Chronological Aging And Response To Stress

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It has been proposed that aging in nondividing yeast cells is largely under the control of the transcription factors Msn2 and Msn4 (Fabrizio et al., 2001). Msn2 and Msn4 bind to stress response elements (STRE) contained in the promoters of many genes coding for proteins involved in adaptation to starvation and stress, such as heat shock proteins, catalase, superoxide dismutase, and glycogen and trehalose biosynthetic enzymes (Smith et al., 1998). Msn2 and Msn4 are repressed by the nutrient responsive kinases TOR, PKA, and Sch9, which promote phosphory-lation and exclusion of Msn2/4 from the nucleus. Mutation of CYR1 or deletion of SCH9 fails to increase chronological life span in an msn2D msn4D double mutant, consistent with the idea the enhanced longevity seen in these mutants is due to activation of Msn2/4-dependent targets (Fabrizio et al., 2001).

In many ways the function of Msn2 and Msn4 as transcriptional regulators of the yeast chronological aging program parallels the role of Daf-16 in the C. elegans aging process. Msn2/4 and Daf-16 are downstream targets of pathways that regulate the rate of aging in response to nutrients or growth factors, and both sets of proteins are transcriptional activators of genes involved in stress response and starvation response.

The similarity between yeast chronological aging and adult aging in the nematode is perhaps not surprising, as adult C. elegans are thought to be completely postmitotic (with the exception of the germ line). This similarity extends beyond transcriptional regulation in response to nutrients, as evidenced by the fact that at least some of the downstream effectors impacting longevity are also conserved. As is the case for yeast chronological life span, Daf-16-dependent up-regulation of superoxide dismutase accounts for a portion of the life span extension seen in long-lived insulin/IGF-1 pathway mutants in C. elegans (Honda and Honda, 1999), and activation of the heat shock responsive transcription factor Hsf1 increases both chronological life span in yeast (Harris et al., 2001) and adult life span in the nematode (Morley and Morimoto, 2004). Further studies will likely uncover additional shared longevity determinants, and it will be particularly interesting to see how highly conserved the aging process is for nondividing cells in evolutionarily divergent eukaryotes.

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