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Uncoupling metabolism and aging: Testing the uncoupling to survive hypothesis

Reference	BB/C516228/1
Principal Investigator / Supervisor	Professor John Speakman
Co-Investigators / Co-Supervisors
Institution	University of Aberdeen
Department	School of Medical Sciences
Funding type	Research
Value (£)	444,019
Status	Completed
Type	Research Grant
Start date	23/05/2005
End date	22/05/2009
Duration	48 months

Abstract

When mitochondria are uncoupled by the presence of uncoupling proteins on the inner mitochodnrial membrane they become inefficient because the UCPs provide routes for protons in the inter-membrane space to enter the matrix without synthesising ATP. At a given demand for ATP therefore uncoupled animals must consume greater amounts of oxygen. However, offsetting this disadvantage of uncoupling, the reduced potential across the inner mitochodnrial membrane has been suggested to reduce production of oxygen free-radicals at complex III of the electron transport chain. Thus higher uncoupling in theory leads to both elevated oxygen consumption lowered free-radical production, lowered radical induced damage and slowed aging with consequently extended lifespans, the uncoupling to survive hypothesis. We recently tested these ideas in a population of mice and found the predicted positive association of lifespan to metabolism, completely contrary to the classical rate of living hypothesis. In these same mice we also showed that UCP-3 in skeletal muscle was more activated. However, alternative explanations for these data exist. The mice with higher metabolic rates were more active, for example, so their elevated lifespans may have been a result of the increased energy expenditure on exercise, and unrelated to the uncoupling. Alternatively perhaps the mice that lived longer had greater levels of oxidative protection (eg catalase, superoxide dismutase and glutathione peroxidase levels) and repair (eg proteosome levels) and the increased levels of these enzymes caused the increased metabolism. In this work we will explore and test these alternative ideas, and will perform two additional tests of the uncoupling to survive hypothesis. These additional tests will involve upregulating levels of uncoupling proteins, first by transgenic methods and second by a pharmaceutical methods. We will use mice that have transgenic over-expression of UCP-3 in skeletal muscle. We will compare the lifespans and mortality patterns of these mice with wildtype and UCP-3 KO animals. Finally, we will administer thyroxine (T4) to mice to increase their levels of uncoupling and oxygen consumption and explore the consequences of this manipulation for lifespan. In all the manipulations we will measure parallel cohorts of mice to examine changes in levels of UCPs and also changes in oxidative protection and repair mechanisms.

Summary

unavailable

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Ageing
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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