Late-onset caloric restriction improves cognitive performance and restores circadian patterns of neurotrophic, clock and epigenetic factors in the hippocampus of male old rats

Fernando Gabriel Altamirano, Ivanna Castro-Pascual, Ivana Tamara Ponce, Cinthia Daiana Coria-Lucero, Ethelina Cargnelutti, Mariana Lucila Ferramola, Marcela Silvia Delgado, Ana Cecilia Anzulovich, María Gabriela Lacoste
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Abstract

Aging is a complex multifactorial process that results in a general functional decline, including cognitive impairment. Caloric restriction (CR) can positively influence the aging processes and delay cognitive decline. There is a rhythmic variation in memory and learning processes throughout the day, indicating the involvement of the circadian clock in the regulation of these processes. Despite growing evidence on the efficacy of CR, it has not yet been fully determined whether starting this strategy at an advanced age is beneficial for improving quality of life and eventually, for protection against age-related diseases. Here, we investigated the effect of late-onset CR on the temporal organization of the molecular clock machinery, molecules related to cognitive processes and epigenetic regulation, in the hippocampus of male old rats maintained under constant darkness conditions. Our results evidenced the existence of a highly coordinated temporal organization of Bmal1, Clock, Bdnf, Trkb, Dnmts, Sirt1, and Pgc-1α in the hippocampus of young adult rats. We observed that aging led to cognitive deficits and loss of circadian oscillations of all the above variables. Interestingly, CR restored circadian rhythmicity in all cases and, in addition, improved the cognitive performance of the old animals. This work would highlight the importance of the circadian clock and its synchronization with feeding signals, as the basis of the beneficial effects of CR. Thus, lifestyle modifications, such as CR, might be a powerful intervention to preserve hippocampal circadian organization and cognitive health during aging.
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晚期热量限制可改善雄性老年大鼠的认知能力,并恢复其海马区神经营养因子、时钟因子和表观遗传因子的昼夜节律模式
衰老是一个复杂的多因素过程,会导致包括认知障碍在内的整体功能衰退。热量限制(CR)可以对衰老过程产生积极影响,并延缓认知能力的衰退。记忆和学习过程在一天中存在节律性变化,这表明昼夜节律参与了这些过程的调节。尽管有越来越多的证据表明昼夜节律的功效,但尚未完全确定在高龄时开始这一策略是否有利于提高生活质量,并最终预防与年龄相关的疾病。在这里,我们研究了晚期CR对在恒定黑暗条件下饲养的雄性老年大鼠海马中分子时钟机制的时间组织、与认知过程和表观遗传调控有关的分子的影响。我们的研究结果证明,在年轻成年大鼠的海马中,Bmal1、Clock、Bdnf、Trkb、Dnmts、Sirt1和Pgc-1α存在高度协调的时间组织。我们观察到,衰老会导致认知缺陷和上述所有变量昼夜节律振荡的丧失。有趣的是,CR 在所有情况下都能恢复昼夜节律,而且还能改善老年动物的认知能力。这项研究强调了昼夜节律及其与进食信号同步的重要性,这是 CR 产生有益影响的基础。因此,在衰老过程中,改变生活方式(如CR)可能是保护海马昼夜节律组织和认知健康的有力干预措施。
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