Exercise Immunity & AgingExercise, Immunity & Aging
Chair, ImmunobiologyProfessor,
KINES/IMBIO/[email protected]
An Exercise StoryI started playing tennis and skiing in my forties. On a skiing trip, I broke a rib. The doctor said my spine was so bad he did not know how I did anything. I tried to stay active as long as possible. As the years passed, I developed bad back pain. The doctor said he could not help me that I was too old Also I washe could not help me, that I was too old. Also, I was diagnosed with emphysema. I could not breathe well and was wheezing. The doctor said I would never improve. I thought I would never climb stairs again. I tired easily. I tried an exercise program at a local medical center For si eeks I orked o t threemedical center. For six weeks, I worked out three times a week, two to three hours a day. I did weight training, treadmill, bicycle and breathing exercises. Even when I felt bad, I kept at it. I never let anyone discourage me. Eventually, the wheezing stopped, my breathing improved and the back pain disappeared. I was able to walk with energy to spare! I exercise regularly. My doctor says he has never seen anyone "get better!" I attribute my improvement to exercise.
Name: Grace
Age: 91
Location:
California
Activity: Walking Yoga Tennis Weight improvement to exercise.Activity: Walking, Yoga, Tennis, Weight Lifting
Exercise, aging and non-infectious
• Heart disease • Osteoarthritis
, g gdisease
• Heart disease• Hypertension• Diabetes
• Osteoarthritis• COPD (emphysema)• Frailty/disability
• Obesity• Osteoporosis• Alzheimer’s
• Renal disease• Depression• AnxietyAlzheimer s
• Stroke• Cancer
Anxiety• Falls/balance• Cognition
? Effect of exercise on infectious disease / immunitydisease / immunity
• Clinical evidence for immunologic dysfunction in older populationsolder populations
• FIRST APPROACH: Pilot studyFIRST APPROACH: Pilot study
• Goal: To develop preliminary data in support of hypothesis (mouse or human model?)
Influenza / Pneumonia
• 7th leading cause of death in U.S. (all )ages)
• 5th leading cause of death (age 65+)3 d l di f d th ( 85 )• 3rd leading cause of death (age 85+)
• ~ 40,000 deaths annually• >90% of mortality in individuals > age 65• Influenza vaccine efficacy rates 70-90% in
d l 17 53% i ldyoung, and only 17-53% in old (Goodwin K. 2006)
Influenza Virus Types A, B, C
Virus Structure8 segments of ss RNA inside- HA=hemagglutininHA hemagglutinin- NA=neuraminidase
3 Virus Strains in seasonal vaccineV SA/New Caledonia/20/99 H1N1, (A/California/7/2009 H1N1)A Panama/2007/99 H3N2, (A/Perth/16/2009 H3N2)B/Hong Kong/330/2001 (B/Brisbane/60/2008)g g ( )
Antibody response to vaccinationvaccination
80
506070
203040
> 1:40 titer increase
010
YoungH1N1
Young B OlderH1N1
Older BFagiolo, et a. Aging Clin. Exp Res.H1N1 H1N1 Fagiolo, et a. Aging Clin. Exp Res.5:451=458, 1993
Pilot study
• Survey physical activity, collect blood post-immunization to assess antibody level y
– Active: exercise > 3 times/week, with increase in heart rate, breathing, sweat
– Moderately active – some exercise, but at lower amount or intensity than active grouplower amount or intensity than active group
– Sedentary – no physical activity
Active Moderately active
SedentarySedentary
IgG anti-influenza antibody
S d t
*5
nm)
SedentaryMod ActiveActive
orba
nce
(40 3.0 +
Abs
o
2 5
Reciprocal Serum Dilution
2.525 125
Intervention Study – Phase Irandomized controlled trialrandomized controlled trial
(Subjects all sedentary initially)• Exercise treatment group (3x wk, ~1 year)• Control sedentary group• Young adults (age comparison)
– Vaccination pre/post intervention
Exercise and the J curve theoryct
ion
of In
fec
Ris
k o
None Moderate Exhaustive
Pre-vaccineblood
4wk postblood
12wk postblood
Pre-vaccineblood
4wk postblood
12wk postblood
Exercise treatment 10 months
Control treatment 10 months(Young subjects)
Control treatment 10 months
InfluenzaVaccine #1
InfluenzaVaccine #2
Ch i I fl A H1N1 A ib d i f i i i
Exercise improves antibody response to vaccination in older adults
Change in Influenza A H1N1 Antibody titer from pre-immunization
0.25
0.50
0.75
H1N
1 H
I tit
er
-0.50
-0.25
0.00
CON EX og
(10)
Influ
enza
A H
4 week 3 month-0.75 YOUNG
Change in Influenza B Antibody titer from pre-immunization
ter
0 75
Lo0)
Influ
enza
B H
I tit
0 25
0.50
0.75
4 week 3 month
Log
(10
0.00
0.25
This measure of the cytotoxic T cell’s ability to destroy influenza-virus infected cells was improved by moderate aerobic exercise in older adults
Cytotoxic T cell function14
g pr
otei
n)
10
12
14CON-OLD EX-OLD YOUNG
* *
me
B (u
nits
/mg
6
8
Gra
nzym
0
2
4
H1N1 H3N2 B0
Summary Phase 1• A long-term aerobic exercise intervention increased
antibody response to influenza vaccine (Influenza A H1N1 & H3N2). Antibody levels remained lower thanH1N1 & H3N2). Antibody levels remained lower than young adults.
