An Assessment of miRNA Manipulation on Senescence and Ageing Phenotypes in vitro and in vivo

Abstract

Ageing has been widely described as a progressive functional deterioration of tissues that causes diminished organ function and increased mortality risk. It has been established that the proportion of senescent cells in tissues rises with age in many organs and in age-related illnesses, suggesting that cellular senescence plays a significant role in the functional decline related to ageing. Correspondingly, it has previously been shown in animal models that eliminating senescent cells might mitigate the deleterious consequences of ageing. As a key regulator of several cellular mechanisms, there are microRNAs (miRNAs) known to be associated with senescence. However, miRNAs that may directly trigger or reverse senescence remain to be elucidated. Here, the first goal of thesis was to identify the miRNA profile of proliferating, senescent, and rescued senescent endothelial cells to determine miRNAs that may be causal or influential of cellular senescence. I found that miR-361-5p not only associated with senescence but also reduced the load of senescent cells in vitro in human endothelial cells upon induction in late passage cells. Secondly, C. elegans was used to examine the role of miR-361-5p targeted genes on ageing in vivo. I found that 56% of genes which were dysregulated in vitro adversely affected healthspan and/or lifespan in vivo. Finally, a previous finding from our lab (Holly et al., 2015) identified three miRNAs-associated with human ageing and senescence in human primary fibroblasts of which miR-15b-5p may reduce senescence markers and secretory phenotypes (SASP) in the human dermal fibroblast cells. This thesis presents new miRNAs (miR-361-5p and miR-15b-5p) which may be involved in the aetiology of senescence and may be used in future in ageing intervention.