Journal of Gerontology: BIOLOGICAL SCIENCES
1998, Vol. 53A, No. 5, B347-B353
Copyright 1998 by The Gerontological Society of America
Stress Exacerbates Age-Related Decrements
in the Immune Response to an Experimental
Influenza Viral Infection
David A. Padgett,1 Robert C. MacCallum,23 and John F. Sheridan 1,3
'Department of Oral Biology, College of Dentistry, and Department of Medical Microbiology and Immunology,
College of Medicine, department of Psychology, College of Social and Behavioral Sciences,
and 'Institute for Behavioral Medicine Research, The Ohio State University.
To test the hypothesis that stress exacerbates immune decrements associated with aging, the impact of restraint
stress on immunosenescence was assessed using an experimental model of influenza A/Puerto Rico/8/34 viral infection. Beginning one day prior to infection, male C57BL/6 mice, 3 and 22 months of age, were subjected nightly to
12 hours of restraint stress. In both age groups, restraint induced a comparable increase in serum corticosterone
levels. However, in contrast to the 3-month-old controls, serum corticosterone levels in 22-month-old mice returned
to baseline slower after removal of the stressor. The characteristic influenza-driven increase in cellularity of the
lung and draining lymph node was decreased by age and further suppressed by stress. Natural killer cell activity
and virus-specific T helper cell function were also blunted by age and almost completely abrogated by stress. Furthermore, due to the weak immune response to viral infection, aged animals subjected to stress had a lower survival
rate than age-matched controls.
A
DVANCING age brings with it an increased vulnerabilL ity to infectious agents where infection is the fourth
most common cause of death (1). In addition, hospitalization of elderly individuals with disabling diseases, such as
viral pneumonia, requires a major investment of medical
care. Associated with advancing age is a parallel decline in
immune function (immunosenescence), which is a major
contributing factor to the high incidence of influenza in the
elderly population. Virtually every human being who survives into advanced adulthood expresses an aspect of this
immunodeficient state (2,3). Among the decrements in
immune function associated with age is a decline in the formation of high-affinity antibodies, an inability to generate
long-lasting memory after vaccination, and a decreased
reactivity to antigens initially encountered earlier in life
(4,5). To gain a better understanding of the mechanisms
underlying immunosenescence, immunogerontologists have
been attempting to map age-associated changes in immune
responses to critical cellular alterations. From these studies,
we have learned that many of the deficient immune responses have been mapped to decrements in immunoregulation, with specific attention being paid to helper T cell
activity (6).
It is important to address immunosenescence together
with the neuroendocrine influences of stress because many
of the underlying regulatory mechanisms controlling immune and neuroendocrine functions are shared (7). Common receptors and ligands among the immune, endocrine,
and nervous systems suggest that physiologic changes in
one system may impact regulation of the others (8,9). For
example, interleukin-1 (IL-1) and IL-6 produced during
inflammatory reactions not only activate immune function
but also modulate the hypothalamic-pituitary-adrenal (HPA)
axis. Products of HPA activation can regulate, in a feedback manner, the newly activated immune responses (10).
However, pathophysiologic perturbation of the HPA axis
by exogenous stressors can have significant consequences
for homeostasis and the health of the host. For example, the
physiologic changes associated with stress, such as the rise
in serum glucocorticoids (GC), are implicated in suppression of T cell immunity and a subsequent increase in the
pathophysiology of both herpes (11,12) and influenza viral
infections (13-15). Many of the changes in immune function associated with stress, such as decreases in proinflammatory cytokine responses, natural killer cell activity, and
T-helper cell activation (13,15) are comparable to those
noted with advancing age (16,17).
Therefore, these experiments were designed to test the
hypothesis that stress-mediated modulation of anti-viral
immunity would exacerbate age-related decrements in
immune function. First, the inflammatory response to influenza A virus infection was compared between 3- and 22month-old C57BL/6 mice. Next, antiviral immunity including natural killer (NK) cell responses and virus-specific
T-helper cell cytokine production was assessed. Finally, to
investigate the potential mechanism by which stress exacerbated immunosenescence, serum corticosterone levels
were measured.
