The dissociation of Sir2 from CR in yeast has profound implications for the likelihood that downstream molecular events associated with CR are conserved across evolutionarily divergent organisms. It seems certain that ERCs are a mechanism of aging private to yeast, as there is no evidence that ERCs accumulate with age or cause senescence in the cells of multicellular eukaryotes. CR, on the other hand, slows aging in nearly every organism studied. If CR is not regulating yeast longevity by altering ERC levels through up-regulation of Sir2, this raises the possibility that the downstream effectors of CR might also be conserved (Kaeberlein and Kennedy, 2005).
Many of the pathways responsible for mediating the response of yeast cells to limited nutrients are well characterized. Among these pathways, the glucose-activated kinases protein kinase A (PKA) and Sch9 play an important role in replicative aging. Deletion of Sch9 (Fabrizio et al., 2004b; Kaeberlein et al., 2005a) or one of several mutations resulting in decreased PKA activity, including gpa2D, gpr1D, cdc25-10, and cyr1-1 (Lin et al., 2000), result in a 30-40% increase in replicative life span. CR by growth on low glucose is known to decrease both PKA and Sch9 activity (Kaeberlein et al., 2005a), suggesting that mutations in these pathways are genetic mimetics of CR.
From an ongoing genome-wide study of yeast replica-tive aging (Kaeberlein and Kennedy, 2005), we have uncovered evidence that a third nutrient sensing pathway, defined by the nitrogen responsive kinases Tort and Tor2, also plays a profound role in determining replicative life span (Kaeberlein et al., 2005b). Tori and Tor2 regulate many of the same downstream targets as Sch9 and PKA, including genes involved in ribosome biogenesis, genes involved in autophagy, regulators of cell size and cell cycle progression, and the stress responsive transcription factors Msn2 and Msn4 (Beck and Hall, 1999). Interestingly, mutations that decrease the activity of Sch9 (Fabrizio et al., 2001) or PKA (Fabrizio et al., 2001) are also reported to increase chronological life span (see Nutrient Sensing and Chronological Aging). The fact that decreased activity of proteins orthologous to Sch9 or Tor1/Tor2 increases life span in worms (Vellai et al., 2003) and flies (Kapahi et al., 2004) indicates the evolutionary conservation of these nutrient responsive kinases as regulators of eukaryotic aging. The potential relevance of these observations is discussed further in Relationship between Replicative and Chronological Aging.
At this point it remains unclear which of the downstream targets shared by these nutrient sensing pathways are ultimately responsible for enhanced longevity in response to CR. The Msn2/Msn4-mediated stress response can be ruled out as necessary for increased replicative life span, since deletion of both MSN2 and MSN4 fails to prevent replicative life-span extension in response to either CR (Lin et al., 2000) or deletion of Sch9 (Fabrizio et al., 2004b). Decreased ribosome production or protein translation may be important for the effect of CR on replicative aging, as evidenced by the fact that deletion of individual genes coding for redundant ribosomal subunits is sufficient to confer replicative lifespan extension comparable to that of CR (Kaeberlein et al., 2005b). Although the molecular mechanism accounting for this effect remains poorly understood, an intriguing parallel can be drawn between yeast and flies, with the observation that mutation of S6 kinase, which functions downstream of TOR to promote ribosomal function and translation, increases life span in D. melanogaster (Kapahi et al., 2004).
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