Metformin induces S-adenosylmethionine restriction to extend the Caenorhabditis elegans healthspan through H3K4me3 modifiers

Metformin, a widely prescribed first-line drug for the treatment of type II diabetes mellitus, has been shown to extend lifespan and delay the onset of age-related diseases. The precisely mechanisms by which these effects are realized remain elusive. We find that metformin exposure is restricted to adults, which is sufficient to extend lifespan. However, limiting metformin exposure to the larvae has no significant effect on Caenorhabditis elegans longevity. Here, we show that after metformin treatment, the level of S-adenosylmethionine (SAM) is reduced in adults but not in the larvae. Potential mechanisms by which reduced SAM might increase lifespan include altering the histone methylation. However, the molecular connections between metformin, SAM limitation, methyltransferases, and healthspan-associated phenotypes are unclear. Through genetic screening of C. elegans, we find that metformin promotes the healthspan through an H3K4 methyltransferase/demethylase complex to downregulate the targets, including mTOR and S6 kinase. Thus, our studies provide molecular links between meformin, SAM limitation, histone methylation, and healthspan and elucidate the mode action of metformin-regulated healthspan extension will boost its therapeutic application in the treatment of human aging and age-related diseases.

Automated summary

Metformin, a commonly used drug for type II diabetes, has shown potential for extending lifespan and delaying age-related diseases. This study explores the molecular mechanisms behind these effects, finding that metformin exposure in adults, but not larvae, is sufficient to extend lifespan. Reduced levels of S-adenosylmethionine (SAM) and altered histone methylation may contribute to the lifespan extension. Through genetic screening in C. elegans, the study identifies an H3K4 methyltransferase/demethylase complex that is involved in metformin's promotion of healthspan by downregulating mTOR and S6 kinase. These findings provide molecular links between metformin, SAM limitation, histone methylation, and healthspan.