circRNAs as markers of life stress and experience during aging

About This Grant

PROJECT SUMMARY Aging is a major risk factor for numerous diseases and is modulated by both genetic and environmental factors. However, dissecting the interplay between environmental stressors and aging remains challenging. This is partly because traditional stress markers are transient, complicating the retrospective analysis of environmental stimuli and their contribution to the aging process. Consequently, there is a critical need for novel, stable markers that can track both the aging trajectory and the life stress history of an organism, including exposure to toxins and underlying health conditions. Such markers could significantly enhance our ability to predict the propensity to develop age-related disorders. Circular RNAs (circRNAs) are a highly stable and abundant class of RNA generated by circularization of specific exons. Their stability allows them to accumulate with age, particularly in non-dividing cells such as neurons. Indeed, our findings indicate that circRNAs exhibit very long half-lives (exceeding 20 days) in the Drosophila brain, with some showing no degradation over the animal’s lifetime. Moreover, we found that circRNAs can accurately track age, and that their levels are influenced by environmental stimuli such as oxidative stress, temperature, light exposure, and starvation. This combination of exceptional stability, capability to function as age markers, and induction by environmental stimuli implies that circRNAs can serve as life experience markers. Indeed, flies subjected to a ten-day regimen at 29°C exhibit higher levels of specific circRNAs even six weeks after returning to standard conditions, indicating that circRNAs can reveal past exposure to environmental stimuli. This positions circRNAs as unique molecules capable of integrating aging and stress information which could help uncover early-stage stages of disease or organ malfunction and determine if animals have been exposed to dangerous substances in the past. Additionally, these results suggests that circRNAs induced upon exposure to stimuli could be relevant for the responses upon re-exposure to the stressor. In this project, we aim to establish circRNAs as robust markers for tracking the integrated transcriptome and stress history of populations during aging. In this context, we plan to: 1) Identify circRNA subsets for tracking chronological age, aging and environmental stress exposure. and 2) Determine the encoding capacity of circRNAs as life experience and aging markers. By refining circRNA signatures to accurately reveal the stress history of Drosophila populations and their relationship to aging, we aim to develop new predictive markers for age-related diseases. This project is particularly relevant in the context of an aging human population and in the search of new markers that could predict the presence and predisposition to age-related diseases.