Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.586167
Title: The role of cell senescence and inflammation in mouse ageing
Author: Jurk, Diana
Awarding Body: University of Newcastle Upon Tyne
Current Institution: University of Newcastle upon Tyne
Date of Award: 2011
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Abstract:
Senescent cells secrete bioactive molecules, including reactive oxygen species (ROS) and pro-inflammatory cytokines. Conversely, pro-inflammatory signalling stabilizes the senescent phenotype. Cell senescence and chronic low-level inflammation increase with age have been proposed as causal factors in ageing. In this thesis I demonstrate that senescent cells accumulate with age in mouse liver and are temporally and spatially associated with markers of oxidative stress and inflammation, including activation of hepatic stellate cells which is generally associated with fibrosis. Moreover, I show that hepatocyte senescence is driven by DNA damage at the level of telomeres as shown by an age-dependent exponential Increase in the number of TIF, occurring independently of telomere length. In order to test experimentally, a potential link between inflammation and cellular senescence, I analyzed markers of cell senescence and features of age-related functional decline in several tissues from mice lacking the transcription factor nfkb1-1. I found that compromised signalling through NF-KB led to a pro-inflammatory phenotype and stabilized cell senescence in vitro as well as in multiple tissues in vivo. Accordingly, regenerative capacity in the liver, absorptive area in the intestine, epidermal thickness of the skin and accumulated fat mass in various depots were all reduced and both healthspan and lifespan of nfkb 1-1- mice were shortened. This data shows for the first time that widespread cell senescence resulting from persistent pro- inflammatory signalling can seriously accelerate mammalian ageing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.586167  DOI: Not available
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