Our current knowledge of the genetics of aging has relied greatly on studies in simple model systems such as S. cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster. The recent discovery that aging, similarly to other fundamental biological processes, is regulated by a conserved set of genes has attracted many researchers interested in the basic mechanisms of human aging and diseases to the ''model system'' field. Yeast are particularly amenable to aging studies because of their relatively short life span, the straightforward genetic manipulation techniques available, and the high-throughput technologies recently developed specifically for this unicellular eukaryote. Yeast life span can be measured as replicative potential (replicative or budding life span) by counting the number of buds produced by individual mother cells (Mortimer, 1959) or chronologically by monitoring mean and maximum survival of populations of nondividing yeast (chronological life span). C. elegans represents the second simplest and perhaps the more widely studied model system for aging research. Being made up of only about 1000 somatic cells, it provides the advantages of both a multicellular organism and those of a relatively simple genetic system. Together with D. melanogaster, C. elegans is playing a key role in elucidating both the cell autonomous and non-autonomous regulation of aging. The fourth major model system, Mus musculis, has the disadvantage of being much more complex and difficult to study but it is obviously an essential system because of its much closer phylogenetic relationship to humans. Thus, yeast, worms, and flies are simple systems—amenable to rapid genetic manipulation, highly characterized—and have a short life span (6 to 60 days). By contrast, the mouse has a much longer life span (30 months and more) and is much more difficult to manipulate genetically, but it is a key model system to begin to face the complexity of human aging and diseases. Given the existence of evolutionary conserved aging pathways (Kenyon, 2001; Longo and Finch, 2003), a possibility offered to the geneticists is to study simple organisms such as yeast, worms, or flies to perform genome-wide screens/selections for long-lived mutants and then test whether analogous mutations can cause similar effects in mice. In fact, some of the proteins whose modified activity was shown to extend the life span of the three simple model systems have been shown to play a similar role in mice. For example, insulin/IGF-1-like pathways have been implicated in the regulation of aging in worms, flies and mice. Notably, homologs of two of the major proteins in the insulin/IGF-1-like pathway in mice were shown to regulate the life span of S. cerevisiae (Figure 19.2) (Longo and Finch, 2003). Furthermore, increased antioxidant activity has been shown to cause small but significant extension of the life span of all the genetics model systems of aging (Fabrizio et al., 2003; Harris et al., 2003; Melov et al., 2000; Orr and Sohal, 1994; Parkes et al., 1998; Schriner et al., 2005; Sun and Tower, 1999).
In this chapter we will provide methods to perform yeast chronological survival measurements and comprehensive genome-wide selections to isolate novel long-lived mutants. We will review the genetics of aging in yeast with particular emphasis on the genes that affect the chronological life span. We will also review
Handbook of Models for Human Aging
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the genetics of aging in worms, flies, and mice, focusing mainly on the insulin-IGF-1 signaling and on the conserved characteristics shared by the long-lived mutants of different species.
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