• Cytotoxic T cell function against Influenza virus was• Cytotoxic T cell function against Influenza virus was improved by exercise, and reached levels similar to young adults. (Cytotoxic T cell important in viral clearance)clearance)
• Depression, stress did not mediate effects of exercise
Intervention Study – Phase 2randomized controlled trialrandomized controlled trial
multi-site (DMU & ISU)
• Aerobic Exercise treatment group (n=50) • Flexibility/strength treatment group (n=50)
– Vaccination pre/post intervention– Inflammation assessment
Psychosocial factors– Psychosocial factors
How might exercise alter immunity/inflammation?immunity/inflammation?
Exercise
Psychosocial factors
IExercise Immune response
Neuroendocrine factors
Pre-vaccineBlood
4wk postblood
12wk postblood
Pre-vaccineblood
4wk postblood
12wk postblood
Aerobic Exercise treatment 10 months
Flexibility/strength treatment 10 monthsFlexibility/strength treatment 10 months
InfluenzaVaccine #1
InfluenzaVaccine #2
Psychosocialsurveys
Psychosocial factors generally improved with either type of exercise intervention
Group FLEX-Strength CARDIO-Aerobic
Time PRE POST PRE POSTTime PRE POST PRE POSTDepression 3.2+0.4 2.8+0.4* 2.5 + 0.3 1.8+0.7*
PSS 14 2 + 0 8 14 8 + 0 9 16 6 +0 7 14 9 +1 0aPSS(stress)
14.2 + 0.8 14.8 + 0.9 16.6 +0.7 14.9 +1.0a
Sense h
75.1 + 0.9 77.5 +1.0* 73.1+1.3 76.5+1.3*coherence
LOToptimism
61.7+0.8 62.8+1.2* 61.2+1.0 64.6+0.8*
p
Obesity (BMI>30) was associated with decreased antibody response to influenza immunization (pre intervention)
on -
pre)
1.5
response to influenza immunization (pre-intervention)-im
mun
izat
io
1.0
Non-ob obese
+
*
dy ti
ter (
post
0.5
*+
nge
in a
ntib
od
0 04wk A-H1N1 12wk A-H1N1 4 wk A-H3N2 12 wk A-H3N2C
han 0.0
Antibody response to vaccine after the exercise intervention is dependent on improvement in fitness
10 improve fit non-ob +
p pte
r
8
9
NC fit non-ob improve fit ob NC fit ob
++
Log
(2) H
I tit
7
8 +
6
5A H1N1 4wk B 12wkB 4wkA H1N1 12wk
T cell response to vaccine after the intervention is associated with change in fitness and obesity
1.0 improve fit non-ob NC fit b
with change in fitness and obesity30
nm 0.8
NC fit non-ob improve fit ob NC fit ob
**
** * *+
dens
ity a
t 6
0.4
0.6+ +
Opt
ical
0.2
0.0A H1N1 4wk A H3N2 4 wk B 4 wk
Summary of vaccine response
• Overall improvement in aerobic fitness rather than specific type of exercise is associated withthan specific type of exercise is associated with increased antibody response to vaccine in both obese and non-obese
• T-cell response to vaccine was greater in subjects that improved aerobic fitnesssubjects that improved aerobic fitness regardless of exercise treatment, and lower in obese subjects
Impact of exercise intervention on serum inflammatory factorsserum inflammatory factors
T f i• Type of exercise
• Role of psychosocial factors• Role of psychosocial factors
• Role of neuroendocrine (catecholamines)( )
S “i fl t ” IL 6 d d b di bi i
7
Serum “inflammatory” IL-6 reduced by cardio-aerobic exercise
/ml) 5
6
IL-6
(pg/
3
4
FLEX
PRE POST1
2FLEX CARDIO FLEX B-block CARDIO B-block
PRE POST
Serum “inflammatory” IL-18 reduced by cardio-aerobic exercise
65
y y
ml)
55
60
IL-1
8 (p
g/m
40
45
50
30
35
40
FLEX CARDIO FLEX B-block CARDIO B-block
PRE POST
CRPSerum C-reactive protein reduced by cardio-aerobic exercise
6
Serum C reactive protein reduced by cardio aerobic exercise
L)
4
5
CR
P (m
g/L
2
3
0
1 FLEX CARDIO FLEX B-block CARDIO B-block
PRE POST
Summary of exercise and inflammatory factorsfactors
• Cardio-aerobic exercise reduced serum inflammatory factors to greater extent thaninflammatory factors to greater extent than flex/strength exercise
• The effect of exercise on inflammatory factors was independent of changes in psychosocial factors catecholamines and body fatfactors, catecholamines, and body fat.
Influenza Infection
1) Does exercise protect against infectionwith live virus?with live virus?
