Chronobiology and Sleep Institute and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Aging Cell. 2022 Jun;21(6):e13598. doi: 10.1111/acel.13598. Epub 2022 Apr 30.
As the aging population grows, the need to understand age-related changes in health is vital. Two prominent behavioral changes that occur with age are disrupted sleep and impaired cognition. Sleep disruptions lead to perturbations in proteostasis and endoplasmic reticulum (ER) stress in mice. Further, consolidated sleep and protein synthesis are necessary for memory formation. With age, the molecular mechanisms that relieve cellular stress and ensure proper protein folding become less efficient. It is unclear if a causal relationship links proteostasis, sleep quality, and cognition in aging. Here, we used a mouse model of aging to determine if supplementing chaperone levels reduces ER stress and improves sleep quality and memory. We administered the chemical chaperone 4-phenyl butyrate (PBA) to aged and young mice, and monitored sleep and cognitive behavior. We found that chaperone treatment consolidates sleep and wake, and improves learning in aged mice. These data correlate with reduced ER stress in the cortex and hippocampus of aged mice. Chaperone treatment increased p-CREB, which is involved in memory formation and synaptic plasticity, in hippocampi of chaperone-treated aged mice. Hippocampal overexpression of the endogenous chaperone, binding immunoglobulin protein (BiP), improved cognition, reduced ER stress, and increased p-CREB in aged mice, suggesting that supplementing BiP levels are sufficient to restore some cognitive function. Together, these results indicate that restoring proteostasis improves sleep and cognition in a wild-type mouse model of aging. The implications of these results could have an impact on the development of therapies to improve health span across the aging population.
随着人口老龄化的增长，了解与年龄相关的健康变化至关重要。随着年龄的增长，两个突出的行为变化是睡眠紊乱和认知障碍。睡眠紊乱会导致小鼠蛋白质稳态和内质网（ER）应激的紊乱。此外，巩固的睡眠和蛋白质合成对于记忆形成是必要的。随着年龄的增长，缓解细胞应激和确保正确蛋白质折叠的分子机制效率降低。目前尚不清楚蛋白质稳态、睡眠质量和认知之间是否存在因果关系。在这里，我们使用衰老小鼠模型来确定是否补充伴侣蛋白水平可以减轻 ER 应激并改善睡眠质量和记忆力。我们给老年和年轻小鼠施用化学伴侣 4-苯基丁酸（PBA），并监测睡眠和认知行为。我们发现伴侣蛋白治疗可巩固睡眠和觉醒，并改善老年小鼠的学习能力。这些数据与衰老小鼠大脑皮层和海马区 ER 应激减少相关。伴侣蛋白治疗增加了 p-CREB，这与记忆形成和突触可塑性有关，在伴侣蛋白治疗的老年小鼠海马体中。内源性伴侣蛋白结合免疫球蛋白蛋白（BiP）的过表达改善了认知，减少了 ER 应激，并增加了衰老小鼠中的 p-CREB，这表明补充 BiP 水平足以恢复一些认知功能。总之，这些结果表明，恢复蛋白质稳态可改善野生型衰老小鼠模型的睡眠和认知能力。这些结果的意义可能会对开发改善整个老龄化人口健康跨度的疗法产生影响。
