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The role of ageing in atherogenesis: Two in vivo models.

Fenton, M.; (2006) The role of ageing in atherogenesis: Two in vivo models. Doctoral thesis , University of London. Green open access

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Abstract

Most mammalian cells grown in culture undergo only a limited number of rounds of replicative activity. This exhaustion of proliferative capacity is termed replicative senescence. There is some evidence that replicative senescence may also occur in vivo, and it has been postulated that such cellular ageing may contribute to age-related pathologies such as atherosclerosis, and to organismic ageing itself. The aim of this thesis is to explore the associations between replicative senescence, organismic ageing and atherosclerosis. It was found that a cytochemical assay, senescence-associated P-galactosidase (SA-p- gal), could detect in vitro replicative senescence in human endothelial cells (ECs) and rabbit vascular smooth muscle cells (VSMCs). Endothelial denudation was then undertaken in rabbit carotid arteries, and in some experiments repeated six weeks later. Morphometric analysis of SA-p-gal activity demonstrated mat senescent ECs and VSMCs accumulated in the injured vessel wall, a second denudation augmenting mis accumulation. Further analysis suggested that these senescent cells showed no proliferative or apoptotic activity. An animal model of accelerated organismic ageing, the senescence-accelerated prone mouse (SAM-P), and mice from a related strain showing normal ageing (SAM-R), were fed a Western-type diet. Morphometric analysis of lipid deposition in their aortic roots demonstrated increased lipid deposition in SAM-P compared with SAM-R mice, despite lower serum cholesterol levels in SAM-P mice. Study of telomere lengths and SA-p-gal activity showed no evidence of accelerated cellular ageing in SAM-P mice. It is concluded that cellular ageing can occur in the vasculature, and that a murine strain which ages at an accelerated rate shows a greater susceptibility to atherogenesis. Since no evidence of accelerated cellular ageing was found in this strain, it is postulated that the increased susceptibility of SAM-P mice to atherogenesis, and perhaps also their ageing phenotype, may be attributable to other abnormalities in these mice, such as increased oxidative status.

Type: Thesis (Doctoral)
Title: The role of ageing in atherogenesis: Two in vivo models.
Identifier: PQ ETD:592765
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by Proquest
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/1445443
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