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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.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.

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.


Related in: MedlinePlus

The PKA pathway is vital for ComboDT to enhance CLS and stress resistance.(A) The effect of drugs on the CLS of WT and pka1Δ cells are shown. (B) Spot-dilution (10-fold from left to right) assays show the response of WT and pka1Δ cells from CLS day 1 to heat or hydrogen peroxide stress treatment. (C) Influence of drugs on expression of the glucose-repressible fbp1-lacZ reporter gene are shown.
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pone.0121877.g004: The PKA pathway is vital for ComboDT to enhance CLS and stress resistance.(A) The effect of drugs on the CLS of WT and pka1Δ cells are shown. (B) Spot-dilution (10-fold from left to right) assays show the response of WT and pka1Δ cells from CLS day 1 to heat or hydrogen peroxide stress treatment. (C) Influence of drugs on expression of the glucose-repressible fbp1-lacZ reporter gene are shown.

Mentions: Down-regulation of the glucose-responsive PKA pathway in S. pombe [21] as well as in S. cerevisiae [42, 43] and mice [44] enhances lifespan. Generally, a high level of glucose activates the PKA pathway and suppresses longevity (promotes aging) while a low level of glucose, as in some dietary restriction protocols including in fission yeasts [23], promote longevity in ways that are only partially understood, even in budding yeasts where this pathway has been examined in greatest detail [45–47]. To determine if the PKA pathway in S. pombe is used by ComboDT to enhance CLS, we examined a pka1Δ mutant and matched WT strain that have been used in previous lifespan studies [21]. As shown before, the CLS of untreated pka1Δ cells is greatly enhanced relative to untreated WT cells but only slightly enhanced compared to ComboDT-WT cells (Fig. 4A). ComboDT reduces the CLS of pka1Δ cells about 10-fold (Fig. 4A) and this is likely due to rapamycin in ComboDT, because rapamycin treatment reduces the CLS of pka1Δ cells to about the same extent as ComboDT. Myriocin treatment has no effect on the CLS of pka1Δ. In addition, the resistance of pka1Δ cells to heat and oxidative stress is reduced by rapamycin treatment or ComboDT while myriocin treatment slightly increases stress resistance (Fig. 4B). From these data we conclude that the PKA pathway is necessary for ComboDT to produce its maximal effect on lifespan and heat and oxidative stress resistance. These data also reveal that a low dose of either myriocin or rapamycin modulate lifespan and stress resistance in distinct ways.


Drug synergy drives conserved pathways to increase fission yeast lifespan.

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

The PKA pathway is vital for ComboDT to enhance CLS and stress resistance.(A) The effect of drugs on the CLS of WT and pka1Δ cells are shown. (B) Spot-dilution (10-fold from left to right) assays show the response of WT and pka1Δ cells from CLS day 1 to heat or hydrogen peroxide stress treatment. (C) Influence of drugs on expression of the glucose-repressible fbp1-lacZ reporter gene are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0121877.g004: The PKA pathway is vital for ComboDT to enhance CLS and stress resistance.(A) The effect of drugs on the CLS of WT and pka1Δ cells are shown. (B) Spot-dilution (10-fold from left to right) assays show the response of WT and pka1Δ cells from CLS day 1 to heat or hydrogen peroxide stress treatment. (C) Influence of drugs on expression of the glucose-repressible fbp1-lacZ reporter gene are shown.
Mentions: Down-regulation of the glucose-responsive PKA pathway in S. pombe [21] as well as in S. cerevisiae [42, 43] and mice [44] enhances lifespan. Generally, a high level of glucose activates the PKA pathway and suppresses longevity (promotes aging) while a low level of glucose, as in some dietary restriction protocols including in fission yeasts [23], promote longevity in ways that are only partially understood, even in budding yeasts where this pathway has been examined in greatest detail [45–47]. To determine if the PKA pathway in S. pombe is used by ComboDT to enhance CLS, we examined a pka1Δ mutant and matched WT strain that have been used in previous lifespan studies [21]. As shown before, the CLS of untreated pka1Δ cells is greatly enhanced relative to untreated WT cells but only slightly enhanced compared to ComboDT-WT cells (Fig. 4A). ComboDT reduces the CLS of pka1Δ cells about 10-fold (Fig. 4A) and this is likely due to rapamycin in ComboDT, because rapamycin treatment reduces the CLS of pka1Δ cells to about the same extent as ComboDT. Myriocin treatment has no effect on the CLS of pka1Δ. In addition, the resistance of pka1Δ cells to heat and oxidative stress is reduced by rapamycin treatment or ComboDT while myriocin treatment slightly increases stress resistance (Fig. 4B). From these data we conclude that the PKA pathway is necessary for ComboDT to produce its maximal effect on lifespan and heat and oxidative stress resistance. These data also reveal that a low dose of either myriocin or rapamycin modulate lifespan and stress resistance in distinct ways.

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.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.

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.


Related in: MedlinePlus