Abstract
Sepsis, defined as a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. The excessive host inflammatory response can induce immediate and persistent cognitive decline, which can be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young and old mice of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. Few miR were modified in a similar manner across age or sex and these few miR were generally associated with neuroprotection against inflammation. Similar to previous work examining transcription, young females exhibited a better recovery of the miR profile from day 1 to day 4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day 1 and day 4 and many of the miR upregulated on day 1 and day 4 were linked to neurodegeneration, increased neuroinflammation, and cognitive impairment. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis.
Highlights
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to infection [1,2,3,4]
The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis
A recent nationwide population-based study revealed that dementia is commonly present in a substantial proportion (>11%) of adults ≥65 years of age hospitalized with sepsis [11]
Summary
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host immune response to infection [1,2,3,4]. Sepsis can induce immediate and persistent cognitive decline, with worse outcomes in older and Alzheimer’s Disease and Alzheimer’s Disease Related Dementia (AD/ADRD)diagnosed patients [6]. AD/ADRD has been labeled sepsis-associated encephalopathy and is commonly seen in older adults [7]. Sepsis has been labeled ‘a disease of the aged,’ as 60% of septic individuals are older than 65 years [8, 9]. Greater than 50% of sepsis survivors suffer from cognitive dysfunction after hospital discharge, including issues with general memory, attention, verbal fluency, and executive function [10]. A recent nationwide population-based study revealed that dementia is commonly present in a substantial proportion (>11%) of adults ≥65 years of age hospitalized with sepsis [11]
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