Sugar-Induced Obesity and Insulin Resistance Are Uncoupled from Shortened Survival in Drosophila

Abstract

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.

Gut Bacterial Species Distinctively Impact Host Purine Metabolites during Aging in Drosophila

“…The increased allantoin level by adenine feeding was correlated with shortened lifespan ( Figure S3 C), consistent with the previous report ( van Dam et al., 2020 ). Other dietary nutrients, such as sugars and amino acids, can provide with substrates for purine biosynthesis.…”

“…Other dietary nutrients, such as sugars and amino acids, can provide with substrates for purine biosynthesis. A high-sugar diet causes early mortality due to the increased uric acid production and concomitant renal stones in flies ( van Dam et al., 2020 ). High-yeast feeding also induces uric acid accumulation and shortens the lifespan of Uro knockdown flies ( Lang et al., 2019 ).…”

“…The increase of pro-longevity allantoin can be an adaptive response to aging, or the increase serves simply as a marker for increased total purine levels. Some purines and uric acid levels are also increased in conditions with high allantoin levels, and uric acid accumulation is a cause of shortened lifespan by high-purine diets ( van Dam et al., 2020 ; Lang et al., 2019 ). It might be interesting to test whether Uro overexpression can extend lifespan.…”

“…It might be interesting to test whether Uro overexpression can extend lifespan. Intriguingly, high-sugar diet induces dehydration, and the shortened lifespan of flies with the diet is fully restored by water supplementation ( van Dam et al., 2020 ). High-yeast diet can also induce dehydration, implying that water loss is the common mechanism to increase purine levels by these dietary conditions ( Ja et al., 2009 ).…”

The Target of Rapamycin Signalling Pathway in Ageing and Lifespan Regulation

“…Purine metabolism has recently been highlighted as a longevity target with dietary sugar intake strongly predicting circulating purine levels in humans. In addition, high-sugar diets promote accumulation of uric acid, an end-product of purine catabolism [ 77 ] and regulating uric acid production impacts on lifespan in a water-dependent manner [ 77 ]. Synthesis of pyrimidines is also promoted by TORC1, via its down-stream effector S6K, which phosphorylates and activates CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase), a rate limiting enzymes in the first steps of pyrimidine de novo synthesis [ 78 , 79 ].…”