A Progressive Failure of Glucose Regulation in the Aging Brain
There has long been a school of thought on Alzheimer's disease that consideres it a form of diabetes, in which dysregulated glucose metabolism features prominently. This dysregulation certainly occurs; the study noted here isn't the only one to show that the aging brain no longer manages glucose adequately. The question is whether this mechanism is important relative to all of the other processes thought to contribute to the pathology of Alzheimer's disease and other neurodegenerative conditions, and where it fits in a chain of cause and consequence. Finding ways to demonstrate the relative importance of different mechanisms remains the primary challenge in developing a sufficient understanding of aging and age-related disease to make rapid progress towards effective therapies.
Defective brain glucose utilization is a hallmark of Alzheimer's disease (AD) while Type II diabetes and elevated blood glucose escalate the risk for AD in later life. Isolating contributions of normal aging from coincident metabolic or brain diseases could lead to refined approaches to manage specific health risks and optimize treatments targeted to susceptible older individuals.
We evaluated metabolic, neuroendocrine, and neurobiological differences between young adult (6 months) and aged (24 months) male rats. Compared to young adults, blood glucose was significantly greater in aged rats at the start of the dark phase of the day but not during the light phase. When challenged with physical restraint, a potent stressor, aged rats effected no change in blood glucose whereas blood glucose increased in young adults. Tissues were evaluated for markers of oxidative phosphorylation (OXPHOS), neuronal glucose transport, and synapses.
Outright differences in protein levels between age groups were not evident, but circadian blood glucose was inversely related to OXPHOS proteins in hippocampal synaptosomes, independent of age. The neuronal glucose transporter, GLUT3, was positively associated with circadian blood glucose in young adults whereas aged rats tended to show the opposite trend. Our data demonstrate aging increases daily fluctuations in blood glucose and, at the level of individual differences, negatively associates with proteins related to synaptic OXPHOS. Our findings imply that glucose dyshomeostasis may exacerbate metabolic aspects of synaptic dysfunction that contribute to risk for age-related brain disorders.