The Universality of Yeast Aging Mechanisms and Future Outlook

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The short telomere senescence phenotypes of yeast have clear parallels with human cells. Both systems utilize telomerase and ATM family members in telomere metabolism and short telomere signaling. Both systems have telomere-associated proteins that can be released to function at other sites (the SIR proteins in yeast and the Rif1 and TRF2 proteins in human cells). Thus, telomere shortening in both systems has the potential to release associated proteins that may play roles in lifespan regulation. While the orthologs affected in these processes may not always show an exact one-to-one correspondence, the conservation of general biological mechanisms from one system can guide the model building in the other.

The yeast strains that can replicate telomeres without telomerase have telomeres similar to those of human ALT cell lines and tumors. It therefore seems likely that some of the mechanisms that give rise to these cell types are conserved. The advantage of the yeast system is that one can test a variety of candidate genes for changes in how cells survive shortening telomeres and if this mode of survival in the absence of telomerase is susceptible to different anti-cancer drugs. One can then identify a class of protein targets and families of chemical compounds to study in human cells.

Another major advantage of yeast is the rapid phenotypic testing of candidate longevity genes. For example, the ease of gene deletion in yeast means that one can find a gene whose expression is up-regulated in a microarray experiment under one growth condition, and then delete this gene to determine if this up-regulation is actually required for this growth condition. When this experiment was done with all budding yeast genes, it was found that only 7% of yeast genes that were up-regulated were actually required for optimal growth under the test condition (Giaever et al., 2002). This sobering result means that many of the genes identified by microarray approaches in organisms such as humans are probably not the most important genes affecting the aging process, and some sort of validation is required. Since such gene deletion studies and aging experiments are difficult and long in mammalian systems, budding and fission yeast will be good first steps for identifying evolutionarily conserved processes that alter lifespan to augment the discoveries made in microarray experiments. Research in the yeast aging field is expanding rapidly, and the biggest challenge to the researcher may be sorting the future flow of information to define the biological processes that are universally conserved.

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