Oxygen and brain death; back from the brink

New Findings• What is the topic of this review? To explore the unique evolutionary origins of the human brain and critically appraise its energy budget, including limits of oxygen and glucose deprivation during anoxia and ischaemia. • What advances does it highlight? The brain appears to be more resilient to substrate depletion than traditionally thought, highlighting greater resilience and an underappreciated capacity for functional recovery.Abstract The human brain has evolved into an unusually large, complex and metabolically expensive organ that relies entirely on a continuous supply of O 2 and glucose. It has traditionally been assumed that its exorbitant energy budget, combined with little to no energy reserves, renders it especially vulnerable to anoxia and ischaemia, with substrate depletion and progression towards cell death largely irreversible and rapid. However, new and exciting evidence suggests that neurons can survive for longer than previously thought, highlighting an unexpected resilience and underappreciated capacity for functional recovery that has changed the way we think about brain cell death. Nature has the potential to unlock some of the mysteries underlying ischaemic survival, with select vertebrates having solved the problem of anoxia–hypoxia tolerance over millions of years of evolution. Better understanding of their survival strategies, including remarkable adaptations in brain physiology and redox homeostasis, might help to identify new therapeutic targets for human diseases characterized by O 2 deprivation, ischaemia–reperfusion injury and ageing.