Exercise, Immunity & Aging Chair, Immunobiology Professor, KINES/IMBIO/GERONTOL mkohut@iastate.edu
Name: Grace Age: 91 Location California : Activity: Walking, Yoga, Tennis, Weight improvement to exercise. Lifting An Exercise Story I 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 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 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.
Exercise, aging g and non-infectious disease Heart disease Osteoarthritis Hypertension COPD (emphysema) Diabetes Frailty/disability Obesity Renal disease Osteoporosis Depression Alzheimer s Anxiety Stroke Falls/balance Cancer Cognition
? Effect of exercise on infectious disease / immunity Clinical evidence for immunologic dysfunction in older populations FIRST APPROACH: Pilot study Goal: To develop preliminary data in support of hypothesis (mouse or human model?)
Influenza / Pneumonia 7 th leading cause of death in U.S. (all ages) 5 th leading cause of death (age 65+) 3 rd leading cause of death (age 85+) ~ 40,000 deaths annually >90% of mortality in individuals > age 65 Influenza vaccine efficacy rates 70-90% in young, and only 17-53% in old (Goodwin K. 2006)
Influenza Virus Types A, B, C Virus Structure 8 segments of ss RNA inside - HA=hemagglutinin - NA=neuraminidase 3 Virus Strains in seasonal vaccine A/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)
Antibody response to vaccination 80 70 60 50 40 30 > 1:40 titer increase 20 10 0 Young H1N1 Young B Older H1N1 Older B Fagiolo, et a. Aging Clin. Exp Res. 5:451=458, 1993
Pilot study Survey physical activity, collect blood postimmunization to assess antibody level Active: exercise > 3 times/week, with increase in heart rate, breathing, sweat Moderately active some exercise, but at lower amount or intensity than active group Sedentary no physical activity
Active Moderately active Sedentary
* IgG anti-influenza antibody 5 nm) Abso orbance (40 Sedentary Mod Active Active 3.0 + 25 2.5 25 125 Reciprocal Serum Dilution
Intervention Study Phase I randomized 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 theory ction of Infec Risk o None Moderate Exhaustive
Pre-vaccine blood 4wk post blood 12wk post blood Pre-vaccine blood 4wk post blood 12wk post blood Exercise treatment 10 months Control treatment 10 months (Young subjects) Influenza Vaccine #1 Influenza Vaccine #2
Exercise improves antibody response to vaccination in older adults Change in Influenza A H1N1 Antibody titer from pre-immunization i i Lo og (10) Influenza A H1N1 HI titer 0.75 0.50 0.25 0.00-0.25-0.50-0.75 4 week 3 month Change in Influenza B Antibody titer from pre-immunization CON EX YOUNG Influenza B HI tit ter Log (10 0) 075 0.75 0.50 025 0.25 0.00 4 week 3 month
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 function Granzym me B (units/mg protein) 14 12 10 8 6 4 2 * * CON-OLD EX-OLD YOUNG 0 H1N1 H3N2 B
Summary Phase 1 A long-term aerobic exercise intervention increased antibody response to influenza vaccine (Influenza A H1N1 & H3N2). Antibody levels remained lower than young adults. 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) Depression, stress did not mediate effects of exercise
Intervention Study Phase 2 randomized 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
How might exercise alter immunity/inflammation? Psychosocial factors Exercise Immune response Neuroendocrine factors
Pre-vaccine Blood 4wk post blood 12wk post blood Pre-vaccine blood 4wk post blood 12wk post blood Aerobic Exercise treatment 10 months Flexibility/strength treatment 10 months Influenza Vaccine #1 Psychosocial surveys Influenza Vaccine #2
Psychosocial factors generally improved with either type of exercise intervention Group FLEX-Strength CARDIO-Aerobic Time PRE POST PRE POST Depression 3.2+0.4 2.8+0.4* 2.5 + 0.3 1.8+0.7* PSS 14.2 + 08 0.8 14.8 + 09 0.9 16.66 +0.7 14.9 +1.0 a (stress) Sense coherence LOT optimism 75.1 + 0.9 77.5 +1.0* 73.1+1.3 76.5+1.3* 61.7+0.8 62.8+1.2* 61.2+1.0 64.6+0.8*
Obesity (BMI>30) was associated with decreased antibody response to influenza immunization (pre-intervention) -immunizatio on - pre) Chan nge in antibod dy titer (post 1.5 1.0 0.5 00 0.0 + * 4wk A-H1N1 12wk A-H1N1 4 wk A-H3N2 12 wk A-H3N2 * + Non-ob obese
