Document Detail

Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila.
MedLine Citation:
PMID:  23236133     Owner:  NLM     Status:  MEDLINE    
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.
Michael Rera; Rebecca I Clark; David W Walker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-12
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-27     Completed Date:  2013-02-21     Revised Date:  2013-11-08    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21528-33     Citation Subset:  IM    
Department of Integrative Biology and Physiology, University of California, Los Angeles, CA 90095, USA.
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MeSH Terms
Aging / metabolism*,  pathology*
Antimicrobial Cationic Peptides / metabolism
Biological Markers / metabolism
Drosophila Proteins / metabolism
Drosophila melanogaster / metabolism*
Green Fluorescent Proteins / metabolism
Inflammation / metabolism*
Insulin / metabolism
Intestines / metabolism*,  physiopathology*
Mitochondria / metabolism
Signal Transduction
Grant Support
R01 AG037514/AG/NIA NIH HHS; R01 AG037514/AG/NIA NIH HHS; R01 AG040288/AG/NIA NIH HHS; R01 AG040288/AG/NIA NIH HHS
Reg. No./Substance:
0/Antimicrobial Cationic Peptides; 0/Biological Markers; 0/Drosophila Proteins; 0/Insulin; 147336-22-9/Green Fluorescent Proteins

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