Longevity pathways in stress resistance: targeting NAD and sirtuins to treat the pathophysiology of hemorrhagic shock.

Abstract

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.