Metabolic Control and Gene Dysregulation in Yeast Aging

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Abstract
Life span in the yeast Saccharomyces cerevisiae is usually measured by the number of divisions individual cells complete. Four broad physiologic processes that determine yeast life span have been identified: metabolic control, resistance to stress, chromatin‐dependent gene regulation, and genetic stability. A pathway of interorganelle communication involving mitochondria, the nucleus, and peroxisomes has provided a molecular mechanism of aging based on metabolic control. This pathway functions continuously, rather than as an on‐off switch, in determining life span. The longevity gene RAS2 modulates this pathway. RAS2 also modulates a variety of other cellular processes, including stress responses and chromatin‐dependent gene regulation. An optimal level of Ras2p activity is required for maximum longevity. This may be due to the integration of life maintenance processes by RAS2, which functions as a homeostatic device in yeast longevity. Loss of transcriptional silencing of heterochromatic regions of the genome is a mark of yeast aging. It is now clear that the functional status of chromatin plays an important role in aging. Changes in this functional status result in gene dysregulation, which can be altered by manipulation of the histone deacetylase genes. Silencing of ribosomal DNA appears to be of particular importance. Extrachromosomal ribosomal DNA circles are neither sufficient nor necessary for yeast aging.