METHODS
Animals.—Virus-antibody-free C57BL/6 male mice at 3
and 22 months of age were obtained from Charles River,
Inc. (Wilmington, MA) and allowed to acclimate to their
B347
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PADGETT ETAL.
surroundings for 7-10 days before initiation of any experimental procedures. All mice were housed 5 per cage and
provided free access to food and water. The American
Association for the Accreditation of Laboratory Animal
Care (AAALAC) accredited facility is maintained on a 12hour light/dark cycle (lights on at 0600 h).
Virus stock.—Influenza A/Puerto Rico/8/34 (A/PR8)
virus was obtained from the American Type Culture Collection (Rockville, MD) and propagated in the allantoic cavity
of 10-day-old embryonated chicken eggs. Infectious allantoic fluid was collected, clarified by low-speed centrifugation, and stored at -70°C. The virus titer was determined to
be 1280 hemagglutinating units (HAU) per ml, using
human type O erythrocytes.
Infection of mice.—Mice were infected with .05 ml containing influenza A/PR8 virus diluted in PBS and instilled
intranasally. For survival studies mice were infected with
24 HAU A/PR8. For cellular studies, however, it was necessary to use a lower dose of virus (16 HAU) to ensure that
sufficient numbers of control animals survived for assay at
days 7 and 10. Prior to infection, all mice were anesthetized
with an intramuscular injection (.05 ml) of 10% Rompun
(Haver-Lockhart, Shawnee, KS) plus 10% Ketaset (Bristol
Labs, Syracuse, NY). Infection was verified by seroconversion using a flu-specific IgG ELISA. Preinfection serum
samples were routinely screened for antibody to influenza
virus to assure that all mice were seronegative prior to
experimentation.
Restraint stress paradigm.—To reliably and reproducibly
activate core stress responses including the HPA axis, mice
were placed in well-ventilated 50 ml centrifuge tubes for
one cycle of restraint prior to infection and six subsequent
cycles. Individual mice were placed in tubes at 2100 h
(lights out at 1800 h) and removed at 0900 h (lights on at
0600 h). Control mice were food- and water-deprived
(FWD) during the same time period. However, these FWD
animals were free to roam in their cages.
Isolation of mononuclear cells.—To determine the influences of age and stress on NK activity and cytokine production, lymphoid cells were isolated from the spleen and
the mediastinal lymph node, which drains the lower respiratory tract, by macerating the tissues in Hanks' balanced
salt solution (HBSS) using glass homogenizers. Mononuclear cells were obtained from the lung by digestion with
collagenase for 90 minutes at 4°C. Cells from each group
of animals were pooled, washed three times, and resuspended at a density of 2.0 X 106 viable cells/ml in Dulbecco's modified Eagle's medium (DMEM) supplemented
with 5% (v/v) heat-inactivated FBS, 100 U/ml penicillin,
100 ug/ml streptomycin sulfate, 20 mm Hepes buffer,
.075% (w/v) sodium bicarbonate, 2.0 mm glutamine, and
50uM 2-mercaptoethanol.
Measurement of NK cell cytotoxicity.—NK cell activity
was measured using a standard chromium release assay
(18). Briefly, serial dilutions of effector cells (in 0.1 ml vol-
ume) beginning at 1.0 X 107 cells/ml were plated with 1.0
X 104 [5lCr]-labeled YAC-1 target cells (.05 ml) in 96-well
V-bottom microtiter plates. All samples were prepared in
triplicate. To obtain maximum and minimum [5lCr] release,
YAC-1 cells were added to 0.1 ml sodium dodecyl sulfate
(SDS) or RPMI 1640, respectively. After a 5-hour incubation at 37°C, plates were centrifuged at 200 X g for 5 minutes, and 0.1 ml of supernatant was removed from each
well. Supernatants were assayed for 5lCr content using a
gamma counter, and percent cytolysis was calculated using
the following equation.
„
, .
cpm (sample) - cpm
(spontaneous)
% cytolysis = v ,v—.
