Dietary restriction (DR) is the most robust environmental method of lifespan extension in species as diverse as yeast, worms, fruit flies and rodents. Dietary restriction (DR) has been hypothesized to influence longevity through a shift in metabolic investment away from reproduction and growth toward somatic maintenance, allowing longer survival. The TOR (target of rapamycin) pathway, conserved from yeast to humans, links nutrients in the environment to organismal growth. We have identified the TOR pathway to play a critical role in modulating lifespan upon dietary restriction in D. melanogaster (fruit fly). We have discovered a critical and novel role for mRNA translation, downstream of the TOR pathway in determining lifespan in both D. melanogaster and C. elegans. This component uses an interdisciplinary approach combining different methodologies to examine the impact of mRNA translation on lifespan and metabolism utilizing three different model systems, flies, worms and mammalian cells. The interdisciplinary aims in this component are beyond the scope of a single laboratory, therefore investigators with diverse expertise have come together to critically examine the role of mRNA translation in aging and cancer. Completion of these aims will allow integration of data from different model systems which will provide a unique perspective of mRNA translation in gerosciences. This proposal will undertake the following specific aims:
Aim 1 Examine the metabolic consequences of inhibition of the TOR pathway and DR in D. melanogaster.
Aim 2. Genome wide analysis to identify and characterize the differentially translated genes in long lived C. elegans.
Aim 3. Examine the conservation of metabolic effects of inhibiting TOR signaling in mammalian cells. The role of the TOR pathway and translation regulation of gene expression is becoming recognized in various age related diseases including diabetes, cancer and neurodegeneration. Since a high degree of genetic similarity exists between humans and model organisms like flies and worms, we believe that taking an interdisciplinary approach by combining different approaches in various model systems will yield revealing insights into aging and age related diseases in humans.
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