S‐adenosyl‐L‐homocysteine extends lifespan through methionine restriction effects

Methionine restriction (MetR) can extend lifespan and delay the onset of aging‐associated pathologies in most model organisms. Previously, we showed that supplementation with the metabolite S‐adenosyl‐L‐homocysteine (SAH) extends lifespan and activates the energy sensor AMP‐activated protein kinase (AMPK) in the budding yeast Saccharomyces cerevisiae. However, the mechanism involved and whether SAH can extend metazoan lifespan have remained unknown. Here, we show that SAH supplementation reduces Met levels and recapitulates many physiological and molecular effects of MetR. In yeast, SAH supplementation leads to inhibition of the target of rapamycin complex 1 (TORC1) and activation of autophagy. Furthermore, in Caenorhabditis elegans SAH treatment extends lifespan by activating AMPK and providing benefits of MetR. Therefore, we propose that SAH can be used as an intervention to lower intracellular Met and confer benefits of MetR.