\ v—^7-.
cpm (maximum) - cpm (spontaneous)
Measurement of IFN-y and IL-10.—Mononuclear cells
were placed in triplicate wells of a sterile 96-well flat bottom tissue culture plate at a concentration of 2.0 X 105 cells
in 100 ul of supplemented DMEM. To each well, an additional 50 ul volume of medium containing 10 HAU of
influenza A/PR8 virus was added. Cultures were incubated
at 37°C in 10% CO2 for 48 hours. Cell-free supernatants
were collected and stored at -20°C before being assayed for
production of IFN-y and IL-10. The levels of IFN-y and
IL-10 in culture supernatants were quantitated via sandwich
Ag ELISAs as previously reported (19). The concentrations
of cytokines in culture supernatants were determined by
comparison to standard curves generated using fourfold
dilutions of recombinant mouse cytokines (Pharmingen, San
Diego, CA). The sensitivity of each ELISA was taken as
three standard deviations above the mean value from three
negative (media only) control wells. The sensitivities of the
cytokine ELISAs were 40 pg/ml for IFN-y, and 50 pg/ml
for IL-10. For statistical purposes, a cytokine level falling
below the detectable limits of the ELISA was assigned the
value corresponding to the sensitivity of the assay.
Determination of serum corticosterone levels.—To guard
against fluctuations in serum corticosterone levels due to
circadian rhythm, blood samples were obtained at 0900 h
each day of assessment. Mice were briefly restrained (less
than 2 minutes) in polystyrene tubes, and blood was taken
from the tail vein. Sera was stored at -70°C until assayed
for corticosterone by radioimmunoassay. [l25I]corticosterone
kits for rats and mice (ICN Biomedical, Costa Mesa, CA)
were used to determine serum corticosterone levels. Levels
were determined from individual mice using a standard
curve and expressed in ng/ml.
Statistical analyses.—Statistical analyses of differences in
survival between the control and restraint-stressed groups
were assessed using chi-square analysis of survival rates 12
days post-infection. Effects of age and restraint stress on
other outcome variables were assessed using analysis of
variance (ANOVA). For serum corticosterone, the ANOVA
design was Age X Time, with measurements at 5 timepoints. For the other dependent variables (lymph node cellularity, infiltration of the lung, NK cell cytotoxicity, and
helper T cell activation as indicated by IFN-y and IL-10)
the design was Age X Restraint-Stress-Group X Time. Of
B349
STRESS AND IMMUNOSENESCENCE
primary interest in the ANOVA results were the main
effects of age and restraint stress, and the interaction of
these factors.
Power analyses indicated that the design was adequate
for detecting large effects of age and restraint stress. For
example, considering a given dependent variable, if the true
difference between the means for 3-month-old mice and
22-month-old mice was 1.5 times the standard deviation of
the variable, the effect would be considered large. Based on
this criterion, power for detecting main effects of age and
restraint stress, and the interaction of these factors, using
five animals per cell and a = .05, would be approximately
.85 for each effect. In fact, results to be described show
many effects much larger than this. Power estimates based
on observed effects were nearly all >.95, except for a few
interactions.
RESULTS
Influence of age and stress on survival from influenza A
viral infection.—The first set of experiments was designed
to examine the effects of stress and age on the survival of
influenza A-infected mice. As shown in Figure 1, 22-monthold mice had a higher level of mortality when infected with
influenza A virus as compared to 3-month-old animals. Furthermore, restraint stress increased mortality of 22-monthold animals while not impacting survival of 3-month-old
C57BL/6 male mice. Because of the stress and age-associated increase in influenza-mediated mortality, subsequent
experiments were designed to examine their influences on
the anti-viral immune responses.
Effect of age and stress on lymph node cellularity.—Following infection with influenza A virus, there is a character-
100-
-©-•-Q--«~
•-—«
80-
istic swelling of draining lymph nodes and accumulation of
mononuclear cells within the parenchyma and alveolar
spaces of the lung. The mediastinal lymph node (MLN)
drains the lower respiratory tract and serves as an important
locus of antigen-presentation for clonal expansion of antigen-specific lymphocytes. ANOVA results for lymph node
cellularity yielded significant main effects of age [F(l,16) =
146.15, p < .01], restraint stress [F( 1,16) = 70.62, p < .01],
and the interaction of these factors [F(l,16) = 6.36, p <
.05]. Inspection of the means (Figure 2) shows overall
higher lymph node cell numbers in 3-month-old vs 22month-old mice, and higher cell numbers in control vs
restraint-stressed animals. In 3-month-old animals, infection with 16 HAU A/PR8 resulted in an increase in MLN
cell numbers by 3 days post infection (p.i.), increasing further by 5 days p.i., and reaching a peak 7 days p.i. (Figure
2). Both age and restraint had a significant effect on lymph
node cell numbers. Restraint stress suppressed peak infiltration of cells by greater than 50% in 3-month-old mice. Similarly, lymph node cell numbers obtained from unstressed
22-month-old mice were comparable to those obtained
from stressed, 3-month-old animals. Restraint stress of the
22-month-old animal further suppressed the cellularity to the
point that the cellularity of the lymph node resembled that
of an uninfected animal.
