C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction

C. elegans as Model for the Study of High Glucose– Mediated Life Span Reduction Andreas Schlotterer 1 , Georgi Kukudov 1 , Farastuk Bozorgmehr 1 , Harald Hutter 2 , Xueliang Du 3 , Dimitrios Oikonomou 1 , Youssef Ibrahim 1 , Friederike Pfisterer 1 , Naila Rabbani 4 , Paul Thornalley 4 , Ahmed Sayed 1 , Thomas Fleming 1 , Per Humpert 1 , Vedat Schwenger 1 , Martin Zeier 1 , Andreas Hamann 1 , 5 , David Stern 6 , Michael Brownlee 3 , Angelika Bierhaus 1 , Peter Nawroth 1 and Michael Morcos 1 1 Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany; 2 Simon Fraser University, Department of Biological Sciences, Burnaby, Canada; 3 Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York; 4 Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry, U.K.; 5 Diabetes-Clinic, Center for Vascular Medicine, Bad Nauheim, Germany; 6 College of Medicine, University of Cincinnati, Cincinnati, Ohio. Corresponding author: Andreas Schlotterer, andreas.schlotterer{at}med.uni-heidelberg.de . A.S., G.K., and F.B. contributed equally to this study. Abstract OBJECTIVE Establishing Caenorhabditis elegans as a model for glucose toxicity–mediated life span reduction. RESEARCH DESIGN AND METHODS C. elegans were maintained to achieve glucose concentrations resembling the hyperglycemic conditions in diabetic patients. The effects of high glucose on life span, glyoxalase-1 activity, advanced glycation end products (AGEs), and reactive oxygen species (ROS) formation and on mitochondrial function were studied. RESULTS High glucose conditions reduced mean life span from 18.5 ± 0.4 to 16.5 ± 0.6 days and maximum life span from 25.9 ± 0.4 to 23.2 ± 0.4 days, independent of glucose effects on cuticle or bacterial metabolization of glucose. The formation of methylglyoxal-modified mitochondrial proteins and ROS was significantly increased by high glucose conditions and reduced by mitochondrial uncoupling and complex IIIQo inhibition. Overexpression of the methylglyoxal–detoxifying enzyme glyoxalase-1 attenuated the life-shortening effect of glucose by reducing AGE accumulation (by 65%) and ROS formation (by 50%) and restored mean (16.5 ± 0.6 to 20.6 ± 0.4 days) and maximum life span (23.2 ± 0.4 to 27.7 ± 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced mean (16.5 ± 0.6 to 13.9 ± 0.7 days) and maximum life span (23.2 ± 0.4 to 20.3 ± 1.1 da