Physiological Regulation,
Adaptation, and Survival
Claude A. Piantadosi, M.D.
Professor of Medicine
Duke University Medical Center
Durham, N.C. USA
Physiology of extreme environments

Objectives

Learn common physiological principles involved in defense of
homeostasis in extreme environments

Survival limits



Time at DT, DP, DG, D Sv
Cold, heat, high
Efforts to adapt


Tolerance, adaptation, and resilience
Requirements


Water and energy
Vulnerable populations



Very young
Very sick
Very old
Physiology of extreme environments

Survival Biology— Definitions

Homeostasis

`Stability of inner medium is actively regulated



Claude Bernard’s “milieu-interieur”
Walter Cannon’s “Wisdom of the Body”
Stress and strain

An external force—stressor or adaptagent—sufficiently intense to
exceed a threshold and invoke a biological response produces strain.
Physiology of extreme environments

General Adaptation Syndrome (Hans Seyle;1907–1982)


Stress is a “non-specific response by the body to any demand,”
physical or psychological.
General Adaptation Syndrome represents timed development
of the “stress response” to the prolonged action of stressors



initial “alarm reaction” or “shock” phase
second “resistance” or “contra-shock” stage
final “exhaustion” stage
Physiology of extreme environments

Survival Biology— Definitions

Tolerance


Adaptation to a stimulus of constant intensity allows the intensity of
the response to decrease over time. Also called habituation.
Fatigue

A diminishing strength of response under the repeated or prolonged
influence of a constant stimulus
Physiology of extreme environments

Survival Biology— Definitions

Adaptation


Any functional, structural or molecular change that occurs in
the individual as a result of a change in environment
Accommodation, acclimation, acclimatization


We acclimatize to complex environments
Maladaptation

Disease
Physiology of Extreme Environments

Survival analysis


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
“Time to event” analysis
In medicine, estimate of differences in time until death
of patient or cohort
Kaplan-Meier plot displays observed cumulative
survival function for individual data
Analog in engineering sciences is "reliability
analysis" or "failure-time analysis”

Predicts time for mechanical or electronic
components to break down
Physiology of extreme environments
Kaplan-Meier Plot
Probability of Survival
1.00
0.75
Drug
0.50
.025
Placebo
0
0
6
12
18
Survival time (months)
24
Physiology of extreme environments

Stress and acclimation
High
Positive
acclimation
Intensity
of stress
or strain
Negative
acclimation
Low
0
1
2
3
4
Short  Time to tolerance failure  Long
Physiology of extreme environments
Human survival analysis
1.00
Probability of Survival

0.75
0.50
Acclimation
0.25
0
0
1
2
3
4
5
Survival time (arbitrary interval)
6
7
Adaptation—the “Master” Gland

Integrated NE stress response— HPA axis

Fight or Flight
Heat shock factors (HSF)
Uncoupling proteins (UCP)
Hypoxia-inducible factors (HIF)
Anti-oxidant response (ARE)
Neuroendocrine
cells
Stalk
Posterior pituitary
(Neurohypophysis)
Anterior pituitary
Hormone-secreting
cells
Cold stress
ACTH
TSH
Fast
Heat stress
AVP
Generalized
stress responses
(Adrenal-rapid)
Slow
Programmed
cell stress
responses
Long term
Adaptation
Physiology of extreme environments

Some things to think about:

How long can you live without water?


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Can you adapt to water deprivation?
How long can you live without food?
Which is harder to adapt to— heat or cold?
What is cold water and why is it so dangerous?
What limits exercise capacity at altitude?
What is limits altitude acclimatization in humans?
Physiology of extreme environments
News Headlines

Missing Hiker Ate Ants, Centipedes to
Survive


27-year-old Oregon man is recovering from a broken
ankle and five days lost on Mt Adams…
Survivor claims he was lost at sea for 13
months


37 year old Salvadoran man lived on fish, birds and
turtles before washing ashore on the remote Marshall
Islands thousands of miles away…
Physiology of Extreme Environments
Physiology of Extreme Environments
Physiology of extreme environments

