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Stress as a Major Factor of
Cardiovascular Disease
George P. Chrousos, MD, MACE, MACP, FRCP
Professor of Pediatrics and Endocrinology
Emeritus,
National and Kapodistrian University of Athens,
Athens, Greece
(No diclosures)
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G.P. Chrousos 3
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Physical and Emotional Stress
• Stress Concepts-Complexity
• Stress Mechanisms
• Effects of Stress on Metabolism,
Cardiovascular Disease and
Longevity
G.P. Chrousos
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“Πολλά τα δεινά κ’ουδέν ανθρώπου
δεινότερον πέλλει….”
'There are many wonderful things and
nothing is more wonderful than the
human ...”
Σοφοκλής
Sophocles
496-406 BCE
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HUMAN COMPLEXITY: POST(EPI)GENOMIC ERA
Human genome:
About 3 billion bases (98% Junk?)
About 18 thousand protein-coding genes
About 24 thousand ncRNA-coding genes
About 16 thousand pseudogenes
About 100-140 thousand transcripts
(mRNA, ncRNA)
About 200-260 thousand proteins
Single nucleotide polymorphisms (snp’s or snv’s),
microsatellites or copy number variants :
About >25 million snp’s (snv’s), 1.5 million indels
About 20 million microsatellites
>5000 cnv’s (many million bases)
Over 100 k disease-related mutations
60% of promoters have CpG islands
EPIGENETICS-EPIMUTATIONS
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HUMAN COMPLEXITY: SOME HUMAN BRAIN NUMBERS
~ 100 billion neurons (100x1012) x >10.000 synapses per neuron = >1018 synapses)
~ 100.000 km of fibers
~ 1 trillion or more glial cells
~ 1.25 terabytes
~ 15 Watt lamp (2% of BW uses 20% energy)
PLASTICITY
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Chaisson E, New Scientist 2009
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Pythagoras 6th century BCEG.P. Chrousos
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Disturbing
Forces
HarmonyEquilibrium
Balance
Counteracting
Reestablishing
Forces
IIIIII
Stressors HomeostasisAdaptive
Response(Physical,
Emotional)
Pythagoras= Harmony
Alcmaeon=Iso-nomia
Walter Cannon= Homeostasis
Complex Systems Theory
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Stress is the State of
Threatened (or Perceived
as Threatened)
Homeostasis
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Pythagoras The Harmony of the Cosmos
(580-489 BC)
Alkmaion The intellect is based in the brain
(c. 500 BC) Health is the equipose of opposing forces: «Isonomia»
Empedocles Matter consists of essential elements and qualities in
(500-430 BC) opposition or alliance to one another
Hippocrates A harmonious balance of the elements and qualities of life
(460-375 BC) is health-Dysharmony is disease
«Nouson physeis iatroi =Vis medicatrix naturae»
Aristotle Unity of mind and body, “Eudaimonia"
Stoics/Sceptics Ataraxia (imperturbability of mind, equanimity)
Epicurus Ataraxia (imperturbability of mind), Aponia (no pain) and “Hedone”(341-270 BC) (tranquil, non sensual pleasure) as desirable states
«Eustachius» = Good balance, Carpe diem= seize the day
Thomas Sydenham Symptoms and signs of a disease arise also from the reaction of the
(AD 1624-1689 patients system
Claude Bernard The “milieu interieur”(1813-1878)
Walter Cannon Homeostasis/Stress
(1871-1945) Bodily responses to emotions
Fight or flight (and freeze) reaction
Hans Selye The general adaptation syndrome (the stress syndrome)
(1907-1982) Diseases of adaptation, Distress vs. Eustress
STRESS CONCEPTS
G.P. Chrousos
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Human StressorsDaily hassles
Work stress (Effort Reward Imbalance, ERI)
Life transitions
Natural and unnatural catastrophies
Starvation, Excessive nutrition, Deficient exercise, Excessive exercise, Obesity
Socioeconomic status, Minority status (Dignity)
Job loss, Downsizing, Loss of control
Bereavement
Caretaking/ Pathologic empathy/Unprincipled compassion
Addictions/ Toxic substances
Inflammations (Traumatic, Infectious, Autoimmune, Allergic)
