Tor1

PI3-like kinase

tori D

TPK1/TPK2/TPK3

Protein kinase A catalytic subunits

tpkl D tpk2-63 tpk3D

glucose (Kaeberlein et al., 2005a; Lin et al., 2000). CR is reported to increase replicative life span in multiple yeast strain backgrounds from 30 to 50% (e.g., see Anderson et al., 2003a; Anderson et al., 2003b; Kaeberlein et al., 2002a; Kaeberlein et al., 2004a; Kaeberlein et al., 2004b; Lin et al., 2000; Lin et al., 2002), comparable in magnitude to the effect of CR in other organisms (Houthoofd et al., 2003; Lakowski and Hekimi, 1998; Weindruch and Walford, 1988).

The mechanism(s) by which CR increases life span in yeast and other organisms remains a mystery. It was initially proposed that CR slows aging in yeast by activating Sir2 (Lin et al., 2000). This idea was supported by the fact that deletion of SIR2 prevents life span extension by growth on low glucose (Kaeberlein et al., 2004a) or by genetic models of CR (Lin et al., 2000). Several models have described possible molecular mechanisms by which CR might enhance Sir2 activity, including elevated NAD+ (a substrate of Sir2), resulting from a metabolic shift toward respiratory growth (Lin et al., 2002); decreased nicotinamide (an inhibitor of Sir2), due to transcriptional up-regulation of the gene coding for nicotinamidase, PNC1 (Anderson et al., 2003a); and decreased NADH (an inhibitor of Sir2) (Lin et al., 2004).

The link between Sir2 and CR has been called into question, however, with the observation that CR slows aging even in the absence of Sir2, as long as ERC levels are kept low (Kaeberlein et al., 2004b). Deletion of FOB1 suppresses the short life span of cells lacking Sir2 and dramatically reduces ERC levels, even below that observed in wild-type cells (Kaeberlein et al., 1999). In cells deleted for both SIR2 and FOB1, CR increases life span to a greater extent than in wild-type cells (Kaeberlein et al., 2004b), demonstrating the existence of a Sir2-independent pathway by which CR slows aging. Further support for Sir2 and CR acting in parallel pathways is provided by the observation that growth of cells overexpressing SIR2 on reduced glucose media results in an additive increase in life span (Kaeberlein et al., 2004b). It remains to be determined whether CR acts in both a Sir2-dependent and Sir2-independent fashion, or if the longevity effects of CR are completely independent of Sir2.

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