ISCO2023
OIST/Okinawa

March 1, 2023

Toward seamless approach to build up
fusion healthcare-medicare-solutions platformYasuyoshi Watanabe, MD, PhD
Team Leader, Laboratory for Pathophysiological & Health
Science/RIKEN Center for Biosystems Dynamics ResearchPresident, Japanese Society of Fatigue Science
President, Japan Recovery Association

1

ISCO2023

March 1, 2023

Main contributers:
RIKEN:Kei Mizuno, Kyosuke Watanabe, Satoshi Kume,
Kei Taneishi, Hisashi Doi, Yasuhiro Wada, Kayo Onoe,
Yosky Kataoka, Hiroshi Ohno, Toshimori Kitami,
Yoshihide Hayashizaki, Emi Yamano, Kyoko Ebisu
Osaka Metropolitan University:
Hirohiko Kuratsune, Kouzi Yamaguti, Sanae Fukuda,
Masaaki Tanaka, Akira Ishii, Yasuhito Nakatomi
MI Clinic:
Akira Kida, Yasuo Iwamoto, Mamoru Furuyashiki,
Ami IgesakaPrecision Healthcare Research Organization:
Chiaki Urata, and all staffs

2Extending healthy life expectancy through establishment of seamless social system fromacquisition of precise health indices, prediction pathway analyses, personalized diseasesource imaging diagnosis, to maximize the effects of solutions for individual healthy life
User-friendly Health Measure
１．Positioning Map for Integrated
Health Scores
２．Point of care
３．Street Medical City

Precise Medical Examination

AI

Fusion Imaging on Problemed Foci１．Fusion Imaging among PET, MRI, fMRI,
MEG, CT, Optical & Photoacoustic Imaging,
2. Multimodal & Multi-molecular Imaging

Open Innovation!!

1. Diseases & Their Predicting Biomarkers
2. Omics Analyses
3. Liquid Biopsy
4. Precise multi-stage functional analyses

Development of Solutions & Therapeutics
1. Prediction of & Prevention from Vulnerability
2. Promotion of Upgrading Health State
3. Delay of Onset, Anti-fatigue & Anti-stress
4. Solutions from Synthetic Biology, Biofoundry
5. Theranostics
6. Regeneratiive Medicine, Cell therapy

Seamless Approach with Precision Healthcare & Precision Medicine
toward Maximization of Personalized Health Solution (SPHM)
3

“Fatigue Science for Human Health”
Watanbe, Y., Evengård, B., Natelson, B., Jason, L.D.,
Kuratsune, H., eds., Springer, 2008.

The molecular/neural mechanisms and the ways toovercome & prevent from “fatigue” are great hints
for health promotion, prevention from onset of
diseases, anti-ageing, and vitality/regeneration!!!

4

Symptomatology-driven

Fatigue & Ahead Sick Science
Toward Pre-emptive Medicine
疲労と未病の科学：有効な先制医療へ

5

Health Science and Pre-emptive Medicine

Biomarkers[Conc. up in plasma]

Biomarkers[Low conc. in plasma,High conc. in the
focal tissue]

Biomarkers[Normal range inplasma]Depression

Cancer

DiseaseAhead Sick (ME-BYO)
Symptoms:
pain, fatigue, etc.

HealthyMore Healthy

Defense system (Recovery system)

Pre-emptive Medicine

Health Science

Life-style Dementia
Seamless approach
between H and M!!! Related Disease6

Reciprocity
Multiplicationof Stress

Low-quality Sleep/Sleep DisturbanceBig Social& Economic
Problem!!

Metabolic Syndrome/
Life-style Related Diseases

Fatigue/
Chronic Fatigue

Motivational
Loss
Depression
7

Projects for Fatigue and Chronic Fatigue Syndrome• Investigational group under MHW (1991-1999, T. Kitani)
Chronic Fatigue Syndrome (CFS), Diagnostic criteria• Special Coordination Funds from MEXT (1999-2005, Y. Watanabe)
26 Universities & Institutes, Measures of Fatigue, Statistics, Animal models,
Mechanisms of fatigue & chronic fatigue• 21st Century COE Program “Base to Overcome Fatigue” from MEXT (2004-2009, Y.
Watanabe)
Osaka City Univ., Fatigue & CFS, Anti-fatigue projects• Learning motivation and children’s chronic fatigue from JST, RISTEX (2005-2009, Y.
Watanabe)
Motivational loss and fatigue, Childhood CFS• Discordant twin ME/CFS PET study on serotonergic system and neuroinflammation
by Special Grant from Tekeda Science Foundation (2010-2019, Y. Watanabe)• Novel Biomarkers and Therapeutics for ME/CFS patients under AMED (2016-2019,
Y. Watanabe)• AMED GAPFREE2 project, Biomarkers and Therapeutics for ME/CFS (2016-2021, Y.
Watanabe)8Statistics in Japan（2,742 answers）- 2004 Ministry of Education, Culture, Sports, Science & Technology -Are you tired?

No (44%)

Yes (56%)< 6 months

Period?

(17%)> 6 months(39%)

Quit job or school (1.2%)

Disturbance indaily life
Cause of chronic
fatigue

None (55%)

Yes (37%)

Often disturbed (7.4%)
DiseaseUnknown (39%)
Overwork (42%)
(19%)
9

9

Three Major Bio-alarm Systems:
Sensing abnormality, alarming andcontrolling defense system

Pain

Fever

Fatigue

Causative
mechanisms

Bradykinin
Prostaglandins
Nociceptin
Neurokinin

Endotoxin
Interleukins
Prostaglandin

Oxygen radicals
Cytokines
Low amino acids
Low repair energy

Resetsubstance(s)Serotonin
Nocistatina-MSH

Anti-oxidants
Repair energy
10Subjective Fatigue Scale
1. Visual Analog Scale (VAS)
2. Face Scale
3. Chalder’s Fatigue Score
4. Questionnaire on Fatigue
5. Questionnaire PC version
11

Objective Fatigue Scale
Objective quantitative scales are essential for:1. Elucidation of molecular/neuralmechanisms of fatigue, chronic fatigue(CF), and CFS
2. Development of therapeutics andpreventive medicine for CF and CFS
3. Development of daily food and products
for recovery and prevention from fatigue
12

Development of Biomarkers for Quantification of Fatigue
・Cortical function: Attention, Concentration, & WM
Advanced Trail Making Test (ATMT)
Dual Task Test (DTT), n-back task, kana-picking up
・Evaluation by behavioral measures
Actigraph (Gyroscope-type)
Motion capture
・Autonomic nerve function
Acceleration plethysmography (APG), ECG
・Biochemical markers in the plasma and saliva
Immune & Endocrine biomarkers, Amino acids, Iron,
Heme, Oxidative stress, Viruses, Auto-antibodies, andNIR- factors
13Development of the System for Fatigue Measurement
FMCC-VSM301(then VSM500)
Fatigue/Stress detection system