Anxiety, Depression, Personality disorder
Sleep deficiency, Sleep excess
Uncoupling of the Clock: Jet-lag, “Social-jetlag”
Behavioral addictions: “Meta-modern”, “Cyborg stress”
G.P. Chrousos
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Homeostasis over Time
Healthy Baseline Homeostasis Baseline Homeostasis=Eustasis
Deteriorated Homeostasis=Cacostasis
Improved Homeostasis=Hyperstasis
Distress/Eustress
Catabasis
Anabasis
Elevated mood
Constitutional mood
Suppressed mood
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“CRITICAL” PERIODS OF LIFE
Prenatal, Early Childhood, Puberty
(Human brain ontogeny complete at 25-27 y)
Organizational Effects of Hormones
Epigenetics
(CRH, glucocorticoids, sex steroids, cytokines)
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HOMEOSTATIC SYSTEMS
• Amygdala, fear/anger
• MCLS, reward/punishment
• Stress - CRH/LC-NE
• Cardiorespiratory
• Metabolic
• Immune/Inflammatory
• Fatigue - Pain
• Wakefulness/Sleep
• Clock
Pre-/Frontal Lobe/Logos
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Physical and Emotional Stress
• Stress Concepts-Complexity
• Stress Mechanisms
• Effects of Stress on Metabolism,
Cardiovascular Disease and Longevity
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What Mediates the Adaptive
Response?
The Stress System
a. CNS
1. CRH system
2. Locus caeruleus (LC)-norepinephrine (NE)/autonomic (sympathetic) systems
b. Periphery
1. HPA axis
2. Autonomic (sympathetic) systems
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+
CRH
NE
CRH LC-NE
ANS
+
-
-
Stress System
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Stress System
Chrousos
JAMA 1992G.P. Chrousos 22
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The Reward System
ML
MC
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Structures related to emotional regulation
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Acute Stress
MCLS AMYGDALA
CRH
PVN
CRH/AVP
LC/NE
+
+
+
+
-
-
HIPPO-
CAMPUS
Cortisol Catecholamines/IL-6
Behavioral
adaptation
Physical
adaptation
G.P. Chrousos
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MC/ML System Tone
Stress System Tone
+ acute
- chronic-
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GH/IGF-1
LH/T
TSH/T3
F NE/E
iCRHIL-6
STRESS SYSTEM
Amygdala CRH
HIPPOCAMPUS
CRH/AVP LC/NE
ACTH
Inflammation
+
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Immune Function
CRH/AVP
ACTH
Glucocorticoids
Target Tissues
Mediators
(Eicosanoids,
PAF, Serotonin)
Inflammatory
(TNFa, IL-1, IL-6 …)Cytokines
CRH TRH
ACTH
Glucocorticoids
TSH
T4
Target Tissues
T3
Target Tissues
GHRH
GH
SmC
STSSTS
Growth and Thyroid Function
CRHLHRH
ACTH
Glucocorticoids
LH, FSH
Target Tissues
Reproduction
-endorphin
Testosterone,
Estradiol
G.P. Chrousos JAMA 1992
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SICKNESS SYNDROME
ANOREXIA/NAUSEA
FATIGUE AND/OR DEPRESSED AFFECT
SOMNOLENCE
HYPERALGESIA ± HEADACHE
ELEVATED TEMPERATURE/ FEVER
INCREASED METABOLIC RATE
MOLECULAR EFFECTORS
INFLAMMATORY CYTOKINES/MEDIATORS
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THE ADAPTIVE RESPONSE= STRESS
SYNDROME
Phenomenology
a. CNS Functions
- Facilitation-arousal, alertness, vigilance, cognition
attention, aggression
- Inhibition – vegetative functions
(reproduction, feeding, growth)
- Counteregulatory feedback
b. Peripheral Functions
● Oxygenation – nutrition
cardiovascular tone, respiration,
metabolism (catabolism, inhibition
of reproduction and growth)
● Detoxification
● Counteregulatory feedback (immunosuppression)
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Fatigue
Pain/Neural
Afferent
Program
Stress
Syndrome,
Stress Behavior
Sickness
Behavior
Acute Phase
Reaction
Inflammatory (Sickness)
Syndrome
Stress
Syndrome
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Sickness Syndrome
Manifestations
Peripheral
Infections
Post
Partum
Period
Stress Autoimmune
Disease
Neurodegenerative
Disease
Stroke,
Trauma
Intracerebral
Infections
Peripheral Immune
Activation and
Cytokine Secretion
Central Secretion
of Cytokines
(TNFa, IL-1,
IL-6, etc.)
