CircRNAs expressed in human peripheral blood are associated with human aging phenotypes, cellular senescence and mouse lifespan

Shahnaz Haque,Lorna W Harries,Karen Moore,Luke C Pilling,Luigi Ferrucci,Stefania Bandinelli,Ryan M Ames,Luanne L Peters

doi:10.1007/s11357-019-00120-z

Shahnaz Haque, Lorna W Harries + Show 6 more

Open Access

https://doi.org/10.1007/s11357-019-00120-z

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Abstract

Circular RNAs (circRNAs) are an emerging class of non-coding RNA molecules that are thought to regulate gene expression and human disease. Despite the observation that circRNAs are known to accumulate in older organisms and have been reported in cellular senescence, their role in aging remains relatively unexplored. Here, we have assessed circRNA expression in aging human blood and followed up age-associated circRNA in relation to human aging phenotypes, mammalian longevity as measured by mouse median strain lifespan and cellular senescence in four different primary human cell types. We found that circRNAs circDEF6, circEP300, circFOXO3 and circFNDC3B demonstrate associations with parental longevity or hand grip strength in 306 subjects from the InCHIANTI study of aging, and furthermore, circFOXO3 and circEP300 also demonstrate differential expression in one or more human senescent cell types. Finally, four circRNAs tested showed evidence of conservation in mouse. Expression levels of one of these, circPlekhm1, was nominally associated with lifespan. These data suggest that circRNA may represent a novel class of regulatory RNA involved in the determination of aging phenotypes, which may show future promise as both biomarkers and future therapeutic targets for age-related disease.

Highlights

Aging is a multifactorial process leading to gradual deterioration of physical and physiological functionality at the cellular, tissue and organ levels
We present here evidence that effects on age itself did not replicate in the wider sample set, the expression levels of circEP300 (β = − 0.065, P = 0.001) and circFOXO3 (β = − 0.060, P = 0.002) were negatively associated with parental longevity score. circDEF6 was positively associated with parental longevity score (β = 0.070, P = 0.024) this did not reach multiple testing thresholds. circFNDC3B was nominally associated with hand grip strength (β = 0.004, P = 0.039). circRNAs (7/12 (58%)) expressed in senescent human primary astrocytes, endothelial cells, fibroblasts or cardiomyocytes demonstrated dysregulated expression in one or more cell types
We demonstrated no associations with age itself, we did identify associations between some circRNAs and human aging phenotypes. circEP300 and circFOXO3 both demonstrated negative associations with combined parental longevity score (β = − 0.065 and − 0.060; P = 0.001 and 0.002 respectively), after adjustment for multiple testing. circDEF6 was positively correlated with parental longevity scores but demonstrated nominal significance only (β = 0.070, P = 0.024) (Table 3, Fig. 2)

Summary

Introduction

Aging is a multifactorial process leading to gradual deterioration of physical and physiological functionality at the cellular, tissue and organ levels It is the primary risk factor for chronic aging pathologies such as cancer, sarcopenia, diabetes, cardiovascular disorders and neurodegenerative illnesses that account for the bulk of morbidity and mortality in both the developed as well as developing world (Kirkland 2016 ). Physiological parameters such as loss of muscle mass, frailty, immobility and cognitive impairment increase the risk of developing geriatric syndromes (Fabbri et al 2016; Narici and Maffulli 2010). Non-coding RNAs demonstrate associations with aging or senescence and may be of equal importance (Abdelmohsen et al 2012; Boulias and Horvitz 2012; Gorospe and Abdelmohsen 2011)

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