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)

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

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)

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)

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 (%

)

Appearance of db/db Mice at 90 Weeks of Age

Non-Irradiated

Irradiated

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

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

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

abcde

0.35 mGy/hr

1.2 mGy/hr

Prolongation of life span in MRL-lpr/lpr mice with chronic low dose rate irradiation

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)

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+

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

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 (%

)

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.

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

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)

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)

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)

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

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

Collaborators in CRIEPI

T. Iwasaki

Y. Hoshi T. Nomura

Y. Ina

H. Tanooka