Award details

S6 kinase 1 and ageing

Reference	BB/H020527/2
Principal Investigator / Supervisor	Professor Dominic Withers
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Dept of Medicine
Funding type	Research
Value (£)	429,424
Status	Completed
Type	Research Grant
Start date	01/10/2010
End date	01/10/2014
Duration	48 months

Abstract

Reduced activity of TOR or its substrate, S6 kinase, leads to lifespan extension in disparate eukaryotic organisms. Preliminary data from our groups indicate that mice lacking one of two S6 kinase orthologs, S6K1, also have enhanced longevity and are protected from age-associated diseases. We will therefore undertake detailed analysis of S6K1 functions pertinent to aging by addressing the following objectives: 1) To generate tissue-specific S6K1 knockout mice and assess their response to diet-induced obesity and examine age- associated pathology in these animals. We will delete S6K1 in liver, fat and neuronal tissues using floxed mouse alleles of S6K1 recently created in the Withers and Kennedy labs. Mice will be phenotyped on a standard diet and for potential protective effects from diet-induced obesity and age-related pathologies. 2) To analyse interactions of S6K1 signalling with insulin/IGF-1 signalling- Insulin resistant IRS1-/- mice, which have reduced S6K1 activity, are long-lived. However, S6K1 may also act in a negative feedback loop to suppress insulin signaling. Therefore an alternative hypothesis is that S6K1-/- mice are long-lived due to enhanced insulin/IGF-1 activity. To address this apparent conundrum we will undertake detailed analysis of the signaling components in response to insulin, fasting and feeding and high fat diet both in tissues derived from our tissue-specific S6K1 knockout mice and from cell lines derived from these animals to dissect the interactions between signaling pathways. 3) To assess altered translation in S6K1-/- mice - S6K1 phosphorylates ribosomal protein RPS6. A major consequence of activation of this pathway is increased translation, particularly of messages with 5' TOP sequences. We will assess the changes in translation that accompany S6K1 knockout using polysome analysis as a measure of global translation levels and translation state array analysis to identify specific changes at the transcript level.

Summary

Life expectancy is increasing steadily in developed countries, and a major challenge for medical research is to keep people in good health as they age. As they age many people experience deterioration in physical performance and well-being and therefore understanding the mechanisms that promote healthy ageing is important. Recent research to which the co-applicants have made significant contributions has revealed that changes to single genes regulates normal lifespan and can make laboratory animals live longer and healthier lives. Alterations in genes that manufacture components of the signalling pathway related to insulin do this in yeast, worms, fruit flies and mice, implying that these simpler and shorter-lived animals could be used to understand the normal human ageing process. In this collaborative research programme, we will focus on one specific insulin pathway inside cells. This pathway which is called the mTOR/S6K pathway is involved in regulating how cells make protein. It also has an important role acting as a sort of thermostat on insulin signalling preventing the insulin pathway from being overactive. In our two laboratories we have shown that alterations in the genes that produce mTOR/S6K extend lifespan, initially in yeast and now in mice. Furthermore the mice with altered mTOR/S6K appear to be healthier as they age. In our proposed collaborative studies we shall find out how these genetic alterations work to regulate normal ageing by undertaking three related types of experiment. Firstly, we will make new mice to refine our understanding of which tissues are important for the lifespan effects we see. Secondly, we will also look in detail to determine the effects of the changes we make in the mice upon how hormones such as insulin work. Finally, we will also identify the changes in the production of proteins in mice to see if specific proteins are involved in the ageing process. These studies will give new insights into how normal ageing is regulated.This may be of future benefit in identifying risk factors for the deterioration in physical function and health that occur during normal ageing. Furthermore, the genes and molecules we are looking at are also being studied for their roles in diseases such as cancer. This means that there are active and productive drug discovery efforts and that there is the real possibility over the coming years that drugs that act on this pathway will be developed. This means that if we define how this pathway works in ageing then these drugs may be useful to prevent the deterioration in health and function that occur during normal ageing. Therefore our studies are essential if we are to find targets where drugs might promote healthy ageing.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Ageing, Diet and Health
Research Priority	Ageing Research: Lifelong Health and Wellbeing
Research Initiative	Collaborative Research on the Biology of Ageing (USAGE) [2009]
Funding Scheme	X – not Funded via a specific Funding Scheme

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