Alterations in
Neurochemical
Systems
(NE, 5-HT,
CRH, etc.)
G.P. Chrousos
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Physical and Emotional Stress
• Stress Concepts-Complexity
• Stress Mechanisms
• Effects Stress on Metabolism,
Cardiovascular Disease and
Longevity
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Physical and Emotional Stress
• Timing (Critical
periods=prenatal, first 5 y and
adolescence)
• Acuity
• Chronicity
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THE STRESS SYSTEM
PathophysiologyAcute effects of stress system activation
● Asthma, eczema, urticaria
● Migraine and tension headache
● Gastrointestinal pain
● Hypertensive episode, CVA, death (compromised host)
● Cardiac ischemia, MI, Arrhythmia, death (compromised host)
● Psychotic episode
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THE STRESS SYSTEM
Pathophysiology
Chronic effects of stress system activation:
• Anxiety, depression, addiction, anti-social behavior, psychosomatic disorders, fatigue, pain
• Loss of weight, poor growth, obesity, metabolic syndrome, T2DM, smoldering inflammation, Immune dysfunction, atherosclerosis, CVD
• Osteoporosis
• Premature aging of all vulnerable organs, including the brain (neurodegeneration) and the skin
• Vulnerability to infections and cancer
CHRONIC NONCOMMUNICABLE DISEASES
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Acute Stress
MCLS AMYGDALA
CRH
PVN
CRH/AVP
LC/NE
+
+
+
+
-
-
HIPPO-
CAMPUS
Cortisol Catecholamines/IL-6
Stress Hyper-responsive
Child/Adult
MCLSAMYGDALA
CRH
PVN
CRH/AVP
LC/NE
-
+
+
+
--
HIPPO-
CAMPUS
Cortisol Catecholamines/IL-6
Somatic consequences
Growth retardation
Metabolic syndrome X
/T2DM
Cardiovascular disease
Osteoporosis
Behavioral consequences
Maladjustment disorders
Anxiety, Depression
Personality disorders
Addiction, Psychosomatics
+
Adjusment vs.Maladjustment
Sickness s.
