How does a fly die? Insights into ageing from the pathophysiology of Drosophila mortality.

The fruit fly Drosophila melanogaster is a common animal model in ageing research. Large populations of flies are used to study the impact of genetic, nutritional and pharmacological interventions on survival. However, the processes through which flies die and their relative prevalence in Drosophila populations are still comparatively unknown. Understanding the causes of death in an animal model is essential to dissect the lifespan-extending interventions that are organism- or disease-specific from those broadly applicable to ageing. Here, we review the pathophysiological processes that can lead to fly death and discuss their relation to ageing.

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

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.

Carotid Body Dysfunction in Diet-Induced Insulin Resistance Is Associated with Alterations in Its Morphology.

The carotid body (CB) is organized in clusters of lobules containing type I cells and type II cells, in a ratio of approximately 4:1. The CB undergoes structural and functional changes during perinatal development, in response to a variety of environmental stimuli and in pathological conditions. Knowing that the CB acts as a metabolic sensor involved in the control of peripheral insulin sensitivity and that its overactivation contributes to the genesis of metabolic disturbances, herein we tested if diet-induced insulin resistance is associated with morphological alterations in the proportion of type I and type II cells in the CB. Diet induced insulin resistant model (HFHSu) was obtained by submitting Wistar rats to 14 weeks of 60% lipid-rich diet and 35% of sucrose in drinking water. The HFHSu group was compared with an aged-matched control group. Glucose tolerance and insulin sensitivity were measured in conscious animals before diet administration and 14 weeks after the diet protocol. The expression of tyrosine hydroxylase (TH) and nestin were assessed by immunohistochemistry to identify type I and type II cells, respectively. TH expression was also quantified by Western blot. As expected, 14 weeks of HFHSu diet induced a decrease in insulin sensitivity as well as in glucose tolerance. HFHsu diet increased the number of TH-positive type I cells by 192% and decreased nestin-postive type 2 cells by 74%. This increase in type II cells observed by immunohistochemistry correlates with an increase by 107% in TH expression quantified by Western blot. These results suggest that changes in CB morphology are associated with metabolic disturbances invoked by administration of a hypercaloric diet.