Characterization of the Sch9 Longevity Pathway in Yeast

University Of Kentucky, Lexington KY

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Abstract

Dietary restriction and drugs such as rapamycin are promising ways to reduce the incidence and severity of diseases including cancer, neurodegeneration and diabetes that diminish health in the elderly. These and other ways to slow aging work, in part, by lowering activity of the target of rapamycin complex 1 (TORC1) protein kinase that senses amino acids (AAs) and adjusts growth and metabolism to their availability. Protein and AA restriction show promise in controlling aging and improving human health, but current strategies require dietary changes that few humans are likely to adhere to. We have identified a novel way to lower free AA pools and increase lifespan. We showed previously that chronological lifespan (CLS) can be increased in budding and fission yeasts by decreasing the rate of sphingolipid synthesis and a similar approach has been shown to increase lifespan in the nematode Caenorhabditis elegans. Slower sphingolipid synthesis was achieved by genetic or pharmacological (myriocin, Myr) approaches that target the conserved, initial enzyme in sphingolipid biosynthesis, serine palmitoyltransferase. We now find that Myr treatment lowers the free pool of at least 15 AAs, at least partly, by reducing AA uptake in budding yeast. We posit that the drug perturbs membrane functions, creating a state of AA restriction that lowers TORC1 activity and increases activity of the other conserved AA-sensing pathway, Gcn2 (general control nonrepressible 2). To test this hypothesis we will identify the AA transporters whose activity is lowered by Myr treatment (Aim 1). Second, we will determine how drug treatment lowers AA transport activity (Aim 2). Third, the temporal effects of drug treatment that induce AA-restriction will be identified (Aim 3). Finally, the sphingolipid(s) responsible for lowering AA pools and other lipid species, if they are involved, will be identified. We will accomplish these goals by using molecular biology, biochemistry and yeast genetic techniques. Our results are likely to stimulate studies in model organisms such as worms and mice to identify novel drug targets for lowering AA pools in ways that are more likely to be used by humans to improve health than are currently available strategies.