 1.4

25.2 ± 1.6< 0.001

E-CHO (mg/dL)

110.2 ± 2.1

91.2 ± 6.8< 0.05TG (mg/dL)

91.6 ± 6.8

95.7 ± 9.1

NS

PL (mg/dL)

255.0 ± 7.7

228.0 ± 16.0

NS

NEFA (μEq/L)

1359.5 ± 70.5

1015.5 ± 91.0

< 0.01LDL-C (mg/dL)

3.5 ± 0.4

6.0 ± 0.9

< 0.05

HDL-C (mg/dL)

88.6 ± 2.1

65.7 ± 5.2< 0.01

GLU (mg/dL)

184.6 ± 5.7

183.3 ± 25.6

NS

Scores are presented as the mean ± standard error ; NS = nonsignificant.

Fig 2. Grading scores of SAMR1 and SAMP8 mice at end of thefeeding period.
Black bar represents SAMR1 mice and gray bar indicates SAMP8
mice. Scores are presented as the mean ± standard error ; * : p < 0.05,*** : p < 0.0001

Grading score and passive avoidance test in SAMR1 and SAMP8
mice
To investigate the difference in aging between SAMR1 and
SAMP8 mice, we recorded the grade score of reactivity, passivity, glossiness, coarseness, hair loss, and catarrhal change in the
periophthalmic lesions at the end of the feeding period (Fig. 1, 2).
SAMR1 mice were granted grade 1 for reactivity (restless movement) and passivity (getaway speed was slow) while SAMP8
mice were granted grade 2 (walk slowly and did not getaway)
for the same traits. Grades for coarseness, reduction in hair size,and catarrhal change in the both periophthalmic lesions werelower in SAMR1 than in SAMP8 mice.
The passive avoidance test was performed at the 8th-weeksince initiation of the experiment. SAMR1 mice spent, on average, 60 seconds entering the dark box from the bright box, while
SAMP8 group mice spent 15 seconds on the task, before they
were exposed to an electric shock on first day (data not shown).
On the second day, after being released into the bright box again,
SAMR1 and SAMP8 mice spent 133 and 56 seconds entering thedark box, respectively (Fig. 3).

Fig 3. SAMR1 mice spent more time entering the dark box frombright box than did SAMP8 mice on the second day.
Black bar represents SAMR1 mice and gray bar indicates SAMP8
mice. Scores are presented as the mean ± standard error ; ** : p < 0.01.

Organ weight and blood analysis in SAMP8 mice feeding on olive oil
SAMP8 mice were fed a diet consisting of either a western
diet D17052602px including 6% soy oil, supplemented with 1%
olive oil (olive oil group) or 7% soy oil. No significant differencesin organ weight or blood markers (except in the case of TG level)
were noted between the two groups (Tables 4 and 5, respectively).

Table 4. Body and organ weight of SAMP8 mice fed on different
diets, after 24 weeks.

Fig 1. SAMR1, SAMP8 mice, and the olive oil group (SAMP8 mice)at end of the feeding period.

Control

Olive

P values

Body weight (g)39.75 ± 1.51

37.44 ± 0.99

NS

Liver (g)2.03 3 ± 0.082

2.03 5 ± 0.197

NS

Kidney (g)0.475 ± 0.026

0.499 ± 0.014

NS

Spleen (g)0.156 ± 0.020

0.194 ± 0.077

NS

Mesenteric fat (g)0.597 ± 0.079

0.446 ± 0.053

NS

Perirenal fat (g)0.728 ± 0.097

0.600 ± 0.085

NS

Epididymal fat (g)1.170 ± 0.071

1.10 7 ± 0.156

NS

Intestinal length (cm)7.1 ± 0.2

7.0 ± 0.2

NS

Scores are presented as the mean ± standard error ; NS = nonsignificant.

M. Bando, et al. Effects of olive oil in SAMP8 mice

244

Table 5. Analyses of the plasma from SAMP8 mice after 24 weeks
Control

Olive oilP values

AST (IU/L)

77.1 ± 5.4

127.2 ± 54.9

NS

ALT (IU/L)

74.7 ± 11.0

81.6 ± 23.0

NS

T-CHO (mg/dL)

116.4 ± 8.1

106.2 ± 9.6

NS

F-CHO (mg/dL)

25.2 ± 1.6

25.5 ± 2.3

NS

E-CHO (mg/dL)

91.2 ± 6.8

80.7 ± 8.6

NSTG (mg/dL)

95.7 ± 9.1

63 ± 6.6< 0.05PL (mg/dL)

228 ± 16.0

211.2 ± 16.6

NS

NEFA (μEq/L)

1015.5 ± 91.0

889.8 ± 114.0

NS

LDL-C (mg/dL)

6 ± 0.9

6.3 ± 1.1NS

HDL-C (mg/dL)

65.7 ± 5.2

60.9 ± 7.2

NSGLU (mg/dL)

183.3 ± 25.6

183 ± 12.9

NS

Fig 5. Time taken by mice to enter the black box.

