Confidential

Keio University Global Research InstituteLongevity Initiative
April 14, 2018

Longevity Research in Keio University.

Hideyuki Okano
Dean, Keio University Graduate School of Medicine
Professor and Chair, Department of Physiology
Keio University School of Medicine
Global Future Council on the Future of Biotechnologies,
World Economic Forum
Copyright © 2010 Keio University All Rights Reserved.

Populations are getting older

2050
2045
2040
2035
2030
2025
2020
2015

1. Dementia
2. Supercentenarian Study
3. Neurodegenerative Disease Model Marmoset

SOCIAL COSTS FOR DEMENTIA IN JAPAN• 14.5 trillion Yens per Year (~3% of GDP)Including
Medical Expenses (1.9 trillion Yens)
Care Costs (6.4 trillion Yens)
Informal Care Costs (6.2 trillion Yens)
Dr. Michihiro Sado at Keio University School of Medicine

To prevent the increase of this ratio, preemptive approaches against dementia are indispensable.
Preemptive Medicine includes Early Detection of the diseases and Early Interventions.

PreemptiveApproaches forAlzheimer Disease
Development ofNew Therapies

New Diagnosis
MethodPathogenesis

AD Patient
Increase of b Amyloid(Tau Phosphorylation in cortical neurons)
Skin Biopsy
Reprogramming Factors

Fibroblasts

NeuronalDifferentiation

AD-iPS cell

AD-neurons

Ito, Okano, Suzuki: Annals of Neurol, 2012; Imaizumi et al.: Stem Cell Reports, 2015

Preemptive Medicine for Alzheimer Disease in Keio
Keio University
Shinanomachi Campus
2015-June
Keio University Hospita

Early Intervention

Memory Clinic,iPS cell Clinicl(Preventive Medicine Center)

Early Diagnosis(iPS cell Research Center)(Keio Center for Supercentenarian Medical Research)2. Supercentenarian Study
Toward a comprehensive understanding of healthy longevity

Yasumichi Arai, Hideyuki Okano, Nobuyoshi Hirose,
Center for Supercentenarian Medical Research
Keio University School of Medicine

Number of Centenarians in Japan from 1963 to 2015
70000

61,763 in 2015
60000

50000

40000

30000

20000
Supercentenarian
10000

33
In 2005

78146
In 2015

In 2010

0S38 S4０ S42 S44 S46 S48 S50 S52 S54 S56 S58 S60 S62 H1
male

H3

femaleH5H7

H9 H11 H13 H15 H17 H19 H21 H23 H25 H27

Number & ratio of SSC and SC in Japan in 2015
Increase from 2010

-0.8%
Total Population
127,000,000

Ratio to Total
population

129%

153%

187%

Centenarian
61,763Semi-SC
3,916

Super centenarian146

1 / 2,000

1 / 32,000

1 / 870,000Nation-wide recruitment of Japanese Semi-supercentenarian Study

Successful Brain Aging in Supercentenarians～Four Brain Autopsy Cases ～Case 1 (111 yo)

Case 2 (111 yo)

Case 3 (114 yo)

Case 4 (110 yo)

HT-, DM-

HT-, DM-

HT-, DM-

HT+, DM-

2/3
0.5

2/3
NA

3/3
03/3
NA

Brain weight (fresh)

460 (left hemisphere)

925

1,015

1,115

Atrophy
AD pathologicalchanges (NIA-Reagan)
AD pathologicalchanges (NIA-AA)

F, T

F, T

F, T

T

Intermediate

Intermediate

Unclassified

Intermediate

Intermediate

Intermediate

Low
PART possible

Intermediate

NoneNone

None

None

Vascular injury

Multiple cortical infartcs

None

None

None

Arteriolosclerosis

Mild to moderate

Mild to moderate

Mild to moderate

Mild to moderate

Past medical history
Apo ECDR

Lewy body pathology

Takao M, et al. Acta Neuropathologica CommunicationsNeuroscience of Disease 20164:97. modified

Possible Implications of Supercentenarian Study<Supercentenarian Study><Basic Aging Science>

Deep Phenotyping
Biomedical and Psychosocial
aspects

Demography

GenomeSequencing

Multi-omics

iPS
technology
Autopsy
Healthy tissue

Identification of“Biological pathways &Molecular markers”
Changes inbehavior

Health carepolicyCommunity
revitalization

Comprehensive Approach to healthy Aging Society

for healthy Longevity
・Validation in the general elderly
population
・Screening for high risk population
・Health Promotion Program・Active participation & contribution<Kawasaki-Tomomachi Wellbeing Project>

3. Neurodegenerative Disease Model Marmoset

Hideyuki Okano,Department of Physiology
Keio University School of Medicine

Abnormal Protein Assembly is a Common Mechanism for
Triggering Neurodegeneration including Alzheimer D, Parkinson D, ALS and etc.
Abnormal Protein
AssmbliesTauAmyloid βTDP-43FUSa-synuclein
etc.

Cell Death

Abnormal Protein Assembly

Normal Neurons

Severity

Loss ofNeuronal
Functions

Disruption
Decline Neuronal of Neuronal
Onset
Functions
Circuits
405060

Clinical
Symptoms
7080
Years Old

Pre-symptomatic Stage
Preemptive Approach: Early Therapeutic Interventions to prevent Disease Progression

Generation of Genetically Modified Marmoset

Lentiviral vector injection

わかばわかば翡翠翡翠Embryo transfer tosurrogate mother

ばん子
Transgenic marmoset

Lentivirus: Sasaki
et al., Nature, 2009
ばん子
Genome Editing: Sato et al. Cell Stem Cell, 2016
蛍蛍光光

Patented in USA, Europe, China,Korea, Singapore, Australia and Japan

Motor symptoms in patients with PD
Symptoms of Parkinson's Disease in humanextremely
early stage
・sleep disorder・olfactory disturbanceearly stage

advanced stage・tremor・akinesia
・muscle rigidity
・gait disturbance・dementia
・speech defect・mind symptoms

NormalParkinson’s

It is said that motor symptoms of PD appear when more than 80% of DA neurons
at Substantia Nigra are lost by the disease.

Progression of Parkinsonism in a-Synuclein Tg model marmoset
Symptoms of Parkinson's Disease in humanextremelyearly stage
・sleep disorder・olfactory disturbanceearly stage

advanced stage・tremor・akinesia
・muscle rigidity
・gait disturbance・dementia
・speech defect・mind symptoms

Future issues to be addressed using PD model transgenic marmoset• What are the neuronal circuits damaged at the each clinical stage?
• Any relationship between the Pathogenic protein accumulation andeach clinical symptom?
• Prediction of the Onset of each clinical symptom• Development of the drugs to slow-down the Disease Progression asa Preemptive ApproachKeio Tonomachi campus for Wellbeing Research
Development Plan 2020

Innovation Center ofNano Medicine(iCONM)

Haneda International AirportKanagawa
Life Innovation Center(Regenratvie medicine)

Tama River

J&J Tokyo Science Center

Central Institute forExperimental Animals(CIEA)

KeioTonomachi campus(planned 2017)

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