High-sugar diets cause thirst, obesity, and metabolic dysregulation, leading to diseases including type 2 diabetes and shortened lifespan. However, the impact of obesity and water imbalance on health and survival is complex and difficult to disentangle. Here, we show that high sugar induces dehydration in adult Drosophila, and water supplementation fully rescues their lifespan. Conversely, the metabolic defects are water-independent, showing uncoupling between sugar-induced obesity and insulin resistance with reduced survival in vivo. High-sugar diets promote accumulation of uric acid, an end-product of purine catabolism, and the formation of renal stones, a process aggravated by dehydration and physiological acidification. Importantly, regulating uric acid production impacts on lifespan in a water-dependent manner. Furthermore, metabolomics analysis in a human cohort reveals that dietary sugar intake strongly predicts circulating purine levels. Our model explains the pathophysiology of high-sugar diets independently of obesity and insulin resistance and highlights purine metabolism as a pro-longevity target.

中文翻译：

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糖诱导的肥胖和胰岛素抵抗与果蝇的生存期缩短无关。

高糖饮食会导致口渴、肥胖和代谢失调，导致包括 2 型糖尿病在内的疾病和缩短寿命。然而，肥胖和水分失衡对健康和生存的影响是复杂的，难以解开。在这里，我们表明高糖会导致成年果蝇脱水，而补水可以完全挽救它们的寿命。相反，代谢缺陷与水无关，显示糖诱导的肥胖和胰岛素抵抗之间的脱钩，降低了体内存活率。高糖饮食会促进尿酸（嘌呤分解代谢的最终产物）的积累和肾结石的形成，脱水和生理酸化会加剧这一过程。重要的是，调节尿酸产生以依赖水的方式影响寿命。此外，人类队列中的代谢组学分析表明，饮食中的糖摄入量强烈预测循环嘌呤水平。我们的模型独立于肥胖和胰岛素抵抗解释了高糖饮食的病理生理学，并强调嘌呤代谢是促进长寿的目标。