Transcript Slide 1

Effects of Air Pollution on the Health of Older Adults
What is the Nature of Aging?
Nancy L. Nadon, Ph.D.
Biology of Aging Program
National Institute on Aging
What is the Nature of Aging?
• Overview of biology of aging at the tissue,
cellular and molecular level
• Age-related changes in the pulmonary system
• Age-related changes in the immune system
• Interaction of the age effect with the response to
air pollution
• Use of animal models to study the effect of air
pollution on the aged
Aging • Loss of cells or cell function leading to a
reduction of function at the physiological level
• Separate from age-related diseases, although
may be related mechanistically
• Effects of pollution exposure are likely impacted
by both normal aging changes and age-related
diseases
Aging • Cell death
• Reduction in ability of stem cells or progenitor
cells to divide and differentiate
• Reduction in repair of cellular components
• Accumulation of oxidative damage
• Genomic instability and changes in gene
expression
Stressors: Inflammation, Oxidative stress,
Nutrition, Environmental exposures
Cell loss, damage or dysfunction
Age-related loss of function – frailty, susceptibility
to disease, etc.
Damage / Repair Balance Changes with Age
Young
Aged
Repair
Repair
Damage
Loss
Damage
Loss
Example - Sarcopenia
Molecular changes in satellite cells with
decrease in signaling capacity
Reduction in proliferation and differentiation
needed to injured muscle cells
Loss of muscle
Frailty
Age-related changes in Respiratory Function
Static Elastic Recoil
Chest wall compliance
Respiratory muscle strength
Gas exchange surface area
Response to hypoxia
Lung volume
Maximum inspiratory and expiratory pressure
Aging
Disease
Pulmonary Function
Environmental
Exposures
Other Exposures
Studies in animal models allow control of some of
the factors that influence pulmonary function:
•
•
•
•
Environment – air quality
Diet
Health status
Genetic background
Genetic differences between rodent strains can be
used to model specific aspects of human aging,
disease, and response to stressors.
No one model is optimal for all aspects of aging.
Awareness of the differences between strains and
substrains is important when using rodent
models.
Sprague Dawley rats and F344 rats have a
significant difference in thoracic gas volume, even
when corrected for body weight.
Specific thoracic
gas volume (ml/Kg)
Significant at p< 0.05
From Boyd et al., 1982
SD
F344
22.2
19.1
SD rats had an age-associated increase (69%) in
air spaces while F344 rats did not have a
significant change.
From Kerr et al., 1990, Exp. Gerontol. 25:563-574.
One study demonstrated an increase in lung
volume in F344 with age, but this increase
correlated with an increase in body weight.
From Pinkerton et al., 1982, Am. J. Anat. 164:155-74
Age-related changes in innervation may play a role
in the decreased response to stress in aged.
• Innervation of the smooth muscle of the trachea
and the bronchial tree is reduced in aged rats.
• Innervation of pulmonary artery is decreased in
aged rats.
From Ricci et al., 1997, Mech. Ageing Dev. 99:245-255.
NO production decreases with age in the aorta but
not in the pulmonary artery.
From Tschudi et al., 1996, J. Clin. Invest. 98:899-905.
Immune system function also decreases with age
• Elderly have higher rates of respiratory
infections, do not mount as robust a response to
infection as do the young.
• Changes in innate immunity with age also
impact response to pollution.
• Age-related changes in the pulmonary system
decrease effectiveness of the cough, reduce the
ability to clear mucous, increasing susceptibility
to infection.
Macrophage function declines with age:
•
•
•
•
•
iNOS expression decreases
Synthesis of NO intermediates decreases
ROS production decreases
Expression of IL-6 and TNFα decrease
PGE2 production increases
• Contributes to reduced dendritic cell function
• Contributes to impaired T cell response
From Plackett et al., 2004, J. Leukocyte Biol. 76:291-299
Other age-associated changes in innate immunity
• Neutrophils – defects in intracellular signaling
that reduce microbiocidal function
• Dendritic cells – reduced ability to stimulate B
and T cells
• NK cells – decreased tumoricidal activity
Interactions between age effects and effects of
exposure to pollution
Some effects of age and exposure to pollution are
similar and may have common mechanisms.
Caloric restriction:
• Moderates and/or delays onset of ageassociated phenotypes
• Protects against ozone-induced damage to
lungs*
* From Elsayed, 2001, Toxicol. 159:171-182.
Response to pollution is specific for type of
pollutant
• Fine particle pollution – almost 10-fold increase
in incidience of arrythmias
• Gaseous pllution – no significant increase in
arrythmias
From Nadziejko et al., 2004, Inhal. Tox. 16:373-380.
With ozone-induced injury models, there is
evidence of an age effect on level of injury
• 24 month old F344 rats had a higher level of
injury to alveolar ducts and epithelium than 9
mo. old.