Hitachi Systems, Ltd./muRata/Fatigue
Science Lab. Inc./FMCC/our group14

Guideline of Evaluation for Chronic Fatigue:
Ministry of Health, Labor, and Welfare of Japanese
Government (Proposal, 2009-2015) through our work
1. Autonomic nerve function;
sympathetic/parasympathetic
2. Activity and Sleep problems
3. Oxidative stress
4. Metabolome, Proteome, & Transcriptome
5. Biological evaluation (virus, etc.)
6. Others (Auto-antibody, Serum amino acids,
Endocrine & immunological abnormality,
Near-infrared analysis, etc.)
15Extension of Fatigue Research to Clinical Centers
Chronic Fatigue Syndrome
Chronic Fatigue
with Diseases

Stressand
AcuteFatigue

Chronic
Fatigue

Renal Failure/Art. Dialysis
Lifestyle related diseases
Cancer-related
Hepatic Diseases
Allergic Disorders
Neuropsychiatric Disorders
Sergical Operation
Side effects of drugs
16Complex Cause of Fatigue
PsycologicalStressEnvironmental
StressLabor &
Excersize

Fatigue

Infection

NOT SOEASY FORRESEARCH!!

Sleep & Rhythm
Disturbance

Chronic
WastingIllness17

Core mechanisms of fatigue & chronic fatigue
Activities

Chronic
Fatigue

Sensed by
Immune Cells

Unrecoverable
Cellular Disorders

3.Local inflammation/
Immunity

Mental Fatigue
Neural &Glia

Chronic Cytokines

Motivational
Loss

Chronic
Pain

SlightFever

Insufficient
ATP Production

2.Less Repair Energy

Energy Demand

Exercise Fatigue
Muscles
Neurons

Further ATP Production

Reactive
Oxygen Species

Overwork

Oxidized & Injured Parts

Generation of ROS
By-productInsufficient Reducing Power

Elimination by
Reducing Power

Oxidation of Major Proteins
and Membrane Phospholipids

1.Oxidation/Oxygenation

Planning, simulation,& Exsecusion

Immunological Fatigue
Immunecells
Sometimes

Large Amountof ATP

Repair Factory Replaced by(Lysosome) New Products

Sufficient
ATP Production
Sensed by
Immune Cells

Oxidized Parts
OutputDirectly!!

Usual
RecoveryRecovery to the
Healthy Cells/Tissues

Recovery Orderby the Brain

Transmitted to the Brain by Cytokine Signals
YW/KM

18

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome(ME/CFS) 筋痛性脳脊髄炎/慢性疲労症候群

Diagnostic Criteria [CDC(USA), MHLW(JPN)]
Major criteria
1. Intolerable fatigue longer than 6 months
2. Exclusion of any other precedent diseases
Minor criteria
1. Symptomatic criteria 6/11 items (self-report)
2. Physical findings by medical doctors 2/3 items
Prevalence rate
0.26% in JAPAN
0.2-0.5% in the world
19

Biomarkers of ME/CFS
1. Specific genetic background: Not yet found despite many challenges
2. Specific features of low energy production!!
Fukuda, S. et al. Ubiquinol-10 supplementation improves autonomic nervous function
and cognitive function in chronic fatigue syndrome. Biofactors 42, 431-440 (2016)
Yamano, E. et al. Index markers of chronic fatigue syndrome with dysfunction of TCA
and urea cycles. Sci. Rep. 6, 34990 (2016)

3. Specific features of immune activation & dysfunction!!
Klimas, N. G., Broderick, G. & Fletcher, M. A. Biomarkers for chronic fatigue. Brain. Behav.
Immun. 26, 1202-1210 (2012)
Montoya, J. G. et al. Cytokine signature associated with disease severity in chronic fatigue

syndrome patients. Proc. Natl. Acad. Sci. U. S. A. 114, E7150-E7158 (2017)

4. Specific features of autonomic nerve dysfunction, HPA axis dysfunction,
increased oxidative stress and less anti-oxidant potential!!
20

Scientific Reports, 10: 19933, November 16, 2020

Deep Phenotyping of Myalgic Encephalomyelitis/
Chronic Fatigue Syndrome in Japanese Population
Toshimori Kitami1†*, Sanae Fukuda2-4†, Tamotsu Kato1†, Kouzi Yamaguti2,
Yasuhito Nakatomi2,5, Emi Yamano2,4,6, Yosky Kataoka2,4,6-7, Kei Mizuno2,4,6,
Yuuri Tsuboi8,Yasushi Kogo9, Harukazu Suzuki1, Masayoshi Itoh9,
Masaki Suimye Morioka1, Hideya Kawaji1,9, Haruhiko Koseki1, Jun Kikuchi8,10-11,
Yoshihide Hayashizaki9, Hiroshi Ohno1,11, Hirohiko Kuratsune2-6,
Yasuyoshi Watanabe2,4,6*
1RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
2Osaka City University Graduate School of Medicine, Osaka, Japan.
3Kansai University of Welfare Sciences, Osaka, Japan.
4RIKEN Center for Biosystems Dynamics Research, Hyogo, Japan.

5Nakatomi Fatigue Care Clinic, Osaka, Japan.
6RIKEN Compass to Healthy Life Research Complex Program, Hyogo, Japan.
7RIKEN Baton Zone Project, RIKEN-JEOL Collaboration Center, Hyogo, Japan.
8RIKEN Center for Sustainable Resource Sciences, Kanagawa, Japan.
9RIKEN Preventive Medicine and Diagnosis Innovation Program, Saitama, Japan.

10Graduate School of Bioagricultural Sciences, Nagoya University, Aichi, Japan.
11Graduate School of Medical and Life Sciences, Yokohama City University,

Kanagawa, Japan.
21

22

Non-molecular measures of fatigue

Sleep and activity pattern within an
average 24 hour period were measured
using actigraphy. Cognitive performance
was assessed by administration of simple
mathematical problems.
P values were determined by two-tailed Mann-Whitney U-test with Benjamini-Hochberg
correction, adjusted for false discovery rate (FDR) of less than 0.20. *P < 0.05, **P < 0.01,***P < 0.001, ****P < 0.0001, or not significant (n.s.).

23

Summary results of the molecular platform-1

24

Summary results of the molecular platform-2

25

Combinatorial analysis of molecular markers
Combination of top 26 molecular markers for distinguishing ME/CFS patients from healthy
controls (HC). (A) Partial least squares discriminant analysis (PLS-DA) of top 26 molecularmarkers. (B) Variable importance of projection (VIP) scores for distinguishing ME/CFS
patients from HC based on component 1.

