Methylglyoxal is a highly reactive dicarbonyl compound, which is widely distributed in food products and beverages, and is particularly high in Manuka honey. In addition to its antibacterial effects, methylglyoxal is also known as a major precursor of advanced glycation end products (AGEs), that produces altered macromolecules (such as proteins and DNA), leading to abnormal physiological changes. However, the effects of methylglyoxal on development is unclear. Thus, this study aimed to determine the role of methylglyoxal in this aspect using Caenorhabditis elegans (C. elegans). Treatment of methylglyoxal at 0.1 mM and 1 mM for 48 h significantly inhibited development of C. elegans and reduced pumping rate. Activity, measured by moving speed, was increased with 0.1 mM methylglyoxal, but reduced with 1 mM methylglyoxal. Lifespan of C. elegans was not influenced by methylglyoxal at 0.1 mM, but was shortened at 1 mM. Treatment methylglyoxal on the mutant, lin-41, which has a precocious phenotype, could alleviate the implication on wild-type worms. These results suggested that methylglyoxal significantly influenced the development of C. elegans through the heterochronic pathway.

Robustness is a ubiquitous property of biological systems, however, underlying mechanisms that help reinforce the optimal phenotypes despite environmental or physiological perturbations are poorly understood. C. elegans development consists of four larval stages (L1-L4) and well-characterized invariant cell lineages, within which the heterochronic pathway controls the order and timing of cell-fates. Environmental or physiological stress signals can slow or temporarily halt larval stage progression; remarkably, however, temporal cell-fate progression remains unaffected. We show that two widely conserved signaling pathways, insulin and TGF- β, that regulate C. elegans larval stage progression in response to starvation and crowding, respectively, also regulate a rewiring of the heterochronic pathway so that cell-fates remain temporally anchored to appropriate larval stages. This rewiring is mediated by the nuclear hormone receptor DAF-12, and it involves a shift from the reliance on let-7-family microRNAs to the reliance on LIN-46 for proper downregulation of the transcription factor, Hunchback-like-1 (HBL-1), which promotes L2 cell-fates and opposes L3 cell-fates. LIN-46 (which is a homolog of bacterial molybdopterin molybdenum transferase (moeA) and human gephyrin) post-translationally inhibits HBL-1 activity. LIN-46 expression is repressed by the RNA-binding protein LIN-28 at the early stages to permit HBL-1 activity and hence the proper execution of L2 cell-fates. Our results indicate that robustness mechanisms of temporal cell-fate progression in C. elegans involves 1) coordinated regulation of temporal cell-fates and larval stage progression and 2) collaboration between translational regulation exerted by microRNAs and post-translational regulation exerted by LIN-46 to coordinate HBL-1 downregulation with stage progression.