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Drug synergy drives conserved pathways to increase fission yeast lifespan.

Huang X, Leggas M, Dickson RC - PLoS ONE (2015)

Bottom Line: Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought.We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan.These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America. nc.ude.utjws.emoh@gnauhehnix.

ABSTRACT
Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.

No MeSH data available.


Both Sck1 and Sck2 are required for lifespan enhancement by ComboDT.(A) The effect of drugs on CLS are shown for WT, sck1Δ, sck2Δ and sck1Δ sck2Δ double mutant cells. (B) The effect of drugs on TORC1-regulated phosphorylation of HA-tagged Sck1 and Sck2 was examined by immunoblotting. Numbers below each lane indicate the ratio of the Anti-HA signal to the Anti-Tubulin signal, which served as a protein loading control. This experiment was performed twice with duplicate cultures and similar results were observed each time.
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pone.0121877.g003: Both Sck1 and Sck2 are required for lifespan enhancement by ComboDT.(A) The effect of drugs on CLS are shown for WT, sck1Δ, sck2Δ and sck1Δ sck2Δ double mutant cells. (B) The effect of drugs on TORC1-regulated phosphorylation of HA-tagged Sck1 and Sck2 was examined by immunoblotting. Numbers below each lane indicate the ratio of the Anti-HA signal to the Anti-Tubulin signal, which served as a protein loading control. This experiment was performed twice with duplicate cultures and similar results were observed each time.

Mentions: The Sck1 and Sck2 protein kinases were also examined since they are substrates of TORC1 with roles in lifespan [21, 22, 33]. We find that the CLS of untreated sck1Δ cells is lower than WT cells, but they do respond to ComboDT and live longer than untreated mutant cells, although not as long as ComboDT-WT cells (Fig. 3A). Untreated sck2Δ cells live longer than WT cells, similar to what others have observed [21, 22, 24]. They too respond to ComboDT and have an enhanced CLS which, surprisingly, is higher than ComboDT-WT cells (Fig. 3A). Finally, the CLS of untreated sck1Δ sck2Δ double mutant cells is like the sck2Δ cells, but the CLS of the double mutant is not enhanced by ComboDT. These data point to Sck1 and Sck2 as vital components in the mechanisms of lifespan enhancement controlled by ComboDT, with each kinase providing unique inputs.


Drug synergy drives conserved pathways to increase fission yeast lifespan.

Huang X, Leggas M, Dickson RC - PLoS ONE (2015)

Both Sck1 and Sck2 are required for lifespan enhancement by ComboDT.(A) The effect of drugs on CLS are shown for WT, sck1Δ, sck2Δ and sck1Δ sck2Δ double mutant cells. (B) The effect of drugs on TORC1-regulated phosphorylation of HA-tagged Sck1 and Sck2 was examined by immunoblotting. Numbers below each lane indicate the ratio of the Anti-HA signal to the Anti-Tubulin signal, which served as a protein loading control. This experiment was performed twice with duplicate cultures and similar results were observed each time.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4364780&req=5

pone.0121877.g003: Both Sck1 and Sck2 are required for lifespan enhancement by ComboDT.(A) The effect of drugs on CLS are shown for WT, sck1Δ, sck2Δ and sck1Δ sck2Δ double mutant cells. (B) The effect of drugs on TORC1-regulated phosphorylation of HA-tagged Sck1 and Sck2 was examined by immunoblotting. Numbers below each lane indicate the ratio of the Anti-HA signal to the Anti-Tubulin signal, which served as a protein loading control. This experiment was performed twice with duplicate cultures and similar results were observed each time.
Mentions: The Sck1 and Sck2 protein kinases were also examined since they are substrates of TORC1 with roles in lifespan [21, 22, 33]. We find that the CLS of untreated sck1Δ cells is lower than WT cells, but they do respond to ComboDT and live longer than untreated mutant cells, although not as long as ComboDT-WT cells (Fig. 3A). Untreated sck2Δ cells live longer than WT cells, similar to what others have observed [21, 22, 24]. They too respond to ComboDT and have an enhanced CLS which, surprisingly, is higher than ComboDT-WT cells (Fig. 3A). Finally, the CLS of untreated sck1Δ sck2Δ double mutant cells is like the sck2Δ cells, but the CLS of the double mutant is not enhanced by ComboDT. These data point to Sck1 and Sck2 as vital components in the mechanisms of lifespan enhancement controlled by ComboDT, with each kinase providing unique inputs.

Bottom Line: Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought.We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan.These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry and the Lucille Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America. nc.ude.utjws.emoh@gnauhehnix.

ABSTRACT
Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker's yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.

No MeSH data available.