Resilience: ability to maintain normal physical and
psychological function when exposed to even
extraordinary levels of stress and trauma (avoidance of
serious mental and physical illness)
Russo, SJ et al. Nat Neurosci 15: 1475, 2012
Physiology of extreme environments

Development of stress resilience
Stress “inoculation”
• Environment
• Early life experiences
• Resilience training
Genetics
• Genome
• HPA axis
• Neuropetides (NPY, 5-HT)
Epigenetic events
• K channel induction/ neuronal silencing
• DNA methylation
• Changes in gene expression
Stress resilience
• Active coping (behavioral adaptation)
• Increased fitness
Modified from Russo, SJ et al. Nat Neurosci 15: 1475, 2012
Physiology of extreme environments
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
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Antarctica is the world’s greatest desert!
Cold; Similar to surface of Mars (-128oF)
Dry; Rainfall ~ Sahara (2”/year); 70-90%
world’s fresh water
High; South polar plateau 9,300 ft (PB 10,500
ft due to polar low; SaO2 ~87%)
The Race for the Pole 1911-1912
Amundsen at the Pole
December 14, 1911
Round trip ~1,850 miles
Scott at the Pole
“I am just going outside and may be some time.”
Captain L. Oates
The Race for the Pole 1911-1912
“Every detail of our food supplies, clothing and depots worked
out to perfection... We have missed getting through by a
narrow margin which was justifiably within the risk of such a
journey."
Final journal, Robert F. Scott
"I may say that this is the greatest factor—the way in which
the expedition is equipped—the way in which every
difficulty is foreseen, and precautions taken for meeting or
avoiding it. Victory awaits him who has everything in order
–luck, people call it. Defeat is certain for him who has
neglected to take the necessary precautions in time; this
is called bad luck."
The South Pole, Roald Amundsen
Physiology of extreme environments

Why is cold so hard for us?

We are tropical creatures; therefore, we adapt better to
heat than to cold

Migration of mitochondrial genome (mitochondrial Eve)
Hypothermia— Medical School
Body Temperature (oC)
37
35
Hypothermia
Confusion
Start re-warming
Afterdrop
30
Shivering stops
Unassisted recovery is not possible
Coma
Death
25
Duration of exposure
Skin Freezing Times (Cheek)
P. Tikuisis and A. Keefe
Muscle Performance in the Cold
Physiology of extreme environments
Survival in extreme cold





Avoid wind chill— hastens hypothermia
Avoid frostbite— immobilizes
Shivering— requires extra nutrition
Water for drinking— Need fuel to melt ice
Fatal Hypothermia in Water
How do we adapt to the cold?
Cold stress
Rapid
Loss of body heat
Slow
Conserve/produce heat
Habituation
Shiver
Vasoconstriction
Less shivering
Less vasoconstriction
Costs energy
Conserves energy
Keeps up
Falls short
(support metabolism)
(add insulation)
Add body fat
Seek shelter
Hibernation
Clothing
Heating
All vertebrates  Behavioral Adaptation  Humans only
Cold acclimation— Heat production

Increased heat
production


Shivering
Mitochondrial uncoupling


Primarily in brown fat;
mainly newborn in humans
Requires a few days
NE- norepinephrine
b- receptor
G protein
AC-adenylate cyclase
ATP-adenosine triphosphate
ADP-adenosine diphosphate
cAMP-cyclic adenosine monophosphate
PKA-protein kinase A
UCP-uncoupling protein
HSL-heat-sensitive lipase
H+- hydrogen ion
AS- ATP synthase
ETC- electron transport chain
FFA- free fatty acids
b G
AC
NE
ATP
cAMP
PKA
HSL
UCP
FFA
H+
UCP
ATP
AS
ADP
ETC
H+
Physiology of extreme environments

