Sir-dependent downregulation of various aging processes.

Using a new genetic selection approach in yeast termed fitness-based interferential genetics (FIG), genes that are in an antagonistic relationship with the Sir complexes were selected. Many of the functionally well-defined genes belong to various aging processes occurring in this organism. Three genes are somehow involved in glucose utilization (HXT4,YIL107c, EMI2). Another gene, CDC25, encodes the main regulator of the cyclic AMP pathway in response to glucose. STM1 has been implicated in the control of apoptosis, and indeed, this work shows that disruption of this gene results, among other phenotypes, in resistance to aging. LCB4, encoding a sphingoid bases kinase is linked to the cell integrity pathway. Two other genes, FHL1 and PEP5, are involved in the control of ribosome formation and vacuole biogenesis, respectively; and five genes, presently having unknown functions, could be new potentially interesting candidates for further studies in relation to yeast replicative aging. It is proposed that most, if not all, selected genes are downregulated by the Sir complexes. In addition to changing our view of the mechanisms used by the Sir complexes for extending life span in yeast, these findings could contribute to a better understanding of the role of the Sir complexes in the higher eukaryotes.