Pharmacological protection against a bad diet: a Drosophila model

Secondary Supervisor(s): Dr Andres Pires da Silva

University of Registration: University of Warwick

BBSRC Research Themes: Integrated Understanding of Health (Ageing, Diet and Health, Pharmaceuticals)

Project Outline

Maintaining metabolic function is key to lifelong health. Changes in metabolism that disrupt cellular energy balance are now considered causative factors for multiple human diseases including diabetes, cancer and neurodegeneration.

For successful metabolic homeostasis, nutrient intake must be coordinated to the energy demands of the organism across multiple tissues of the body. Such signals are coordinated through highly conserved cell signalling networks, the concerted actions of which are essential to produce a balanced phenotypic response to changes in the nutritional environment. But these signals are disrupted under poor dietary regimes, such as those we face in the modern world, leading to disease.

The core metabolic pathways that regulate energy homeostasis have been remarkably well conserved through evolution not only at the molecular level but also at the level of physiological output. For example, the highly conserved insulin/IGF-like signalling pathway functions across diverse species to orchestrate the allocation of nutrients amongst different tissues to coordinate growth, metabolism and cellular maintenance. We use the fruit-fly, Drosophila melanogaster, as a genetically tractable model system to study dietary effects on insulin/IGF-like signalling, particularly in the context of metabolic-related diseases. And we have recently discovered that a pharmacological inhibitor of insulin/IGF-like signalling – trametinib - protects against the adverse effects of a sugar-dense diet.

Aims and Objectives

This project will further investigate the molecular basis for these effects of trametinib in our Drosophila model. Key objectives of the project are to:

(1) Identify candidate cellular targets for the protective effects of trametinib by examining the phosphorylation status of key metabolic enzymes in response to poor diet and drug treatment.

(2) Test the effects of these phosphorylation changes using the power of Drosophila as a genetically tractable system to manipulate the expression and/or activity of these phospho-targets.

Identifying the molecular mechanisms that drive the protective effects of trametinib will be a key focus of this research.

Key References

Laskovs M, Partridge L, Slack C. Molecular inhibition of RAS signalling to target ageing and age-related health (2022). Disease Models & Mechanisms 15 (10): dmm049627.

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.

Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.

Will the drugs work? Investigating the molecular basis for variability in the responses to anti-ageing interventions

Secondary Supervisor(s): Dr Andre Pires da Silva

University of Registration: University of Warwick

BBSRC Research Themes:

• Integrated Understanding of Health (Ageing, Diet and Health, Pharmaceuticals)
• Understanding the Rules of Life (Systems Biology)

Project Outline

Increased age is the major risk factor for multiple chronic/debilitating diseases. As global populations get increasingly older, the concurrent rises in disease incidence are of growing concern. Novel strategies to promote lifelong health are therefore urgently needed. Laboratory studies using simple animal models have demonstrated that ageing is a malleable process amenable to genetic, environmental and (importantly) pharmacological interventions. Several geroprotectors - therapeutics that could be used to improve health during ageing – have now been described that offer real translational potential to prevent age-related morbidity.

But we already know that heterogeneity between individuals through variation in genetics, physiology and lifestyle has an important influence on the outcomes of drug treatment. For example, of all patients treated with an FDA approved drug, ~30% will not respond as expected or even respond at all. As such, a detailed mechanistic understanding of the molecular signatures that determine successful outcomes to treatment with any geroprotector will be essential to optimise its benefits and reduce possible side-effects.

In this project, we will harness the power of the fruit-fly, Drosophila melanogaster, as an experimentally tractable model system to study the ageing response to pharmacological intervention in diverse populations. Such studies are almost impossible to perform in mammals due to the sheer number of animals needed and their longer lifespan. Drosophila are widely used to study the fundamental biology of ageing and are used in our laboratory to characterise responses to geroprotectors at cell, tissue and organism levels.

