Age, exercise, and the outcome of sepsis
Banerjee and Opal Critical Care
Age, exercise, and the outcome of sepsis
Debasree Banerjee 0 1
Steven M. Opal 0 1
0 Lifespan Hospital System , Providence, RI , USA
1 Department of Medicine, Warren Alpert Medical School of Brown University , 593 Eddy St., Providence, RI 02903 , USA
We report on the increasingly important need to diagnose and care for the elderly with sepsis as a distinct patient population. We share an overview of age-related changes in sepsis physiology and the potential role of exercise.
Sepsis; Septic shock; Aging and immunity; Immunosenescence; Exercise and infections; Sepsis in the elderly
For all the supposed benefits attributable to moderate
exercise in the elderly population (better cardiovascular
fitness, improved microcirculation, less obesity, etc.) [
improved outcome from sepsis has not been listed among
them until now [
]. At least in inbred, old mice, voluntary
exercise appears to provide a survival benefit from
experimentally induced intra-abdominal sepsis. If these results
could be translated into aging human populations, the
ramifications would be substantial indeed.
Sepsis is a critical issue in old age and is among
the top causes for intensive care unit (ICU) admission
in the elderly [
]. The incidence of sepsis in our
aging population is predicted to rise precipitously in
the next decade as the “baby boomer” population
reaches old age. Older adults and particularly nursing
home residents have higher rates of ICU admission,
longer length of stay, and increased hospital mortality
than younger adults [
The mechanism(s) underpinning the disproportionate
susceptibility to sepsis in the elderly is not yet fully
understood. Elderly patients are at higher risk for sepsis
likely related to the higher rates of comorbidities,
including dementia, poor dentition, and diabetes. With
age, intact integument and physiologic reflexes (intact
cough reflex, balance, and mobility) that contribute to
the body’s physical defense mechanisms to infection
can degrade. Additionally, institutionalization,
implanted devices, and surgical procedures can predispose
patients to infection [
All mammals age over their lifetime, manifest by gradual
development of telomere shortening of chromosomes,
degenerative arthritis, loss of hair, inactivity, atherosclerosis,
impaired T- and B-cell responses, and age-related
]. Mice age over a 2-year lifespan rather than
the typical 80-year lifespan of humans, making mice a
convenient animal model to study the effects of aging on a
range of pathophysiologic responses.
Elderly septic patients often do not have typical clinical
responses to sepsis, making diagnosis by the Sepsis-3
quick Sepsis-Related Organ Failure Assessment (qSOFA)
criteria difficult. Older patients may present with inverse
signs and symptoms (hypothermia, leukopenia), or
nonspecific signs of infection [
]. Accepted thresholds for
biomarkers levels for diagnosis may not be appropriate
in the older population, particularly among patients with
pre-existing organ dysfunction. Thus, given the protean
manifestations of infection in the elderly, diagnosis of
sepsis is often delayed.
Once infected, older patients experience a
disadvantaged host immune response with defects in humoral
and cellular immune function [
]. The pattern of
cytokine release during sepsis in the elderly demonstrates
higher levels of tumor necrosis factor (TNF)-α,
interleukin (IL)-1β, and IL-6 [
]. A smoldering inflammatory
state during aging termed “inflammaging” can affect sepsis
physiology . However, despite evidence of increased
baseline inflammation, after insult, an immunosuppressed
state is commonly observed in the elderly. This is part of
the “immunosenescence” of aging, which results in
quantitative and qualitative changes in lymphocytes (CD4, CD8
T cells and B cells) and myeloid cells [
elderly patients experience attenuated cell-mediated
immunity in the form of a truncated T-cell repertoire,
decreased IL-12 release, decreased lymphocyte proliferation,
and dampened signal transduction. Humoral immunity is
also adversely affected with aging. Decreased B-cell
function with blunted antibody responses to neoantigens
is commonplace due to lack of helper T-cell signals and
decreased expression of costimulatory molecules .
Elderly mice experience many of the same age-related
defects in immune function and increased risk of infection
as observed in the older adult human patients [
mice are more susceptible than young mice to
endotoxininduced systemic inflammation, and are more likely to
succumb as a result of systemic infection in pneumonia
models and from intra-abdominal infection following cecal
ligation and puncture [
]. While it might be speculated
that exercised old mice in good cardiovascular fitness
might fare better in sepsis than nonexercised, aged mice,
limited experimental data exist to answer this question.
A recent report now directly challenges the potential role
of exercise in an isolated, controlled setting where other
variables were minimized [
]. These investigators induced
sepsis by an intraperitoneal injection of a fecal slurry in
male, nonobese C57BL/6 mice. Exercised older mice
(22 months old) had a better outcome with significantly
lower systemic cytokine and chemokine response and had
a less pronounced procoagulant response than
nonexercised, aged mice subjected to the same infectious challenge.
Intriguingly, consistent upregulation of endogenous
endothelial nitric oxide synthase (eNOS) was observed
in exercised mice compared to nonexercised mice [
Nitric oxide is a potent vasodilator and has the capacity
to limit neutrophil and platelet adherence to endothelial
]. Exercise in older human subjects is known
to improve endothelial function, increase eNOS
expression, and promote microcirculatory responsiveness [
Like many innovative investigations, the results of this
study pose more questions than they answer. Would the
advantageous effects of exercise work as well in outbred
mice, females (both premenopausal and
postmenopausal), and how long does the protective effect of
exercise last in aged mice after exercise succession? How
much exercise is enough, when should it start, and is
there a dose-response effect to exercise conditioning?
Does exercise work better in obese or nonobese
subjects? The most critical question is, of course, how well
do these study findings in mice translate to improved
outcomes in human sepsis? The data collected thus far
in older humans indicate that while the effects of
exercise on inflammatory biomarkers is measurable, the
effect size is rather small and often confounded by obesity
Should future surviving sepsis campaigns recommend
daily exercise for older patients to stave off the risk of
death from sepsis potentially lurking in their future?
Should octogenarians be encouraged to do some daily
exercise? Based on this study, one of the purported
benefits might be a more constrained and appropriate host
response to systemic infection.
Additional animal models would likely be needed to
confirm these findings as retrospective, observational
studies in humans would be susceptible to selection
bias and randomized trials would be very difficult to
organize. Randomly assigning people to the nonexercise
group would pose an ethical challenge considering the
many common benefits of light physical activity in
aging populations [
]. If confirmed in further studies,
we might find ourselves someday encouraging our
senior citizens to prevent sepsis by giving up their
rocking chairs for the exercise bike and the jogging
C57BL/6: Black 6 mouse; CD: Cluster of differentiation; eNOS: Endothelial
nitric oxide synthase; ICU: Intensive care unit; IL: Interleukin; qSOFA: Quick
Sepsis-Related Organ Failure Assessment; TNF: Tumor necrosis factor
Availability of data and materials
DB drafted this editorial. SMO edited and finalized the manuscript. Both
authors read and approved the final manuscript.
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The authors declare that they have no competing interests.
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