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.

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Excess dietary sugar adversely affects human health by promoting the development of metabolic disorders such as obesity and type-2 diabetes (Figure 1). Sugar-rich diets are commonly used to replicate and investigate metabolic diseases in animal models, including the fruit fly Drosophila melanogaster [1]. High-sugar diets also shorten survival, which was widely attributed to these diabetic-like metabolic defects. However, our recent work in Drosophila reveals that longevity can be uncoupled from obesity and insulin resistance [2].