prolongation of life span of disease model mice by low...
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Prolongation of Life Span of Disease Model Mice by Low Dose Rate Irradiation
Kazuo Sakai
Low Dose Radiation Research CenterCentral Research Institute of Electric Power Industry
(Presently: National Institute of Radiological Sciences)
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Effects of Low Dose Rate Irradiation on Mice
• Suppression of Tumorigenesis– Radiation-Induced Thymic Lymphoma– Chemically-Induced Skin Tumor
• Suppression of Disease Development– Diabetes, Type I and Type II– Fatty Liver by CCl4
• Life Span Prolongation
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1. Type II Diabetes
Female BKS.Cg-+Leprdb/+Leprdb/Jcl (C57BL/KsJ-db/db)
Dose Rate: 0.70mGy/ hr(10 Weeks Old at the Beginning of the Irradiation)
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0 100 150500
20
40
60
80
100
Prolongation of Life Span of db/db Miceby Low Dose Rate Irradiation
0.70mGy/hr
Non IrradiatedSur
viva
l (%
)
Age (Weeks)
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Effects of Low Dose Rate Irradiation on Life Span of db Mice
15012090603000
20
40
60
80
100
Non-Irradiated0.35 mGy/hr Irradiated0.70 mGy/hr Irradiated1.2 mGy/hr Irradiated
Su
rviv
ial R
atio
(%
)
1501209060300Week of Age
89.3 ± 4.8 103.3 ± 4.2*Life Span (Weeks)
142
134
Irradiated from 10 weeks
- -
Sur
viva
l (%
)
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Appearance of db/db Mice at 90 Weeks of Age
Non-Irradiated
Irradiated
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Abnormal Glucose Metabolism etc.
Decreased Insulin Level Increased Glucose Level
Glucose Radicals
Tissue Damage through Glycation
Complications
Shorter Life Span
Impaired B Cell Function
Possible Mechanism for Life Span Prolongation in Diabetic Mice
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Abnormal Glucose Metabolism etc.
Decreased Insulin Level Increased Glucose Level
Glucose Radicals
Tissue Damage through Glycation
Complications
Shorter Life Span
Impaired B Cell Function
Possible Mechanism for Life Span Prolongation in Diabetic Mice
IncreasedAntioxidants
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Female MRL-lpr/lpr Mice
Lack in Apoptosis, Which Removes Self-Attacking Lymphocytes.
Y
2. Severe Autoimmune Diseases
Dose Rate: 0.35 or 1.2mGy/ hrDuration: 7wk to 12wk of Age
orLife Span Long
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abcde
0.35 mGy/hr
1.2 mGy/hr
Prolongation of life span in MRL-lpr/lpr mice with chronic low dose rate irradiation
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Effects of Low Dose Rate Irradiation on Immunological Parameters
0
0.5
1
1.5
2
2.5R
elat
ive
Imm
unol
ogic
al P
aram
eter
s
0 0.35 1.2
Dose Rate (mGy/hr)
CD8+ cells in spleen
(Measured after 7 wk irradiation)
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0
0.2
0.4
0.6
0.8
1
1.2
Rel
ativ
e Im
mun
olog
ical
Par
amet
ers
0 0.35 1.2
Dose Rate (mGy/hr)
(Measured after 7 wk irradiation)
Effects of Low Dose Rate Irradiation on Immunological Parameters
CD3+B220+
B220+CD40+
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3. Klotho: A Premature Aging Model Mouse
Established in An Attempt to make disease model mice by shot-gun strategy.
Short life.Show symptoms similar to premature aging syndromes.Responsible gene is involved in calcium metabolism.
For Examination of Low Dose Rate Effect,Female 4 wks oldDose Rates 0.35, 0.70 or 1.2 mGy/hr 137Cs Gamma-RaysLife Long Irradiation from 4th week of age
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Effects of Low Dose Rate Irradiation on Life Span of klotho mice
Start at28 days
8060402000
20
40
60
80
100
Time after Irradiation
Su
rviv
al R
atio
(%
)
Non-Irradiated0.35 mGy/hr Irradiated0.70 mGy/hr Irradiated1.2 mGy/hr Irradiated
(weeks)6420
(days)
12010080604020
Age (days)
8 10 12
Sur
viva
l (%
)
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Effects of very low dose rate gamma irradiationon life span in C57BL/6 mice (1)
Caratero et al., Gerontology 44, 272-276 (1998)
Irradiated with gamma rays from thorium nitrate placed under the floor of cages.
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Research Institute of Environmental Sciences(Rokkasho, Aomori)
continuous exposure to low dose rate radiation0 mGy/day0.05 mGy/day1.1 mGy/day21 mGy/day
Starts at50 days old
Stops at 450 days old
natural death& autopsy, pathology
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Survival curves of B6C3F1 mice
Age (days) Age (days)
Sur
viva
l (%
)
A : Male B : Female
Tanaka, S. et.al. Rad. Res. 160: 376 - 79. (2003)
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Effects of very low dose rate gamma irradiationon life span in C57BL/6 mice (2)
Courtade et al. Int. J. Radiat. Biol. 78, 845-855 (2002)
(10 mGy/yr)
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Summary of Effects of Very Low Dose Rate Irradiation on C57BL/6 Mice
Same as above2710
SPFLess Crowded
270
Same as above2414
Same as above247
Conventional More Crowded
200
Conditions for Animal Care
50 % Survival Time (months)
Dose Rate(cGy/yr)
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Summary of Effects of Low Dose Rate Irradiation on Life Span in Mice
NoSPFB6C3F1NoSPFC57BL/6
YesConventionalC57BL/6YesSPFklothoYesSPFlprYesSPFdb
Life Span Prolongation
Conditions for Animal Care
Strain
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Low Dose Rate Irradiation and Life Span
Maximum Life Span
Shortened Life Span
Untoward Conditions(Physical)
(Environmental)
Low Dose RateIrradiation
Enhancement of Bio-Protective Functions
Resistance againstUntoward Conditions
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Collaborators in CRIEPI
T. Iwasaki
Y. Hoshi T. Nomura
Y. Ina
H. Tanooka