C-elegans as Model for the Study of High Glucose-Mediated Life Span Reduction
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| Authors: | Schlotterer, A; Kukudov, G; Bozorgmehr, F; Hutter, H; Du, XL; Oikonomou, D; Ibrahim, Y; Pfisterer, F; Rabbani, N; Thornalley, P; Sayed, A; Fleming, T; Humpert, P; Schwenger, V; Zeier, M; Hamann, A; Stern, D; Brownlee, M; Bierhaus, A; Nawroth, P; Morcos, M |
| Year: | 2009 |
| Journal: | Diabetes 58: 2450-2456 Article Link (DOI) |
| Title: | C-elegans as Model for the Study of High Glucose-Mediated Life Span Reduction |
| 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 days). The life span reduction by glyoxalase-1 inhibition was independent from the insulin signaling pathway because high glucose conditions also affected daf-2 knockdown animals in a similar manner. CONCLUSIONS-C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the life span by increasing ROS formation and AGE modification of mitochondrial proteins in a daf-2 independent manner. Most importantly, glucose toxicity can be prevented by improving glyoxalase-l-dependent methylglyoxal detoxification or preventing mitochondrial dysfunction. Diabetes 58:2450-2456, 2009 |
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