Black bar represents control group mice and gray bar represents olive
oil group mice. Scores are presented as the mean ± standard error.

Scores are presented as the mean ± standard error ; NS = nonsignificant.

Grade score and passive avoidance test in olive oil-fed SAMP8 mice
Grade scores were recorded in order to investigate the effect ofolive oil on aging. Mice from both the control (soy oil) and olive oilgroups were graded a score of 2 for reactivity and passivity. This
grade for reactivity represents slow movements when mice leave
the cage, and a grade of 2 for passivity suggests that mice do not
try to get away when their neck is held. Glossiness, coarseness,hair loss, and catarrhal change in periophthalmic lesions were
not significantly different between the two groups (Fig. 1, 4).

Fig 4.

Grading scores of the control group and olive oil group at endof the feeding period.
Black bar represents control group mice and gray bar represents olive
oil group mice. Scores are presented as the mean ± standard error.

The passive avoidance test was performed in both feedinggroups at the 8th week since initiation of the experiment. Micefrom the control or olive oil group spent 15 seconds entering thedark box from the bright box before an electric shock on first day(data not shown). On the second day, the time taken to enter
the dark box increased to 56 and 37 seconds for the control andolive oil-fed mice, respectively (Fig. 5). Although in both cases,
the time taken to enter the dark box was extended, there was no
significant difference between the groups.

DISCUSSIONS
To investigate the difference of aging between SAMR1 and
SAMP8 mice, the both mice were fed on the food including 7%
soy oil during 24 weeks. In general, the primary identifiable
causes of death in these SAM mice strains include contracted
kidney, abscess formation, pneumonia and lymphoid cell neoplasms. SAMP8 mice most likely died of lymphoid cell neoplasms
and contracted kidney (26). Compared with SAMR1 mice, kidney weight was obviously decreased in SAMP8 mice (Table 2).
Furthermore, the blood test for AST and ALT are usually used
as reasonably sensitive indicators of liver damage. The elevated
AST and ALT level in SAMP8 mice in the blood sample may indicate liver damage or injury (Table 3). Compared with SAMR1
mice, T-CHO and HDL-C level significantly decreased in SAMP8
mice (Table 3). Hepatic dysfunction by aging in SAMP8 mice
might also lead to lower blood cholesterol levels than in SAMR1
mice.
We next recorded the grading score of SAMR1 and SAMP8
mice to evaluate their aging (Fig. 2). SAMP8 mice was walking
slowly and do not get away as compared with SAMR1 mice. The
hair of SAMR8 mice was neither smooth nor straight, and became to be severely dried. The passive avoidance test was examined after 8 weeks from starting up Western diet including 7%
soy oil. On the second day after given electric shock, SAMR1 and
SAMP8 mice spent 133 and 56 seconds respectively on entering
to dark box (Fig. 3). Since SAMR1 mice hesitated to enter andchecked the entrance of dark box many times, these mice may
memorize the electric shock of the first day. Judging from theresult that SAMP8 mice entered to dark box early with checking
few times, SAMP8 mice were likely to have a poor memory forthe electric shock of the first day. These results suggested that
SAMP8 mice might be identified as aging mice.
To investigate the effect of olive oil on aging, SAMP8 mice
were fed a diet consisting of either 1% olive oil and 6% soy oil(control) or 7% soy oil only, during the 24 weeks. There were no
significant differences in body weight and organ weight between
control and olive oil group (Table 4). Analysis of blood samples
revealed that the level of TG was significantly reduced in theolive oil group (Table 5). Umezawa et al. reported that T-CHO
and TG level were higher in SAMP8 mice fed on olive oil (rich inthe monounsaturated oleic acid) as compared with those fed safflower oil (rich in the omega-6 polyunsaturated linoleic acid) or
Fish oil (rich in long chain monounsaturated fatty acid) (27). On
the contrary, other research showed that feeding on olive oil, consisting mainly of oleic acid, an omega-9 monounsaturated fatty
acids (MUFA) (28, 29), decreased the levels of T-CHO and TG

