Circular RNAs: New players in Ageing and Age-related Chronic Disease

Abstract

Circular RNAs (circRNAs) are an emerging class of non-coding RNA that may regulate expression during normal and disease states. Although circRNAs accumulate in in vivo models of ageing, their role in this process and its physiological consequences remains largely unanswered. In the course of this thesis, I assessed dysregulation of circRNA expression in RNA samples from ageing human peripheral blood and examined associations of their expression with various ageing outcomes in human, mammalian longevity and senescence in human cell types of various lineages, and in blood and islet samples from patients with type 2 diabetes; an exemplar disease of ageing. Of the 15 circRNAs validated in this study, I identified 4 (circDEF6, circEP300, circFOXO3 and circFNDC3B) that were associated with ageing outcomes (parental longevity or hand grip strength) in the InCHIANTI population study of ageing. CircFOXO3 and circEP300 also demonstrated differential expression in one or more human senescent cell types. 4 ageing outcomes associated circRNAs appeared to be conserved in mouse of which circPlekhm1 nominally correlated with median strain lifespan. As type 2 diabetes is an exemplar chronic disease of ageing, I also aimed to examine the role of circRNA in this disorder. I first defined the circRNA repertoire in human pancreatic islets and assessed their differential expression in conjunction with type 2 diabetes status and genotype at T2D risk loci. Following this, I determined their responsiveness to diabetomimetic stimuli in the human EndoC-βH1 beta cell line, and the potential for use as biomarkers of T2D in human peripheral blood. 4 of the five most abundant circRNAs expressed in human pancreatic islets circCIRBP, circZKSCAN, circRPH3AL and circCAMSAP1, were associated with diabetes status in islets. CircCIRBP and circRPH3AL were also differentially expressed in β-cells in response to elevated fatty acid. Despite this, no associations with T2D diabetes risk loci was identified. Cumulatively, the data generated from my work suggest that circRNAs have potential as regulators of gene expression during ageing and age-related disease, raising the possibility that they may have future utility as biomarkers or therapeutic targets for the management of age-related chronic disease outcomes.