ME/CFS patients (n=22) and HC (n=29) with complete molecular profiling across five platforms(clinical lab tests, metabolome, immunophenotype, transcriptome, microbiome) were used.

26

Correlation between measured phenotypes and molecular markers of ME/CFS(A) Spearman rank correlation between three measures related to fatigue (total
sleep awakening, total sleep time, time to solve math problem) and molecularmarkers. Spearman rank correlation with P < 0.05 are indicated with red (positive
correlation) or blue line (negative correlation).

27

Novel Biomarkers of ME/CFS
1.

Eguchi, A., Fukuda, S. et al. Identification of actin network proteins, talin-1
and filamin-A, in circulating extracellular vesicles as blood biomarkers forhuman myalgic encephalomyelitis/chronic fatigue syndrome. Brain. Behav.
Immun. 84, 106-114 (2020).

Specific features of microbiome, exosome size, exosomal proteins,
exosomal microRNAs!!

28

Statistically significant increase of EV proteins in ME/CFS
Up- and down-regulated
EV proteins (p<0.05)

1st Cohort
66 upregulated
proteins

2nd Cohort

Top12 EV protein abundance in 69 ME/CS compared to 35 HC
Identified proteinsaverage normalized total spectra

Talin-1
Filamin-A
Actin

37
26
18

Alpha-actinin-1
14-3-3 protein zeta/delta
Vinculin
Myosin-9
Gelsolin
Integrin alpha-IIb
14-3-3 protein gamma
14-3-3 protein theta
14-3-3 protein beta/alpha

14
10
9
9
8
8
6
6
6

Top12 EV protein abundance in 32 ME/CS
compared to 8 depression and 6 ICF
Identified proteins

111 upregulated Talin-1
Filamin-A
proteins

average normalized total spectra

Actin

103
87
59

Vinculin
Myosin-9Integrin alpha-IIb
14-3-3 protein zeta/deltaFermitin family homolog 3
Tubulin beta-1 chain
Gelsolin
Alpha-actinin-1
Profilin-1

55
44
42
21
20
13
12
12
11

Eguchi et al. Brain Behavior and Immunity 202029

Pleusible mechanistic structure from ME/CFS studies ona variety of biomarkers integrated with PET/MRI/fMRI/MEG
Overwork
MultipleStressInfection
Pollution+
Genetic
background

Metabolic dysfunction
Malnutrition/Less repair energy
Oxidation/Low anti-oxidative
activity
Endocrinological disorders
Dysfunction of HPA axis

Immune insults/Allergy
Cytokines/Lymphokines
Local/chronic inflammation

Neurochemical changes
Neuroinflammation
Serotonergic deterioration
Glutamatergic deterioration

Morphologicalchangesin spines/synapses/
networks/structures[Gating mechanisms]

Prolonged fatigue/malaise
Intolerable/chronic pain
Slight fever
Autonomic dysfunction
Unrefreshing sleep
Sleep disorder
Rhythm disorder
Cognitive impairment
Motivational loss
Depression
30

Key molecules
for bio-function
Biomarkers
Drug candidates

Imagingtechnologies
Disease models
Perturbations

31

RIKEN Multi-Modal Molecular Imaging
Why is PET central?
For application to human and functioning animals
Ultra-high sensitivity, Broad spectrum of target molecules,
Highly quantitative, High spatial resolution (close to 1 mm)

PET
GREI

SPECT

OpticalImaging

MRI

UltraPhotoacoustic soundImaging

To extend PET molecular probes to other modalities
To develop multi-modal (fusion) molecular imaging
To develop simultaneous multi-molecular imaging tool32

Why is PET central for application
PET to human and functioning animals?
1. Ultra-high sensitivity (thus microdose)
ultra-high specific radioactivity (short half-life):
i.e., injection mass = 0.1-10 nmol (30-3,000 ng, if MW=300)

1’. Little perturbation to intrinsic system
2. Broad spectrum of target molecules
A variety of positron emitters for the radiolabel
11C, 18F, 13N, 15O; “Physiological!”, 64Cu, 68Ga, 76Br, 89Zr, 124I
principally, any organic compounds can be introduced

3. Highly quantitative even in depth of the bodycoincidence detection of annihilation photons
accurate attenuation correction

33

National Grants and RIKEN Biomedical Imaging Researches
2005

2015 20162010

MEXT/Molecular Imaging
Research Program

MEXT/Japan Advanced
Molecular Imaging Program

2022

AMED/Japan Cancer Research Project (Molecular
Imaging Area)

2013

AMED/
P-Promote2023

AMED/Research Center Network for Realization of Regenerative Medicine

2014

2024

AMED/Brain Mapping by Integrated Neurotechnologies for Disease Studies

2005

2008

2015

2019

AMED/Basic Science and Platform Technology Programfor Innovative Biological Medicine

RIKEN Molecular
Imaging Research
Program

2016

2023

AMED/Advanced
program

2019

AMED/Precise biomarkers and diagnosis of ME/CFS

1993

1998

JST ICORP-Swedish STA
Subfemtomole
Biorecognition Project

2016

2021

AMED/GAPFREE2/Development of therapeutics for ME/CFS

2016

2022
AMED/Development of therapeutics for HBV

2020

2015

JST/Compass to Healthy Life Research Complex Program2016
All programs have been done by
Yasuyoshi Watanabe’s research groups!!
A total of the budgets > 14 billion JPY (120 mUSD)

2022
JSPS/A3 Foresight Program on Molecular Imaging

2018

2026

AMED/CiCLE/Theranostics Targetted Alpha Therapy

Governmental organizations: MEXT, Ministry of Education, Culture, Sports, Science and Technology Japan;
AMED, Japan Agency for Medical Research and Development; JST, Japan Science & Technology Agency

34

Fundamental Research Development of novel technologies

Development of antibodybased PET probes

Small animal neuroimaging study
with PET and MRI

4

hPD-1
(-)

hPD-1 HER2(+)(-)

for multi-modal imaging

2

HER2
(+)

3

0

1

SUV

Imaging using head holder underconsciousness (w/o anesthesia)

Trastuzumab

Development of imaging
probe for HBV diagnosis
HBV model

Control

Liver[11C]CBT-078

Yasuyoshi Watanabe, M.D., Ph.D.
Pathophysiological science
using neuroimaging
ADHD Before

After

Imaging of human emotion
Male sex steroids

CC

MonkeyL

Ctl[11C]Cetrozole
Human[11C]TMD-322

Estradiol

Female sex steroids[11C]Cetrozole

200

CLuptake
Liver #3
Control

10

5+Rifampicin0

Bile (selected points) #6
CL
int,bile

Control+Rifampicin
0
0.0
0.5
1.0
AUCliver (0-t) (%dose*min/ml)

