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

Repair

Damage

Loss

Aged

Repair

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

Environmental Exposures

Other Exposures

Pulmonary Function

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.

SD F344

Specific thoracic 22.2 19.1

gas volume (ml/Kg)

Significant at p< 0.05

From Boyd et al., 1982

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 age-associated 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 aged ≈ youngFine particle (FP) aged < youngOzone aged > youngFP + O3 aged > youngLPS aged ≈ youngLPS + FP aged ≈ youngLPS + O3 aged >> youngLPS + FP + O3 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* 0.27 0.25 0.28Residual Capacity (ml)

Total Lung 1.44* 1.01 0.95 0.89Capacity (ml)

Lung 0.126* 0.079 0.057 0.053Compliance (ml/cm H2O)

* Significant at p<0.01

From Tankersley et al., 1999, Am. J. Physiol. 99:764-769.

Total Lung Capacity

0

400

800

1200

1600

2000

129S

1/Svlm

JA/J

BALB/c

ByJ

C3H/H

eJ

C57BL/

6J

FVB/NJ

SWR/j

Strain

uL

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

0

15

30

45

60

75

129S

1/Svlm

JA/J

BALB/c

ByJ

C3H/H

eJ

C57BL/

6J

FVB/NJ

SWR/j

Strain

uL

/ g

Female

Male

From Schulz, MPD 16, Mouse Phenome Database, The Jackson Laboratory, http://www.jax.org/phenome, analyzed 3/19/05.

Respiratory Rate

0

200

400

600

129S

1/Svlm

JA/J

BALB/c

J

C57BL/6

J

DBA/2J

NOD/L

tJ

SJL/J

bre

ath

s p

er m

inu

te

Female

Male

From Kitten et al., MPD 151, Mouse Phenome Database, The Jackson Laboratory, http://www.jax.org/phenome, analyzed 3/19/05.

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/ScientificResources/

• Aged rodent colonies information handbook

• Aged rodent tissue bank

• Aged rodent tissue arrays

• rodents@nia.nih.gov