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Keith C. Meyer
Department of Medicine, University of Wisconsin Medical School, Madison, Wisconsin
Population demographics of the United States and other industrialized countries are gradually shifting toward an increased percentage of elderly adults. Life expectancy in the United States at
birth has gone from 48.3 yr in 1900, to 71.1 yr in 1950, to 79.9 yr
in 2002, while the total United States population has grown from
151 million in 1950 to 288 million in 2002 (1). The number of
adults age 65 yr and older has gone from 12 million in 1950
(8% of the total population) to 36 million (12% of the total
population) in 2002, and there has been a threefold increase in
persons age 65 yr and older and an eightfold increase in persons
age 85 yr and older from 1950 to 2002.
In 2002, inuenza and pneumonia together were the seventh
leading cause of death for all persons in the United States and
the fth leading cause for persons age 65 yr and older (1). Inuenza and pneumonia accounted for 1% of deaths from all causes
in persons 25 to 44 yr of age versus 3.2% of deaths for persons
age 65 yr or older, and pneumonia is the leading cause of death
from infection in the elderly. These statistics indicate that lower
respiratory tract infection is a leading cause of death in the elderly,
and bacterial pneumonia is quite capable of causing premature
death or serious and sustained disability in previously healthy,
elderly adults who had been leading productive lives before their
episode of respiratory infection. Nonetheless, despite statistics
that show that the elderly are more likely to develop pneumonia
and have a fatal outcome of their infection, advanced age by itself
does not signify an immunodecient state that predisposes all
(Received in original form August 1, 2005; accepted in final form September 6, 2005)
Correspondence and requests for reprints should be addressed to Keith C. Meyer,
M.D., K4/930 Clinical Sciences Center, 600 Highland Avenue, Madison, WI 537929988. E-mail: kcm@medicine.wisc.edu
Proc Am Thorac Soc Vol 2. pp 433439, 2005
DOI: 10.1513/pats.200508-081JS
Internet address: www.atsjournals.org
434
TABLE 1. RESPIRATORY SYSTEM CHANGES IN STRUCTURE AND
FUNCTION ASSOCIATED WITH ADVANCING AGE
Structural and anatomic changes in the lungs
Disruption and loss of elastin fibers
Altered cross-linking of matrix (elastin and collagen)
Decrease in diameter of small bronchioles
Enlargement of terminal airspaces
Increased number of pores of Kohn
Loss of total alveolar surface area
Decrease in number of capillaries per alveolus
Other respiratory system changes
Decrease in mucociliary clearance efficiency
Decrease in respiratory muscle function
Decrease in chest wall compliance plus altered chest wall contour
Changes in lung physiology and function
Decrease in lung elastic recoil (increased lung compliance)
Increase in residual volume and FRC
Decrease in FVC and forced expiratory flows (FEV1, FEF2575)
Decrease in inspiratory capacity
Decrease in DLCO
Decrease in PaO2
Decrease in maximal oxygen consumption with exercise
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shift in T-cell subsets and activation markers, increased immunoglobulin and IL-6 concentrations, increased AM oxyradical production, and decreased vascular endothelial growth factor concentrations (3438). These changes may be benecial for immune
surveillance and resisting infection, but they may also reect
dysfunctional immunoregulation, altered responses to environmental factors, an effect of age-associated structural lung
changes, an increased predisposition to aspiration, and a decline
in efcacy of mucociliary clearance. These changes may also
contribute to age-associated changes in matrix components and
the decrease in elastic recoil and structural changes observed in
the aging human lung.