Cold acclimation— Adding fat

Leptin/Ghrelin

Leptin is an adipokine that controls energy balance and food intake





Decreases body weight by suppressing appetite and by promoting energy
expenditure
Targets hypothalamic neurons by binding to LEPRb, long form of leptin
receptor
Leptin-responsive neurons connect widely in the brain forming circuitry
that controls energy intake and expenditure
Leptin resistance leads to obesity
Ghrelin

GI hormone produced by gastric epithelial cells



Stimulant for appetite and feeding
Strong stimulant of GH secretion from anterior pituitary
Increases feeling of hunger
Morris DL, Rui L. Recent advances in understanding leptin signaling and leptin resistance.
Am J Physiol Endocrinol Metab. 297(6):E1247-59, 2009
Leptin/Ghrelin
Satiety
Hunger
Two subpopulations of arcuate (ARC) neurons are leptin responsive
[proopriomelanocortin (POMC) neurons and agouti-related protein (AgRP) neurons]
Physiology of extreme environments
The Hot Deserts: Sand and Sea
Avoiding dehydration
Physiology of extreme environments

Air temperature usually associated with thermal comfort


Mean radiant temperature equally important


In this room, we radiate out to all surfaces and objects and they radiate
back in proportion to their temperature
Heat Index



Determines convective and evaporative heat loss
Shade air temperature/humidity interact to give effective temperature
(how hot it "feels")
Exposure to sunshine increases heat index by up to 15°F (8°C)
Evaporative cooling (water loss) becomes paramount as Tamb = Tbody
Physiology of extreme environments
Heat dissipation
(% of total)
Human heat dissipation is typical of tropical creatures
Cow Camel Horse Human
100
0
Bird
Dog
Cat
Pig
Goat
Sweating
Panting
Physiology of extreme environments

Death by dehydration

The 100-hour rule of thumb
Probability of Survival
1.00
0.75
Cool
Heat
acclimation
0.50
Hot
0.25
Water discipline
0
0
1
2
3
4
Survival time (days)
5
6
7
Physiology of extreme environments

Exercise time in the heat— acclimatization works

Major event is the production of dilute sweat (salt conservation)
100
7
5
% Subjects
still exercising
50
3
Day
1
0
0
15
30
45
60
Exercise Time (min)
75
Physiology of extreme environments

Natural Disaster

Magnitude 7.9 earthquake



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

Courtesy New York Times
May 12, 2008
Sichuan Province, China
69,122 dead /18,000 missing
persons
Same as wiping out Chapel
Hill
368,500 injured
15 million displaced
Physiology of extreme environments

Sichuan Province, May 12, 2008


Mean daily temperature ~75oF (24oC)
26,000-30,000 people buried alive
10000
6,375
<2.5% survival if trapped more than 2 days
<0.1% survival if trapped more than 4 days
1000
Number of
People Rescued
165
100
11
10
2
1
0
1
2
3
4
5
1
1
1
1
6
7
8
9
Days after Initial Earthquake
10
Physiology of extreme environments
Port au Prince Haiti, Jan 12, 2010


Mean daily temperature ~81oF (27oC)
170,000 dead; unknown number buried alive
Haiti Earthquake 1-12-10
Number of Survivors

120
100
N=134
80
60
40
20
0
0
1 2
3
4 5
6
7 8
9 10 11 12 13 14 15
Days after Earthquake
Physiology of extreme environments
Body temperature (oC)
Effect of Dehydration on Performance
39
A
95%
97%
100%
Plasma
volume
95%
B
97%
100%
39
38
38
37
37
0
15
30
45
60
Exercise time (minutes)
0
2.5
5.0
7.5
10
Sweat production (ml/m2/min)
Physiology of extreme environments
Cumulative mortality (%)
Heat Stroke Mortality
100
75
50
42.5oC
25
0
37
39
41
43
Body temperature (oC)
45
Physiology of extreme environments
Heat Shock Response
Phosphorylation
Induction
Heat stress
Oxidative stress
Proteases
Heavy metals
Inflammation
MAPK HSF
hsp
RNA
poly
Hsp
Hsp 70
Nucleus
Hsp 90
ATP
X
ADP
Proteasomal
Degradation
Protection at 24 h
Hsp 60/70
(Importation)
Mitochondrion
Increase protein disposal
Prevent protein degradation
Reduce oxidative stress
Prevent apoptosis
Repair ion channels
Suppress inflammation
High Altitude
Mt Everest 8848m
K2 (Chogori) 8611m
27’59” N PB 253 mm Hg
1953- P summit 14%
35’53” N
1954- P summit 16.5%
Physiology of extreme environments
Altitude (thousands of feet)
0
10
20
30
750
150
Airliner cabin
500
100
Limit human habitation
(5,000 m)
Mt Everest
(8,848 m)
250
50
0
0
0
2
4
6
Altitude (km)
8
10
Inspired PO2 (mmHg)
Barometric pressure (mmHg)
Sea level
Physiology of extreme environments