Antibody response to vaccine after the exercise intervention is dependent on improvement in fitness 10 9 improve fit non-ob + NC fit non-ob improve fit ob NC fit ob Log (2) HI tit ter 8 + 7 + 6 5 A H1N1 4wk A H1N1 12wk B 4wk B 12wk
T cell response to vaccine after the intervention is associated with change in fitness and obesity 30 nm density at 6 1.0 improve fit non-ob NC fit non-ob improve fit ob 0.8 NC fit ob 0.6 0.4 * * + * * + * * Optical 0.2 0.0 A 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 with increased antibody response to vaccine in both obese and non-obese T-cell response to vaccine was greater in subjects that improved aerobic fitness regardless of exercise treatment, and lower in obese subjects
Impact of exercise intervention on serum inflammatory factors Type of exercise Role of psychosocial factors Role of neuroendocrine (catecholamines)
Serum inflammatory IL-6 reduced d by cardio-aerobic exercise 7 6 IL-6 (pg/ /ml) 5 4 3 2 1 FLEX CARDIO FLEX B-block CARDIO B-block PRE POST
Serum inflammatory IL-18 reduced by cardio-aerobic exercise 65 60 55 IL-18 (pg/m ml) 50 45 40 35 30 FLEX CARDIO FLEX B-block CARDIO B-block PRE POST
CRP Serum C-reactive protein reduced by cardio-aerobic aerobic exercise 6 5 4 CRP (mg/l L) 3 2 1 FLEX CARDIO FLEX B-block 0 CARDIO B-block PRE POST
Summary of exercise and inflammatory factors Cardio-aerobic exercise reduced serum inflammatory 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 fat.
Influenza Infection 1) Does exercise protect against infection with live virus? 2) Mechanisms? stochasticscientist.blogspot.com
Influenza Infection i.n. Chronic exercise training ( 45min/d, 5d/wk,12wks) 24 hr rest Rest 12 weeks Acute exercise 45 minutes 1X Control treatment (rest 12 weeks) Euthanize
Body weight loss resulting from infection was reduced to greatest extent in chronic exercised mice -1-2 -3-4 -5 NON-EX A-EX C-EX -6 0 2 4 6 8 10 12 Day post-infection
The viral load in lungs was reduced by both acute and chronic exercise 1e+9 1e+8 NON-EX A-EX C-EX scale) Log viral titer (Log 1e+7 1e+6 1e+5 + * * 1e+4 1e+3 day 2 day 5 day 10
Multiple inflammatory factors in the lung were reduced by both acute and chronic exercise at in lung 2 days post infection 500 400 NON-EX A-EX C-EX pg/ml 300 200 100 0 KC MIP1a MIP1b
By day 5 post-infection, only chronic exercise showed a benefit in terms of reduced inflammatory factors. 600 500 NON-EX A-EX C-EX 400 pg/ml 300 200 100 0 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 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 mice Young BALB/c mice (2 months of age) 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-infection 7 BAL viral tite er 6 5 4 3 * uninfected NON-EX EX Young Log 2 1 0 * BAL titer
Multiple inflammatory factors in the lung were reduced in the exercised mice BAL fluid DAY 4 post-infection 2000 uninfected NON-EX EX Young 1500 + pg/ml 1000 + + 500 0 * G-CSF IP-10 MIG MCP-1 KC +
Lung lesion scores (tissue damage) was reduced in exercised mice by day 10 Lung lesion scores day 8 and 10 post-infection Av verage lesion sc core 2.0 uninfected NON-EX EX 1.5 * Young 1.0 0.5 * * 0.0 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 Optica al density at 40 05nm 2.0 1.5 1.0 0.5 uninfected NON-EX EX Col 8 * * * 0.0 IgM-DAY 7 IgG- DAY7 IgG-DAY10
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 Levels of lung inflammatory factors and immunopathology (tissue damage) are reduced by exercise treatment. Serum anti-influenza IgG antibody is reduced by exercise, and may reflect reduced d viral load There is a short term benefit to one single session of exercise just preceding exposure to virus.
Acute exercise benefit in humans? Single session of exercise immediately following vaccination Y d lt 2009 d i H1N1 Young adults 2009, pandemic H1N1 (A/California/7/2009) vaccine
Blood collection Exercise-moderate 90min; 1x No exercise; rest 90 min 2 wk 4 wk Immunization H1N1 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 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 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. 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!!!