Dissecting the mechanisms underlying lifespan extension in insulin signalling mutant mice

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.

Comparative studies suggest that conserved mechanisms regulate ageing across organisms. Exactly what these mechanisms are is currently unknown, but the insulin/insulin-like growth factor (IGF) signalling (IIS) pathway appears an important and conserved candidate lifespan determinant. I have shown that mice with global deletion of insulin receptor substrate protein 1 (Irs1-/-) are long-lived and that this long-life was accompanied by a resistance to age-related pathology. I will investigate the molecular processes that underlie lifespan extension following reduced IIS in mice, using an integrative approach from whole-animal physiology to molecular biology. I hypothesize that enhanced cellular stress resistance and enhanced mitochondrial function (mitochondrial oxidative phosphorylation, mitochondrial biogenesis, improved ROS metabolism) act to promote the long and healthy lifespan of Irs1-/- mice. I suggest that this improved somatic cellular stress resistance is due to increased antioxidant protection and increased DNA base excision repair. Using gene rescue experiments in an IRS1 fibroblast null background I will then delineate the hypothesized role of IRS1 in this stress resistance. Unpublished hepatic transcriptional data generated by myself indicate that Irs1-/- mice are caloric restriction (CR) mimetics. This suggests that reduced IIS and CR, both of which extend lifespan and delay ageing, act through the same pathway, but it is unknown how IIS mutant mice respond to CR. I will examine the metabolic (e.g. glucose homeostasis) and transcriptional responses of Irs1-/- mice to long-term (1 year) CR. I suggest that genes/pathways showing overlap between reduced IIS and CR are likely to be key candidate lifespan determinants, particularly if they are conserved across tissues.

My impact plan for this research has two main strands to it. Firstly it will promote my research activity to the wider research community and to the general public, and secondly it will identify and protect potentially significant IP generated from this primary research. Communication strategy All generated data from this proposal will be disseminated through publications and presentations at International and National meetings. To ensure that the research findings become immediately visible, we propose to pay journals to ensure our papers become immediately open access and available for download. We have requested £2000 (4 papers x £500) to cover these costs in order that our papers reach the widest public audiences. In addition, to increase our media skills we have requested travel expenses (£500) for the PI and PDRA to travel to a BBSRC media training course during year 2 of the grant. These courses will enable us to present our research through the media in order to promote our science to a significantly larger audience. In addition, we will liaise directly with The University of Aberdeen's Communications Team who promotes the University's national and international profile by highlighting daily press releases on University stories as they break. They publicize corporate news as well as College stories, proactively promoting groundbreaking research initiatives, new grants and the publication of papers in science journals to local, national and international media (following notification of the BBSRC's External Relations Unit). The research undertaken will be also be highlighted on the PI's own website and across the appropriate Departmental and University sites. The impact activities will be undertaken by the PI primarily, with help from the appropriate University of Aberdeen departments. The University of Aberdeen also run a range of core skills courses research staff, with the PDRA expected to attend various courses such as communication skills and entrepreneurship workshops. All transcriptomic data will be deposited in a publically accessed data base such as the Gene Expression Omnibus (GEO) at the National Centre for Biotechnology Information (NCBI). GEO archives and freely disseminates microarray and other high-throughput data generated by the scientific community. The database is fully MIAME compliant for both fully annotated raw and processed data. In addition, GEO supports a collection of user-friendly web-based interfaces and applications to help users effectively data mine, visualise and down-load the experiments and gene expression patterns stored. Exploitation strategy This research is focussed in understanding the mechanisms that underlie the ageing process and therefore have significant potential for exploitation, both commercially and non-commercially. Currently there is no specific partnership, collaborative or exploitation agreements in place for this application. Data/information/technology that could be patented will be scrutinised and assessed by the PI, the collaborators and the Research and Innovation (R & I) Office at The University of Aberdeen. R & I provide help and advice to University of Aberdeen's researchers to maximise their research income from the funding opportunities available and commercialise the output from their research. R & I comprise of two groups who work closely together. In addition, the university's Business Development Team (BDT) also work closely with scientists in order to help maximise each scientist's research income potential. The BDT liaises closely with the university's Commercialisation team to help identify intellectual property opportunities suitable for commercial exploitation. R&I also collaborate closely with external organisations such as other public sector and business enterprises on a wide range of initiatives. There are a number of schemes designed to encourage Business-University interaction including CASE studentships, proof of concept grants etc.