Journal
EXPERIMENTAL GERONTOLOGY
Volume 39, Issue 7, Pages 999-1009Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2004.03.026
Keywords
aging; sphingolipids; cell signaling; longevity genes
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Funding
- NIA NIH HHS [F32 AG005710-03, F32 AG005710-02, F32 AG005710-01, F32 AG005710] Funding Source: Medline
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Individual yeast cells display a finite replicative capacity. LAG1 was identified as a gene that is differentially expressed during the yeast replicative life span and was shown to play a role in determining yeast longevity. This gene is not essential, but simultaneous deletion of LAG1 and its close homologue LACI is lethal, Lag1p and Lac I p have been found to be an essential component of ceramide synthase. In this study, multicopy suppressors of the lethality of a lag1Delta lac1Delta double mutant were isolated to help clarify the role of LAG1 in yeast longevity. The two multicopy suppressors YBR183w (YPC1) and YPL087w (YDC1) encode ceramidases unrelated to Lag1p and Lag1p, which were previously found to support the reverse reaction of ceramide synthesis. Multiple copies of YPC1 were much more efficient than YDC1 in rescuing cell growth. They were also much more effective in rescuing the life span of a lag1Delta 1ac1Delta double mutant, sustaining a life span approaching that obtained by the restoration of LAG1 expression. Neither deletion of LAC1 nor overexpression of YPC1 had a detectable effect on wild-type life span. However, the overexpression of LAG1 had a bimodal effect on longevity, with moderate expression resulting in increased longevity and with higher expression curtailing life span. These results suggest that subtle changes in ceramide/sphingolipid metabolism are important in determining yeast longevity. They also indicate that Lag1p plays a special role in this relationship. Homologues of Lag1p have been identified in higher eukaryotes, including human, raising the possibility that ceramide and other sphingolipid metabolites play a wider role in biological aging. (C) 2004 Elsevier Inc. All rights reserved.
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