Effect of age and stress on mononuclear cell infiltration
of the lung.—As with the MLN, during infection with
influenza A/PR8 there is extensive recruitment of mononuclear cells into the lung parenchyma, which is characteristic
of interstitial pneumonia. Infiltration of cells into the lung
parenchyma is important for the development of antigenspecific immunity. Several sets of results are available to
assess the effects of age and stress on such infiltration. Figure 3 depicts data from two replicate experiments based on
pooled samples from multiple animals. Closely paralleling
Control, 3-Month
RST, 3-Month
Control, 22-Month
RST, 22-Month
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Days Post Infection
Figure 1. Age and stress increase the mortality associated with influenza infection. 3- and 22-month-old male C57BL/6 mice were infected
intranasally with 24 HAU influenza A/PR8 virus. Restraint stress (RST)
was initiated 1 day prior to infection and continued nightly throughout.
Differences in survival were determined 12 days after infection when no
additional virus-mediated mortality was expected. Numbers in parentheses = (number of survivors/total animals per group). *p < .05 compared to
3-month controls, **p < .05 compared to 22-month controls.
Figure 2. Effect of age and stress on lymph node cell numbers. Both
age and restraint stress (RST) decreased the number of cells and the rate
of accumulation of cells within the lymph node draining the lungs of
influenza-infected mice. After infection with 16 HAU influenza A/PR8
virus, on each day represented, five animals per group were sacrificed,
and mononuclear cells were obtained from the mediastinal lymph node.
Data represent the mean ± SD.
PADGETT ETAL.
B350
A
12
3-Month
3-Month/RST
22-Month
22-Month/RST
I
I 3-Month Control
• M 3-Month RST
22-Month Control
22-Month RST
Day 3
Day 5
Day 7
Days Post Infection
3
5
7
Days Post Infection
Figure 3. Age and stress reduced the infiltration of mononuclear cells
into the lungs of influenza-infected mice. After infection with 16 HAU
influenza A/PR8 virus, five animals per group were sacrificed on each day
represented. Lungs were removed, pooled, and digested with collagenase
to allow assessment of the mononuclear cell infiltration induced by virus
infection. The two replicate experiments are represented as A (Experiment 1) and B (Experiment 2).
the change in cellularity of the lymph nodes, infection of 3month-old control animals with influenza A/PR8 resulted in
an increase in the number of cells obtained from the lung
between 3 and 5 days post infection. Peak levels were
obtained 7 days post infection. Again, restraint had a significant effect on lung cellularity, suppressing peak infiltration
of cells by greater than 40% in 3-month-old mice. Advancing age similarly limited the infiltration of cells into the
lungs. Between 5 and 7 days post infection, lung mononuclear cell numbers obtained from unstressed 22-month-old
mice were comparable to those obtained from stressed, 3month-old animals. Furthermore, restraint stress of the 22month-old animals further suppressed the cellularity.
In a third experiment, data were available on individual
animals at 3, 5, and 7 days p.i. These data were analyzed
via ANOVA and showed significant effects of age [F(l,16)
= 53.60, p < .01] and restraint stress [F(l,16) = 65.87, p <
.01] with no significant interaction. The means from these
data (data not presented) yield the same interpretation of
these effects as do the results presented in Figure 3.
