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Title: Does antiretroviral therapy accelerate the speed of physiological ageing through the clonal expansion of mitochondrial DNA mutations?
Authors: Bayerri, Carla Roca
Issue Date: 2020
Publisher: Newcastle University
Abstract: The accumulation of mitochondrial DNA (mtDNA) mutations is well described in normal human ageing as well as in several diseases of older age. It has been suggested that the accumulation of mtDNA mutations within tissues with ageing is likely to be predominantly due to the clonal expansion of existing mutations within cells, rather than high levels of mutagenesis. Antiretroviral treated HIV-infected persons achieve good immune reconstitution, but nevertheless experience an increase in many of the common diseases and physiological changes of older age. Given the known links between mitochondria and ageing, and mitochondria and HIV infection, it is plausible that increased mitochondrial damage may be a biological mediator of ageing in HIV. MtDNA damage in human brain was investigated in a cohort of HIV+ individuals and HIV-uninfected controls. HIV+ cases showed an increase in mtDNA deletions and a decrease in mtDNA content. In both cases these accentuated the changes seen with age. A novel derivative from the PolgA ‘mutator’ mouse model was developed to test the role of clonal expansion. The mouse model (‘WtN+’) contained multiple germline heteroplasmic mtDNA point mutations on a wild-type inbred nuclear background. Mice were aged to different time points, and a subset was dosed with zidovudine, a nucleoside analogue antiretroviral drug, known to inhibit mtDNA replication. Clonal expansion of mtDNA mutations were analysed in post-mitotic (skeletal muscle) and mitotic (colonic crypts) tissues using a combination of molecular and immunohistochemical assays. This novel mouse model showed evidence of clonal expansion of mtDNA mutations, and a mild frailty phenotype. In summary, these experiments increase our understanding of the natural history of mtDNA mutations in ageing and antiretroviral therapy.
Description: PhD Thesis
Appears in Collections:Institute of Neuroscience

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