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Abstract: The increasingly recognized role played by reactive oxygen species in cellular signaling during health and disease underscores the prominence of redox biology in driving physiological responses. Although most of the research in this area has focused on elucidating the impacts of dysregulated oxidant generation on human disease, I have also been studying the role of redox signaling in mediating physiological responses in animals adapted to extreme conditions. Elephant seals are a prime example of extreme physiological adaptation as they can hold their breath for extended periods while diving and sleeping. Remarkably, extended breath-holding in seals is associated with severe hypoxemia and ischemia but does not result in the cardiovascular complications observed in humans that suffer from heart attacks, pulmonary embolism or sleep apnea. Similarly, elephant seals undergo spontaneous long-term absolute food/water deprivation while breeding, molting, and weaning. Prolonged fasting in elephant seals promotes a pro-inflammatory phenotype (insulin resistance, increased angiotensin II/cortisol, increased oxidant generation) similar to that observed in long-term insulin resistant/type II diabetic human subjects. My previous work shows that neither prolonged fasting nor extended breath-holding induces oxidative stress or inflammation in seals. The cellular mechanisms that drive seals’ tolerance to those conditions, however, remain largely unknown. Hence, I have established cell culture systems (myoblasts, flow-adapted endothelial cells) to study how seal cells respond to different stressors and physiological adjustments associated with fasting and breath-holding. I will now use those systems and conduct additional organismal physiology studies to dissect the cellular mechanisms that drive seals’ tolerance to such conditions. Elucidating the mechanisms that drive seals’ tolerance to hypoxemia/ischemia and insulin resistance could not only increase our knowledge of the fascinating adaptations evolved by these animals but have translatable value for the current understanding and treatment of cardiovascular and respiratory pathologies in humans.