title: Stimulating S-adenosyl-l-methionine synthesis extends lifespan via activation of AMPK.
abstract: 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.
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Tsubakiyama
authors.affiliation: National Research Institute of Brewing, Higashi-Hiroshima, Hiroshima 739-0046, Japan.
authors.forename: Muneyoshi
authors.initials: M
authors.lastname: Kanai
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Koyama
authors.affiliation: National Research Institute of Brewing, Higashi-Hiroshima, Hiroshima 739-0046, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.affiliation: National Research Institute of Brewing, Higashi-Hiroshima, Hiroshima 739-0046, Japan.
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Iefuji
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kume
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Tokichi
authors.initials: T
authors.lastname: Miyakawa
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan.
authors.forename: Dai
authors.initials: D
authors.lastname: Hirata
authors.affiliation: Hiroshima Research Center for Healthy Aging, Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima, Hiroshima 739-8530, Japan; mmizu49120@hiroshima-u.ac.jp.
authors.forename: Masaki
authors.initials: M
authors.lastname: Mizunuma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D031204:Caloric Restriction; D004843:Epistasis, Genetic; D005799:Genes, Dominant; D043326:Glucan 1,3-beta-Glucosidase / Q000235:genetics / Q000378:metabolism; D008136:Longevity; D053858:Metabolic Networks and Pathways; D008715:Methionine / Q000378:metabolism; D009154:Mutation; D012436:S-Adenosylmethionine / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D012436:S-Adenosylmethionine; D000255:Adenosine Triphosphate; D008715:Methionine; D055372:AMP-Activated Protein Kinases; D043326:Glucan 1,3-beta-Glucosidase; C117648:beta-1,3-exoglucanase
keywords: AMP-activated protein kinase; S-adenosyl-l-homocysteine; S-adenosyl-l-methionine; calorie restriction; yeast