Braunstein Paul W, Horovitz David J, Hampton Andreina M, Hollis Fiona, Newman Lori A, Enos Reilly T, McQuail Joseph A
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, USA.
Department of Neuroscience, University of Florida, Gainesville, FL, USA.
Aging Brain. 2024 Apr 5;5:100116. doi: 10.1016/j.nbas.2024.100116. eCollection 2024.
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.
脑葡萄糖利用缺陷是阿尔茨海默病（AD）的一个标志，而II型糖尿病和血糖升高会增加晚年患AD的风险。区分正常衰老与同时存在的代谢或脑部疾病的影响，可能会带来更精准的方法来管理特定的健康风险，并优化针对易感老年个体的治疗。我们评估了年轻成年（6个月）和老年（24个月）雄性大鼠之间的代谢、神经内分泌和神经生物学差异。与年轻成年大鼠相比，老年大鼠在一天的黑暗阶段开始时血糖显著更高，但在光照阶段则不然。当受到身体束缚这一强烈应激源的刺激时，老年大鼠的血糖没有变化，而年轻成年大鼠的血糖则升高。对组织进行了氧化磷酸化（OXPHOS）、神经元葡萄糖转运和突触标志物的评估。不同年龄组之间蛋白质水平的明显差异并不显著，但昼夜血糖与海马突触体中的OXPHOS蛋白呈负相关，与年龄无关。神经元葡萄糖转运体GLUT3在年轻成年大鼠中与昼夜血糖呈正相关，而老年大鼠则倾向于呈现相反的趋势。我们的数据表明，衰老会增加血糖的每日波动，并且在个体差异层面上，与突触OXPHOS相关蛋白呈负相关。我们的研究结果表明，葡萄糖稳态失衡可能会加剧突触功能障碍的代谢方面，从而增加与年龄相关的脑部疾病的风险。
