Validation of Telomere Length, a biomarker of ageing in a cross-sectional Ageing Well study and the role of dietary fatty acids on markers of cellular senescence and telomere length
Creators: name: Thekkemuriyil, Linnet
Publisher: name: Cardiff Metropolitan University
Year: 2023
Subjects: classificationCode: 340406
subject: Molecular medicine

description: Telomere length has been considered as a well-established biological marker of ageing, and telomere length dynamics plays a pivotal role in the regulation of various cellular processes. Shortening of telomere length has been associated with age, various age-associated diseases such as cardiovascular diseases and cancer. Currently, multitude of methodologies for telomere length measurements exist that are applicable in cross-sectional and epidemiological studies, exploring telomere length dynamics. In recent times, dietary intervention has emerged as a powerful tool to prevent or at least delay chronic age-associated diseases, in parallel with research into mechanisms underlying the onset of many age-related conditions, specifically, inflammation and oxidative stress. Supportively, few cross-sectional studies have also implicated that adherence to a Mediterranean-type diet were associated with longer telomere length. Most of the studies have explored the putative link between diet and oxidative stress by employing antioxidant supplements or diet rich in bioactive components to test their effects on markers of oxidative stress however, sporadic data remains available on the effects of dietary lipids specifically polyunsaturated/saturated fatty acids on markers associated with cellular ageing (senescence) and telomere length. Thus, the present research aimed to firstly validate two well established telomere length measurement techniques (qPCR and TRF analysis), and identify potential associations of telomere length with various bio-nutritional variables collected as part of a cross-sectional study (Ageing well project). Secondly, based on the correlational telomere length associations obtained from the project, this thesis also further elucidated the effects of polyunsaturated (PUFA)/saturated fatty acids on markers associated with cellular ageing (senescence) and telomere length, utilizing an in vitro model.Data from this thesis exhibited significant telomere length association with chronological age, augmentation index (AIx) determined in the supine position and saturated fat and sugars intake. In vitro analysis determined CLA (conjugated linoleic acid) pre-treatment of endothelial cells prior to H2O2 oxidant exposure, significantly reduced markers of cellular senescence and inflammation such as SA-β-gal activity, p16, ICAM-1 levels in comparison to LA (linoleic acid). Both the fatty acids did not modulate significant telomere length changes in comparison to the H2O2 treated control. A mechanistic pathway was explored to elucidate the FA mediating effects on markers of senescence, and it was observed that CLA and LA mediated effects also VII significantly modulated other signalling proteins such as 1) LA mediated downregulation of antioxidant proteins SOD1, catalase 2) LA mediated downregulation of eNOS and Sirt1 and CLA mediated downregulation of Sirt1 3) CLA mediated upregulation of ERK phosphorylation and LA mediated increase of NF-κB p65 expression.In conclusion, pre-treatment of endothelial cells with CLA prior to exposure with H2O2, appeared to delay the manifestation of markers of cellular senescence in endothelial cells via ERK activation and reduction of NF-κB p65 expression, in conjunction with affecting a plethora of proteins pertinent to the senescence pathway when compared against LA. It is likely, however, that other proteins might also regulate the lipid signalling and senescence process, and a distinct pathway identification has yet to be elucidated. Nonetheless, this study provides preliminary evidence that dietary FAs could modulate markers associated with endothelial cellular senescence, and that this data may contribute to the existing research in developing strategies to counteract the development of age-related diseases.