Reduced Ssy1-Ptr3-Ssy5 (SPS) signaling extends replicative life span by enhancing NAD<sup>+</sup> homeostasis in Saccharomyces cerevisiae

Felicia Tsang, Christol James, Michiko Kato, Victoria Myers, Irtqa Ilyas, Matthew Tsang, Su Ju Lin

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


Attenuated nutrient signaling extends the 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 (ssy5Δ) increases replicative life span (RLS) by ∼ 50%. Our results demonstrate that several NAD<sup>+</sup> homeostasis factors play key roles in this life span extension. First, expression of the putative malate-pyruvate NADH shuttle increases in ssy5Δ 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 ssy5Δ increasesNR salvaging. This increase contributes to NAD<sup>+</sup> homeostasis, partially ameliorating the NAD<sup>+</sup> deficiency and rescuing the short life span of the npt1Δ mutant. Moreover, we observed that vacuolar phosphatase, Pho8, is partially required for ssy5Δ-mediated NR increase and RLS extension. Together, our studies present evidence that supports SPS signaling is a novel NAD<sup>+</sup> homeostasis factor and ssy5Δ-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<sup>+</sup> metabolism, cellular life span, and diseases associated with NAD<sup>+</sup> deficiency and aging.

Original languageEnglish (US)
Pages (from-to)12753-12764
Number of pages12
JournalJournal of Biological Chemistry
Issue number20
StatePublished - May 15 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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