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.
Highlights
Most organisms show signs of aging, characterized by the gradual but progressive loss of physiological functions over time
The concentration of drugs used in combination drug treatment (ComboDT) (150 nM or 60 ng/ml myriocin and 50 nM or 46 ng/ml rapamycin) did not interfere with cell density at 48 hrs (S2 Fig.) and, cells treated with myriocin or ComboDT grew to a slightly higher density than without drug treatment, similar to what we have observed in budding yeasts [9, 19]
To determine if ComboDT can produce a synergistic increase in S. pombe chronological lifespan (CLS), we searched for low concentrations of each drug showing little or no effect on lifespan but that produced a large and potentially synergistic increase in lifespan when used in combination
Summary
Most organisms show signs of aging, characterized by the gradual but progressive loss of physiological functions over time. TORC1 is a central regulator of aging and longevity, since down-regulating its activity by treatment with the natural product rapamycin or related synthetic compounds, reduces signs of aging and extends lifespan in model organisms ranging from yeast to mice [4,5,6,7,8]. These seminal results have spawned an array of TOR-related research including work from our laboratory which identified a strategy that produces a synergistic increase in the chronological lifespan (CLS) of the Baker’s yeast Saccharomyces cerevisiae [9]. We verify this prediction by using the fission yeast Schizosaccharomyces pombe, a distant and divergent relative of budding yeast
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