++
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HYPERCYTOKINEMIA
TRAUMA/ BURNS
INFECTIOUS ILLNESSES
AUTOIMMUNE INFLAMMATORY DISEASES
ALLERGIC INFLAMMATIONS
CNS INFLAMMATIONS
NONINFLAMMATORY STRESS
OBESITY/VISCERAL OBESITY
AGING
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0
2
4
6
8
10
12
20 30 40 50 60
IL-6
(pg/m
l)
r = .790
p = .000
0
1
2
3
4
5
20 30 40 50 60
TN
Fa
(pg/m
l)r = .400
p = .014
BMI
Both IL-6 and TNFa correlate with BMI
Vgontzas et al. JCEM 1997
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GENETIC VARIATION
DEVELOPMENTAL HISTORY STRESSReal or perceived
HPA axis
Endothelial Dysfunction/Inflammation
Atherosclerosis
Cardiovascular Disease
Insulin resistance
Visceral Obesity/Sarcopenia
=Metabolic
Syndrome, DM type2TG
LDL
HDL
ABP
APR
Cytokines
Stress systemCRH/AVP-LC/NE
GH/IGF-1
LH, T, E2
TSH, T3Cortisol NE, E, IL-6Target Tissues
Systemic Sympathetic
Adrenomedullary Systems
Dyscoagulation
AGING
NUTRITION
Osteoporosis
Sleep Apnea
PCOS
Sickness
Syndrome
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InflammatoryNutritional
Oxidative
Cellular Stress
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Cellular Stress
Inflammatory
NF-kBNFAT5
Nutritional
IR
Oxidative
MitochondriaKeap1 (SH sensor)-Nrf2-ΑRΕ
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Al-Attas et al. EJE 2010
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G.P. Chrousos 45
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G.P. Chrousos 46
“Grief and fear when lingering
provoke melancholia”
Hippocrates 460-479 BCE
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STRESS SYSTEM
HYPERACTIVITY AND
PARADOXIC OBESITY
IN DEPRESSION
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Clock Time (hh:mm)
08:00 12:00 16:00 20:00 00:00 04:00 08:00
0
2
4
6
8
10 Controls
Depressed
Pla
sm
a IL
-6 (
pg
/ml)
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Clock time (hh:mm)
Controls
Depressed
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Correlation coefficient Probability value
Appetite -0.61 0.07
Concentration -0.64 0.05
Craving -0.45 0.19
Guilt -0.82 0.004*
Physical discomfort -0.35 0.32
Sadness -0.72 0.02
Self-esteem -0.86 0.002*
Suicidal thoughts -0.88 0.0007*
Tiredness -0.75 0.02
Withdrawal -0.21 0.56
Pearson’s correlations between mean 0800-2300 h
plasma IL-6 levels and MVAS scores.
Note: For each measure, a higher VAS score denoted better feelings.
*Correlations of IL-6 with guilt, self-esteem and suicidal thoughts remained
significant after Bonferroni correction.
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Antidepressants
Sickness Behavior,
Depression Equates
an Inflammatory
Condition?
Peripheral
Infections
Post
Partum
Period
Stress Autoimmune
Disease
Neurodegenerative
Disease
Stroke,
Trauma
Intracerebral
Infections
Peripheral Immune
Activation and
Cytokine Secretion
Central Secretion
of Cytokines
(TNFa, IL-1,
IL-6, etc.)
Alterations in
Neurochemical
Systems
(NE, 5-HT,
CRH, etc.)
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Acute Stress
MCLS AMYGDALA
CRH
PVN
CRH/AVP
LC/NE
+
+
+
+
-
-
HIPPO-
CAMPUS
Cortisol Catecholamines
+IL-6
Melancholic Depression
MCLSAMYGDALA
CRH
PVN
CRH/AVP
LC/NE
-
+
+
+
--
HIPPO-
CAMPUS
Cortisol Catecholamines+IL-6
Somatic consequences
Metabolic syndrome X
Cardiovascular disease
Osteoporosis
Behavioral consequences
Anhedonia,Fatigue,
Insomnia, Anorexia.
Loss of libido
+
+
Sickness syndrome
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56
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24 H SAMPLING OVERNIGHT
DEXAMETHASONE TESTA.
B.
