Intermittent fasting (IF) and its mimetic, rapamycin extend lifespan and healthspan through mechanisms that are not fully understood. We investigated different short-term durations of IF and rapamycin on cellular and molecular changes in the brains of young (6–10 months) and old (26–31 months) zebrafish. Interestingly, our results showed that IF significantly lowered glucose levels while increasing DCAMKL1 in both young and old animals. This proliferative effect of IF was supported by the upregulation of foxm1 transcript in old animals. Rapamycin did not change glucose levels in young and old animals but had differential effects depending on age. In young zebrafish, proliferating cell nuclear antigen and the LC3-II/LC3-I ratio was decreased, whereas glial fibrillary acidic protein and gephyrin were decreased in old animals. The changes in proliferative markers and a marker of autophagic flux suggest an age-dependent interplay between autophagy and cell proliferation. Additionally, changes in glia and inhibitory tone suggest a suppressive effect on neuroinflammation but may push the brain toward a more excitable state. Mammalian target of rapamycin (mTOR) activity in the brain following the IF and rapamycin treatment was differentially regulated by age. Interestingly, rapamycin inhibited mTOR more potently in young animals than IF. Principal component analysis supported our conclusion that the regulatory effects of IF and rapamycin were age-specific, since we observed different patterns in the expression levels and clustering of young and old animals. Taken together, our results suggest that even a short-term duration of IF and rapamycin have significant effects in the brain at young and old ages, and that these are age and treatment dependent.

中文翻译：

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抑制雷帕霉素活性的哺乳动物靶标的饮食和药理学干预以年龄和治疗相关的方式改变神经源性和神经胶质标志物的大脑表达水平。

间歇性禁食 (IF) 及其模拟物雷帕霉素通过尚未完全了解的机制延长寿命和健康寿命。我们研究了不同短期持续时间的 IF 和雷帕霉素对年轻（6-10 个月）和年长（26-31 个月）斑马鱼大脑细胞和分子变化的影响。有趣的是，我们的结果显示 IF 显着降低了葡萄糖水平，同时增加了年轻和年老动物的 DCAMKL1。Foxm1的上调支持了 IF 的这种增殖作用旧动物的转录本。雷帕霉素不会改变年轻和年老动物的葡萄糖水平，但会根据年龄产生不同的影响。在年轻的斑马鱼中，增殖细胞核抗原和 LC3-II/LC3-I 比率降低，而老年动物的胶质纤维酸性蛋白和 gephyrin 降低。增殖标志物和自噬通量标志物的变化表明自噬和细胞增殖之间存在年龄依赖性相互作用。此外，胶质细胞和抑制性音调的变化表明对神经炎症有抑制作用，但可能会将大脑推向更兴奋的状态。IF 和雷帕霉素治疗后大脑中的哺乳动物雷帕霉素靶标 (mTOR) 活性受年龄差异调节。有趣的是，雷帕霉素在年轻动物中比 IF 更有效地抑制 mTOR。主成分分析支持我们的结论，即 IF 和雷帕霉素的调节作用具有年龄特异性，因为我们观察到不同的表达水平和年轻和年老动物的聚类模式。综上所述，我们的结果表明，即使是短期的 IF 和雷帕霉素对年轻人和老年人的大脑都有显着影响，而且这些影响取决于年龄和治疗。