Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL, United States.
Alcohol. 2023 Mar;107:4-11. doi: 10.1016/j.alcohol.2022.04.005. Epub 2022 Apr 30.
There is growing interest in understanding how ethanol use interacts with advancing age to influence the brain and cognition. Animal models are employed to investigate the cellular and molecular mechanisms of brain aging and age-related neurodegenerative diseases that underlie cognitive decline. However, all too often research on problems and diseases of the elderly are conducted in healthy young animals, providing little clinical relevance. The validity of animal models is discussed, and confounds due to age-related differences in anxiety, sensory-motor function, and procedural learning are highlighted in order to enhance the successful translation of preclinical results into clinical settings. The mechanism of action of ethanol on brain aging will depend on the dose, acute or chronic treatment, or withdrawal from treatment and the age examined. Due to the fact that humans experience alcohol use throughout life, important questions concern the effects of the dose and duration of ethanol treatment on the trajectory of cognitive function. Central to this research will be questions of the specificity of alcohol effects on cognitive functions and related brain regions that decline with age, as well as the interaction of alcohol with mechanisms or biomarkers of brain aging. Alternatively, moderate alcohol use may provide a source of reserve and resilience against brain aging. Longitudinal studies have the advantage of being sensitive to detecting the effects of treatment on the emergence of cognitive impairment in middle age and can minimize effects of stress/anxiety associated with the novelty of alcohol exposure and behavioral testing, which disproportionately influence aged animals. Finally, the effect of alcohol on senescent neurophysiology and biomarkers of brain aging are discussed. In particular, the interaction of age and effects of alcohol on inflammation, oxidative stress, N-methyl-d-aspartate receptor function, and the balance of excitatory and inhibitory synaptic transmission are highlighted.
人们越来越关注乙醇的使用如何与年龄的增长相互作用，从而影响大脑和认知能力。动物模型被用于研究大脑衰老和与年龄相关的神经退行性疾病的细胞和分子机制，这些疾病是认知能力下降的基础。然而，研究老年人的问题和疾病通常是在健康的年轻动物中进行的，这使得研究结果与临床相关性不大。本文讨论了动物模型的有效性，并强调了由于年龄相关的焦虑、感觉运动功能和程序性学习差异而产生的混淆，以提高将临床前结果成功转化为临床环境的能力。乙醇对大脑衰老的作用机制将取决于剂量、急性或慢性治疗、或停止治疗以及所检查的年龄。由于人类在一生中都经历着酒精的使用，因此一个重要的问题是乙醇剂量和治疗持续时间对认知功能轨迹的影响。这一研究的核心将是关于酒精对认知功能和与年龄相关的大脑区域的特异性作用的问题，以及酒精与大脑衰老的机制或生物标志物的相互作用。或者，适度饮酒可能为大脑衰老提供储备和恢复能力。纵向研究具有优势，能够敏感地检测到治疗对中年认知障碍发生的影响，并能最大限度地减少与酒精暴露和行为测试的新奇性相关的应激/焦虑的影响，而这些影响在老年动物中不成比例地存在。最后，讨论了酒精对衰老神经生理学和大脑衰老生物标志物的影响。特别是，强调了年龄和酒精对炎症、氧化应激、N-甲基-D-天冬氨酸受体功能以及兴奋性和抑制性突触传递平衡的影响之间的相互作用。
