Exercise Immunity & AgingExercise, Immunity & Aging

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