We study how genes control life processes in homeostasis and organismic responses to extreme physical chemical conditions. Low temperature (hypothermia) and reduced oxygen (hypoxia) pervasively affect cellular metabolism and physiology, decelerate organismic biological time and trigger instinctive animal behaviors. Many species in nature have evolved unique traits to respond and adapt to severe hypothermia/hyperthermia/hypoxia. We use 1) genetically tractable C. elegans mutants isolated from large-scale screens with abnormal behavioral and extremophile-like phenotypes and 2) Mangrove Killifish, the only known self-fertilizing vertebrate with genetics similar to that of C. elegans and known extreme physiological phenotypes, as discovery tools. In addition, we culture mammalian neural stem cells ex vivo from hibernating ground squirrels to unravel cellular intrinsic mechanisms of hypoxia/hypothermia tolerance. With multidisciplinary approaches and technologies, our long-term goal is to understand how animals integrate interoceptive states with environmental stimuli through nervous/vascular/respiratory systems to coordinate internal homeostasis and tolerance of severe abiotic stresses. This will identify new mechanisms of extreme physiology and general principles of biological adaptation, with potential applications in organ transplantation, reversible cryo-preservation and novel therapeutics to treat metabolic, neurological and ischemic disorders.