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
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For all the supposed benefits attributable to moderate
exercise in the elderly population (better cardiovascular
fitness, improved microcirculation, less obesity, etc.) [
1–3
],
improved outcome from sepsis has not been listed among
them until now [
4
]. 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 [
5
]. 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 [
6
].
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 [
7
].
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
malignancies [
7, 8
]. 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 [
6
]. 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 [
9
]. 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 [
7, 10
]. A smoldering inflammatory
state during aging termed “inflammaging” can affect sepsis
physiology [11]. 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 [
12, 13
]. Specifically,
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 [13].
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 [
7
]. Aged
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 [
8
]. 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 answe (...truncated)