Studies in worms and yeast have linked lifespan extension by dietary restriction to altered translational regulation. Consistently, reduced TOR signaling or S6 kinase activity leads to increased lifespan in both invertebrates, and delays the onset of age-related diseases in mammals. In addition to Protein Kinase A (PKA), TOR and Sch9 make three nutrient-responsive kinases linked to yeast longevity modulation. In this proposal, we employ yeast as a model organism to address the mechanisms by reduced nutrient signaling, dietary restriction, or altered translational regulation that lead to extension of yeast replicative lifespan. As a result of a genome-wide screen for long-lived yeast gene deletion strains, we identified a number of ribosomal large subunit gene deletions that result in reduced 60S subunit biogenesis. One mechanism by which reduced 60S subunit biogenesis lead to lifespan extension is through enhanced translation of the GCN4 transcription factor. GCN4 translation is also induced by reduced TOR signaling and required for maximum lifespan extension in this setting, making this a common mechanism modulating yeast aging. Gcn4 targets include amino acid biosynthetic genes as well as stress responsive and mitochondrial factors. The regulatory system controlling Gcn4 translation is highly conserved in all eukaryotes including humans.
In Aim 1 of this proposal, we perform a series of experiments to determine the mechanisms leading to GCN4 activation and the targets of GCN4 important for yeast aging. While enhanced GCN4 translation is one mechanism underlying lifespan extension by reduced 60S subunit biogenesis and nutrient signaling, our evidence indicates that others exist as well. Therefore, in Aim 2 we describe efforts to identify these GCN4- independent mechanisms using a series of approaches both unbiased and directed. Finally, in Aim 3 we address a second major question: does reduced ribosome biogenesis lead to lifespan extension in mammals. To test this, we will determine the longevity of mice lacking ribosomal large subunit genes chosen because of similar mutations extend lifespan in worms and yeast. We will also test a series of age-associated phenotypes, focusing on metabolic outputs. Together, these studies will better define the mechanisms linking reduced nutrient signaling and ribosome biogenesis to aging and test whether their effects extend to mammals.
It is increasingly becoming recognized that interventions to slow aging will provide broad spectrum benefits to age-related diseases including neurodegeneration, cancer and cardiovascular disease. In this proposal, we address at the mechanistic level the relationship between protein translation and aging. Through achieving a better understand of the modulatory role played by regulated protein translation in aging, we will be able to pinpoint key targets for pharmacological interventions.
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