Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA.
Center for Circadian Biology, University of California, San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California, San Diego, La Jolla, CA, USA; Veterans Affairs San Diego Healthcare System, San Diego, CA, USA.
Cell Metab. 2023 Oct 3;35(10):1704-1721.e6. doi: 10.1016/j.cmet.2023.07.014. Epub 2023 Aug 21.
Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.
昼夜节律紊乱几乎影响所有阿尔茨海默病(AD)患者,这强调了它们在发病机制中的潜在作用,以及研究昼夜节律调节干预治疗潜力的迫切需求。在这里,我们展示了限时喂养(TRF)而不限制热量可改善包括行为定时、疾病病理学、海马转录和记忆在内的关键疾病成分,在两种 AD 转基因(TG)小鼠模型中均有改善。我们发现,TRF 具有显著的能力,可同时减少淀粉样蛋白沉积、增加 Aβ42 清除、改善睡眠和记忆,并使包括与 AD 和神经炎症相关的基因在内的多个基因的日常转录模式正常化。因此,我们的研究首次揭示了定时喂养对 AD 的多效性,其影响远远超出代谢范围,可改善神经退行性变和昼夜节律的失调。由于 TRF 可以极大地改变疾病进程,因此这种干预具有直接的转化潜力,满足了人们对可获得的方法的迫切需求,以减少或阻止 AD 的进展。
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