The mitochondrial basis of ageing and neurodegeneration

Ingram, Thomas Liam (2020) The mitochondrial basis of ageing and neurodegeneration. PhD thesis, University of Nottingham.

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Abstract

One of the greatest achievements of the past 150 years is the extraordinary extension of average human lifespan. However, increasing average lifespan is coupled to an insidious rise in age-related cognitive decline and muscle loss. Indeed, progressive age is the number one risk factor for non-communicable diseases. Understanding the underlying biological mechanisms which drive ageing is a mammoth task. Mitochondrial dysfunction has emerged as a critical feature of ageing. This Thesis explored the biochemical changes to mitochondria with age and diseases of age.

Firstly, in mouse brain and muscle mitochondria, the expression of potential biological markers of ageing, carbonic anhydrase-II and -III were shown across adulthood. A window of increasing carbonic anhydrase expression between 12-18 months of age was identified. Targeted inhibition of C. elegans CA orthologue, cah-2, at middle age significantly increased lifespan. Treatment of C. elegans with the carbonic anhydrase-II inhibitor, dorzolamide hydrochloride, at middle age showed a trend toward increased lifespan, but this did not reach significance.

Secondly, the long-lived bat (P. pipistrellus) was shown to have high levels of fatty acid binding protein 3 (FABP3) in muscle mitochondria, compared to short-lived mice. Increasing FABP3 levels was connected to high free fatty acid levels. Knockdown of FABP3 C. elegans orthologues altered mitochondrial morphology, oxygen consumption and significantly reduced lifespan.

Thirdly, the healthspan promoting lifestyle intervention, exercise, was assessed. D. melanogaster were exercised on the bespoke Ingram Counterbalanced Exercise machine. The proteomic profiles of mitochondria isolated from exercised and non-exercised wild-type and Pink1-/- D. melanogaster were examined. The mitochondrial proteome displayed exercise-related changes. Interestingly, exercise caused sweeping mitochondrial protein expression reductions to Pink1-/- D. melanogaster with exercise.

Fourthly, the cerebellar mitochondrial inflammatory marker profiles of females and males with and without Parkinson’s disease were surveyed. This study found that inflammatory marker changes manifest differently with disease progression between sexes. Interestingly, the control female group showed a distinctive inflammatory profile, characterised by highly variant inflammatory marker levels.

This Thesis describes biochemical alterations to mitochondria with ageing and diseases of age. These findings highlight the diverse changes that mitochondria undergo with ageing, potential markers of longevity and interventions that may improve healthspan.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Chakrabarti, Lisa
Stöger, Reinhard
Voigt, Peter
Keywords: Mitochondria, Ageing, Neurodegeneration, Comparative biology, Parkinson's disease
Subjects: Q Science > QH Natural history. Biology
Faculties/Schools: UK Campuses > Faculty of Medicine and Health Sciences > School of Veterinary Medicine and Science
Item ID: 60760
Depositing User: Ingram, Thomas
Date Deposited: 04 Aug 2020 11:12
Last Modified: 04 Aug 2020 11:14
URI: http://eprints.nottingham.ac.uk/id/eprint/60760

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