[
International Worm Meeting,
2005]
Increased generation of reactive oxygen species contribute to an enhanced formation of posttranscriptionally modified proteins (AGEs), known to accumulate during aging. One AGE-detoxifying mechanism is the glyoxalase pathway. Glyoxalase-1 (Gly1) metabolizes the AGE-precursor methylglyoxal (MG) to D-lactate using reduced glutathione as a co-substrate. The aim of this study was to identify Gly1 in the model organism C. elegans and to study its role in determining life span. We identified a Gly1 homologue in the C. elegans genome data bank. Quantitative PCR revealed that expression of a C. elegans glyoxalase-I homologue (CeGly1) is significantly reduced in 12 day old C. elegans by 70%; (p<0.0001). Overexpression of CeGly1 decreased formation of methylglyoxal derived AGEs, CML-modified proteins and ROS-formation in 12 day old C. elegans (p<0.01) and increased life span (p<0.001). CeGly reduced significantly age-dependent mitochondrial methylglyoxal modifications in 12 –day old C. elegans and mitochondrial superoxide formation. To further study a causal relationship between mitochondrial AGE-modification and aging, C. elegans were treated with the mitochondrial uncoupler FCCP and the complex III inhibitor myxothiazole. Both reduced mitochondrial ROS formation and increased life span only in wild type animals, but had no effect in CeGly animals. Our data demonstrate the downregulation of enzymatic defense systems during aging. Overcoming this downregulation by overexpressing Gly1 restores mitochondrial function and prolongs life span. Hence posttranscriptional protein modification by MG-derived adducts plays a central role in determining life span.