Investigation of mitochondria-associated proteins in the ageing process

Lead Research Organisation: University of Nottingham
Department Name: School of Veterinary Medicine and Sci

Abstract

In the past century it has become apparent that many countries in the developed World are encountering a demographic shift towards an older population. With an intrinsic human desire to live for as long as possible we have pushed sanitation and medical advances with a result of much increased life expectancy. This brings many advantages but also we now have increased numbers of people affected by diseases that are more common with advancing age. Many of these diseases which include cancers, neurodegeneration, sarcopenia and metabolic syndrome have a complex aetiology and are thought to be affected by triggers that are experience through life. At a cellular level there is interest in how affected parts of the body control energy making processes. The mitochondrial organelle has a significant part to play in cellular energetics and other processes such as B oxidation of lipids, processes seen to be altered in ageing and associated disease. This project focusses on the role of the mitochondria in ageing.

Aims
The project aims to interrogate mitochondria associated proteins that have previously been shown to be regulated by the ageing process, by applying different lifecourse pressures. The models used will be the fruit fly and the nematode worm in addition to cell cultures. Major interests are the effects of reduced oxygen (hypoxia) and exercise upon the mitochondria and particularly on the levels/activity of the mitochondrial proteins we have previously identified.

Objectives
To measure the 'plasticity' of the mitochondrial proteome and it's particular response to life long pressures including sub-optimal oxygenation and acute versus chronic exercise.

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M008770/1 01/10/2015 31/10/2024
1644980 Studentship BB/M008770/1 01/10/2015 31/01/2020
 
Description 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.
Exploitation Route This work can easily be extended to continue following the identified potential biological markers of ageing and add to their relevance. Clinical trials targeting these biological markers.
The designed fly exercise machine may generate numerous collaborative activities.
Sectors Education,Healthcare