2) Mechanisms?
stochasticscientist.blogspot.com
InfluenzaInfection i.n.
Chronic exercise training ( 45min/d, 5d/wk,12wks)24 hrrest
Acute exercise45 minutes 1XRest 12 weeks 45 minutes 1XRest 12 weeks
Control treatment (rest 12 weeks)
Euthanize
Body weight loss resulting from infection wasy g greduced to greatest extent in chronic exercised mice
-3
-2
-1
-5
-4
-3
NON-EXA-EXC-EX
Day post-infection0 2 4 6 8 10 12
-6
The viral load in lungs was reduced by both acute and chronic exercise
1e+9
sca
le)
1e+7
1e+8
NON-EXA-EX C-EX
+
*
vira
l tite
r (Lo
g
1e+5
1e+6
*
Log
v
1e+3
1e+4
day 2 day 5 day 101e 3
Multiple inflammatory factors in the lung were reduced by both acute and chronic exercise at inreduced by both acute and chronic exercise at in
lung 2 days post infection
400
500NON-EXA-EXC-EX
pg/m
l
200
300
KC MIP1a MIP1b0
100
By day 5 post-infection, only chronic exercise showed a benefit in terms ofexercise showed a benefit in terms of
reduced inflammatory factors.
400
500
600
NON-EXA-EX C-EX
pg/m
l
200
300
400
IL-6 IL-12p40 IL-170
100
IL 6 IL 12p40 IL 17
Aged mice – is benefit of exercise present?
• Aged BALB/c mice (16-17 months of age)– Exercise: 5 d/week, 45 min/day, moderate intensity e c se 5 d/ ee , 5 /day, ode ate te s ty
for 8-12 weeks; infected 24 hours after last exercise session
– Non-exercise: exposed to similar noise/handling stress; infected at the same time as exercised micestress; infected at the same time as exercised mice
• Young BALB/c mice (2 months of age)Age control comparison group infected at same time– Age control comparison group, infected at same time as aged mice
Lung viral load was reduced by exercise in aged mice
BAL viral titer Day 4 post-infection7
aged miceer 5
6
7
uninfected NON-EX EX Young
*
BA
L vi
ral t
ite
3
4
g
Log
1
2
BAL titer0 *
Multiple inflammatory factors in the lung were reduced in the exercised mice
BAL fluid DAY 4 post-infection
2000 uninfected+
1500
2000 uninfected NON-EX EX Young
pg/m
l
1000+ +
500
*
+
G-CSF IP-10 MIG MCP-1 KC0
Lung lesion scores (tissue damage) was reduced in exercised mice by day 10
Lung lesion scores day 8 and 10 post-infection
reduced in exercised mice by day 10
*core
1.5
2.0 uninfected NON-EX EX Young
*
vera
ge le
sion
sc
1.0*
Lesion day 8 Lesion day 10
Av
0.0
0.5
Lesion day 8 Lesion day 10
Exercise was associated with reduced serum anti-influenza antibody
Serum anti-influenza IgM and IgG - 7 days post-infection
serum anti-influenza antibody05
nm 1.5
2.0uninfected NON-EX EX Col 8
*
al d
ensi
ty a
t 40
1.0 *
Opt
ica
0.0
0.5*
IgM-DAY 7 IgG- DAY7 IgG-DAY100.0
Summary of mouse studies• Viral load in the lungs of exercised mice is reduced – (as
early as 12 hours post-infection)
Symptom severity is reduced in exercised mice• Symptom severity is reduced in exercised mice
• Levels of lung inflammatory factors and immunopathology (tissue damage) are reduced byimmunopathology (tissue damage) are reduced by exercise treatment.
• Serum anti-influenza IgG antibody is reduced by i d fl t d d i l l dexercise, and may reflect reduced viral load
• There is a short term benefit to one single session of exercise just preceding exposure to virusexercise just preceding exposure to virus.
Acute exercise benefit in humans?
• Single session of exercise immediately f ll i i tifollowing vaccination
Y d lt 2009 d i H1N1• Young adults – 2009, pandemic H1N1 (A/California/7/2009) vaccine
Blood collection
Exercise-moderate 90min; 1x
N i 90 i 2 k 4 kNo exercise; rest 90 min 2 wk 4 wk
ImmunizationImmunizationH1N1 monovalent
vaccine
Serum IgG antibody response to influenza vaccine was increased by a single session
of exercise post-immunization
Clinical implications?
• Moderate aerobic exercise in older adults appears to be more effective at reducing serum inflammatory factorsmore effective at reducing serum inflammatory factors than strength/flexibility exercise. (Many chronic diseases have inflammatory component).
• An overall improvement in aerobic fitness in obese and non-obese individuals (rather than type of exercise) is associated with improved immunity to vaccineassociated with improved immunity to vaccine
• Obesity impairs immune response to vaccination
Clinical Implications?• Regular moderate exercise, as well as a single
session of exercise improve host resistance to respiratory infection with influenza virus.respiratory infection with influenza virus.
• One mechanism of improved host resistance involves an early reduction in lung viral load.
E i t th ti f i i ti• Exercise at the time of immunization may improve antibody response to vaccine
Thank you!!!y