STR

R

RAD

CCFS

Novel tumor probe for L-type
Amino Acid Transporter

THA
PUT

Estrone

300

0
10
20
AUC(0-t)/Cb(t) (min)AMY

Testosterone

15R-[11C]TIC-Me

100

3-month methylphenidate treatment

Aromatase

PET study platform for PK/PD

Pathophysiology& Health Science

Novel probetargeting
HBV-capsid

Androstenedione

Multi-click platform molecule

X(t) (%dose)

Nivolumab

64Cu-DOTA-IGBP-

X(t)/Cb(t) (ml/kg)

64Cu-DOTA-

Therapy+
Delivery+Imaging,
etc…

Clinical Research

THAFirst-in-human study of [18F]AA-7

35

International Collaboration

Asia 3: Japan,
China, & Korea

KI, Uppsala U., SciLifeLab, Sweden
Tubingen Univ.

UCL

Singapore, RIKEN-NTU-KI

36

4D Super Multi-modal Imaging Project-1
by integrated approaches of PET/MRI/MEG
Horizontal

PET

Molecular
Dynamics
MRI

Morphology

fMRI, MEG,
EEG

NeuroFunction37

Brain region(s) and neural pathway responsible
for fatigue sensation and chronic fatigue
1. PET/fMRI/MEG studies
in normal human volunteers
in patients with chronic fatigue
2. microPET, IEG expression studies
in primate fatigue models
in different animal models
38Outcome from
Magnetoencephalogram(MEG) studies
39

39

Mechanisms to cause chronic fatigue(Hypothesis)
Overactivation

Fatigue

Overwork
StressChronic fatigue

Overprotection
Conditioning

Fatiguesensation

The posterior cingulate cortex
The insular cortex

The posterior cingulate cortex
The insular cortex

Protection40Outcome from fMRI andmorphometry studies

41

New concept of fatigability in ME/CFS patients(Tanaka et al., BMC Neurology, 2006)

Functional MRI study during visual task:
revealed vulnerability of task-unrelated brain regions.

Self-defense mechanism!!
2.0
HealthyResponse

1.5

1.0
0.5
0

Left temporal
auditory cortex

ME/CFS patients-0.5
0

The activity decreased during visual task

50

100
150
Trial number

200
42

MRI Morphometry in patients with ME/CFS
Especially that in right prefrontal
cortex focus well correlates withthe extent of their functional loss
t-valuet-value
0.45

Rt PFC volume (mL)

Volume reductionin prefrontal cortices

0.4
0.35
0.3
0.25
0.2
0.15
0

2

4

6

8

10

Performance status

43
Okada, T. et al., BMC Neurol., 200443

“Cortical Plasticity” Brain, 2008
Increase in prefrontal cortical volume following cognitive
behavioural therapy in patients with ME/CFS
Floris P. de Lange,1 Anda Koers,1 Joke S. Kalkman,2 Gijs Bleijenberg,2Peter Hagoort,1,3 Jos W. M. van de Meer4 and IvanToni1,3
1F.C. Donders Centre for Cognitive Neuroimaging,
Radboud University Nijmegen,
2Expert Center Chronic Fatigue, Radboud
University Nijmegen Medical Center,
3Nijmegen Institute for Cognition and Information,
Radboud University Nijmegen and
4Department of General Internal Medicine,Radboud University Nijmegen Medical Center,
Netherlands

4444Outcome from Positron
Emission Tomography(PET) studies
45

45

Standardized VAS score

Brain region associated with fatigue sensation

Orbitofrontal cortex(BA 10/11)

100
80
60
40
20
0

1st 2nd 3rd 4th 5th 6th 7th 8th 9th 10th

Trail number of the PET scan (10 min)rCBF ( ml/100g/min)

20

R = 0.496***

10
0
-10
-20

Tajima, S. et al.

050Standardized VAS score

100

46

PET study in patients with ME/CFS

Kuratsune, H. et al., NeuroImage, 2002 47

47

Serotonergic system
1. Indication of endocrine abnormality induced by
dysfunction of 5-HT system in ME/CFS(Bakheit et al., 1992; Cleare et al., 1995 )2. 5-HT transporter gene polymorphism in ME/CFS patients(Narita M. et al., 2003)
3. Dysfunction in 5-HT system in the animal models(Katafuchi T. et al., 2004)
4. One third of the ME/CFS patients responded to SSRI
(Kuratsune H. et al., in Japan)---> PET study with 5-HT transporter ligand
48

Reduced binding potential of 5-HTT in ME/CFS

Binding potential (BP) of the rostral
subdivision of anterior cingulate cortex(Brodmann’s area 24/32) was significantly
reduced (corrected, p=0.008, Z=4.95) in CFS
patients.
Yamamoto, S. et al., NeuroReport, 200449

Correlation between BP of 5-HTT and pain score in
ME/CFS patients

BP in the dorsal subdivision of anterior
cingulate cortex (Brodmann’s area 24) was
negatively correlated (uncorrected,
p<0.00001, Z=4.71) with the pain score.
50

Summary of PET studies with ME/CFS patients:
Sectors in the Anterior Cingulate
Pain center
Negative correlation between
BP value of 5-HTT and pain score

Attention center
Decreased acetyl-L-carnitine
uptakeDecrease in BP of 5-HTT

Fatigue center
rCBF decrease51

Higher uptake of L-[11C]DOPA in the amygdala of ME/CFS patients

8 ME/CFS patients49.3 ± 4.5 years old
8 healthy controls
49.5 ± 4.2 years old
uncorrected
P = 0.001
52

Hypothesis: Neural and molecularmechanisms leading to chronic fatigue
Infections
virus (including reactivation), bacteria,
mycoplasma, chlamydia, etc.

BDV, unknown factors
Life history

Psycho-social
StressGenetic backgroundC N S
Auto-antibodies, Low NK activity

Immune system

H P A axis

abnormal production of cytokines

HPA dysfunction

TNF ?
IL-2 ?
IL-6 ?
IL-10?

DHEA-SIFN

TGF-b

2-5 AS ↑Glutamine synthasein astrocytes

acetylcarnitine transferase

Acetylcarnitine dysbolism

1. serum acetylcarnitine
2. acetylcarnitine uptake in the brain

Abnormal RNase L

5-HT transporter◆Increase (acute)◆Decrease (chronic)(in the brain)

several cortices, anterior cingulate,basal ganglia, and brain stem
• Glutamate, GABA, Asparate in anterior cingulate, prefrontal cortex• Serotonergic, Dopaminergic neuron, Muscarinic acetylcholine neuron

Brain dysfunction

Prolonged fatigue, Short-term memory
problems, Autonomic imbalance etc.