Aims and Objectives

Our previous research has shown that a small molecule inhibitor of the highly conserved RAS/MAPK signalling pathway – called trametinib – acts a robust geroprotector to extend lifespan and improve age-related physiology in Drosophila. But these effects of trametinib show important differences depending on the sex of the animal and the diet that it feeds on. Our goal is to map this variance in response to trametinib during ageing, particularly under different dietary regimes, to identify the mechanisms behind these differences.

We will utilise a panel of inbred Drosophila isolines available through the Drosophila Genetic Reference Panel to screen for variation in the lifespan response to trametinib. This represents a collection of ~205 isogenic inbred lines derived from a wild population. They are fully sequenced with a high degree of genetic diversity between them and show variation in all phenotypic traits examined so far including ageing. Genome wide association studies alongside differential gene expression analysis will then allow us to identify the molecular signatures of positive responders and importantly, non-responders, to the effects of trametinib on ageing. We will then test these mechanisms directly using functional genetics.

Key References

Laskovs M, Partridge L, Slack C. Molecular inhibition of RAS signalling to target ageing and age-related health (2022). Disease Models & Mechanisms 15 (10): dmm049627.

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.

Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.

Investigating sex-based differences in ageing

Secondary Supervisor(s): Professor Ioannis Nezis

University of Registration: University of Warwick

BBSRC Research Themes:

• Integrated Understanding of Health (Ageing, Diet and Health, Pharmaceuticals)
• Understanding the Rules of Life (Stem Cells)

Project Outline

Sex is a key determinant of almost all aspects of animal physiology. Fundamental biological differences between males and females result in sexually dimorphic responses across a diverse array of phenotypes including ageing. Furthermore, sex impacts on the pathogenesis of most, if not all, diseases, including those commonly associated with ageing including obesity, diabetes, cancers and neurodegeneration. Yet despite the prevalence of sexual dimorphisms on phenotype, sex has historically been ignored in basic and preclinical research and so the underlying mechanisms that lead to many sex-specific effects are not well understood. As such, there is an urgent priority to redress this gap in the knowledge particularly where sex differences could impact on clinical outcomes.

The fruit-fly, Drosophila melanogaster, is a well-established and powerful model for the in vivo study of genes that influence ageing. As a sexually dimorphic species, we will use Drosophila to further understand how sex differences impact on lifespan. We are particularly interested in investigating sex differences in ribosome biogenesis and protein translation and how these processes impact on age-related physiology.

Aims and Objectives

The main goals for the project are to:

(1) Characterise the structural and functional differences in ribosome biogenesis/protein translation between males and females. We will also determine whether any sex differences in these processes are localised to specific tissues or occur during specific phases of the life history (for example, after mating or post-reproductively).

(2) Determine if these sex differences are cell intrinsic. In Drosophila, sex is determined in a cell-autonomous manner and so we have genetic tools that allow us to change the sex of specific subsets of cells. We will therefore investigate what happens if we feminise male cells or masculinise female cells.

(3) Investigate whether the sex differences in ribosome biogenesis/translation account for the sex-specific effects of pro-longevity manipulations. There are several pharmaceutical interventions that promote healthy ageing in Drosophila, such as the anti-cancer drug, trametinib. But they show effects predominantly in females and not in males. Using the power of Drosophila as a genetically tractable model, we can ask whether differences in ribosome biogenesis/protein translation account for these sex-biassed lifespan responses.

Together, these studies will reveal fundamental new insights into the complex relationship between sex, cellular metabolism and ageing.

Key References

Regan JC, Lu YX, Ureña E, Meilenbrock RL, Catterson JH, Kißler D, Fröhlich J, Funk E, Partridge L (2022). Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin. Nature Aging 2(12):1145-1158.

Laskovs M, Partridge L, Slack C (2022). Molecular inhibition of RAS signalling to target ageing and age-related health. Disease Models & Mechanisms: 15(10): dmm049627. doi: 10.1242/dmm.049627.

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.

Slack C and Partridge L (2013) Genes, pathways and metabolism in ageing. Drug Discovery Today: Disease Models 10: e87-e93.