title: Changes in transcription and metabolism during the early stage of replicative cellular senescence in budding yeast.
abstract: Age-related damage accumulates and a variety of biological activities and functions deteriorate in senescent cells. However, little is known about when cellular aging behaviors begin and what cellular aging processes change. Previous research demonstrated age-related mRNA changes in budding yeast by the 18th to 20th generation, which is the average replicative lifespan of yeast (i.e. about half of the population is dead by this time point). Here, we performed transcriptional and metabolic profiling for yeast at early stages of senescence (4th, 7th, and 11th generation), that is, for populations in which most cells are still alive. Transcriptional profiles showed up- and down-regulation for ∼20% of the genes profiled after the first four generations, few further changes by the 7th generation, and an additional 12% of the genes were up- and down-regulated after 11 generations. Pathway analysis revealed that these 11th generation cells had accumulated transcripts coding for enzymes involved in sugar metabolism, the TCA cycle, and amino acid degradation and showed decreased levels of mRNAs coding for enzymes involved in amino acid biosynthetic pathways. These observations were consistent with the metabolomic profiles of aging cells: an accumulation of pyruvic acid and TCA cycle intermediates and depletion of most amino acids, especially branched-chain amino acids. Stationary phase-induced genes were highly expressed after 11 generations even though the growth medium contained adequate levels of nutrients, indicating deterioration of the nutrient sensing and/or signaling pathways by the 11th generation. These changes are presumably early indications of replicative senescence.
authors.affiliation: Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan and.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kamei
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tamada
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Yasumune
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Department of Biotechnology, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871, Japan.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Fukusaki
authors.affiliation: Department of Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga 526-0829, Japan and. Electronic address: y_mukai@nagahama-i-bio.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Mukai
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000597:Amino Acids, Branched-Chain / Q000737:chemistry; D016922:Cellular Senescence; D002952:Citric Acid Cycle; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D055432:Metabolomics; D020411:Oligonucleotide Array Sequence Analysis; D019289:Pyruvic Acid / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D004718:Saccharomycetales; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D000596:Amino Acids; D000597:Amino Acids, Branched-Chain; D029701:Saccharomyces cerevisiae Proteins; D019289:Pyruvic Acid
keywords: Branched-chain Amino Acids; Cellular Senescence; Metabolomics; Replicative Lifespan; Saccharomyces cerevisiae; Transcriptomics; Tricarboxylic Acid Cycle (TCA Cycle) (Krebs Cycle)