Peripheral abnormalities(circulation, respiration, muscles, GI tract, temperature, etc.)

53

PET study on Neuroinflammationin ME/CFS patients
Elevation of cytokine levels in theplasma of the ME/CFS patients:
LTa, IL-6, IL-1a, IL-1b, IL-2, IL-4
54

11C-PK11195

binds to the translocator protein (PBR),
the index of Activated Microglia

11C-PK11195

Scarf, et al., J. Med. Chem., 2009.

Venneti, et al., Prog. Neurobiol., 2006.

55

Correlation: Neuroinflammation and deterioration
L

R

L

R

L

15

6

10

4

5

y=-2

y=-18

0

16

16

4

30

12

8

r = 0.88
p= 0.0017

CES-D score

r = 0.94
p= 0.0002

0

Hippocampus

Thalamuspain score

cognitive impairment score

Amygdala

8

8
6
4
2

2

y=-18

0

12

R

25

20

15

r = 0.91
p= 0.0008

10

4
5

0

0

0
0

0.1

0.2

BP of [11C](R)-PK11195

0

0.15

0.3

BP of [11C](R)-PK11195

0

0.1

0.2

BP of [11C](R)-PK11195

56

Latest PET study
Serotonergic dysfunction[11C]DASBCorrelation?

Neuroinflammation[11C]PK11195

ME/CFS vs. HVquestionnaire: Chalder, VAS, CES-D, BDI, STAI, FP
autonomic function: APG, active tracer
sleep quality: actigraph, EEG
blood sample: proinflammatory cytokines
oxidative stressmetabolome, transcriptome, chemokine
SNPsbrain MRI

57

Serotonin Transporter: 11C-DASB BPnd

Correlation between Neuroinflammation and Serotonin dysfunction
Amygdala
2.5

Striatumr = -0.69
p < 0.05

2.0

2.5

1.5

1.5

1.0

1.0

0.5

0.5

0.0

r = -0.71
p < 0.05

2.0

0.0
0.00

0.02

0.04

0.06

0.00

Thalamus
2.0

0.02

0.03

0.04

0.05

Pons

r = -0.77
p < 0.05

1.5

0.01

2.0

1.0

1.0

0.5

0.5

0.0

r = -0.78
p < 0.05

1.5

0.0
0.00

0.05

0.10

0.15

0.00

0.05

0.10

0.15

Neuroinflammation：11C-(R)-PK11195 BPnd

58

Neural correlates of fatigue: from acute to chronic phase: Brain regions with low
rCBF in chronic fatigue
New Learning
Planning
Motivation

6

8B

Evaluation of fatigue extent
in mental/physical fatigue

9
BA9/46d32

Elevation of activity
in fatigue sensation

23, 31

19

BA24, 33

46

Attention
Concentration MM-STS
10/11

Sensory Emotion
Motivation
Raphe N.

59

Summarized from MEG/PET/MRI studies

59

REVIEWS from our research group
1. Tanaka M & Watanabe Y: A new hypothesis of chronic fatigue
syndrome: co-conditioning theory. Med. Hypotheses, 75: 244-249,
2010.
2. Tanaka M & Watanabe Y: Supraspinal regulation of physicalfatigue. Neurosci. Biobehav. Rev., 36:727-734, 2012.
3. Tanaka M, Ishii A, Watanabe Y: Neural mechanisms underlying
chronic fatigue. Rev. Neurosci., 24:617-624, 2013.
4. Ishii A, Tanaka M, Watanabe Y: Neural mechanisms of mental
fatigue. Rev. Neurosci., 25:469-479, 2014.
5. Tanaka M et al.: Frontier studies on fatigue, autonomic nerve
dysfunction, and sleep-rhythm disorder. J. Physiol. Sci., 65:483-498,
2015.
6. Watanabe Y: PET/SPECT/MRI/fMRI Studies in the Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. In: PET and SPECTin Psychiatry (Dierckx RAJO, Otte A, de Vries EFJ, wan Waarde A,
Sommer IE, eds.), pp. Springer, 2021.
60

Pleusible mechanistic structure from ME/CFS studies ona variety of biomarkers integrated with PET/MRI/fMRI/MEG
Overwork
MultipleStressInfection
Pollution+
Genetic
background

Metabolic dysfunction
Malnutrition/Less repair energy
Oxidation/Low anti-oxidative
activity
Endocrinological disorders
Dysfunction of HPA axis

Immune insults/Allergy
Cytokines/Lymphokines
Local/chronic inflammation

Neurochemical changes
Neuroinflammation
Serotonergic deterioration
Glutamatergic deterioration

Morphologicalchangesin spines/synapses/
networks/structures[Gating mechanisms]

Prolonged fatigue/malaise
Intolerable/chronic pain
Slight fever
Autonomic dysfunction
Unrefreshing sleep
Sleep disorder
Rhythm disorder
Cognitive impairment
Motivational loss
Depression

61How to acquire much
more health and vitality[Regeneration]?
How to personalize??
62

For the development of solution,
we should have multi-angle indicesof individual health!!

Invention of “Personalized Healthstate Positioning Map”
63

Intervention:
Anti-fatigue Products
Toward Pre-emptive Medicine
抗疲労・癒しの科学：有効な先制医療へ

64Methods for Recovery from Fatigue: 1,300 JapaneseAnimal therapy Laugh(by MEXT Fatigue Res.
2001)

Aromatherapy

Efficiency (%)

Hot spring Massage
Gymnastics

Acupressure
Herbalmedicine

Better?

Music

Bathing

Drink

Good posture

GarlicLiquorGreen tea Coffee

Frequency (%)

65

Anti-fatigue food and medicine develop. project
Physiological Test
BT BP
Actigraph
Muscle stiffness
Advanced TMTGeneral biochemical
Endocrine
Vitamines, Ions
Cytokines

APG

Amino acids

Freq. Comp.

10.0

96 Healthy Volunteers
Cross-over design

1.5

4-hr session at 4 w intervals

7.5

Mental tasks

5.0

Physical tasks

変化率

Change rate

12.5

Biochemical Test

RelaxedTotal a.a.