Figure 4. Effect of age and stress on NK cell cytotoxicity in the lungs
of influenza-infected 3- and 22-month-old mice. After infection with 16
HAU influenza A/PR8, 5 animals per group were sacrificed on each day
represented. Mononuclear cells obtained from collagenase digested lungs
were tested for their ability to lyse 51CR-labeled YAC-1 target cells. The
effector to target ratio was set at 100:1. NK cytotoxicity was not detected
in 3- or 22-month-old uninfected animals. Both age and restraint stress
(RST) suppressed NK cell cytotoxicity from the lungs 3, 5, and 7 days
post infection. Data represent the mean ± SD from 5 animals each with
triplicate cultures.
Influence of age and stress on NK cell cytotoxicity.—The
present experiments were designed to directly compare the
effects of age and/or stress on innate immunity as represented by the cytotoxic activity of natural killer cells. Natural killer activity was assayed from the lungs of influenzainfected 3- and 22-month-old mice 3, 5, and 7 days p.i.
ANOVA results yielded significant main effects of age
[F(l,56) = 233.89, p < .01] and restraint stress [F(l,56) =
450.09, p < .01], as well as a significant interaction of these
factors [F(l,56) = 34.96, p < .01]. Inspection of means
(Figure 4) reveals higher NK cell activity for 3-month-old
versus 22-month-old mice, and for control versus restraintstress mice. Natural killer cell activity was undetectable in
the lungs of both 3- and 22-month-old uninfected animals.
The data show that 3 days p.i. NK activity was significantly
lower in 22-month-old animals as compared to 3-month-old
mice. Restraint stress significantly reduced NK activity in
3-month-old mice to levels similar to that obtained from
cells from 22-month-old nonstressed animals. Restraint further suppressed NK activity in 22-month-old animals.
Influence of age and stress on helper T cell activation.—
To assess an important aspect of acquired anti-viral T cell
immunity, we analyzed T-cell cytokine production. Interferon-7 (THl-type) and IL-10 (TH2-type) were measured in
supernatants of lymph node cells restimulated with viral
B351
STRESS AND IMMUNOSENESCENCE
antigen in vitro. ANOVA results for IFN--y yielded significant main effects of age [F(l,16) = 44.78, p < .01] and
restraint stress [F(l,16) = 85.50, p < .01], and a nonsignificant interaction. Results for IL-10 followed the same pattern
with significant main effects of age [F(l,16) = 19.68, p <
.01] and restraint stress [F(l,16) = 54.06, p < .01]. As seen
with NK cell activity, cytokine production by cells from 22month-old animals was significantly lower than that from
3-month-old mice (Figure 5). Both IFN-7 and IL-10 were
lower in 22-month-old animals. Restraint further suppressed
cytokine production by cells in 22-month-old animals.
the activation of the hypothalamic-pituitary-adrenal axis
between the 3- and 22-month-old mice, we noted a slower
return to baseline in the old animal. Two days after removal
of restraint stress (6 total cycles), 3-month-old mice had
serum corticosterone levels below 100 ng/ml (baseline of 56
ng/ml), whereas 22-month-old animals still had serum corticosterone levels above 200 ng/ml. Furthermore, after the 4th
day post stress, corticosterone levels in the old mice were
still twice those of their pre-stress baseline. At the same time
post stress, the 3-month-old mice had levels within two
standard deviations of their baseline.
Elevation of serum corticosterone by restraint stress.—
Previous reports have established the role of glucocorticoid
hormones in the suppression of anti-viral immunity (e.g.,
inflammation, IFN-7 production) during stress (15,20).
