Aging cellMay 20, 2026

Limiting Methionine Extends Yeast Lifespan by Triggering a Special Cell Recycling Process Through Reduced Protein Methylation

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 28, 2026

Abstract

Essence

In yeast, methionine restriction extended chronological and replicative lifespan by lowering SAM-dependent PP2A methylation and sustaining autophagy.

Evidence

This mechanistic yeast aging study used lifespan assays plus gene deletions and Npr2 phosphomimetic mutants to link reduced PP2A methylation, Npr2 phosphorylation, and non-nitrogen-starvation-induced autophagy to longer lifespan.

Caveat

The evidence is confined to budding yeast and pathway perturbation experiments, so it does not show that the same mechanism or therapeutic effect applies in humans.

Simplified

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.

Full Text

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Limiting Methionine Extends Yeast Lifespan by Triggering a Special Cell Recycling Process Through Reduced Protein Methylation

Abstract

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