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Figure 18.2. Evolutionarily conserved determinants of longevity in yeast. CR increases life span from yeast to mammals. In addition, orthologs to the yeast-aging genes Hsfl, Rpd3, Sch9, Sir2, Sodl/ Sod2, and Tor1/Tor2 similarly modify aging in at least one multicellular eukaryote.

Figure 18.2. Evolutionarily conserved determinants of longevity in yeast. CR increases life span from yeast to mammals. In addition, orthologs to the yeast-aging genes Hsfl, Rpd3, Sch9, Sir2, Sodl/ Sod2, and Tor1/Tor2 similarly modify aging in at least one multicellular eukaryote.

Sir3 and Sir4, promotes transcriptional silencing near telomeres (Aparicio et al., 1991) and silent mating (HM) loci (Ivy et al., 1986; Rine and Herskowitz, 1987). Sir2, acting independently of Sir3 and Sir4, localizes to the nucleolus where it transcriptionally represses pollI transcribed genes (Bryk et al., 1997; Smith and Boeke, 1997) and inhibits rDNA recombination (Gottlieb and Espo-sito, 1989). Deletion of SIR2 causes an approximately 10-fold increase in rDNA recombination and shortens life span by about 50% (Kaeberlein et al., 1999). Overexpression of SIR2 in wild-type cells has the opposite effect, resulting in a 30-40% increase in life span, comparable to that observed upon deletion of FOB1 (Kaeberlein et al., 1999); however, overexpression of SIR2 fails to further increase the life span of long-lived fob1D cells, consistent with the model that Sir2 and Fob1 both impact aging by altering ERC levels.

Sir2 represents the first example of a conserved determinant of longevity that was initially discovered in yeast (Figure 18.2).

Following on the finding that overexpression of Sir2 increases yeast replicative life span, two groups have independently reported that overexpression of the Sir2-orthologs, Sir-2.1 and dSir2, increases life span in the nematode, Caenorhabditis elegans, and the fly, Drosophila melanogaster, respectively (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001). While it remains unclear what role, if any, Sir2-like proteins play in mammalian aging, several proteins involved in important cellular processes, including Foxo3a (Motta et al., 2004), p53 (Luo et al., 2001; Vaziri et al., 2001), and PGC1-a (Nemoto et al., 2005), have been suggested as targets for deacetylation by the mammalian Sir2 ortholog, SirT1.

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