C. elegans as model for the study of high glucose- mediated life span reduction.
OBJECTIVE
Establishing Caenorhabditis elegans as a model for glucose toxicity-mediated life span reduction.


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 + or - 0.4 to 16.5 + or - 0.6 days and maximum life span from 25.9 + or - 0.4 to 23.2 + or - 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 + or - 0.6 to 20.6 + or - 0.4 days) and maximum life span (23.2 + or - 0.4 to 27.7 + or - 2.3 days). In contrast, inhibition of glyoxalase-1 by RNAi further reduced mean (16.5 + or - 0.6 to 13.9 + or - 0.7 days) and maximum life span (23.2 + or - 0.4 to 20.3 + or - 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-1-dependent methylglyoxal detoxification or preventing mitochondrial dysfunction.
Schlotterer
Andreas
A
Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany. andreas.schlotterer@med.uniheidelberg.de
Kukudov
Georgi
G
Bozorgmehr
Farastuk
F
Hutter
Harald
H
Du
Xueliang
X
Oikonomou
Dimitrios
D
Ibrahim
Youssef
Y
Pfisterer
Friederike
F
Rabbani
Naila
N
Thornalley
Paul
P
Sayed
Ahmed
A
Fleming
Thomas
T
Humpert
Per
P
Schwenger
Vedat
V
Zeier
Martin
M
Hamann
Andreas
A
Stern
David
D
Brownlee
Michael
M
Bierhaus
Angelika
A
Nawroth
Peter
P
Morcos
Michael
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D008017:Life Expectancy / Q000639:trends; D008136:Longevity / Q000502:physiology*; D008855:Microscopy, Electron, Scanning; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D005947:Glucose
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