Therefore, to investigate the influence of age on activation
of the HPA axis, serum corticosterone levels were measured
in uninfected animals. ANOVA results indicated a significant effect of age [F(l,16) = 84.14, p < .01]. Inspection of
group means (Figure 6) shows this age effect to be essentially nonexistent at pre-stress baseline. After restraint for 12
hours on six consecutive days, 3-month-old mice had peak
serum corticosterone levels of 376 ± 26 ng/ml. The response
to the stressor (i.e., glucocorticoid elevation) was comparable in the 22-month-old animals with peak levels of 387.4 ±
23 ng/ml. Although there was no discernible difference in
DISCUSSION
1250
A) IFN-y
The increased vulnerability to infectious agents that arises
with advancing age is undoubtedly due, in part, to the welldocumented age-associated decrements in immune function
(21-23). Therefore, it should come as no surprise that aging
is accompanied by a decrease in survival from an influenza
viral infection, as is reported herein. However, the data
show that stress and the accompanying activation of the
HPA axis further suppressed immune function in aged animals. While aged animals have a reduced capacity to mount
both innate and virus-specific immune responses, restraint
stress markedly abrogated the response to infection. The
characteristic antigen-driven increase in cellularity of the
lung and draining lymph node was decreased by age and
further suppressed by stress. Natural killer cell activity,
needed for early clearance of virus-infected cells within the
lung (24,25), was also notably decreased by age and further
depressed by stress. The subsequent activation of virusspecific T cells was likewise blunted by age and almost
1000 -
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Young
Young/RST
Old
Old/RST
1
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300 -
600
B) IL-10
200 -
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1
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2
6
2-Days After 4-Days After
Days of Stress
3
5
7
Days Post Infection
Figure 5. Effect of age and stress on IFN--y and IL-10 secretion within
the draining lymph node. Both age and restraint stress (RST) suppressed
the production of IFN--y and IL-10 from lymph node cells after infection
with influenza A/PR8 virus and restimulation with viral antigen in vitro.
Data represent the mean ± SD from 5 animals each with triplicate cultures.
Figure 6. Effect of restraint and age on serum corticosterone levels.
Three- and 22-month-old C57BL/6 male mice were restrained nightly in
well-ventilated tubes for 12 hours beginning at 2100 h. After the second
and sixth days of stress, upon removal from the restraint tubes, blood was
collected and assayed by radioimmunoassay for serum corticosterone.
Corticosterone was measured at 0900 h 2 and 4 days after restraint stress
was concluded. Data represent the mean ± SD of 10 animals at each time
point.
B352
PADGETTETAL.
completely negated by stress. This 50% reduction of already
low NK and T cell responses appears to be sufficient to
impair the immune response and lead to lower survival.
Therefore, one of the long-term objectives of research on
aging must be to define the mechanisms underlying age and
stress-related changes in immunocompetence and susceptibility to infection. For example, why do elderly people
remain at risk for influenza despite years of intense work on
the efficacy of influenza viral vaccines? And similarly, how
does behavior (i.e., stress) increase the occurrence of respiratory infections in elders, seen in such circumstances as caregiving to patients with Alzheimer's disease? (26). To provide
answers, it is important to address both aging and stress
simultaneously, as some of the underlying mechanisms may
be shared with regard to modulation of immunity.
Systemic theories of aging have been based on the progressive deterioration of regulatory networks that are responsible for integrating and adapting the functions of
cells, tissues, and their responses to internal and external
stimuli. These theories have focused on two major physiologic networks, the neuroendocrine and immune systems.
The neuroendocrine theory is based on the notion that the
hypothalamus, pituitary, neurosecretory components, and
pituitary-dependent target glands (i.e., adrenal) control
every function of the body (27,28). Conversely, the immunologic theory of aging is based on the notion that the
immune system, and its many cellular and humoral components, is solely responsible for maintaining the overall
"health" of the body (16). However, the discovery of the
complex interactions working among the neuroendocrine
and immune systems has revealed that some age-associated
alterations in both systems are mutually interdependent.
Evidence from a wide variety of fields indicates that
neuroendocrine-immune interactions provide a biological
mechanism for resistance or susceptibility to disease (2932). Although specific central pathways through which the
neuroendocrine system interacts with the immune system
have not been completely elucidated, two major efferent
pathways involve hormonal mediators and autonomic
innervation. Given the interactions that exist between the
neuroendocrine and immune systems, age-associated alterations in the neuroendocrine system are predicted to contribute to declining immune responses in aged persons.
Therefore, as an alternative to an "either or" hypothesis,
where aging results from a decline in either the neuroendocrine or the immune systems, the dysfunctions associated
with aging may instead be a result of a loss of interactions
between these two physiologic systems during the aging
process. Although the mechanisms behind immunosenescence are still being unraveled, it is becoming increasingly
clear that many of the physiologic changes associated with
aging are characterized by deficient communication within
and among the complex regulatory networks.
This close functional relationship between the neuroendocrine system and the immune system is highlighted during the stress response. Generally defined, a stressor is any
stimulus that disrupts normal physiologic equilibrium or
homeostasis, and the stress response is the set of neural and
endocrine adaptations directed at restoring homeostasis.
