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.

尽管脓毒症（sepsis）的住院死亡率已有所下降，但存活患者往往会出现持续的躯体与认知功能缺损。此外，老年群体更易出现与脓毒症相关的长期并发症。本研究采用小鼠模型（murine model），探究年龄与性别对脓毒症后脑组织应答及恢复过程的影响。研究选取4月龄左右的年轻小鼠与20月龄左右的老年C57BL/6品系小鼠，雌雄各半，均接受盲肠结扎穿刺术（cecal ligation and puncture, CLP）联合束缚应激（restraint stress）造模。分别在脓毒症造模后第1天和第4天，对年龄与性别匹配的对照组小鼠的海马体转录组（hippocampal transcriptome）进行检测分析。整体而言，脓毒症造模后第1天，与免疫及应激相关的基因表达上调，而神经元、突触及神经胶质相关基因表达下调。但在脓毒症初始应答及第4天的恢复速率上，均观察到显著的年龄与性别差异。与年轻雄性小鼠及老年雌性小鼠相比，年轻雌性小鼠的转录应答更为平缓。老年雌性小鼠在造模后第1天即出现显著的基因转录变化，尽管多数基因表达在后续恢复至基线水平，但与神经发生（neurogenesis）及髓鞘形成（myelination）相关的基因在第4天仍持续下调。与之形成对比的是，老年雄性小鼠对脓毒症的应答更为延迟或持久：至第4天时，神经元与突触相关基因的表达仍持续降低，而免疫应答相关基因的表达仍处于上调状态。上述结果表明，衰老与脓毒症后的恢复延迟相关，这一现象在雄性个体中尤为显著。