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.
Highlights
Senescence is the biological process of age-related cellular and organismal deterioration in function
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 cell fractions were used for DNA microarray and gas chromatography mass spectrometry (GC-MS) analyses, as described below
Summary
Senescence is the biological process of age-related cellular and organismal deterioration in function. 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. In mother cells during the budding process, oxidative stress, protein aggregation, and extrachromosomal rDNA circles (selfreplicating circles of ribosomal DNA) accumulate and cause senescence [9] These accumulations are relieved by calorie restriction, which helps slow aging and extend the lifespan in yeast and higher organisms [11]. The expression of stationary phase-induced genes was highly enhanced after 11 generations, despite the presence of adequate nutrients in the medium These observations suggest that nutrient sensing and/or signaling begin to deteriorate in the early stage of replicative senescence
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