PL
AS
MA
CO
RT
ISO
L
8 am 8 pm 8 am
TARGET TISSUE SENSITIVITY
TA
RG
ET
TIS
SU
E R
ES
PO
NS
E
CORTISOL CONCENTRATION
HS N R THRESHOLD
FOR HARMFULNESS
-D
-D
+D
+D
NS CS
NS CS
24 H
CO
RT
ISO
L
DARK
Chrousos JCEM 1998
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Results #1: Clock/Bmal1 Represses GR
Transcriptional Activity through Acetylation
GREs
GR
GR-induced Transcriptional
Activity
In the Absence of Acetylation by CLOCK
Bmal1
ClockAcetylation
GRE Binding
GREs
A A
A A
In the Presence of Acetylation by CLOCK
GR-induced Transcriptional
Activity
HRNTD DBD LBD
GR
Acetylation Sites Interaction with Clock
K480K492K494K495
1 420 480 520 777
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Uncoupling between Circadian Rhythm of SerumCortisol and Tissue Glucocorticoid Sensitivity
8 am 8 amDark
Ta
rge
t T
iss
ue
Glu
co
co
rtic
oid
Se
ns
itiv
ity
CIRCADIAN TISSUE GLUCOCORTICOID SENSITIVITY/GR ACETYLATION
OVERNIGHT
DEXAMETHASONE TEST
Se
rum
Co
rtis
ol
-D
-D
+D
+D
NS SS8 am 8 am
24 H SAMPLING
Normal Stress
GR Acetylation
GR
Ac
ety
latio
n
at T
arg
et T
iss
ue
s
Target Tissue
Glucocorticoid Sensitivity
Dark
Shift
Functional
Glucocorticoid
Hypersensitivity
Pathologic Consequences
8 pm
8 pm
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Serum cortisol levels before and through fasting month:
NS
P< 0.01
SHAABAN RAMADAN
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MUSCLE MASS
Best predictor of morbidity
and life expectancy
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DEFINITIONS
• Lean Osteosarcopenia vs. Paradoxic
“Obesity” vs. Osteosarcopenic Obesity
Decreased bone mass:
Osteopenia vs. Osteoporosis
T-scores from -1 to -2.5 vs. <2.5
Decreased muscle mass:
Sarcopenia vs. Lipoatrophy + Sarcasthenia (frailty)
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ΜΕΤΡΗΣΕΙΣWeight + Height
Hologic -DXA BIA-ACC
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Deming plot with fat mass in kg
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Participants were 99571 adult Caucasians
(29624 males and 60047 females), ages
20-80 y, grouped by:
BMI: Lean, Overweight, Obese
Presence of Medically Unexplained
Symptoms = MUS
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The MUS Examined*:
(i) persistent tiredness or fatigue,
(ii) depressive symptomatology,
(iii) persistent insomnia or night awakenings,
(iv) persistent drowsiness during the day,
(v) anxiety,
(vi) apathy,
(vii) panic attacks,
(viii) changes in heart rate (arrhythmias/tachycardia) at rest,
(ix) changes in appetite (appetite loss or excessive hunger),
(x) night binge eating,
(xi) stomach cramps, bloating or gastro-esophageal reflux disease (GORD),
(xii) presence of irritable bowel syndrome (IBS) symptoms,
(xiii) cold hands and feet,
(xiv) sweating during sleep.
*Presence of MUS was defined as a positive answer to more than 3 of
the above 14 questions.
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Evaluation included:
Advanced Body Composition Analysis by BIA-
ACC
Indices of Inflammation: hsCRP, Interleukin-6
Indices of Stress: am and pm Salivary Cortisol,
Delta-Cortisol (am-pm)
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Grouping:
10 416 lean subjects (8810 males) with no
MUS (Group A),
58 710 lean subjects (5581 males) with MUS
(Group B), and
30 445 overweight/obese subjects (15133
males) with no MUS (Group C).
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Healthy Overweight/Obese Youth: Early Osteosarcopenic
Obesity Features.
Stefanaki C, Peppa M, Boschiero D, Chrousos GP.
Eur J Clin Invest. 2016 Jul 19. doi: 10.1111/eci.12659.
[Epub ahead of print]
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Overall, 2551 subjects (974 males) aged 18–
21 years participated in the study.
The healthy lean group included 1072 participants [900 males
(84%) and 172 females (16%)].