1.0

0.5

2.5
0.0

PhysicalMentalPhysicalMentalRelaxedRelaxed

0.0

Soiken 66

Health evaluation parameters[indices for prediction and prevention]◆ Basic data：BW/BL（BMI）, comp. analysis, bone density, blood pressure, etc.
◆ Standardized questionnaires [daily life habit, stress, sleep, fatigue,
motivation, mood/depression, etc.]◆ Various VAS（Visual Analogue Scale）◆ Autonomic nerve function[sympathetic, parasympathetic; power and balance]◆ Vascular function, Vascular pattern, Blood flow, Cutaneous & Sub-cutaneousfunction◆ Muscle volume, Muscle power, Activity [Locomotor & Psychomotor]◆ Sleep [Time & Quality], Fatigue◆ Biological oxidation [dROMs, etc.] & Anti-oxidation activity {BAP, etc.]◆ Metabolome analysis -→ Core metabolite analysis [4-6 components]◆ Microbiome analysis◆ General biochemical and blood cells biomarkers◆ Inflammatory and immune biomarkers◆ Cognitive function & Communication function◆ Morphometry, tractography, and resting state function by MRI

67

Symbolic collaborations with many industries
Compass to Healthy Life Research Complex Program (launched at Dec. 2015)
traffic

devicemobile/wearable
ICT

Computer
Science

exerciseLife Science
Nano-Technology

Living/climate

medicine /pharmaceutical
dietary life
eating habits

Various types of Businesses / Industry X Fusion Research among Various Fields
Creation of Health Science Innovation and Brand-new Industries

Accumulation concerning
Health Information / Data
・Dietary Life・Physical/Health Condition
・Exercise Log
・Cure Log ... etc

Big Database and Accumulation of“State-of-the-Art” Data Analyses
with Post-Kei Super Computer Program

Maximization of the
Evidence-Based Health Prediction

Integrated understandingof the health condition
Realization of the prediction

playing an important role in full-life time68

Development and Establishment of Cross-pollination Field

Compass to Healthy Life
Research Complex Program

Clinical Study

Development of the Cross-pollination / the Advanced Science
Establishment of the First-in-human Facilities
Creation of the Seamless System for Health Science Innovation

Innovation

Living-human
Creation of a Social System toEstablish Medical Agencies /Healthcare Facilities functioning
Medical / Healthcare Professional

Realistic-humanDevelopment of Networking andFostering Frontiers for Creation of
Healthcare / Science Innovation
and/or Product / Service

Scalable-humanNano-human

Basic Research
In silico-human

Orchestration and Development of Advanced Institutes
and Cross-disciplinary Scientists concerning Ahead
Sick / Weakening of Human Health健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group69

The “Compass to Healthy Life” Research Complex program
Organization and Participating Institutions

Total 157

Core Institution : RIKEN (Kobe)
Prefectures and Ordinance-Designated Cities : Hyogo Prefecture & Kobe City
Participating Institutions :25 universities and research institutes, 125 companies and organizations, and 3 observer-participant institute(listed in alphabetical order, as of December 01, 2019)
Universities, etc.
Foundation for Biomedical Research and Innovation at Kobe., Gunma University, Hyogo College of Medicine, Kagawa University, Kansai University,
Kansai University of Welfare Sciences, Keio Research Institute at SFC, Kobe University, Kobe Yamate University, Konan University,
Kumamoto University, Kwansei Gakuin University, Kyoto University, Nara Institute of Science and Technology, Niigata University, Osaka City University,
Osaka Prefecture University, Osaka Shoin Woman's University, Osaka University, The University of Shiga Prefecture, Tokushima University,
Tokyo Institute of Technology, University of Hyogo, University of Tokyo, Yamaguchi University

25

Companies

126

ACOS Co.,LTD., Aflac Life Insurance Japan Ltd., Ancient Tree, Asahi Soft Drinks Co.,Ltd., ASICS Corporation, Atonarp Inc., Atto Co.,Ltd.,AXION RESARCH Inc., Bayer Yakuhin, Ltd., Biogrid Center Kansai, CMIC HOLDINGS Co.,Ltd., communitylink.npo, Consumers Co-Operative KOBE,
COPEL consulting Co.,Ltd, CORONA CORPORATION, COSMO HEALTH Co., Ltd., Cykinso, Inc., Dai Nippon Printing Co.,Ltd., Dai-ichi Life Holdings, Inc.,
Daikin Industries Ltd., Dentsu ScienceJam inc., EcoNaviSta Co.,Ltd., ExaWizards Inc., Ezaki Glico Co.,Ltd., Familiar Ltd., Fatigue Science Laboratory Inc.,
FUJICCO Co., Ltd., Fujitsu Network Solutions Ltd., Fuji Xerox Co., Ltd., GUNZE LIMITED, Hankyu Hanshin Holdings Inc., HA-PPY Co., Ltd,
Hitachi Systems, Ltd., Icomes Lab Co.,Ltd., INTAGE Healthcare Inc., ITOCHU Corporation, iuto, J. Morita MFG. Corp., Japan Blood Products Organization,
Japan Preventive Medicine Inc., KAN Research Institute Inc., Kaneka Corporation, Kaneka Techno Research Corporation,
KANSAI Association of Health and Welfare, Kenlab, Kitahama Global Management Corporation, KNC Laboratories Co.,Ltd., Kochi Health Check-ups Clinic,
Kokorotics Inc., KOKUYO Co.,Ltd., Kyocera Corporation, LaSuite Co.,Ltd., Lion Corporation, Loarant Corporatopn, Maruyanagi Foods Inc., Maxell, Ltd.,
Mediplus Research Institute, Inc., MediThink Inc., MEETSHOP INC., Merodian Co.,Ltd., MetLife Insurance K.K., Mikasa Shoji Co.,Ltd.,
Mitsubishi Tanabe Pharma Corporation, Mitsui Knowledge Industry Co.,Ltd., MIZUTA Seisakusho, Inc., MS&AD Insurance Group Holdings, Inc.,
Murata Manufacturing Co., Ltd., Nagase & Co., Ltd., NEC Corporation, Nihon Trim Co.,Ltd., Nippon Life Insurance Company, Nishikawa Co., Ltd.,
Noritz Corporation, OBAYASHI CORPORATION, Odakyu Electric Railway Co., Ltd., OKEIOS Co., Ltd., OM Kobe KK, OMRON HEALTHCARE Co., Ltd.,ORIX Life Insurance Corporation, Osaka Gas Co.,Ltd., Otsuka Holdings Co.,Ltd., Otsuka Pharmaceutical Co.,Ltd., PAL Corp., P&G Innovation,
Platinum data science Co.,Ltd, RE⁻Engineering Partners, Resona Bank, Ltd., Ricoh Company Ltd., Rohto Pharmaceutical Co.,Ltd., Sekisui House, Ltd.,
Sharp Corporation, Shionogi & Co.,Ltd, Shiseido Company, Limited, Soiken, Sompo Japan Nipponkoa Himawari Life Insurance, Inc., Splink, Inc.,
Sumita Optical Glass Co.,Ltd., Sumitomo Mitsui Banking Corporation, Suntory Wellness Ltd., Sysmex Corporation, Taisho Pharmaceutical Co., Ltd.,
Takeda Consumer Healthcare Co.,Ltd., TechnoPro, Inc., The Asahi Culture Center（Inc.）,
The Incorporated Association of Future Design for Healthy Life and Health-Care Living, The Kobe Chamber of Commerce and Industry,
The Minato Bank Ltd., The Osaka Chamber of Commerce and Industry, The Senshu Ikeda Bank, Ltd., The Tokio Marine Life Insurance Co., Ltd.,TOA Corporation, Tokio Marine ＆ Nichido Fire Insurance Co., Ltd., Total Brain Care Co.,Ltd., Toyobo Co.,Ltd., Triple W Japan Inc.,
Urban Innovation Institute, UT-Heart Inc., VENEX Corporation, Wellness Supply Co.,Ltd., Yamadenki Co.,Ltd., YAMATO LOGISTICS CO., LTD.,YCH Medical & Healthcare Community Co., Ltd., and three other companies

