Dissecting the mechanisms underlying lifespan extension in insulin signalling mutant mice

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Our population is ageing rapidly, and by 2050 there will be an estimated 250000 centenarians in the UK compared to only 10000 in 2004. Ageing is accompanied by a physical decline which can result in disability, a profound loss of independence and a resultant decrease in quality of life. In addition, ageing is the major risk factor for a number of diseases including Alzheimer's, various cancers, osteoporosis and type-2 diabetes. Therefore, identifying the processes that cause ageing is of fundamental importance if we have any hope of maintaining quality of life into old age. Currently, it is not understood what processes cause ageing, although the ability of cells to withstand stress, the ability of cells to protect against damage and repair this damage, and how the cells consume energy all appear important. To examine this I will use a novel mouse model in which a specific gene (insulin receptor substrate protein 1, Irs1 null) has been removed from all tissues. I have previously shown that these mice are exceptionally long-lived and are resistant to the infirmities of old age. In addition I will expose these mice to caloric restriction (CR). CR also extends lifespan and improves health in many animals and by using this comparative approach I will identify common genes and pathways across both life-extending treatments. I suggest that these overlapping genes/pathways are likely to be central to ageing in mammals. The information generated by this proposal will provide new insights into the fundamental biology of mammalian ageing and may ultimately help identify potential therapeutic pathways for treatment of the diseases of ageing in humans.