Veech Richard L, Bradshaw Patrick C, Clarke Kieran, Curtis William, Pawlosky Robert, King M Todd
Lab of Metabolic Control, NIH/NIAAA, Rockville, MD, USA.
East Tennessee State University College of Medicine, Johnson City, TN, USA.
IUBMB Life. 2017 May;69(5):305-314. doi: 10.1002/iub.1627. Epub 2017 Apr 3.
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.
从酵母、秀丽隐杆线虫到灵长类动物，人们对热量限制延长寿命进行了跨物种研究。目前尚未提出被普遍接受的理论来解释这些观察结果。在此，我们提出热量限制所产生的寿命延长可以通过酮症诱导的代谢变化来复制。从线虫到小鼠，寿命延长是由于胰岛素/胰岛素样生长因子受体信号通路（IIS）的信号传导减少所致。IIS的减少会减少磷脂酰肌醇（3,4,5）三磷酸（PIP）的产生，导致PI3K和AKT激酶活性降低以及叉头框O转录因子（FOXO）磷酸化减少，使FOXO蛋白能够留在细胞核中。在细胞核中，FOXO蛋白会增加编码抗氧化酶的基因的转录，包括超氧化物歧化酶2、过氧化氢酶、谷胱甘肽过氧化物酶以及数百个其他基因。一种对抗自由基损伤的有效方法是通过酮体的代谢来实现的，酮症是从果蝇到灵长类动物热量限制所带来的特征性生理变化。一种膳食酮酯也会降低循环中的葡萄糖和胰岛素水平，导致IIS减少。酮体d-β-羟基丁酸（d-βHB）是I类和IIa类组蛋白去乙酰化酶的天然抑制剂，这些酶会抑制FOXO3a基因的转录。因此，酮症会导致抗氧化途径的酶的转录。此外，酮体的代谢会导致NADP抗氧化系统的氧化还原电位更负，而NADP抗氧化系统是氧自由基的最终破坏者。向秀丽隐杆线虫培养物中添加d-βHB可延长其寿命。我们假设提高酮体水平也会延长人类的寿命，并且热量限制至少部分是通过提高酮体水平来延长寿命的。一种外源性酮酯为模拟热量限制的效果提供了一种新工具，可用于未来的研究。对于因丙酮酸脱氢酶抑制而氧化葡萄糖代谢物能力有限的老年个体，为其线粒体提供能量的能力为衰老及衰老相关疾病的预防措施和治疗开辟了新的研究方向。© 2017作者，IUBMB Life由Wiley Periodicals, Inc.代表国际生物化学与分子生物学联盟出版，2017年，69(5):305 - 314。
