C. elegans as model for the study of high glucose mediated lifespan reduction

  1. Andreas Schlotterer (Andreas.Schlotterer{at},
  2. Georgi Kukudov1,
  3. Farastuk Bozorgmehr1,
  4. Harald Hutter2,
  5. Xueliang Du3,
  6. Dimitrios Oikonomou1,
  7. Youssef Ibrahim1,
  8. Friederike Pfisterer1,
  9. Naila Rabbani4,
  10. Paul Thornalley4,
  11. Ahmed Sayed1,
  12. Thomas Fleming1,
  13. Per Humpert1,
  14. Vedat Schwenger1,
  15. Martin Zeier1,
  16. Andreas Hamann1,5,
  17. David Stern6,
  18. Michael Brownlee3,
  19. Angelika Bierhaus1,
  20. Peter Nawroth1 and
  21. Michael Morcos1
  1. 1Department of Medicine I and Clinical Chemistry, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
  2. 2Simon Fraser University, Department of Biological Sciences, 8888 University Drive, Burnaby, Canada
  3. 3Departments of Medicine and Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York, USA
  4. 4Warwick Medical School, Clinical Sciences Research Institute, University of Warwick, University Hospital, Coventry CV2 2DX, United Kingdom
  5. 5Diabetes-Clinic, Center for Vascular Medicine, Ludwigstraße 37-39, 61231 Bad Nauheim, Germany
  6. 6College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA


    Objective: Establishing C. elegans as a model for glucose toxicity mediated lifespan 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 lifespan, 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 lifespan from 18.5±0.4 to 16.5±0.6 days and maximum lifespan 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 II 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 lifespan (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 lifespan (23.2±0.4 to 20.3±1.1 days). The lifespan reduction by glyoxalase-1-inhibition was independent from the insulin signaling pathway, since high glucose conditions also affected daf-2 knock-down animals in a similar manner.

    Conclusions: C. elegans is a suitable model organism to study glucose toxicity, in which high glucose conditions limit the lifespan 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-1 dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.


      • Received April 22, 2009.
      • Accepted July 22, 2009.