The healthy overweight/obese group included 1479
participants [74 males (5%) and 1405 females (95%)].
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Overall, 2551 subjects (974 males) aged 18–
21 years participated in the study.
The healthy lean group included 1072 participants [900 males
(84%) and 172 females (16%)].
The healthy overweight/obese group included 1479
participants [74 males (5%) and 1405 females (95%)].
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F(3,2547)
=
2824.545,
p<0.001,
Eta
squared
=0.76
**
**
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F(3,254
7)=
2824.54
5,
p<0.001,
Eta
squared
=0.76
** **
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F(3,254
7)=
793.640,
p<0.001,
Eta
squared
=0.48
p =0.99
**
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F(3,2547)=
892.223,
p<0.001,
Eta squared
=0.51
p =0.99
**
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F(3,25
47)=
554.67
9,
p<0.00
1,
Eta
square
d=0.39
**
**
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F(3,2547)
=
1679.870,
p<0.001,
Eta
squared
=0.66
**
**
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F(3,2547)
=
935.110,
p<0.001,
Eta
squared
=0.52
** **
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F(3,2547)
= 10.901,
p<0.001,
Eta
squared
=0.012
****
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F(3,2547)
=
368.272,
p<0.001,
Eta
squared
=0.3
**
**
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CONCLUSIONS• Osteosarcopenic phenotype is common and exists even in the
young, suggesting early start of prevention and treatment.
• “Healthy” overweight or obese populations demonstrate:
1. Decreased bone mass;
2. Decreased muscle mass;
3. Increased hsCRP concentrations;
4. Flattening of cortisol circadian rhythm;
5. MUS
• BIA-ACC is a highly potent device that may detect osteosarcopenic
phenotypes, and may be used for early intervention.
• Future cohort studies are needed to establish the definite causative
factors behind the negative relations between fat, bone & muscle
mass.
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Stress/inflammation
Social
stressful
conditions:
Inequality,
Dignity, etc.
“Chronic Stress and Inflammation
Syndrome” (CSIS)Psychologic and somatic manifestations:
MUS, Anxiety, Depressive symptomatology, Obesity,
Osteosarcopenia, etc.
Sleep disorders,
Accelerated Aging
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Life course
Inadequate response
to stressors
Developmental epigenetic
plasticity
No intervention
Late intervention
Late intervention
impactful for
vulnerable groups
Earlier intervention
improves functional
capacity & responses
to new challenges
Early intervention
Chronic
Noncommunicable
Accumulating
Disease Risk
Mother and Fetus
Infant
Childhood &
Adolescence
Adulthood
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ANTI-STRESS- Beta-blockers, Anti-depressants, CEI, AT2-blockers
ANTI-INFLAMMATION- ω3 Fatty Acids, Unsaturated Fatty Acids, Statins,
PPAR-g agonists
ANTI-OXIDATION- Phytoestrogens, sulforafane
INSULIN SENSITIZATION- Diet, Exercise, Μetformin, PPAR-g agonists
ANTI-COAGULATION- Anti-platelet agents
Anti-stress, anti-inflammatory and
nutritional and other potential life
extenders
G.P. Chrousos
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• Jeanne Calment (1885-1997), 122 years and 164 days.
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Longevity Hotspots
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Study of 400 Greek Centenarians:
Female:Male 1.7:1, Key Features
• No Hx of Obesity, Maintain good BMI
• No Hx of Depression, No Loneliness
• Little Hx of Smoking
• Stable Daily Activity Schedule
• Resilience to Stress
• High optimism, Adaptability
• Spirituality
Tigani et al. BMC Geriatrics 1011, Tigani et al. Arch Gerontol Geriatrics 2012
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IndividualSpecies vs.
