Abstract
In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.
Highlights
Aging and metabolic syndrome are among the major issues in contemporary medicine. The mechanisms underlying these health problems remain incompletely understood, it has been demonstrated that aging and metabolism are intimately related, and that gut homeostasis plays an important role in regulation of these processes [1,2,3]
Flies and life span assays w1118, EP2372, P[Δ2–3], P112087, Cyo/sp;TM3,Ser/TM6, Cop-Gal4 (NP3270), daughterlessGal4 and UAS-GFP fly stocks were obtained from the Bloomington Drosophila Stock Center
To identify novel genes involved in metabolic regulation, we set up a genetic screen for starvation resistance using P-element-mediated mutagenesis in D. melanogaster
Summary
Aging and metabolic syndrome are among the major issues in contemporary medicine. The mechanisms underlying these health problems remain incompletely understood, it has been demonstrated that aging and metabolism are intimately related, and that gut homeostasis plays an important role in regulation of these processes [1,2,3]. PLOS ONE | DOI:10.1371/journal.pone.0139722 October 5, 2015
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