• Repair of damage, as measured by cell division
to replace damaged cells, was as good in the
old as in the young rats.
From Vincent and Adamson, 1995, Am. J. Pathol. 146:1008-1016.
Pulmonary inflammatory response to inhaled
ultrafine particles is modified by age, ozone
exposure, and bacterial toxin.
Elder AC, Gelein R, Finkelstein JN, Cox C,
Oberdorster G.
Inhal Toxicol. 2000;12 Suppl 4:227-46.
Age alone influenced the response to fine particle
pollution
• Aged rats showed:
– 30% decrease in neutrophils from
bronchoalveolar lavage
– 86% increase in resting respiratory burst
– 129% increase in PMA-stimulated respiratory
burst
From Elder et al., 2000, Inhal Toxicol. 12 Suppl 4:227-46.
Age influenced the effect of ozone exposure,
endotoxin exposure and fine particle exposure
Treatment
Effect on unstimulated
Respiratory Burst
No treatment
Fine particle (FP)
Ozone
FP + O3
LPS
LPS + FP
LPS + O3
LPS + FP + O3
aged ≈ young
aged < young
aged > young
aged > young
aged ≈ young
aged ≈ young
aged >> young
aged >>>> young
From Elder et al., 2000, Inhal Toxicol. 12 Suppl 4:227-46.
Working with rodent models
• Advantages:
Control diet, environment, health, genetics
• Many considerations:
appropriate ages and number of time points,
sample sizes, choice of strain
The Development of Emphysema in
Cigarette Smoke-exposed Mice Is Strain
Dependent
Guerassimov et al., Am. J. Resp. Crit. Care Med.
170:974-980, 2004.
5 strains compared:
NZWLac/J, C57BL6/J, A/J, SJL/J, AKR/J
• 4 of the 5 strains showed significant increases in
Lm
• The same 4 of 5 strains showed significant
increases in inflammatory cells and cytokines
• 1 of the 5 strains (NZW) did not have a
significant change in Lm
• NZW also did not have a significant change in
inflammatory cells or cytokines
From Guerassimov et al., Am. J. Resp. Crit. Care Med. 170:974-980, 2004
Phenotypic variation in cardiovascular responses to
acute hypoxic and hypercapnic exposure in mice
Campen et al., 2004, Physiol. Genomics 20: 15-20.
A/J, BALBc/J, C3H/HeJ, C57BL/6J, CBA/J, DBA/2J, FVB/J
DBA/2J showed a different response than the other 6
strains, huge increase in frequency of arrythmias
Strain differences in lung mechanics
C3H/HeJ
A/J
C57BL/6J
B6C3F1
Functional 0.37*
Residual
Capacity (ml)
0.27
0.25
0.28
Total Lung 1.44*
Capacity (ml)
1.01
0.95
0.89
Lung
0.126*
Compliance
0.079 0.057
(ml/cm H2O)
* Significant at p<0.01
From Tankersley et al., 1999, Am. J. Physiol. 99:764-769.
0.053
Total Lung Capacity
2000
uL
1600
1200
800
400
/j
R
SW
J
FV
B/
N
C
57
B
L/
6J
eJ
/H
3H
C
LB
/c
By
J
A/
J
BA
12
9S
1/
Sv
lm
J
0
Strain
Female
Male
From Schulz, MPD 16, Mouse Phenome Database, The Jackson
Laboratory, http://www.jax.org/phenome, analyzed 3/19/05.
Lung Capacity / Body Weight
75
uL / g
60
45
30
15
/j
SW
R
J
FV
B/
N
LB
/c
By
J
C
3H
/H
eJ
C
57
B
L/
6J
A/
J
BA
12
9S
1/
Sv
lm
J
0
Female
Strain
From Schulz, MPD 16, Mouse Phenome Database, The Jackson
Laboratory, http://www.jax.org/phenome, analyzed 3/19/05.
Male
Female
Respiratory Rate
600
400
200
From Kitten et al., MPD 151, Mouse Phenome Database, The Jackson
Laboratory, http://www.jax.org/phenome, analyzed 3/19/05.
L/
J
SJ
O
D/
Lt
J
/2
J
BA
D
N
C
57
BL
/6
J
cJ
LB
/
BA
lm
12
9S
1/
Sv
A/
J
0
J
breaths per minute
Male
Many factors to consider in use of rodents to
model age-related changes in response to
exposure to pollution
• Strain and gender
• Ages and time-points
• Husbandry and housing
NIA Resources
• NIA resources page
http://www.nia.nih.gov/ResearchInformation/ScientificRe
sources/
• Aged rodent colonies information handbook
• Aged rodent tissue bank
• Aged rodent tissue arrays
• [email protected]