Epigenotype
Evolution
Genetics
CNS complexity
Development
Epigenetics
CNS plasticity
ENVIRONMENTAL STRESSORS
Genotype
Starvation
Dehydration
Injurious agents-inflammations
Adversaries-anticipation
Adversaries-avoidance
Injury-minimization
Social bonding disruption
Phenotype
Embryogenesis
Maternal Stress
Perinatal Stress
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95
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Selections of Gene and Epigenetic Networks Participating in Functions
Important for Human Survival and Species Preservation
RESPONSE TO SURVIVAL THREAT SELECTIVE ADVANTAGE CONTEMPORARY DISEASE
Combat starvation Energy conservation Obesity/metabolic syndrome
Combat dehydration Fluid and electrolyte conserve Hypertension
Combat injurious agents Potent immune reaction Autoimmunity/Allergy
Anticipate adversaries Arousal/fear Anxiety/insomnia
Minimize exposure to danger Withdrawal Depression
Prevent tissue strain/damage Retain tissue integrity Pain and fatigue syndromes
Prevent social bond disruption Retain social integrity Dehumanization problems
(“evil”)
Chrousos, Amer J Med 2004
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What can we do about stress?
• Social prerequisites
• Nutrition
• Exercise
• Sleep
• Timing regularity
• Experiencing “Flow”
• Noopedia methods
• Increased reward/punishment ratio: Be
good-do good (thoughts, words, deeds)
• Have a sustained purpose beyond one’s
self (“transcendence”, “meaning”)
G.P. Chrousos
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Fetal Life
Childhood
PubertyFertility
Adulthood
Conception
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«Την προς αρετήν εκ παίδων παιδείαν»
“Παιδεία είναι η διαπαιδαγώγηση προς
την αρετή από τα παιδικά χρόνια”
“Paideia of the virtues should start in
childhood”
ΠΛΑΤΩΝ (Νόμοι 643 Ε)
Plato (Laws 643 E)
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«Εκ του εισοράν γίγνετ’ ανθρώποις το
εράν»
“Through empathy is love generated in
Man ”
, Euripides
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‘Be equanimous and remember
not to believe easily’
Νάφε και μέμνασο απιστείν’
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Physical and Emotional Stress
• Complexity- Human Uniqueness
• Concepts of Homeostasis and Stress
• Stress Mechanisms
• Effects of Stress on the Organism
• Coping with Stress
G.P. Chrousos
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The constituents of Man:
“Φύσις, Εθος, Λόγος”
“Physis, Ethos, Logos”
Aristotle
4th Century BCE
G.P. Chrousos
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What can we do about stress?
• Social prerequisites
• Nutrition
• Exercise
• Sleep
• Timing regularity
• Experiencing “Flow”
• “Noopedia” methods
• “Meaning”
G.P. Chrousos
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Basic Social Prerequisites
• Safety, Security
• Social Integration
• Competence
• Authenticity
• Autonomy
G.P. Chrousos105
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Fear ➔ Anxiety
Sadness ➔ Depression
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Anxiety ➔ Fear
Depression ➔ Sadness
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F Face Fear and Sadness
A Alter Perception
C Cope actively
E Express emotion
S Seek social support
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Helpless- Hopeless- Worthless
MAJOR DEPRESSION
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MC/ML System Tone
Stress System Tone
+ acute
- chronic-
G.P. Chrousos110
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MC/ML System Tone
Stress System Tone
+ acute/- chronic-
Placebo,
Positive thinking, words,
actions.
“Flow”, “Noopedia” methods
“Meaning”
Nocebo, Negative
thinking/words,
actions
No “meaning”
-+
G.P. Chrousos111
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Patient-doctor Relationship=
A Strong Predictor
of Response to any Therapy
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The Epicurian
Tetrapharmacos Prescription
• We are not threatened by divine power
• There is no life after death
• It is easy to acquire what we need to be
happy
• It is easy to endure what makes us suffer
G.P. Chrousos113
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“Κράτιστον δη προς αλυπίαν φάρμακον ο
λόγος και η δια τούτου παρασκευή προς πάσας
του βίου μεταβολάς”.
