Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate.
Low-dose 1,3-butanediol reverses age-associated vascular dysfunction independent of ketone body β-hydroxybutyrate.
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低剂量1,3-丁二醇可逆转与年龄相关的血管功能障碍，与酮体β-羟基丁酸无关。
DOI：
10.1152/ajpheart.00486.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Joe,Bina
中科院分区：
文献类型：
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作者：
McCarthy,CameronG;Waigi,EmilyW;Yeoh,BengSan;Mell,Blair;Vijay-Kumar,Matam;Wenceslau,CamillaF;Joe,Bina
随着全球人口的老龄化，寻找新的治疗方法是必要的，以延长寿命和减少重要的最终器官，如脉管系统的恶化。仲醇1,3-丁二醇（1,3- bd）通常用于刺激最丰富的酮体β-羟基丁酸酯（βHB）的生物合成，以代替营养剥夺。然而，1,3- bd的超药理学浓度是显著增加全身βHB所必需的，并且1,3- bd本身可以在纳摩尔浓度下引起血管舒张。因此，我们假设1,3- bd可能是一种独立于βHB生物合成的新型抗衰老药物。为了验证这一假设，我们给年轻和年老Wistar-Kyoto （WKY）大鼠饮水低剂量（5%）1,3- bd 4周，并测量了治疗后血管功能和代谢指标。我们观察到，低剂量1,3- bd足以逆转与年龄相关的内皮依赖性和独立性功能障碍，这与βHB生物利用度的增加无关。对1,3- bd直接血管扩张机制的进一步分析表明，它主要是一种内皮依赖性血管扩张剂，通过激活钾通道和一氧化氮合酶。总之，我们报道了1,3- bd，在不刺激βHB生物合成的浓度下，可能是一种营养保健品，可以逆转与年龄相关的血管功能下降。这些结果强调1,3- bd具有多种浓度依赖性的作用机制。因此，我们建议采用其他方法来研究βHB的生理和心血管作用。1,3-丁二醇（1,3- bd）通常用于刺激最丰富的酮体β-羟基丁酸酯（βHB）的生物合成，并具有据称的健康作用。在这里，我们报道低剂量的1,3- bd（5%）足以逆转与年龄相关的血管功能障碍，独立于βHB。因此，低剂量的1,3- bd可能是一种新的治疗方法，可以增加血流量，改善老年人的生活质量。
With an aging global population, identifying novel therapeutics are necessary to increase longevity and decrease the deterioration of essential end organs such as the vasculature. Secondary alcohol, 1,3-butanediol (1,3-BD), is commonly administered to stimulate the biosynthesis of the most abundant ketone body β-hydroxybutyrate (βHB), in lieu of nutrient deprivation. However, suprapharmacological concentrations of 1,3-BD are necessary to significantly increase systemic βHB, and 1,3-BD per se can cause vasodilation at nanomolar concentrations. Therefore, we hypothesized that 1,3-BD could be a novel antiaging therapeutic, independent of βHB biosynthesis. To test this hypothesis, we administered a low-dose (5%) 1,3-BD to young and old Wistar-Kyoto (WKY) rats via drinking water for 4 wk and measured indices of vascular function and metabolism posttreatment. We observed that low-dose 1,3-BD was sufficient to reverse age-associated endothelial-dependent and -independent dysfunction, and this was not associated with increased βHB bioavailability. Further analysis of the direct vasodilator mechanisms of 1,3-BD revealed that it is predominantly an endothelium-dependent vasodilator through activation of potassium channels and nitric oxide synthase. In summary, we report that 1,3-BD, at a concentration that does not stimulate βHB biosynthesis, could be a nutraceutical that can reverse the age-associated decline in vascular function. These results emphasize that 1,3-BD has multiple, concentration-dependent mechanisms of action. Therefore, we suggest alternative approaches to study the physiological and cardiovascular effects of βHB.NEW & NOTEWORTHY1,3-Butanediol (1,3-BD) is often administered to stimulate the biosynthesis of the most abundant ketone body, β-hydroxybutyrate (βHB), and its purported salubrious effects. Here, we report that a low dose of 1,3-BD (5%) is sufficient to reverse age-associated vascular dysfunction, independent of βHB. Therefore, low-dose 1,3-BD could be a novel therapeutic to increase blood flow and improve the quality of life in the elderly.