Age and Sex Influence the Hippocampal Response and Recovery Following Sepsis

Although in-hospital mortality rates for sepsis have decreased, survivors often experience lasting physical and cognitive deficits. Moreover, older adults are more vulnerable to long-term complications associated with sepsis. We employed a murine model to examine the influence of age and sex on the brain’s response and recovery following sepsis. Young (~4 months) and old (~20 months) mice (C57BL/6) of both sexes underwent cecal ligation and puncture (CLP) with restraint stress. The hippocampal transcriptome was examined in age and sex-matched controls at 1 and 4 days post-CLP. In general, immune and stress-related genes increased while neuronal, synaptic, and glial genes decreased one day after CLP-induced sepsis. However, specific age and sex differences were observed for the initial responsiveness to sepsis as well as the rate of recovery examined on day 4. Young females exhibited a muted transcriptional response relative to young males and old females. Old females exhibited a robust shift in gene transcription on day 1 and, while most genes recovered, genes linked to neurogenesis and myelination continued to be downregulated by day 4. In contrast, old males exhibited a more delayed or prolonged response to sepsis, such that neuronal and synaptic genes continued to decrease while immune response genes continued to increase on day 4. These results suggest that aging is associated with delayed recovery from sepsis, which is particularly evident in males. This study was conducted on 47 mice either 24 hours or 4 days after sepsis [young male control (n = 4), young male 24 hours post-sepsis (n = 4), young male 4 days post-sepsis (n = 4), old male control (n = 4), old male 24 hours post-sepsis (n = 4), old male 4 days post-sepsis (n = 4), young female control (n = 4), young female 24 hours post-sepsis (n = 4), young female 4 days post-sepsis (n = 4), old female control (n = 4), old female 24 hours post-sepsis (n = 4), and old female 4 days post-sepsis (n = 3)]. Hippocampal mRNA was used to investigate how sepsis altered the response in the brain within different age and sex groups.