Stress resistance correlates with longevity and this pattern has been exploited to help identify genes that can influence lifespan. Reciprocally, genes and pharmacological agents that have been studied primarily in the context of longevity may be an untapped resource for treating acute stresses. Here we summarize the evidence that targeting SIRT1, studied primarily in the context of longevity, can improve outcomes in hemorrhagic shock and resuscitation. Hemorrhagic shock is a potentially fatal condition that occurs when blood loss is so severe that tissues no longer receive adequate oxygen. While stabilizing the blood pressure and reperfusing tissues are necessary, re-introducing oxygen to ischemic tissues generates a burst of reactive oxygen species that can cause secondary tissue damage. Reactive oxygen species not only exacerbate the inflammatory cascade but also can directly damage mitochondria, leading to bioenergetic failure in the affected tissues. Treatments with polyphenol resveratrol and with nicotinamide adenine dinucleotide (NAD) precursors have both shown promising results in rodent models of hemorrhagic shock and resuscitation. Although a number of different mechanisms may be at play in each case, a common theme is that resveratrol and NAD both enhance the activity of SIRT1. Moreover, many of the physiologic improvements observed with resveratrol and NAD precursors are consistent with modulation of known SIRT1 targets. Because small blood vessels and limited blood volume make mice very challenging for the development of hemorrhagic shock models, there is a paucity of direct genetic evidence testing the role of SIRT1. However, the development of more robust methods in mice as well as genetic modifications in rats should allow the study of SIRT1 transgenic and KO rodents in the near future. The potential therapeutic effect of SIRT1 in hemorrhagic shock may serve as an important example supporting the value of considering “longevity” pathways in the mitigation of acute stresses.

抗压性与长寿相关，这种模式已被用来帮助识别可能影响寿命的基因。反过来，主要在长寿背景下研究的基因和药物可能是治疗急性压力的未开发资源。在这里，我们总结了主要在长寿背景下研究的靶向 SIRT1 可以改善失血性休克和复苏的结果的证据。失血性休克是一种潜在的致命疾病，当失血严重到组织不再接受足够的氧气时就会发生这种情况。虽然稳定血压和再灌注组织是必要的，但将氧气重新引入缺血组织会产生大量活性氧，从而导致继发性组织损伤。活性氧不仅会加剧炎症级联反应，而且会直接损伤线粒体，导致受影响组织的生物能量衰竭。使用多酚白藜芦醇和烟酰胺腺嘌呤二核苷酸 (NAD) 前体进行的治疗均在失血性休克和复苏的啮齿动物模型中显示出可喜的结果。尽管在每种情况下可能有许多不同的机制在起作用，但一个共同的主题是白藜芦醇和 NAD 都增强了 SIRT1 的活性。此外，用白藜芦醇和 NAD 前体观察到的许多生理改善与已知 SIRT1 靶点的调节一致。由于小血管和有限的血容量使小鼠对失血性休克模型的开发非常具有挑战性，因此缺乏直接的遗传证据来测试 SIRT1 的作用。然而，在小鼠中开发更强大的方法以及在大鼠中进行基因修饰应该允许在不久的将来研究 SIRT1 转基因和 KO 啮齿动物。SIRT1 在失血性休克中的潜在治疗作用可以作为一个重要的例子，支持考虑“长寿”途径在缓解急性应激方面的价值。