Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila
Authors: David W Walker
Rebecca I Clark
Michael Rera
Journal: Proceedings of the National Academy of Sciences of the United States of America (2012)
Discipline: Multidisciplinary
Keywords: Aging; Intestinal barrier dysfunction; Lifespan; Drosophila; Inflammatory pathways
Affiliations: Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.

Abstract:  Aging is characterized by a growing risk of disease and death, yet the underlying pathophysiology is poorly understood. Indeed, little is known about how the functional decline of individual organ systems relates to the integrative physiology of aging and probability of death of the organism. Here we show that intestinal barrier dysfunction is correlated with lifespan across a range of Drosophila genotypes and environmental conditions, including mitochondrial dysfunction and dietary restriction. Regardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies. Activation of inflammatory pathways has been linked to aging and age-related diseases in humans, and an age-related increase in immunity-related gene expression has been reported in Drosophila. We show that the age-related increase in expression of antimicrobial peptides is tightly linked to intestinal barrier dysfunction. Indeed, increased antimicrobial peptide expression during aging can be used to identify individual flies exhibiting intestinal barrier dysfunction. Similarly, intestinal barrier dysfunction is more accurate than chronological age in identifying individual flies with systemic metabolic defects previously linked to aging, including impaired insulin/insulin-like growth factor signaling, as evidenced by a reduction in Akt activation and up-regulation of dFOXO target genes. Thus, the age-dependent loss of intestinal integrity is associated with altered metabolic and immune signaling and, critically, is a harbinger of death. Our findings suggest that intestinal barrier dysfunction may be an important factor in the pathophysiology of aging in other species as well, including humans. 

Retracted: No

PubPeer comments:
 A recent article (Predicting death by the loss of intestinal function, doi.org 10.1371 journal.pone.0230970) partially contradicts the claims of Rera et al., 2012. Please note:  This study has established a number of important conclusions. **(1) All dyes used have significant negative effects on mean longevity, with decreases ranging from 5 to almost 10 days. (2) Only a small fraction of the flies show the Smurf phenotype prior to death. Over all populations and dyes 22% of males and 34% of females became Smurfs. (3) Among the small fraction that do become Smurfs most (40u201360%) become blue during their last 24 hours of life. Thus, even with daily checks most of the Smurf flies will be dead when initially identified as Smurf making their utility for gene expression studies useless**. As can be seen from Table 1, there was substantial replication, with each population undergoing 6 different dyes and a control. The original dye used in Rera et al. [16], SPS Alfachem, was replicated in 5 different populations, and each population was replicated in 6 different dye environments, allowing for substantial replication across the whole experiment. The three results cited above were consistently seen across all the replicates suggesting that these findings are robust. **These results certainly contradict prior claims [16]. Rera et al [16] suggested that essentially all flies become Smurfs prior to death and that the dyes do not affect survival** https: doi.org 10.1371 journal.pone.0230970 ,