S6 kinase 1 and ageing

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description The programme of research was based on our finding that deletion of the gene S6K1 in all tissues in mice extends lifespan and healthspan. The proposed studies were aimed at discovering the basis for these beneficial phenotypes. Firstly we aimed to generate mice in which we removed S6K1 from specific tissues and studied the responses of the mice to a high fat diet. Secondly we aimed to study the interaction between S6K1 and another gene Irs1 which we have shown to regulate lifespan. Finally as this is a collaborative grant with a lab in the USA we planned to study the alterations in protein production in the S6K1 mice in studies performed in the lab in the USA. During the research we have successfully developed the new mouse model and an additional mouse model lacking S6K2 and studied mice lacking S6K1 in fat tissue and the whole brain. Surprisingly these mice displayed essentially normal phenotypes with respect to bodyweight and metabolism even when exposed to a high fat diet. We also generated mice lacking both S6K1 and S6K2 in defined brain regions and these mice had subtle abnormalities in metabolism. We studied the role of S6K1/2 in defined hypothalamic neuronal populations and revealed as key role in glucose homeostasis. These findings have now been published. Together these findings suggest that the lifespan extension seen in global S6K1 null mice may results from the deletion event in all tissue or have a developmental basis. We attempted to generate mice lacking S6K1 and Irs1 but these animals did not appear to be viable but pursued studies in cells from Irs1 mice to see what the mechanisms of longevity are in this model. Finally studies on protein synthesis did not demonstrate prominent alterations in mass protein synthesis but subtle changes in the production of some protein subtypes. We undertook further studies on the role of S6K1 in the underlying biology of ageing and found a key role for this protein in cellular senescence. These findings have been partly published and are the subject of ongoing studies funded by the Wellcome Trust. In collaborative studies we have also examined the role of S6K1 in the protection against pathology seen in models of muscle dystrophy-associated laminopathies. This work has been published (Cell Discovery volume 3, Article number: 17039 (2017) doi:10.1038/celldisc.2017.39).
Exploitation Route We have used the mice we have generated in this project and the data we have accrued to help secure additional funding and also to pursue the mechanisms of our findings. Our suprising insights into the role of S6K1 in physiology will be published when we have gained additional insights into the underlying biology. We have made some new findings on S6K1 in senescence and Irs1 in longevity and these studies will be published or are published.
Sectors Healthcare

 
Description We have used our data in our own papers and research and for the generation of data for additional grant applications. We are currently using the data in our ongoing studies on ageing as they inform the design of studies. The data will be used as the basis for future publications.
First Year Of Impact 2013
Sector Other
 
Description Wellcome Trust Strategic Award
Amount £1,800,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2013 
End 02/2017
 
Title S6K2 floxed allele 
Description Mouse with a floxed allele of S6K2 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact We are currently using this model to pursue the role of S6K signalling in ageing. 
 
Description BK 
Organisation Buck Institute for Age Research
Country United States 
Sector Charity/Non Profit 
PI Contribution We have an ongoing research collaboration on the role of S6K1 in ageing
Collaborator Contribution We have shared mouse reagents
Impact We will hopefully submit a joint publication on our data with the mouse reagents.
Start Year 2012
 
Description GM 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborations on reagents and techniques resulting in papers
Collaborator Contribution Collaborations on reagents and techniques resulting in papers
Impact Papers published: see publication list
Start Year 2012
 
Description JG 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Collaborative work on senescence in vivo with joint PhD studentship
Collaborator Contribution Collaborative work on senescence in vivo with joint PhD studentship
Impact Paper reported
Start Year 2010
 
Description Partridge 
Organisation University College London
Department Department of Genetics, Evolution and Environment
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaborative work on ageing on model organisms
Collaborator Contribution Contributions ot papers and succesful grant applications.
Impact Large number of published papers and succesful grant applications including a £5m Wellcome Strategic Award