Hypobaric Hypoxia

Unique to mountain environments

Hypoxia disrupts homeostasis leading to complex set of physiological
responses


Hypoxia is the stimulus to acclimatize



Altitude acclimatization
Hyperventilation/respiratory alkalosis
Individual differences in ventilation do matter
Correct term is acclimatization because high altitude is also
cold and dry and air density is low
Physiology of extreme environments
40
Altitude (K)
Altitude (feet)
60,000
50,000
Aircraft
30
20
Decompression
10
Mt Everest
Cabin
40,000
Altitude (m)
0
Flight time
Unconscious
30,000
Conscious
20,000
0
5
Time (minutes)
Altitude acclimatization is real!
10,000
9,000
8,000
7,000
10
Physiology of extreme environments

Benefits of altitude acclimatization
Improved
O2 delivery and utilization
 Restore mental performance (1-2 days)
 Decrease susceptibility to altitude illness (3-5 days)
 Improve sleep quality (5-7 days)
 Improve work performance (10-14 days)
Physiology of extreme environments

Failure to Adapt

High-altitude diseases

Acute mountain sickness (AMS)


High altitude pulmonary edema (HAPE)


Occurrence 40-60% over 10,000 ft
Occurrence 2% over 10,000 ft
High altitude cerebral edema (HACE)

Occurrence 1:1,000 over 10,000 ft
Physiology of extreme environments
Adaptation to Altitude—Limits

Hypoxia limits exercise capacity
100
VO2 max (%)

80
Sea Level
60
Zone of Death (8,000 m)
Acclimatization complete
40
Summit Mt. Everest (8,848 m)
20
Limit PB 240 mmHg (9,250m)
0
0
50
100
Inspired PO2 (mmHg)
American Medical Expedition to Everest (AMREE 1981)
150
Physiology of extreme environments
Cellular Hypoxia
HIF-1a pVHL
Hypoxia-inducible factors
Normoxia
Nucleus
PHDs
HIF-1a
HIF-1b
O2
Ubiquitination
HRE
Transcription
of target genes
Proteasomal
Degradation
mRNA
Translation
VEGF
EPO
HIF-1 Hypoxia Inducible Factor
HRE Hypoxia response element
pVHL Von Hippel-Lindau protein
PH prolyl hydroxylase
EPO erythropoietin
VEGF vascular endothelial growth factor
Physiology of Extreme Environments
Adaptation to High Altitude
Normal Adapted
O2 saturation
(%)
Altitude
Cold
CO
50
Fever
Exercise
2,3 DPG
20
28
15
21
10
14
5
7
0
0
25
50
PO2 (mmHg)
75
100
Blood O2 content
(mL/100mL)
100
Beyond the Limits
Hard Shell
Engineering
Piccard and Kipfer
Physiology of Extreme Environments

First line of defense

Integrated stress response


Cellular/molecular adaptations (slow)

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

(generalized adaptation syndrome— fast)
Underlie integrated physiological response
Redundancy/overlap in pathways
Reversible
Behavioral adaptation



Sensing environmental cues
Knowledge and preparation
Hard shell engineering