Abstract
A methionine-restricted diet robustly improves healthspan in key model organisms. For example, methionine restriction reduces age-related pathologies and extends lifespan up to 45% in rodents. However, the mechanisms underlying these benefits remain largely unknown. We tested whether the yeast chronological aging assay could model the benefits of methionine restriction, and found that this intervention extends lifespan when enforced by either dietary or genetic approaches, and furthermore, that the observed lifespan extension is due primarily to reduced acid accumulation. In addition, methionine restriction-induced lifespan extension requires the activity of the retrograde response, which regulates nuclear gene expression in response to changes in mitochondrial function. Consistent with an involvement of stress-responsive retrograde signaling, we also found that methionine-restricted yeast are more stress tolerant than control cells. Prompted by these findings in yeast, we tested the effects of genetic methionine restriction on the stress tolerance and replicative lifespans of cultured mouse and human fibroblasts. We found that such methionine-restricted mammalian cells are resistant to numerous cytotoxic stresses, and are substantially longer-lived than control cells. In addition, similar to yeast, the extended lifespan of methionine-restricted mammalian cells is associated with NFκB-mediated retrograde signaling. Overall, our data suggest that improved stress tolerance and extension of replicative lifespan may contribute to the improved healthspan observed in methionine-restricted rodents, and also support the possibility that manipulation of the pathways engaged by methionine restriction may improve healthspan in humans.
Highlights
It is well documented in rodents that a diet with a normal caloric content, but containing limiting amounts of methionine, robustly improves healthy lifespan
A key study characterizing methionine restriction (Meth-R) in mice showed that a methioninerestricted diet improves the resistance of hepatocytes to oxidative stress injury by acetaminophen injection in vivo [3], while a more recent report found that methionine-restricted rats have reduced blood levels of oxidative stress biomarkers [5]
We have demonstrated, for the first time, that genetic Meth-R significantly extends the chronological lifespan of yeast, primarily by eliciting changes in metabolism that decrease acid accumulation
Summary
It is well documented in rodents that a diet with a normal caloric content, but containing limiting amounts of methionine, robustly improves healthy lifespan. Rats fed such a diet are up to 45% longer-lived than control rats [1,2]. Skin-derived fibroblasts from long-lived mouse strains are resistant to a number of cytotoxic stresses [12,13,14]. Such findings raise the possibility that interventions that confer organismal lifespan extension, like Meth-R, might do so by improving cellular stress tolerance
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