“The best medicine to attain consolation is
Logos, and through it the preparation for all the
vicissitudes of life”.
Π Πλούταρχος Plutarch
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“Επιστήμη ποιητική ευδαιμονίας”.
“Science brings eudaimonia”.
Πλάτων Plato
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“If you are distressed by anything external or internal,
the pain is not due to the thing itself, but to your estimate of
it; and this you have the power to revoke at any moment.”
Marcus Aurelius(Meditations)
167 CE
G.P. Chrousos116
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G.P. Chrousos
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G.P. Chrousos118
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Lutz et al. 2008
Attention-
based
meditations:
- Focused
Attention
- Open
Monitoring
Lutz et al. 2008 TICS
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120
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Plotinos of Lycopolis, Egypt (ca. CE 204/5–270)
G.P. Chrousos
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“You ask, how can we know the Infinite? I answer, not by
reason. It is the office of reason to distinguish and define. The
Infinite, therefore, cannot be ranked among its objects. You
can only apprehend the Infinite by a faculty superior to reason,
by entering into a state in which you are your finite self no
longer—in which the divine essence is communicated to you.
This is ecstasy. It is the liberation of your mind from its finite
consciousness. Like only can apprehend like; when you
thus cease to be finite, you become one with the Infinite. In the
reduction of your soul to its simplest self, its divine essence,
you realize this union—this identity”.
Ancient Greek sage Plotinos (ca. CE 204/5–270))in a letter to Flaccus.
G.P. Chrousos
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«....έδειξε με τις πράξεις του και την μέθοδο της λογικής του ότι για να είναι κάποιος ευτυχής πρέπει να είναι καλός.....»
“….he showed with his deeds and the method of his logic that for somebody to be happy one has to be good…”
Αριστοτέλης, Επικήδειος στον Πλάτωνα
Aristotle, Eulogy to Plato 4cent BCE
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Epicurean Qualities of Mind that Alleviate
Suffering and Bring Happiness
• Φιλία = friendship, love
• Παρρησία = truth telling, sincerity
• Εύνοια = good will
• Χάρις = gratefulness
G.P. Chrousos
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4 Qualities of Mind that Alleviate Suffering
• Metta = loving kindness
• Karuna = compassion
• Mudita = feeling the joy of others
• Upekkha = ataraxia, equanimity
G.P. Chrousos
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Upekkha=Ataraxia
An equanimous mind holds all things in an ease-filled
balance. From this place of equanimity, when we see
people going about their everyday lives, friendliness
(metta) is our natural response. When we see someone
suffering, compassion (karuna) is our natural response.
When we see someone who's happy, joy in their joy
(mudita) is our natural response.
Sylvia Boorstein, It is easier than you think, 1995
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127
ΕΥΤΥΧΙΑΝ ΕΥΧΟΝ
Search for happiness
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G.P. Chrousos 128
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TIME
HA
PP
INE
SS
HAPPINEES FRAMEWORK
TYPES OF HAPPINESS
PleasureROCK STAR
Chasing the next high
PassionFLOW and ENGAGEMENT
Time flies
Higher Purpose
Meaning, TranscendenceBeing part of something
bigger than yourself
“Noopedia” methods
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Fredrickson BL et al. PNAS 2013; 110 (33): 13684-13689
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Fredrickson BL et al. PNAS 2013; 110 (33): 13684-13689
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«Αποφάσισα να είμαι ευτυχής γιατι
αυτό βελτιώνει την υγεία μου»
“ I decided to be happy because this
improves my health”
Voltaire 1694-1778
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G.P. Chrousos 134
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Carneiro and Heckman 2003
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Stress+Inflammation
Social
conditions:
Inequality/D
ignity, etc.
“Chronic Stress and Inflammation
Syndrome”
(CSIS)
Psychologic and somatic
manifestations,
Sleep disorders,
Accelerated aging