Methionine Restriction Extends Yeast Lifespan by Activating Non-Nitrogen-Starvation-Induced Autophagy Through Limiting Methylation of Protein Phosphatase 2A.

Methionine restriction (MR) extends the lifespan and healthspan of numerous eukaryotic organisms, but the molecular mechanisms at play are unclear. Here we find that the ability of MR to extend the budding yeast chronological and replicative lifespans is the consequence of reduced methionine conversion to the methyl donor S-adenosylmethionine (SAM). Mechanistically, the key antiaging event downregulated by MR is the methylation of protein phosphatase 2A (PP2A). In chronological aging cells under MR, unmethylated PP2A no longer dephosphorylates Npr2, a component of the SEACIT complex, resulting in activation of non-nitrogen-starvation (NNS)-induced autophagy. Deletion of genes encoding components of SEACIT or ATG1 (encoding a central player in the initiation of autophagy) blocked the ability of MR to extend lifespan, showing the critical role of the NNS-induced autophagy pathway in lifespan extension by MR. We identify the relevant Npr2 site dephosphorylated by PP2A as serine 362 and show that Npr2 phosphomimetic mutants are sufficient to extend chronological and replicative lifespan. Finally, we discover that MR only during the early stages of chronological aging is sufficient to prolong autophagy and extend lifespan. In addition to elucidating the molecular mechanism of MR-mediated lifespan extension, this study highlights potential therapeutic targets to achieve lifespan and healthspan extension in humans without the challenging long-term dietary changes required to achieve MR.