Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LoAD). comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LoAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease. Late onset Alzheimer's disease (LOAD) is a complex disease with approximately a 20-year prodromal period 1-3. The prodromal/preclinical phase of AD is associated with brain glucose hypometabolism, which can be detected in at-risk-groups before diagnosis of the disease, and is predictive of disease progression 4-13. Brain glucose hypometabolism, mitochondrial dysfunction, and reduced oxygen flow in the brain are considered primary risk factors for LOAD 14-18. On the cellular level, aging is associated with reduced glucose transporter expression, compromised hexokinase activity, phosphorylated (inactivated) PDH, and altered levels and activities of key enzymes involved in oxidative phosphorylation 19-36. On the molecular level, aging is associated with significant down regulation of nuclear encoded OXPHOS genes 19,37 and disrupted balance of NAD/NADH, AMP/ ATP, purine and pyrimidine pool 38,39. During midlife, females experience both chronological and endocrinological aging. The perimenopausal to menopausal transition is unique to females, and is linked to deficits in brain glucose metabolism and mitochondrial dysfunction 3,19,40 , which could contribute to the twofold greater lifetime risk of AD in females 41-43. Under normal conditions, brain utilizes glucose as its primary fuel source. Under stress conditions, the brain can adapt to utilize auxiliary fuel sources in respon...