Perimenopause is a midlife transition state experienced by women that occurs in the context of a fully functioning neurological system and results in reproductive senescence. Although primarily viewed as a reproductive transition, the symptoms of perimenopause are largely neurological in nature. Neurological symptoms that emerge during perimenopause are indicative of disruption in multiple estrogen-regulated systems (including thermoregulation, sleep, circadian rhythms and sensory processing) and affect multiple domains of cognitive function. Estrogen is a master regulator that functions through a network of estrogen receptors to ensure that the brain effectively responds at rapid, intermediate and long timescales to regulate energy metabolism in the brain via coordinated signalling and transcriptional pathways. The estrogen receptor network becomes uncoupled from the bioenergetic system during the perimenopausal transition and, as a corollary, a hypometabolic state associated with neurological dysfunction can develop. For some women, this hypometabolic state might increase the risk of developing neurodegenerative diseases later in life. The perimenopausal transition might also represent a window of opportunity to prevent age-related neurological diseases. This Review considers the importance of neurological symptoms in perimenopause in the context of their relationship to the network of estrogen receptors that control metabolism in the brain.

Cognitive decline is one of the complications of type 2 diabetes (T2D). Intermittent fasting (IF) is a promising dietary intervention for alleviating T2D symptoms, but its protective effect on diabetes-driven cognitive dysfunction remains elusive. Here, we find that a 28-day IF regimen for diabetic mice improves behavioral impairment via a microbiota-metabolites-brain axis: IF enhances mitochondrial biogenesis and energy metabolism gene expression in hippocampus, restructures the gut microbiota, and improves microbial metabolites that are related to cognitive function. Moreover, strong connections are observed between IF affected genes, microbiota and metabolites, as assessed by integrative modelling. Removing gut microbiota with antibiotics partly abolishes the neuroprotective effects of IF. Administration of 3-indolepropionic acid, serotonin, short chain fatty acids or tauroursodeoxycholic acid shows a similar effect to IF in terms of improving cognitive function. Together, our study purports the microbiota-metabolites-brain axis as a mechanism that can enable therapeutic strategies against metabolism-implicated cognitive pathophysiologies.

The high energy demand of the brain renders it sensitive to changes in energy fuel supply and mitochondrial function. Deficits in glucose availability and mitochondrial function are well-known hallmarks of brain aging and are particularly accentuated in neurodegenerative disorders such as Alzheimer’s disease. As important cellular sources of H2O2, mitochondrial dysfunction is usually associated with altered redox status. Bioenergetic deficits and chronic oxidative stress are both major contributors to cognitive decline associated with brain aging and Alzheimer’s disease. Neuroinflammatory changes, including microglial activation and production of inflammatory cytokines, are observed in neurodegenerative diseases and normal aging. The bioenergetic hypothesis advocates for sequential events from metabolic deficits to propagation of neuronal dysfunction, to aging, and to neurodegeneration, while the inflammatory hypothesis supports microglia activation as the driving force for neuroinflammation. Nevertheless, growing evidence suggests that these diverse mechanisms have redox dysregulation as a common denominator and connector. An independent view of the mechanisms underlying brain aging and neurodegeneration is being replaced by one that entails multiple mechanisms coordinating and interacting with each other. This review focuses on the alterations in energy metabolism and inflammatory responses and their connection via redox regulation in normal brain aging and Alzheimer’s disease. Interactions of these systems is reviewed based on basic research and clinical studies.

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