Age-dependent regulation of clearance and signaling pathways

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DESCRIPTION (provided by applicant): As we age cellular defects accumulate and promote aging of an organism. Conserved clearance pathways, in young individuals maintain cellular homeostasis, through balancing new production with the elimination of old components. In the young there is coordinated regulation between nutritional/growth signaling pathways (i.e. Insulin and Insulin-like Growth Factor, IR/IGF) with downstream components such as autophagy and the ubiquitin-proteasome system (UPS). This balance is essential for healthy aging. Often dysregulation occurs with upstream signaling pathways leading to altered expression profiles of key clearance components. This disconnect appears in part to be the molecular underpinnings behind diseases like metabolic syndrome and type-II diabetes. These disorders are increasing in frequency, accelerate with age and are known risk factors for disorders such as Parkinson and Alzheimer's diseases. My research has focused on macroautophagy (autophagy) and its role with neuronal aging and the clearance of protein aggregates. We have found there is an age-dependent decline in autophagy gene expression and by enhancing message levels of rate-limiting genes (i.e. Atg8a) in the adult CNS we can increase aggregate clearance and the Drosophila lifespan by over 50%. We have also found that defects in the IR signaling have a profound effect on fly longevity and enhance autophagy in aging neural tissues. Other clearance pathways, such as UPS show a profound functional change with age, and are also partly under the control of metabolic signaling. The hypothesis of this proposal is that expression profiles of key components in signaling (i.e. IR, TOR) and clearance (i.e. UPS, autophagy) pathways will be altered with age. This regulatory disconnect, in turn will limit the production of factors required for the effective removal of cellular damage. Once genes are identified that have age-dependent changes to their mRNA profiles; we will use Drosophila genetic/transgenic techniques to preferentially manipulate their expression profiles to a more "youthful" pattern and individually assess their "anti-aging" properties. For Specific Aim 1 we will use Next Generation Sequencing, Microarray and qRT-PCR techniques to determine the transcriptome profiles of young and old neural and muscle tissues. In Specific Aim 2 we will use Drosophila genetic/transgenic technique to alter the expression profiles of select genes and characterize their effect on age-dependent phenotypes. Specific Aim 3 will involve characterizing transcriptome profiles from flies at different ages that have specific mutations or transgenic alterations to IR/IGF or autophagy genes. Specific Aim 4 will extend the analysis of transcriptome profiles to include samples from aged mammalian tissues. The goal of this proposal is to clarify the role that clearance pathways have in cellular aging and to identify conserved genes that could have a profound effect on human aging and neurodegenerative disorders.