Other

3

Health Science Innovation Steering Committee（HSIsc）, Life Intelligence Consortium（LINC）,
Organization of Health Science Business Innovation（OHSbi）（※ Core Eleven Organization and Institutions）

健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group

70© 2018 Riken RCH H.Hori

Procedure for Maximization ofIndividual Health
Step 1．Acquisition of health position in the map
Step 2．Prediction of future health condition

Step 3．Recommendation of personal menu to promotea better health position
Step 4．Verification of such personal menu
Step 5．Realization of the social system
Realization of “Personal Precision Health”
71Why we selected the following core
items for health positioning map?
Resulting from over 30 years research on the mechanismsof fatigue/chronic fatigue and vulnerability of health, there
are “Common mechanisms” among fatigue/chronic fatigue,vulnerability of health, ageing, and disease onset.
1. Progression of biological oxidation and reduced antioxidative capacity“Rust”
2. Reduced repair energy
Delayed repair from “Rust”
３．Immune response to damaged (rusted) cells“Local inflammation”
４．Dysfunction of autonomic nervous system to detect andregulate these vulnerable changes
健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program72

Measurements (242 items)
１．Basics：Body Mass Index, Body components, Bone density, Blood pressure
２．Questionnaires (Personal history, Life habit, Sleep, Fatigue, Mood,
Motivation, Depression, Stress, & other claims）
３．Various VAS’s（Visual Analogue Scale）
４．Autonomic nerve function (Sympathetic /Parasympathetic, Power & Balance)
５．Vascular age, Vascular function, Blood flow, Skin & Sub-cutaneous function)
６．Mass of muscles, Muscle powers, Locomotive activities, Sleep time & quality)
７．Cognitive function
８．Respiratory gas & Skin gas analyses----------------------------------------------------------------------------９．Serum oxidation (dROMs), Anti-oxidative ability (BAP)
10．Energy metabolism (iso-citrate, ornithine, citrulline, etc.）
11. Plasma CoQ10 (reduced & oxidized forms), Vitamins, Minerals
12．Routine plasma biochemistry, Blood cell counts
13．Plasma inflammation biomarkers (hs-CRP, IL-1β, IL-6, etc.)
14. Morphometry, Anisotropy, & resting-state fMRI by MRI (BHQ)＊Items with blue letters are not routinely measured in routine HE.
73

Healthy Participants
健康計測会= 583;
参加人数
1,026（Female
Male = 443）
300

Number

250
200
150
100
50
0

FemaleMale

10-20s
109
63

30s
105
74

40s
134
124

50s
135
91

60s
100
86

70s
0
5
74

Protocol for Data Analyses
Machine Learning
Multi-dimensional
big-data analyses(MDS, scaling)correlation Normamatrix
lization

Normalized
data

HQ(Y)

All
data

HQ(X)
mathematization
Interpretation & characterizationof pre-disease states
Simulation for Intervention
健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group75

Individual health degree positioning map
First in the world!!!

file:///C:/Users/keimi/MotigueKM2018/Motigue/CMIS-CLST/150406_神戸市リサーチコンプレックス/00_RCH-Study/01_RCH-Res/RCH-ResKume/MDS_plot.html

健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program76

worseNovel Health-Degree-Positioning Map
High-risk group of
Mental Health Disorders
in young adults

Mental Health

7.6%

High-risk group of
Life-style related Diseasein middle and old age
13.7%

betterHigh-risk group of
Diabetesin old age

5.7%

betterPhysical Health

worse

77

Health Quotients for Health Prediction
by only 15 items of non-invasive measurements
x-axisHigh-precisionpredictionof health level

Predicted value

R2 = 0.8879

y-axisMeasured value

Achievement
Patent(2018-207611)

Predicted value

R2 = 0.8801

Non-invasive
measurements
Drug shop, Office,Caffe, Community
center, etc.

Measured value

78

Toward Maximization of Individual Health
Perturbation by
Various Solutions

Health Quotients

同意説明

皮膚機能（粘弾性）計測

皮膚機能（色）計測

ヒトデータベース

加齢による自律神経調節力の低下＝健康脆弱化指標
疲労による健康脆弱化の促進を示唆■未病指標開発（健康計測臨床試験）
血流測定
MRI
11項目のチャルダー疲労スコア（7点前後）から疲労あり／疲労なしに分類

採血

ヒトデータベース

年齢■未病指標開発（健康計測臨床試験）

80

加齢による自律神経調節力の低下＝健康脆弱化指標

副交感神経と交感神経

CVRR
10

9

8

6

6

CVRR
n = 43

2

20
0

0

疲労なし

40
4

0
40

加速度脈波

60

80

20
20

40

年齢

60

80

10
0

ln（HF+LF）

10

PG
R

年齢
lnHF

心電波・脈波解析
自律神経機能R

30

2
20

R-R interval(time)