This response is a disparate body-wide set of adaptations,
responding to a specific challenge and to the magnitude of
that stimulus. Neuroendocrine changes set and reset priorities for organs throughout the body and confer a survival
advantage in the face of a stressor (9). Glucose and free
fatty acids are mobilized from storage tissues and made
available for energy production within critical tissues
(brain, heart, skeletal muscle); further energy storage is
halted. Blood is shunted from the skin, mucosa, connective
tissue, and kidneys; blood flow to the heart and skeletal
muscle is increased. Digestion, growth, reproduction, and
immunity are suppressed. During a short-term stressor, the
costs associated with suppression of these systems can be
contained, but, as expected, these responses can be deleterious if activated chronically. Thus, the most important facts
about stress physiology can be summed in two points; (a) if
an organism cannot appropriately initiate a stress response
during an acute stressor, the consequences can be deleterious, and (b) if an organism cannot appropriately terminate a
stress response at the end of stress, or if it is hyperresponsive because of repeated or chronic stressors, numerous
stress-related diseases can emerge. Thus, the stress response is a vital set of adaptations on the part of the body,
but a potentially dangerous one if not tightly regulated.
Aging may be thought of as a time of decreased capacity
to respond appropriately to stressors; the aged individual
may require less of an exogenous insult for homeostasis to
be disrupted or may require longer to reestablish homeostasis once the stressor has occurred. In this study, aged mice
showed a diminished ability to turn off the neuroendocrine
response to the stress once the stressor was removed. Such
dysregulation is also seen with regard to the nervous system after the end of a stressor. Perego and colleagues (33)
have shown that stress induced noradrenaline levels in rat
hypothalamus which, in young animals returned to normal
shortly upon removal of the stressful stimulus, remained
elevated significantly longer in old rats subjected to the
same stressor. This response is not limited to the hypothalamus; plasma catecholamines persisted longer in old than in
young rats following acute stress (34). Thus, these findings
provide evidence that aged organisms respond to stress less
adaptively than do young organisms.
In conclusion, we have confirmed that aging is associated with decrements in immune function. However, we
have also provided evidence that the inability of aged animals to respond adaptively to stress further exacerbates
immunosenescence. Because receptors and ligands are
shared among the immune and neuroendocrine systems,
changes that disrupt equilibrium in one of the systems can
have deleterious consequences for regulation of the other.
Therefore, when defining mechanisms that underlie immunosenescence, it may be important to pay particular attention to
those aspects that control homeostasis and adaptation,
because many of the underlying regulatory mechanisms controlling immune and neuroendocrine function are indistinct
from one another.
ACKNOWLEDGMENTS
This work was supported in part by grants to Dr. John F. Sheridan from
the National Institute of Mental Health (R01-MH46801) and the National
Institute on Aging (P01-AG11585).
STRESS AND IMMUNOSENESCENCE
The authors thank Joseph Rinehart, Julie Dierksheide, and Wendy
Lasekan for their technical support.
Address correspondence to Dr. John F. Sheridan, Box 192, Postle Hall,
The Ohio State University, 305 West 12th Avenue, Columbus, OH 43210.
E-mail: [email protected]
18.
19.
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Received October 17, 1997
Accepted February 25, 1998
How long is 12 years?
For a hummingbird, time for
twelve 2000-mile migrations
from Central America to
Alaska.
For mice, time for
generations to die of old age.
The tiny rufous hummingbird, the size of your thumb, its wings a blur, zips its way
happily through twelve years or more of life. A mouse, not much larger and much less
energetic, barely dodders along for three. What causes the difference?
A child given a kitten will still be a youth when the kitten dies of old age. Why does
the cat age so quickly?
Jeanne Calment retired in 1940 at the age of 65. Thirty-five years later, she was still
merrily bicycling over the hills of France, and in 1996, fifty-six years after retiring, she
tried something new: she released a music/rap CD ("Time's Mistress"). How could she
manage it?
If you're studying biology and these questions (and others like them) interest you, why not join us and
help find the answers? Become a student member in the Biological Sciences section of the
Gerontological Society of America! For one low, highly subsidized fee, you'll receive:
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allows you to expand your interest to gerontology in general, with over 350 major
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