Abstract There is an acute need to develop neuroprotective drugs to prevent or/and protect neuronal cell damage and death caused by ischemia/reperfusion, hypoxia or cytotoxic agents in the brain. Plant- based expression system can be used to produce asialo-rhuEPO, a non-hematopoietic recombinant human EPO derivative lacking sialic acid, which could be used as a neuroprotective agent for preventing and protecting brain damage from ischemia/reperfusion injury. In our previous studies, we found that plant-produced asialo-rhuEPO (asialo-rhuEPOP) is non-erythropoietic and displays excellent neuroprotective effects in a young mouse model of middle cerebral artery occlusion (MCAO) I/R injury. Our previous studies have set the stage for the current proposed research activities. In this SC1 renewal application, we propose to extend asialo-rhuEPOP-mediated neuroprotection studies to aged mice, evaluate long-term neurological outcomes in both young and aged mice, and further understand its neuroprotective mechanisms.