Bacteria-derived metabolite, methylglyoxal, modulates the longevity of <i>C. elegans</i> through TORC2/SGK-1/DAF-16 signaling

Significance The molecular mechanisms by which gut microbes modulate host longevity remain elusive. Using genome-wide lifespan screens and extensive interspecies genetic analysis, we identified that the gut microbe-derived metabolite methylglyoxal (MG) modulated host longevity. MG is a reactive carbonyl species involved in the formation of advanced glycation end products, which are implicated in various human pathologies. We identified that Escherichia coli producing reduced levels of MG increased the lifespan of Caenorhabditis elegans due to inhibition of TORC2/SGK-1 and activation of DAF-16. These findings challenge the current paradigm that MG is toxic due to the formation of glycation adducts on biomolecules. Instead, our results highlight the importance of gut microbe-derived MG in regulating the host TORC2/SGK-1/DAF-16 signaling pathway in the interspecies context.