The Journal of Medical Investigation Vol. 66 August 2019
in Wistar rats (30). Blood fasting and feeding triglyceride levels
decreased in C57BL/6J mice with olive oil-added fat diets in comparison to the high-carbohydrate diet (31). Omega-9 MUFA is anatural agonist of the peroxisome proliferator activated receptor(PPAR) (32). The three PPAR isotypes are PPAR alpha, PPAR
gamma and PPAR delta/beta and these regulate metabolism(33), inﬂammation (34), and infection (35), as described previously (36). Thus, olive oil might decrease TG levels by activating
the PPARs in SAMP8 mice. Although olive oil tended to decrease
T-CHO levels, this difference was not significant. Since mice
were fed 1% olive oil in this study, the effect of olive oil on lipid
metabolism at a high dosage needs to be examined.
Both the control and olive oil treated mice were given a gradescore of 2 for reactivity and passivity (Fig. 4). Grades of glossiness, coarseness, hair loss, and catarrhal change in the periophthalmic lesions occurred at the same degree in two groups. The
passive avoidance in SAMP8 mice fed on olive oil for 8 weeks
indicated that olive oil group spent 37 seconds entering to dark
box with checking the entrance few times on the second day (Fig.
5). This mean that olive oil may not improve forgot a poor memory in SAMP8 mice. As passive avoidance test measures a shortterm memory, long-term tests such as a radial arm maze test(37) or Morris water-maze test (38) are needed in further studies.
The use of Olive oil in diet has been associated with a reduction in mortality due to vascular diseases and cancer (1, 39, 40)
and mitigates inflammation during experimental sepsis (36).
Recently, research has shown that the life span of C. elegans was
extended by dietary MUFAs, but not PUFAs (16). On the other
hand, other studies revealed that dietary oleic acid did not extend wild-type lifespan (41, 42, 43), although they used different
oleic acid supplementation protocols. Our results do not indicate
an enhanced effect of aging and memory by olive oil, albeit at aconcentration of 1%. A range of concentrations needs to be investigated to identify noteworthy trends.
In addition, the type of olive oil and their constituents usedin the experiments may also play a role in the outcome. For
instance, phenols are not present in refined olive oil (ROO) but
virgin olive oil (VOO) and extra virgin olive oil (EVOO) do contain phenols at various concentrations (44, 45). EVOO is known
to be rich in phenols, specifically, the catecholic compounds hydroxytyrosol (3,4-dihydroxyphenyl-ethanol, HT) and oleuropein,which act as potent antioxidants, free radical scavengers, andmodulators of various oxygen-dependent enzymes. The levels ofoxidation markers were not affected by ROO consumption (44),while consumption of EVOO increased the plasma antioxidant
capacity in humans (45). HT also improved the antioxidant effectof plasma and prevented DNA damage in LPS stimulated mousemodel (46). Similarly, VOO containing phenols potentiates
effects related antioxidant stress, which leads to Parkinson’s
disease and aging. Lack of variation in aging score or memory
between control and olive groups may be as a result of the use of
VOO in the present study.
Although the grading score for coarseness of skin in control
and olive oil groups was not significantly different, the ingestionof olive oil tended to decrease the score, while also preventing
hair loss (Fig. 1, 4). The reduction in hair loss in mildly alopecicmonkeys, following administration of PUFA, might be due to adecrease in alopecia-related inflammation, associated with thevaried levels of the anti-inflammatory cytokine IL-10 and theproinflammatory cytokines TNF-α and IL-1β (47). Anti-inflammatory effects of olive oil with respect to protection against hairfall require further examination.

245

CONCLUSION
The organ weight, blood markers, movement, and memory
indicated severe progression of aging in SAMP8 mice. Althougholive oil decreased the levels of TG in blood, the addition of olive
oil (1%) to the food did not affect aging phenotypes and memory.
However, it is evident that olive oil has the tendency to decrease
T-CHO levels and improve hair condition in SAMP8 mice.

CONFLICT OF INTERESTSNone

ACKNOWLEDGEMENTS
We thank Jiro Takeo, Hiroko Miyahara (Central ResearchLaboratory, Nippon Suisan Kaisha) for providing olive oil and fortheir valuable advice.

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