Methionine Restriction Activates the Retrograde Response and Confers Both Stress Tolerance and Lifespan Extension to Yeast, Mouse and Human Cells

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.

Cysteine dietary supplementation reverses the decrease in mitochondrial ROS production at complex I induced by methionine restriction

“…Methionine restriction slows down senescence in yeast (Koziek et al 2014) and human cells (Johnson and Johnson 2014) and extends lifespan in invertebrate animal models (Lee et al 2014). Most importantly, MetR (80 %) also increases both mean and maximum life span in mammals (Richie et al 1994;Miller et al 2005;Sun et al 2009).…”

Methionine restriction slows down senescence in human diploid fibroblasts

“…Thus, MetR decreased oxidative damage in rat brain (Naudi et al ., 2007), decreased visceral fat mass and preserved insulin action in aging rats (Malloy et al ., 2006), increased mitochondrial aerobic capacity in liver and skeletal muscle (Perrone et al ., 2010), and enhanced metabolic flexibility in both fed and fasted rats (Hasek et al ., 2010). Similarly, it was recently shown that MetR increased fat oxidation in obese humans with metabolic syndrome (Plaisance et al ., 2011); however, the effects of methionine restriction in food on aging in humans remained elusive and the only available data correspond to genetic manipulations of methionine synthesis pathway (Johnson & Johnson, 2014). Recently published data in unicellular fungi indicate induction of autophagy as an alternative mechanism for lifespan extension by MetR (Ruckenstuhl et al ., 2014).…”

“…In an alternative concept, it was proposed that MetR extends lifespan by decreasing the protein biosynthesis rate due to methionine limitation (Hipkiss, 2008), consistent with the finding that decreasing the general rate of protein translation can extend lifespan in nematodes (Hansen et al ., 2007; Syntichaki et al ., 2007). In yeast, induction of autophagy and stress-responsive retrograde signaling were shown recently to underly lifespan extension by MetR (Johnson & Johnson, 2014; Ruckenstuhl et al ., 2014). …”

“…It is currently unknown if reduced methionine content in food affects the rate of aging in humans and the only available data correspond to genetic modulations of methionine synthesis pathway (Johnson & Johnson, 2014). A convenient way to study basic mechanisms relevant for human aging is to study cellular senescence in cell culture models (Hayflick, 1997; Campisi, 2011).…”

Aging in the Single-Celled Eukaryote, S. cerevisiae

“…However, the contribution of each amino acid component to aging is still a mystery. Methionine restriction has been shown to improve lifespan from yeast to rodents (Orentreich et al 1993 ;Richie et al 1994 ;Johnson and Johnson, 2014 ). A recent study showed that specifi c amino acid and glucose affect aging through different pathways .…”