Changes in Transcription and Metabolism during the Early Stage of Replicative Cellular Senescence in Budding Yeast [Metabolism]

October 7th, 2014 by Kamei, Y., Tamada, Y., Nakayama, Y., Fukusaki, E., Mukai, Y.

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-20th generation, which is the average replicative lifespan of yeast (i.e., about half 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 about 20% of the genes profiled after the first 4 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 tricarboxylic acid (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.