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Investigating the metabolic effects of Ras inhibition during ageing

Primary Supervisor: Dr Cathy Slack, Life & Health Sciences

Secondary Supervisor: Professor Corinne Spickett, Professor Andrew Pitt

PhD project title: Investigating the metabolic effects of Ras inhibition during ageing.

University of Registration: Aston University

Project outline:

Our metabolism controls how our bodies store and use energy particularly in the form of fats or lipids. As we get older our metabolism changes causing alterations to the composition of the lipids in our body. Some of these lipids make us more susceptible to several long-term metabolic diseases including obesity and type 2 diabetes. Such metabolic disorders increase our risk of developing other diseases as we age including certain cancers, cardiovascular disease and neurodegeneration. But other forms of lipids may actually have beneficial effects on our health as we get older. The progression of age-related ill health may therefore reflect a disturbance in the balance of these 'good' and 'bad' fats. An urgent priority in ageing research is to understand how increased age influences these changes in lipid metabolism given that, although human life expectancy is increasing, there is an associated decrease in the quality of life linked to metabolic dysfunction.

Research using model organisms, such as the fruit-fly, Drosophila melanogaster, has established the biological process of ageing as a viable target for the treatment of age-related diseases. Similar genetic, environmental and pharmacological manipulations not only increase lifespan but also improve health in older animals across a diverse array of evolutionary distinct species. Such animal models are thus providing important new insights into the mechanisms that drive the detrimental effects of age on human health.

Our laboratory uses Drosophila as a model system to study the molecular mechanisms that impact on lifespan and age-related health. We can improve health during ageing in Drosophila if we reduce signalling through a molecular switch known as Ras. Ras signalling is present in all animals and helps to maintain appropriate cell growth in response to environmental signals. The importance of this pathway in human health is highlighted by its prolific role in cancer in that hyperactivation of Ras signalling is responsible for around 30% of all human tumours. In Drosophila, genetic manipulations to reduce Ras activity or feeding flies with a small molecule inhibitor of Ras signalling, called trametinib, improves healthy ageing. Interestingly, a growing body of research has shown that inhibiting other cancer-promoting pathways produces metabolic changes, independently from their role in cancer, which could prove beneficial as during ageing. Indeed, our recent data suggests that reducing Ras activity not only enables flies to live longer but also prevents age-dependent changes in lipid composition providing a direct link between lipid metabolism and a longer, healthier lifespan.

This project therefore focuses on the interplay between dysfunctional lipid metabolism and ageing in Drosophila. By defining the processes involved, we can identify novel cellular targets for therapeutic interventions to promote health during ageing. Our approach will use the powerful combination of mass spectrometry for lipidomics analysis coupled with Drosophila genetics to identify and manipulate age-dependent changes in lipid biosynthesis. A full characterisation of the global age-dependent changes in lipid composition will be performed. Well-established transgenic expression systems will then be used to induce changes in key metabolic pathways followed by physiological characterisation of those strains for age-dependent phenotypes. These strains will then be combined with genetic and pharmacological models of Ras inhibition to test whether these metabolic changes underpin the beneficial changes in ageing observed with reduced Ras activity. Collectively, these studies will help us to better understand the complex relationship between metabolic dysfunction and ageing.

This project would suit applicants with an interest in ageing biology and/or metabolic health.  

References:

  1. Slack C (2017). Ras signalling in aging and metabolic regulation. Nutrition and Healthy Aging 4: 195-205.
  2. Slack C, Alic N, Foley A, Hoddinott M, Cabecinha M, Partidge L (2015). The Ras-Erk-ETS pathway is a drug target for longevity. Cell 62:72-83.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

  • Genetic manipulations using transgenic technologies in Drosophila.
  • Drosophila physiological and behavioural analyses e.g. survival assays, feeding assays, stress response assays.
  • Lipidomic analysis by mass spectrometry.
  • Gene expression analysis by quantitative real-time PCR.
  • Molecular biology e.g. PCR, cloning, genomic engineering.

Contact: Dr Cathy Slack, Aston University