Our earlier mechanistic analyses of estrogen action in brain led to the discovery that estrogen is a masterregulator of the bioenergetic system in brain that promotes glucose transport glucose metabolismmitochondrial respiration and ATP generation. Collectively the data provided compelling evidence for estrogenas a systems biology metabolic regulator in brain and illuminated compensatory mechanisms consistent withan aging female brain that is starving. For estrogen to function as master regulator of the bioenergetic systemin the female brain estrogen must be integrating nuclear and mitochondrial genomic responses. Further from asystems level perspective it would be necessary for estrogen to also regulate cytoplasmic signalingmechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription.The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergeticresponses across two genomic compartments while simultaneously monitoring energetic demand andperformance in real time. The proposed program of research is designed to test two hypotheses. Firstestrogenic control of the bioenergetic system in the female brain requires: 1) both nuclear and mitochondrialgenomes; 2) integration of gene expression across both genomic compartments and 3) activation of rapidsignaling cascades to provide real time feedback on bioenergetic performance. Second we hypothesize thatloss of estrogen in the aging female brain leads to a systematic dis-integration of estrogenic control of nuclearand mitochondrial genomes followed by decline in bioenergetic sensing mechanisms. Estrogenic control of thebioenergetic system of the brain and the dismantling thereof has basic translational and clinical significance.From a discovery perspective the proposed program of research is unique in exploring the mechanismsunderlying estrogenic integration of nuclear and mitochondrial gene expression and the real time feedbackmechanisms that control the bioenergetic system of the brain. Further the process by which this controlsystem is dismantled in the aging female brain is uncharted territory of high significance for understandingbioenergetic aging in brain. Translationally determining the mechanisms underlying the systematic dismantlingof estrogenic integration of bioenergetic compartments in brain has the potential to detect therapeutic targets tosustain bioenergetic function in the aging female brain. Clinically the aging transition of menopause unique tothe female is a process that dismantles both reproductive ability and potentially bioenergetic capacity in brain.This is particularly relevant to age-related neurological conditions associated with deficits in glucosehypometabolism such as Alzheimer's depression and multiple sclerosis which have greater prevalence inpostmenopausal women. Research proposed herein aligns with NIA Strategic Research Goals A and C andthe need to better distinguish patterns of brain aging https://www.nia.nih.gov/about/living-long-well-21st-century-strategic-directions-research-aging and to objectives of Office of Research on Women's Health.