Abstract
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(+) 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 increases NR salvaging. This increase contributes to NAD(+) homeostasis, partially ameliorating the NAD(+) 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(+) 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(+) metabolism, cellular life span, and diseases associated with NAD(+) deficiency and aging.
Highlights
Signaling pathways regulating NADϩ homeostasis and their complex interplay with cell longevity remain unclear
Stp1, a Transcription Factor of the SPS Signaling Pathway, May Directly Bind to the Promoter Regions of Shuttle System Components—In this study we show PHO8, MAE1, and OAC1 are required for ssy5⌬-induced replicative life span (RLS) (Figs. 2D and 4C) and that the expression of these three genes is controlled by SPS signaling (Figs. 2B and 3B)
In this study we characterized a low SPS activity mutant, ssy5⌬ and showed that NADϩ homeostasis plays an important role in ssy5⌬-mediated life span extension (Fig. 5E)
Summary
Signaling pathways regulating NADϩ homeostasis and their complex interplay with cell longevity remain unclear. Results: Attenuated SPS (Ssy1-Ptr3-Ssy5) signaling extends replicative life span, which requires increased nicotinamide riboside salvage and functional NADH shuttle. Significance: Studying SPS signaling as a novel longevity factor helps elucidate the complex regulation of NADϩ homeostasis. 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. 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 studies may advance the understanding of the interconnection and cross-regulation of NADϩ homeostasis, nutrientsensing, and longevity pathways
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have