0

0.4

a

a

0.8
1.2
Time (s)1.6

8

疲労なし 疲労あり

80

6

2.0

6

高相関

FFT

2
0
455

20

40

60

年齢

80

80

60

60

4

40

40

2

20

20

4

Measurement timePower spectrum

LF: 0.04 - 0.15 Hz, 交感神経活動の指標
HF: 0.15 - 0.40 Hz, 副交感神経活動の指標
LF/HF ratio

*

20

40

60

年齢

80

0

4

2

2

2

0

疲労なし

疲労あり

50
25
0

*

疲労なし 疲労あり

疲労あり

疲労なし 疲労あり

疲労あり

300

*

100
0

疲労なし 疲労あり

40
30
20
10
0
疲労なし 疲労あり

疲労なし

TG（中性脂肪）200

自覚症状検査・筋力検査
うつVAS
握力（右） [Kg]
*
100
50
*
80
60
40
20
0

*

0

疲労なし

5.8
5.6
5.4
5.2
5.0

75

0
疲労なし 疲労あり

6

疲労あり

眠気VAS

ln（HF+LF）
8

4

疲労なし 疲労あり

疲労VAS

8

*

6

4

血液検査（脂質・肝機能・生活習慣病関連物質）
γ-GTP
HbA1C/NGSP
ALT（GPT）
100
6.0
*
*
*

10

ECG
APG

60
50
40
30
20
10
0

lnHF
8

6

0

疲労なし 疲労あり

*

*

8

4

AST（GOT）
3

lnLF

*

6

40

lnLF

12

n = 269

60

疲労なし 疲労あり

疲労なし 疲労あり

握力（左） [Kg]
50
40
30
20
10
0

*

疲労なし 疲労あり

Novel methodologies

健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group79

Methods for Recovery from Fatigue: 1,300 JapaneseAnimal therapy Laugh(by MEXT Fatigue Res.
2001)

Aromatherapy

Efficiency (%)

Hot spring Massage
Gymnastics

Acupressure
Herbalmedicine

Better?

Music

Bathing

Drink

Good posture

GarlicLiquorGreen tea Coffee

Frequency (%)

80Anti-fatigue solutions with scientific evidence
Food/Nutrition/Supplement
効果あり (%)

More than 80 RCT

Imidazole dipeptide

ImDP + CoQ10→Clinical trials→Evidence

Reduced CoQ10
頻度 (%)

Fulsultiamine(Vitamin B1 der.)Lemon (Citrate)

Healing pictures

Carbonatedwater
Anti-fatigue recepe

Japanesque intermission

Wooden room

Healing music
Elecrolyzed & bubbled
Hydrogen-rich waterGe-carbonate SPA
Green odor

Communication
robot

Communication/Entertainment

Pellet stove
Air condition
Micro-bubble bath Flow Massage bath

Space/Housing

健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group81

Green Odor(s)
緑のかおり
CHO
CH2OH

cis - 3 - hexenol

trans - 2 - hexenal

82

Anti-fatigue effect by Green Odor
Activity of Normal Rats

Control+ Green
Odor

Activity after Forced Swim

Control+ GreenOdor

83Change of Reaction Time during Simple Task by Mokeys
サル単純課題遂行の反応時間の推移
controlwith Green Odor

Trials84

Activation by Green odor(s) in Anterior Cingulate andDorsolateral Prefrontal Cortices of Monkey Brain: PET study
Control (solvent)Green Odor : Activating frontal and anterior cingulate cortices

85

Hex-Hex Mix (green odor）

Sasabe et al., 2003.
Watanabe et al., 2005.

86

New product derived from collaboration
集中力を高め、ぐったり感を癒す「確か」な香り「緑林の香り」を簡単に体感

周囲の湿度に合わせて水を吸収して蒸発させる自然気化式のペーパー加湿器です。
電源が不要なので、室内のいろいろな所
でお使いいただけます。

水に緑林の香りエキスを加え、ペーパーディ
フューザーを挿したら…

水を吸い上げて色づき始め…

緑林の香り成分を発散させながら
加湿します。

使用量の目安：水・150ml、緑林の香りエキス・約2.5ml
緑林の香りエキス：水、エタノール、香料、界面活性剤、防腐剤
ペーパーディフューザー使用時サイズ：高さ約21cm×幅約15cm

87

Effects of Olive Oil for individuals
PlasmaTriglycerides***

Olive oilPlacebo oilc

TG (mmol/L)

1.6

*

*

1.2
0.8
0.4
0.0
preOOpost

pre POpost

健康”生き活き”羅針盤リサーチコンプレックス（RCH）

Compass to Health Life Research Complex Program

Integrated Research Group88

Anti-Fatigue Substances with Evidence• ApplephenonR (Polyphenol extract from unripe apples) for
Physical Fatigue: Ataka, S. et al., Nutrition 23:419-423, 2007
• Coenzyme Q10 for Physical Fatigue: Mizuno, K. et al.,Nutrition 24: 293-299, 2008
• (-)-Epigallocatechin gallate for Complex Fatigue (an animalmodel): Tanaka, M. et al., Nutrition 24: 599-603, 2008
• CBEX-Dr-containing Drink (Imidazole dipeptide) for
Physical Fatigue: Tanaka, M. et al., Jpn Phramacol Ther 36:
199-212, 2008
• Crocetin (a natural carotenoid dicarboxylic acid from crocus
flower) for Physical Fatigue: Mizuma, H. et al., Nutrition
Res. in press, 200989

Evidence-based

Fe, Cu, Zn, &other minerals

VC, VE, other vitamines

Green Odor
CoQ10

Citrate, NMN
a-lipoic acid
VB1, VB2, VB6, VB12

Anti-fatigue
Anti-aging

DHA, EPA, Arachidonate
Medium chain FA
Amino Acids
Imidazole dipeptides

in best combination!!

BH4(Tetrahydrobiopterin)

Pantothenic acid
Acetyl-L-carnitine

DHEA-S, Polyphenols
Green tea catechins

Electrolyzed Hydrogen-enriched waterRich hydrogen-dissolved water
Carbonated water90

Anti-fatigue food bookpublished in September, 2016

91

RIKEN BDR-DAIKIN Collaboration Center
Fatigue and Hygrothermal Environment
Experimental rooms

Room 3

Room 4

Fatigue

Mental fatigue(VAS score)

Summer res.
30℃×70%RH = bad
30℃×50％RH = good
30℃×30％RH = good
Key is humidity control!!

Sympathetic nerve activity(LF/HF ratio)

good

Control
room

2m
10m
5m

Summer exp.
24, 26, 28, 30［℃］
40, 55, 70［％RH］
Winter exp.
20, 22, 24, 26［℃］
30, 50, 70［%RH］
bad

Room 2

Fatigue-inducing cognitive task for 60 min

All

Room 1

Experiments

Winter res.

Patent(2019-207611)

Humidity

Female

Best

50
%

30
%

50%

30%
20℃

22℃

24℃

20℃

26℃

70
%

Sex differences!!

22℃

24℃

26℃

70%

Best
Humidity

Achievement

70%

Best

Male

ECG record (wireless type)Best condition
Female =22℃×50%RH
Male =
20℃×30%RH
20℃×50%RH

70
%

50
%

50%

Best
Temperature

Temperature

30%

30
%
20℃

22℃

24℃

26℃

20℃

22℃

24℃

26℃

92

Thank you for your attention!! Wishing your better health!!
2018. 6. 28. published by YW&KM

2021. 6. 17. published
Edited by Drs. Masaaki
Sugino & Hideki Katano
93