4.8 Article

Stimulating S-adenosyl-L-methionine synthesis extends lifespan via activation of AMPK

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1604047113

Keywords

S-adenosyl-L-methionine; S-adenosyl-L-homocysteine; calorie restriction; AMP-activated protein kinase; yeast

Funding

  1. Japan Society for the Promotion of Science for Scientific Research from JSPS [24580142, 16H04898]
  2. Japan Society for the Promotion of Science for Young Scientists [DC2]
  3. Grants-in-Aid for Scientific Research [16H04898, 24580142, 16J04341] Funding Source: KAKEN

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Dietary restriction (DR), such as calorie restriction (CR) or methionine (Met) restriction, extends the lifespan of diverse model organisms. Although studies have identified several metabolites that contribute to the beneficial effects of DR, the molecular mechanism underlying the key metabolites responsible for DR regimens is not fully understood. Here we show that stimulating S-adenosyl-L-methionine (AdoMet) synthesis extended the lifespan of the budding yeast Saccharomyces cerevisiae. The AdoMet synthesis-mediated beneficial metabolic effects, which resulted from consuming both Met and ATP, mimicked CR. Indeed, stimulating AdoMet synthesis activated the universal energy-sensing regulator Snf1, which is the S. cerevisiae ortholog of AMP-activated protein kinase (AMPK), resulting in lifespan extension. Furthermore, our findings revealed that S-adenosyl-L-homocysteine contributed to longevity with a higher accumulation of AdoMet only under the severe CR (0.05% glucose) conditions. Thus, our data uncovered molecular links between Met metabolites and lifespan, suggesting a unique function of AdoMet as a reservoir of Met and ATP for cell survival.

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