Reduced Ssy1-Ptr3-Ssy5 (SPS) Signaling Extends Replicative Life Span by Enhancing NAD+ Homeostasis in Saccharomyces cerevisiae [Signal Transduction]

March 30th, 2015 by Tsang, F., James, C., Kato, M., Myers, V., Ilyas, I., Tsang, M., Lin, S.-J.

Attenuated nutrient signaling extends life span in yeast and higher eukaryotes; however, the mechanisms are not completely understood. Here we identify the Ssy1-Ptr3-Ssy5 (SPS) amino acid sensing pathway as a novel longevity factor. A null mutation of SSY5 (ssy5∆) increases replicative life span (RLS) by ~ 50%. Our results demonstrate that several NAD+ homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5∆ cells and deleting components of this shuttle, MAE1 and OAC1, largely abolishes RLS extension. Next, we show that Stp1, a transcription factor of the SPS pathway, directly binds to the promoter of MAE1 and OAC1 to regulate their expression. Additionally, deletion of SSY5 increases nicotinamide riboside (NR) levels and phosphate-responsive (PHO) signaling activity, suggesting that ssy5∆ increases NR salvaging. This increase contributes to NAD+ homeostasis, partially ameliorating the NAD+ deficiency and rescuing the short life span of the npt1∆ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5∆-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD+ homeostasis factor and ssy5∆-mediated life span extension is likely due to concomitantly increased mitochondrial and vacuolar function. Our findings may contribute to understanding the molecular basis of NAD+ metabolism, cellular life span and diseases associated with NAD+ deficiency and aging.
  • Posted in Journal of Biological Chemistry, Publications
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