Original ArticlesThe influence of oxygen toxicity on yeast mother cell-specific aging☆
Introduction
Yeast mother cell-specific aging has been reviewed recently Jazwinski 1999, Johnson et al 1999 and is now a well recognized model system for the aging processes of higher cells and, perhaps, higher organisms. In yeast only the mother cell ages, whereas the daughter cells, with the exception of the daughters of very old mothers (Kennedy et al., 1994), reset their clock to zero (Jazwinski, 1993). This is different from cellular clonal aging as observed in cell cultures of mammalian fibroblasts. However, some of the phenotypic manifestations of senescence are strikingly similar in yeast mother cells and in cultured human cells. For instance, old cells are much bigger than young cells Egilmez et al 1990, Mortimer and Johnston 1959, Nestelbacher et al 1999, they lose cellular polarity (pointing to a cytoskeletal defect) and the cell surface is deformed and looks “folded” (Pichová et al., 1997). The cell cycle (Mortimer and Johnston, 1959) and protein synthesis (Motizuki and Tsurugi, 1992) are much slower than in young cells.
For higher organisms (flies, worms, mammals and others), the so called “oxygen theory of aging” was first formulated by Harman (1962) and is now well established Ames et al 1993, Gems 1999, Orr and Sohal 1994, Sohal and Weindruch 1996, Martin et al 1996. The theory implies that old cells accumulate and ultimately cannot repair or remove biomolecules that have been damaged by reactive oxygen species (ROS) originating from a “leaky” mitochondrial respiratory chain or from other oxidative processes in the cell, generically called “oxidative stress.” This would imply some kind of error catastrophe (damaged molecules leading to the generation of more damaged molecules) or could simply mean that old cellular material accumulates in the mother cell, but not in the daughter cell. Targets for this process may be DNA, proteins, lipids and other molecules. The accumulation of mutations in chromosomal DNA is logically excluded as a cause for yeast mother cell-specific aging because the last daughter cells of old mother cells due to semiconservative replication should carry the same mutations as the mother leading to clonal aging, which is not observed. However, old yeast mother cells do accumulate extrachromosomal rDNA circles (Sinclair and Guarente, 1997) which are very infrequently inherited by daughters because they don’t carry a centromere. Here we want to underscore the fact that yeast mother cell-specific aging is clearly a polygenic process that depends on multiple causative environmental and internal conditions. Thus the theory based on generation of rDNA circles and the oxygen theory of aging are not mutually exclusive, because targets other than DNA for oxidative damage are quite plausible. We expect that oxidative damage could be one, but by no means the only cause of yeast mother cell-specific aging. Surprisingly, very few published investigations of the influence of oxygen toxicity on yeast aging exist. Both, Wawryn et al. (1999) and Barker et al. (1999) show that disruption of the superoxide dismutase (SOD)-encoding genes shorten the life span of yeast. The SODs and catalases together are sufficient to detoxify superoxide. We have therefore undertaken to investigate the influence of mutations in the yeast catalase genes (blocking one pathway for detoxification of ROS) and of changes in oxygen partial pressure on yeast mother cell-specific aging. Our results seem to strongly support a role for oxygen toxicity in yeast mother cell-specific aging.
Section snippets
Strains and growth media
The haploid Saccharomyces cerevisiae strain W303eA (MATa; ura3–1; leu2–3,112; trp1–1; his3–11,15; ade2–1; can1–100) was obtained from P. Slonimski (Gif-sur-Yvette). The haploid S. cerevisiae strain JC482 (MATa; ura3–52; leu2; his4–539) was obtained from J. Cannon (Cannon and Tatchell, 1987). The single and double mutant strains were constructed in W303eA by standard genetic manipulations (Kaiser et al., 1994). Both the CTA1 and CTT1 genes were disrupted by replacement with URA3 and combined by
Results
In this study we used two different haploid wild type (WT) laboratory yeast strains, W303eA and JC482.Yeast aging studies require a strictly isogenic system consisting of a WT strain and the mutant(s) to be studied due to the polygenic nature of the aging process and due to the fact that different WT laboratory strains display a very different replicative life span (Jazwinski, 1993). W303eA is a strain used by the current European program for systematic functional analysis of yeast open reading
Discussion
The above results indicate an important role for oxygen toxicity in the yeast mother cell-specific aging process. It is generally difficult to establish a causal relationship and to discriminate between causal and accidental phenomena in aging research, however, the following observations are in favor of our hypothesis. It was carefully checked that throughout the life span determinations the dividing cells always experienced an excess of nutrients. At the end of the life span determination
Acknowledgements
We are grateful to Ian Dawes for many discussions and for his advice during the course of this work.
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We are grateful for the support from FWF (Austria) (No. P11064-MOB).