Uncovering the links between circRNA accumulation, translation and aging

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Project Summary As advances in clinical and medical sciences lengthen lifespan in developed countries, it is becoming increasingly clear that aging is one of the most important risk factors for disease. The prevalence of diseases including cardiovascular disease, stroke, cancer and dementia increases dramatically in the later years of life. Interventions that prevent or postpone the effects of aging have the potential to transform modern medicine. Therefore, understanding the molecular mechanisms underlying aging is an important goal. Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. Two of these RNAs, CDR1as and Sry, can act as miRNA sponges, but no function is known for the thousands of other circRNAs found in species across the animal kingdom. CircRNAs expression levels are not correlated with the expression of their linear isoforms, indicating a potentially widespread layer of previously unknown gene regulation. Recent work from others and us showed that circRNAs are enriched in neural tissue and accumulate with age in the brain. Moreover, unpublished work from our lab demonstrate that a subset of circRNAs produces protein and that their translation is regulated by starvation and FOXO, pathways strongly related to aging This proposal aims to unravel the interplay between aging, circRNAs translation and function. For doing so, we will utilize state of the art methodologies to: Determine the cellular substrate, temporal requirements and aging pathways involved in the life span extension provoked by downregulation of circSif, circCG31619 and circCG11319. Molecularly characterize the aging related roles of circSif, circGC31619 and circCG11319. Determine the connection between translation of circRNAs and the aging phenotypes. Determine of the connection between circRNA accumulation and function and aging globally.