Because the AM gures prominently in inammatory responses and pulmonary host defense, various aspects of AM
function have been evaluated to some degree in elderly populations and animal models. Examination of macrophage populations in aged animals and in humans have suggested that aging
is associated with a decline in numerous macrophage functions
that include the expression of certain pattern-recognition receptors, such as Toll-like receptors, a reduced capacity for phagocytosis, decreased generation of nitric oxide, and impaired secretion
of certain cytokines and chemokines (39). Because Toll-like receptors are key receptors for macrophage responses to pathogens and
for the initiation of both innate and adaptive immune responses,
impaired Toll-like receptor expression and function by AM may
play a key role in susceptibility to respiratory infections in the
elderly. In addition to the demonstration that macrophages from
aged mice have reduced Toll-like receptor expression (40), AM
from aged rats have been shown to have impaired nitric oxide
production in response to concanavalin A (41) and impaired
tumor necrosis factor- release on stimulation by LPS that
seemed to be linked to decreased protein kinase C activation
and translocation (42). Although little is known about the effects
of advanced age on AM function in humans, Zissel and coworkers (43) have shown a decrease in human AM accessory cell
function that correlated with advanced age but could not demonstrate an effect of age on spontaneous release of tumor necrosis
factor-, transforming growth factor-, or IL-6. Antiinammatory cytokine production by AM in response to proinammatory
stimuli may also be impaired and may have important consequences for resolution of inammation induced by infection
or noninfectious injurious agents. Corsini and coworkers (44)
recently demonstrated that AM from aged rats that were exposed to carrageenan displayed impaired production of IL-10,
which correlated with an accentuated inammatory response in
the lungs of aged rats following carrageenan challenge when
compared with young rats. Interestingly, the Leiden 85-plus
study (45) demonstrated that impaired production of both proinammatory and antiinammatory cytokines by ex vivo whole
blood samples from 85-yr-old subjects predicted a greater than
twofold increase in overall mortality risk that was independent
of the presence of chronic illnesses, and these authors speculate
that impaired innate immunity, as reected by impaired production of cytokines produced by cellular components of the innate
immune system, is predictive of frailty and increased risk of
mortality in the elderly.
One other aspect of innate immune function in the elderly
that may have important consequences for preventing or limiting
bacterial pneumonia is neutrophil function. Although neutrophil
chemotaxis remains essentially intact and N-formyl-methionylleucyl-phenylalanine, (fMLP)-induced superoxide anion production is relatively unaltered, the phagocytic ability of peripheral
blood neutrophils from elderly donors for opsonized bacteria or
yeast has been shown to be impaired (33), which may, in part,
be explained by age-associated reduction in the expression of cell
surface CD16 (46). Additionally, de Martinis and coworkers (47)
436
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Pneumonia is a leading cause of death and debilitation for individuals 65 yr of age or older. Many factors increase the risk of
pneumonia for the elderly and are not necessarily associated
with waning immunity. Systemic immune responses, particular
the cellular and humoral components of adaptive immunity,
however, gradually decline with advancing age and are thought
to be a major risk factor for lower respiratory tract infection.
This age-associated decline in immune function has provided
the rationale for vaccination against the most common bacterial
and viral pathogens (pneumococcus and inuenza A) as a preventive measure against lower respiratory tract infection. Compartmentalized immunity in the lung is highly dependent on
intact innate immune mechanisms and their interaction, when
necessary, with adaptive immune responses. Relatively little is
known about how these immune mechanisms change in the
pulmonary compartment with advancing age, however, especially components of innate immunity. Sampling of airspace secretions suggests that immune cell populations and proles differ
between otherwise healthy elderly versus younger individuals,
but the signicance of these ndings is unknown. Some investigators have found various defects in AM function in aged rodents
and in humans, suggesting that pulmonary innate immunity and
resistance to respiratory infection may be compromised, at least
in part, by a decline in AM immune and inammatory responses
in elderly individuals. Identication and amelioration of risk
factors, vaccination, and prompt recognition and treatment of
pneumonia are all likely to lessen the morbidity and mortality
that pneumonia holds for the elderly. Future research may identify key changes in compartmentalized immune function in the
aged lung that increase the risk of infection for the elderly and
lead to strategies to modulate these changes and maintain a level
of resistance to respiratory infection that is characteristic of
younger individuals.
Conflict of Interest Statement : K.C.M. does not have a financial relationship with
a commercial entity that has an interest in the subject of this manuscript.
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