In women, the disruption of the endocrine environment during menopause amplifies the risk for stroke and neuro-inflammatory disease. Using acyclic female rats to model the postmenopausal state, our studies indicate that these animals sustain greater tissue damage following experimental ischemic stroke as compared to mature (cyclic) adult females. Furthermore, while estrogen treatment is protective to mature adult females, it paradoxically increases tissue damage in older acyclic females. These data are congruent with the WHI study, where the risk for stroke was elevated in older women receiving hormone therapy, and underscores the need for novel therapeutic approaches for this group. Based on our recent studies, we hypothesize that estrogens neuroprotective actions require the cooperative action of insulin-like growth factor (IGF)-1, a neuroprotective peptide hormone, and that age-related decline in IGF-1, which occurs in virtually all species, destabilizes the neuroprotective actions of estrogen. This hypothesis is supported by our studies that (1) IGF-1 levels are reduced in the middle aged (reproductive senescent) female rat, and (2) in a stroke model, IGF-1 infusion to older females overcomes the neurotoxic effects of estrogen in this group. Here we will examine the cooperative interaction of estrogen and IGF-1 on stroke recovery and infarct volume and the extent to which this interaction is altered in reproductive senescence. Secondly, we will examine the extent that estrogen/IGF-1 can improve astrocyte function post stroke in reproductive senescent females. Astrocytes are responsive to both IGF-1 and estrogen and play a crucial role in detoxification of the ischemic environment. Finally we will determine if stroke outcomes can be improved in older females by manipulating epigenetic regulators of IGF-1 like microRNA. MiRNA, a type of small non-coding RNA, regulate large gene networks, and play a central role in cell senescence, proliferation (cancer) and injury (stroke). Specifically, we will identify and manipulate miRNA that regulate IGF-1 to improve stroke recovery on older females. Collectively these studies will provide an understanding of estrogen's age-delimited neuroprotective effects and form the foundation for pre-clinical studies of stroke therapy tailored to older females.