Utilizing these, we have demonstrated, for the first time, that genetic Meth-R significantly extends the Chromocarb chronological lifespan of yeast, primarily by eliciting changes in metabolism that decrease acid accumulation. Notably, we found that Meth-R-dependent lifespan extension is equally robust whether engaged by dietary Meth-R or impairment of the cell��s intrinsic ability to synthesize methionine. We have also found that Meth-R-dependent chronological lifespan extension is associated with improved resistance of yeast to cytotoxic stresses, including heat stress and 1,10-phenanthroline toxicity. These are in addition to the increased resistance of methionine-restricted yeast to oxidative and heavy metal stresses, as demonstrated previously. Exploiting the utility of this system, we explored the genetic requirements for lifespan extension as conferred by genetic Meth-R, and found that that this benefit requires a functional retrograde response. Consistent with our findings, growth in raffinose was reported to confer protection via the retrograde response against acetic acidinduced yeast cell death. We also discovered that a large proportion of genetic Meth-R-induced transcriptional changes require that retrograde signaling remain intact, and further, that such changes are enriched for factors with roles in metabolism and other cellular processes implicated in the control of longevity. For example, a gene encoding spermidine Guanethidine Sulfate synthase was revealed by our analyses to be upregulated by Meth-R in a retrograde signaling-dependent fashion. Spermidine, a natural polyamine, has been shown to extend the lifespan of yeast, flies, worms and human immune cells through activation of autophagy. While we consider it likely that some of the identified expression changes underlie the stress tolerance, and reduced acid accumulation conferred by Meth-R, future studies will be necessary to determine precisely which factors are the key mediators of these phenotypes. In the current study, however, we have been able to make initial exploratory steps towards an elucidation of the mechanisms supporting this intervention.