Uncovering the functions of circRNAs in aging

PROJECT SUMMARY Aging can be described as the progressive loss of cellular homeostasis and an increase in dysfunction over time. One system that seems especially susceptible to the ravages of time is the central nervous system. Brain function requires multilevel control of gene expression. In particular, regulation of RNA metabolism is a major hub for regulation and recent research has shown a strong link between perturbation of RNA metabolism and a number of neurological and neurodegenerative diseases for which aging is the main risk factor and driving force. However, we still don’t know the exact links between RNA metabolism and aging. Circular RNAs (circRNAs) are highly abundant RNAs produced by circularization of specific exons. As circRNA production competes with RNA splicing, their biogenesis is per se a cis regulator of gene expression. Moreover, several circRNAs also have functions in trans in tissues like the muscle and the brain where some of them are translated. Interestingly, circRNAs have been shown to accumulate in an age dependent manner, suggesting that they might be relevant for age-related homeostasis and/or pathogenesis. We recently developed new biochemical and genetic tools that allow us to determine that a subset of circRNAs regulate lifespan. Briefly, we generated a resource to knockdown (KD) circRNAs and identified 24 circRNAs that alter lifespan when knocked down (KD). Interestingly many of the protective-circRNAs (those that diminish lifetime when KD) are translated and are hosted by genes bound by FOXO, a key regulator of aging and translation, suggesting a strong connection between circRNA translation, aging and FOXO. In addition, we found that KD of circKlg and circSideIII result in strong and consistent lifespan extensions, increased health spans as well as “younger transcriptomes” demonstrating a direct impact of these circRNAs on aging. This proposal aims to expand these exciting results and mechanistically dissect the interplay between circRNAs and aging pathways. For doing so, we will: 1) Determine the mechanism behind the aging- promoting circRNAs; 2) determine the extent and requirements for circRNA translation and relationship to aging and 3) define the relationship between the FOXO regulon and circRNAs in aging. In sum, this project will illuminate key regulatory mechanisms of circRNA translation and the relationship of these RNAs with aging. In addition, this project is highly innovative in its analysis of the general functions of circRNAs, builds on strong preliminary results and the unique and constantly evolving expertise of our groups.