Life span extension by glucose restriction is abrogated by methionine supplementation: Cross-talk between glucose and methionine and implication of methionine as a key regulator of life span

Abstract

Caloric restriction (CR) is known to extend life span across species; however, the molecular mechanisms are not well understood. We investigate the mechanism by which glucose restriction (GR) extends yeast replicative life span, by combining ribosome profiling and RNA-seq with microfluidic-based single-cell analysis. We discovered a cross-talk between glucose sensing and the regulation of intracellular methionine: GR down-regulated the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration; external supplementation of methionine cancels the life span extension by GR. Furthermore, genetic perturbations that decrease methionine synthesis/uptake extend life span. These observations suggest that intracellular methionine mediates the life span effects of various nutrient and genetic perturbations, and that the glucose-methionine cross-talk is a general mechanism for coordinating the nutrient status and the translation/growth of a cell. Our work also implicates proteasome as a downstream effector of the life span extension by GR.

Effect of Methionine Restriction on Aging: Its Relationship to Oxidative Stress

“…Therefore, the benefit of protein restriction on lifespan extension and metabolic health may be exerted through MetR. In addition, in yeast, glucose restriction down-regulates the transcription and translation of methionine biosynthetic enzymes and transporters, leading to a decreased intracellular methionine concentration and lifespan extension [ 10 ]. Oxidative stress is closely related to age and impaired metabolic health.…”

Enhancing lifespan of budding yeast by pharmacological lowering of amino acid pools

“…Additional amino acid sensors that could be controlling TORC1 activity [105] in Myr-treated cells need to be examined in the future as some could sense specific amino acids and modulate key metabolic and physiological functions necessary for Myr-induced longevity. One such key amino acid is Met with its established roles in longevity [28][29][30][31][32][33]. Limiting Met availability could reconfigure cellular physiology in many ways to enhance longevity.…”

“…Unlike restriction for a single amino acid, lowering multiple amino acid pools may have effects more related to total protein restriction, which enhances lifespan in organisms ranging from yeasts to mammals [6,7,[109][110][111]. Furthermore, recent studies of caloric restriction implicate reduced intracellular methionine in yeasts [33] and glycine-serine-threonine metabolism (folate and methionine cycles and the transulfuration pathway) in mice [112] as key drivers of longevity. Thus, it's reasonable to propose that the reduction of amino acids in one-carbon and related metabolism (Gly, Ser, Met and Thr) that we observe in myriocin-treated cells, are mediating at least some of the longevity increase.…”

“…Uptake of individual amino acids was examined to identify drug effects on specific AATs. Met uptake was examined because Myr treatment significantly reduces its pool size ( Figure 2) and it plays a central role in metabolism and longevity [33,[52][53][54][55]. Generally, AATs like the high affinity Met transporter, Mup1, are not highly expressed when substrate is present in culture medium [56,57].…”

“…While lowering total protein intake fosters healthful effects, reducing intake of individual or groups of amino acids also improves health across species. Methionine (Met) restriction enhances longevity in organisms ranging from yeasts to worm, flies and mammals including rodents (mice and rats) plus the naked mole rat [28][29][30][31][32][33]. Reduction of branched-chain amino acids leucine, isoleucine and valine also promotes longevity in model organisms [27,34].…”