Ketogenic Diet Modulates NAD(+)-Dependent Enzymes and Reduces DNA Damage in Hippocampus.
Ketogenic Diet Modulates NAD(+)-Dependent Enzymes and Reduces DNA Damage in Hippocampus.
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DOI：
10.3389/fncel.2018.00263
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发表时间：
2018
影响因子：
5.3
通讯作者：
Sacchetti P
中科院分区：
文献类型：
--
作者：
Elamin M;Ruskin DN;Masino SA;Sacchetti P
生酮饮食（KD）的抗癫痫作用早已被记录。最近，它在多种神经退行性和神经发育障碍中的治疗潜力已经显现。然而，仍然缺乏对多种疾病产生有益影响的基本机制的实验证据。我们之前表明，给大鼠喂食生酮饮食会导致海马烟酰胺腺嘌呤二核苷酸+ (NAD+) 早期（2 天内）持续升高，NAD+ 是一种重要的代谢辅酶和信号分子。 NAD+ 是细胞健康的标志物，也是与长寿和 DNA 损伤修复有关的酶的底物，例如去乙酰化酶和聚 ADP 核糖聚合酶 1 (PARP-1)。因此，NAD+ 依赖性酶下游途径的激活可能是 KD 广泛有益作用的根源。在这里，大鼠随意喂食普通食物或 KD 2 天或 3 周，并对海马 Sirtuins、PARP-1 和氧化 DNA 损伤标记物 8-羟基-2'-脱氧鸟苷的水平进行定量。我们发现核 Sirtuin 酶的集体活性显着立即且持续增加，并且 Sirt1 mRNA 在 2 天时显着增加。 PARP-1和8-羟基-2'-脱氧鸟苷的水平在治疗2天后下降，并在3周时进一步下降。我们的数据表明，KD 可以通过作用于 NAD+ 依赖性酶及其下游途径来快速调节能量代谢。因此，KD 治疗可以通过 NAD+ 相关机制潜在地增强大脑健康并延长整体健康寿命，这些机制使细胞对 DNA 损伤和一系列代谢、癫痫、神经退行性或神经发育损伤更具弹性。
The ketogenic diet’s (KD) anti-seizure effects have long been documented. Recently, its therapeutic potential in multiple neurodegenerative and neurodevelopmental disorders has emerged. Yet experimental evidence for a fundamental mechanism underlying beneficial effects across numerous diseases remains lacking. We previously showed that feeding rats a KD produced an early (within 2 days) and persistent elevation of hippocampal nicotinamide adenine dinucleotide+ (NAD+), an essential metabolic coenzyme and signaling molecule. NAD+ is a marker of cellular health and a substrate for enzymes implicated in longevity and DNA damage repair such as sirtuins and poly-ADP ribose polymerase-1 (PARP-1). As a result, activation of NAD+-dependent enzymes’ downstream pathways could be the origin of KD’s broad beneficial effects. Here rats were fed ad libitum regular chow or KD for 2 days or 3 weeks and the levels of hippocampal sirtuins, PARP-1, and the oxidative DNA damage marker 8-hydroxy-2’-deoxyguanosine were quantified. We found a significant immediate and persistent increase in the collective activity of nuclear sirtuin enzymes, and a significant augmentation of Sirt1 mRNA at 2 days. Levels of PARP-1 and 8-hydroxy-2’-deoxyguanosine decreased after 2 days of treatment and further declined at 3 weeks. Our data show that a KD can rapidly modulate energy metabolism by acting on NAD+-dependent enzymes and their downstream pathways. Thus, therapy with a KD can potentially enhance brain health and increase overall healthspan via NAD+-related mechanisms that render cells more resilient against DNA damage and a host of metabolic, epileptic, neurodegenerative, or neurodevelopmental insults.
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影响因子：
1.9
作者：
Islam, Md. Torequl
通讯作者：
Islam, Md. Torequl
DOI：
10.1073/pnas.1718819115
发表时间：
2018-02-20
影响因子：
11.1
作者：
Hou, Yujun;Lautrup, Sofie;Bohr, Vilhelm A.
通讯作者：
Bohr, Vilhelm A.
影响因子：
10.5
作者：
Chen, Danica;Bruno, Joanne;Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
6.1
作者：
Guo C;Sun L;Chen X;Zhang D
通讯作者：
Zhang D
影响因子：
11.4
作者：
Hegedus, Csaba;Virag, Laszlo
通讯作者：
Virag, Laszlo